Short Stature Lecture 2023 By Dr Hussein Abass.pptx

short stature for doctors

1. Short Stature Dr Hussein Abass Consultant of Pediatrics Egypt 2023

2. Dwarfism in Ancient Egypt

3. تابوت من الأسرة الثلاثين ، حوالي القرن الرابع قبل الميلاد موجود بالمتحف المصري بالقاهرة . الأقزام المصريون الذين اشتهروا بأسمائهم بفضل لوحة مقابرهم ونقوشهم و / أو تماثيلهم تشمل : نفر ، سير إنبو ، هيجو (الثلاثة من الأسرة الأولى) ني عنخ دجيدفر (الأسرة الرابعة) سنب (أواخر الرابعة) أو أوائل الأسرة الخامسة خنوم حتب (الأسرة الخامسة).

4. Statue of the dwarf Seneb , his wife and children 4th or 5th dynasty تمثال للقزم سنيب وزوجته وأولاده الأسرة الرابعة أو الخامسة

5. The dwarf deity Bes as depicted on a relief at Dendera القزم بيس كما تم تصويره في دندرة دندرة تبعد نحو 55 كيلومتر شمال الأقصر على شاطيء النيل الشرقي والغربي ، مقابلة مدينة قنا تقريبا على الضفة الأخرى من النيل

6. Growth = Growth involves physical changes in height and weight and appearance of the body . Development = refers to a change in functional ability, such as cognitive, motor, and psychological aspects of the individual.

7. Growth is an extraordinarily complex process governed by multiple factors: genetic, epigenetic, environmental, and psychosocial. As such, growth in children integrates the genetic and environmental influences at the level of individual cells, organs, and the organism as a whole, providing a window into the functioning of any organism, in particular children. Growth is the bellwether of health, and its evaluation is the cornerstone of pediatrics. Children who grow normally must have all the genetic and environmental requisites for growth in place. Those who do not should be looked at carefully to discover the cause, whether it is genetic, environmental, or a systemic disease, either endocrine or nonendocrine.

8. Normal Growth Growth is defined as an irreversible constant increase in size, and Development is defined as growth in psychomotor capacity. Both processes are highly dependent on genetic, nutritional, and environmental factors. Serial measurements of growth are an important parameter in monitoring the health of children. A normal pattern of growth usually suggests good general health, while growth that is slower than normal raises the possibility of an underlying subacute or chronic illness, including an endocrinologic cause of growth failure. Statural growth is a continuous but not linear process. There are three phases of postnatal growth (infantile, childhood, and pubertal), each of which has a distinctive pattern . The phases are similar for boys and girls, but the timing and pace of growth differ, particularly during puberty.

9. Infancy – During the first two years of life (infantile phase), linear growth initially is very rapid and gradually decelerates. Overall growth during this period is approximately 30 to 35 cm. The length (and weight) of premature infants must be corrected for gestational age, at least for the first year. However, growth is often accelerated during the second one-half of the first year in otherwise healthy children born early. An infant's height curve often crosses percentile lines during the first 24 months of life as the growth moves away from the influences of the intrauterine environment and toward the child's genetic potential. As examples, infants born small because of placental or uterine constraint may move upwards across percentile curves ("channeling up"), whereas infants born large because of maternal-fetal overnutrition may cross downward across percentile curves ("channeling down"). After this adjustment period, the correlation between length at two years and adult height is 0.80 . Childhood – The childhood phase is characterized by linear growth at a relatively constant velocity, with some slowing in later childhood. Most children grow at the following rates (representing the 10th to 90th percentiles): • Age two to four years – 5.5 to 9 cm/year (2.2 to 3.5 inches/year) • Age four to six years – 5 to 8.5 cm/year (2 to 3.3 inches/year) • Age six years to puberty: - 4 to 6 cm/year for boys (1.6 to 2.4 inches/year) - 4.5 to 6.5 cm/year for girls (1.8 to 2.6 inches/year) Adolescence – The pubertal phase is characterized by a growth spurt of 8 to 14 cm per year due to the synergistic effects of increasing gonadal steroids and growth hormone [8]. In girls, the pubertal growth spurt typically starts around age 10 but may start as early as age 8 for early maturing girls. In boys, the pubertal growth spurt typically starts around age 12 but may start as early as age 10 in early maturing boys . The "rule of fives" incorporates these typical phases of growth and provides an estimate for normal height and height velocity (HV) in a given age group . Actual height and HV in a healthy child can vary substantially around these approximations.

10. Regulation of Growth Normal human growth can be divided into 3 overlapping stages (the Karlberg model), each under the control of different factors: • Infancy Growth is largely under nutritional regulation, and wide inter-individual variation in rates of growth is seen. Many infants show significant ‘catch-up’ or ‘catch-down’ in weight and length, and by 2 years, length is much more predictive of final adult height than at birth. • Childhood Growth is regulated by growth hormone (GH) and thyroxine. It is characterized by alternating periods of mini-growth spurts with intervening stasis, each phase lasting several weeks. However, over years, a child will tend to maintain their centile position on height charts, with a height velocity between the 25th and 75th centiles. • Puberty The combination of GH and sex hormones promotes bone maturation and a rapid growth acceleration or ‘growth spurt’. In both sexes, oestrogen eventually causes epiphyseal fusion, resulting in the attainment of final height.

11. Biology of Linear Growth Emerging evidence reveals that normal and pathologic variations in linear growth depend on the balance between proliferation and senescence شيخوخة of chondrocytes at the growth plate . This process is regulated by many systems, including : 1. Endocrine mechanisms – Growth hormone, insulin-like growth factor 1 (IGF-1), androgens, and thyroid hormone all stimulate chondrogenesis, while glucocorticoids inhibit chondrogenesis. Estrogens promote linear growth by stimulating growth hormone and IGF-1 secretion, but also accelerate chondrocyte senescence, leading to fusion of the growth plates and cessation of linear growth Male patients with estrogen resistance showed incomplete epiphyseal closure with histories of continued linear growth in adulthood; therefore, it has been demonstrated that estrogen is essential for growth plate closure in both men and women.

12. Biology of Linear Growth 2. Proinflammatory cytokines – Some Cytokines negatively regulate growth plate function. These are elevated in chronic inflammatory diseases, in which they slow linear growth and also growth plate senescence, which permits catch-up growth after the cytokine effect resolves 3. Paracrine mechanisms – Including fibroblast growth factors, bone morphogenetic proteins, parathyroid hormone-related protein, and others 4. Cartilage extracellular matrix – Includes collagens, proteoglycans, and other proteins 5. Intracellular pathways – Chondrocyte transcription factors including SHOX(The short-stature homeobox gene), several SOX genes, and the MAPK signaling pathway.

13. Growth Plate

14. Chondrocytes Chondrocytes are mainly responsible for the production of collagen and the extracellular matrix that will lead to the maintenance of cartilaginous tissues within joints. Initial cartilage is composed of the mesenchyme during the fifth week of development. The mesenchyme activates in areas of chondral development and condenses to make chondrification centers. The mesenchymal cells develop into prechondrocytes , which later become chondroblasts; chondroblasts secrete collagenous fibrils and extracellular matrix. Consequently, collagenous and elastic fibers are stored within the intercellular matrix. The type of matrix composed contributes to cartilaginous typecast; there are mainly three types of cartilage: 1.Hyaline cartilage: This type of cartilage is the most widespread and is usually present within joints. 2.Fibrocartilage: This type of cartilage is part of the intervertebral disc. 3.Elastic cartilage: This type of cartilage is in the Eustachian tubes. Endochondral ossification is crucial for skeletal development, specifically in preexisting cartilaginous models. The primary ossification center in long bones first appears in diaphysis (a portion of a long bone between two ends) that develops into the shaft of a bone. Chondrocytes undergo hypertrophy and enlarge at the sites of ossification. At these sites, the matrix becomes calcified and cellular necrosis appears. Osteochondral ossification is further regulated by the SOX9 transcription factor and the CARM1 (coactivator-associated arginine methyltransferase 1). Long bone elongation takes place at the diaphyseal-epiphyseal junction. Elongation directly correlates to cartilage plates made out of chondral matrix and collagen that proliferate and participate in endochondral osteogenesis and postnatal development.

15. Source : Illustrated Textbook of Paediatrics 6th ed 2022

16. Factors Affecting Growth and Development The growth and development are positively influenced by factors, like parental health and genetic composition, even before conception. Genetic factors play a primary role in growth and development. The genetic factors influencing height is substantial in the adolescence phase. A large longitudinal cohort study of 7755 Dutch twin pairs has suggested that the additive genetic factors predominantly explained the phenotypic correlations across the ages for height and body mass index. Fetal health has a highly influential role in achieving growth and development. Any stimulus or insult during fetal development causes developmental adaptations that produce permanent changes in the latter part of life. After birth, the environmental factors may exert either a beneficial or detrimental effect on growth. Socioeconomic factors : Children of higher socio-economical classes are taller than the children of the same age and sex in the lower socioeconomic groups. Urbanization has positively influenced growth. The secular trend is observed in growth where the kids grow taller and mature more rapidly than the previous generation. This secular trend is observed significantly in developed countries like North America. The family characteristics : Higher family education levels have a positive impact on growth. The inadequate emotional support and inadequate developmental stimulus, including language training, might cause growth and development deterioration. The human-made environment influences human growth and development significantly. Certain ongoing studies have proven the relationship of pollutants in sexual maturation, obesity, and thyroid function. The excess lead exposure antenatally significantly associates with low birth weight. Noise pollution due to transportation sources also has an association with reduced prenatal growth.

17. Nutrition Malnutrition plays a detrimental role in the process of growth and development. Deficiencies of trace minerals can affect growth and development. Iron deficiency usually affects psychomotor development and does not affect growth. Zinc deficiency might cause growth retardation and developmental delay. Selenium, iodine, manganese, and copper also play a significant role. Growth faltering or rapid weight gain in early childhood influences health in the later part of life. The diet in early childhood has a strong association with the likelihood of obesity later in life. 'Early Protein Hypothesis' shows that lowering the protein supply during infancy helps achieve normal growth and reduce obesity in early childhood. This concept of the early protein hypothesis helps in improving the food products for children. Genetic and environmental factors influence the growth and development in a perplexing interrelated pathway. Genetic and environmental risk factors are not mutually exclusive. Plasticity is the potential of a specific genotype to bring out diversified phenotypes in response to diverse environmental factors.The developmental plasticity can happen from the embryonic stage to adolescence and can be passed onto the next generation. Role of experience during early childhood : Exposure to adverse experiences in early childhood might hinder development. Profound neglect during early childhood can impair development. Children adopted before six months of age have similar development when compared to their non-adoptive siblings. If children adopted after six months have a high risk of cognition deficits, behavioral issues, autism, and hyperactivity. Early intervention for children with adverse experiences is the pillar in healthy development.

18. Measurement of Growth Anthropometry is the gold standard by which clinicians can assess nutritional status. The major anthropometric measurements for age up to 2 years are weight, length, weight for length, and head circumference. The major measurements used for children above two years are weight, height, body mass index (BMI), and head circumference for the 2-3 years age group. Length or height : For children less than two years or children with severe cerebral palsy, the length is the ideal way of measuring stature. Length is measured by placing the child supine on an infant measuring board. For children aged more than two years, standing height is measured in the stadiometer after removing shoes. The supine length is usually 1 cm higher than standing height. Length and height can be documented to the closest 0.1 cm. For children with severe cerebral palsy or spinal deformities, upper arm length, tibial length, and knee height can be useful to assess stature . Weight : The kids below one year are weighed on a scale after removing the clothes, shoes, diaper, and documented to the closest 0.01 kg. The kids outside the infancy phase should be measured without shoes, with little or no outer clothing, and documented to the closest 0.1 kg. Head circumference or occipitofrontal circumference : Head circumference is assessed by measuring the largest area from the prominent site at the back (occiput) to the frontal prominence above the supraorbital ridge. Brain growth is maximum in the first three years of life, so head circumference is used in children less than three years. It is measured as the maximum diameter through the supraorbital ridge to the occiput and documented to the closest 0.01 cm. Microcephaly is more than two standard deviations below the mean. Macrocephaly is more than two standard deviations above the mean.

19. Measure of adiposity : Body mass index (BMI) is a useful predictor of adiposity. BMI is calculated with formula,weight (kg) / height (m) squared. BMI is the single best indicator for detecting overweight or obesity < 5th percentile - underweight 5th to 84th percentile - normal 85th to 95th percentile - overweight 95th to 98th percentile - obesity More than 99th percentile - severe obesity The weight to length ratio is an alternative for body mass index in predicting adiposity in less than two years. Self-assessment of the hip to waist ratio can help to guide the measure of central adiposity, Triceps and subscapular skinfolds can also be a useful measure of adiposity.[13] Body proportions The upper segment to lower segment (U/L) ratio is 1.7 at birth, 1.3 at three years, and reaches 1.0 at greater than seven years. A higher U/L ratio is a feature in short-limb dwarfism. Arm span to height ratio is a fixed ratio across all ages. The ratio of more than 1.05:1 is suggestive of Marfan syndrome. Sexual maturity : Tanner's stage can be used to assess sexual maturity. Skeletal maturity : Bone age can be determined by doing Hand & Wrist radiographs from 3 to 18 years of age. Dental assessment : Primary tooth eruption begins with the central incisors at six months. No single tooth by 13 months of age is of concern. Permanent tooth eruption starts at six years of age and continues up to 18 years of age.

20. Sex differences Adult heights differ between ♂ and♀ by, on average, 13cm. However, during childhood, onset of the pubertal growth spurt is earlier in ♀, who are therefore, on average, taller than ♂ between the ages of 10–13 years. Tempo Within each sex, there may also be marked inter-individual differences in tempo of growth (or rate of attainment of final height) and the timing of puberty. Delay or advance of bone maturation is linked with timing of puberty. Constitutional delay in growth and puberty often runs in families, reflecting probable genetic factors. Comparison of bone age (estimated from a hand radiograph) with chronological age is, therefore, an important part of growth assessment. Final Height Final height is estimated as the height reached when growth velocity slows to <2cm/year and can be confirmed by finding epiphyseal fusion on hand radiograph ± knee radiograph. Final height is largely genetically determined, and a target height can be estimated in each individual from their parent’s heights.

21. Prevalence of Short Stature Dwarfism can be caused by one of more than 400 different types with A child with dwarfism is born 1 per 10,000 births per year with an estimated 30,000 people in the U.S. A and 651,700 in the world. Achondroplasia is the most common type of dwarfism. Achondroplasia is a genetic condition that affects about 1 in 15,000 to 1 in 40,000 people.

22. Short Stature in Egypt In Egypt there is no official national census data or other records indicating the exact number of dwarfs living in Egypt. But rough estimates put the number at 75,000, with as many as 400,000 Egyptian families including at least one person of short-stature. Egyptian Central Agency for Public Mobilization and Statistics in 2014 : 14% in Childhood ---- 1:7 21% in Children below 5 years ---- 1:5 2021 There is a clear improvement in the indicators of the nutritional status of children between 2014 and 2021, as the rate of stunting decreased and the rate of weight gain decreased, as it is noted that the percentage of children with short stature (stunting) decreased from (21%) in 2014 to (13%) in 2021 . With the decrease in the percentage of underweight people from (8%) in 2014 to (3%) in 2021. As for the underweight index, it decreased from (6%) to (4%) in 2021.

23. Prevalence of short stature and malnutrition among Egyptian primary school children and their coexistence with Anemia The prevalence of underweight was 8.2%, while obesity and overweight represented 21.8% (9.6 and 12.2% respectively). Overall short stature constituted 17%. The main etiologies of short stature were familial (40.8%) and constitutional (24.2%). Anemia was diagnosed in 26% of children; while concurrent anemia and stunting was reported in 9.9%. Regarding anemia and anemia with stunting were more common among girls (30.0% (OR = 1.50, CI95%: 1.43–1.58) and 11.4% (OR = 1.39, CI95%:1.29–1.49) respectively), who were living in rural areas (33.4% (OR = 1.96, CI 95%:1.87–2.06) &12.7% (OR = 1.72, CI 95%:1.60–1.85)) and those who had low socioeconomic status)34.6% (OR = 2.54, CI 95%:2.29–2.82) & 17.2% (OR = 3.32, CI 95%:2.85–3.88() respectively. Anemia with stunting was significantly higher among children aged ≥9 years old representing 12% (OR = 1.40, CI 95%:1.30–1.51). Source : Italian Journal of Pediatrics

24. المبادرة الرئاسية للكشف المبكر عن أمراض التقزم والسمنة والأنيميا لطلاب المرحلة الإبتدائية منذ عام 2019 فى مصر

25. Definition of Short Stature 1-Height below the 3rd percentile for age and sex 2-Height below -2 SD for age and sex 3-Height more than 1.6 SD below mid parental height : 8.2 cm difference 4-Growth Velocity below 25th Percentile or -2SD on growth velocity chart over 6-12 months 5-Height Deceleration across 2 major percentile lines in growth chart Even if the height is within the normal percentiles but growth velocity is consistently below 25 th percentile over 6 -12 months of observation The term ‘Dwarfism’ is no longer used for short stature . Essential Pediatrics, 7 th Edition, OP Ghai ; Fima Lifschitz - Pediatric Endocrinology Growth failure (GF) is often confused with short stature. By definition, GF is a pathologic state of abnormally low growth rate over time .

26. Short stature is defined as a height more than two standard deviations below the mean for age (less than the 3rd percentile). Tall stature is defined as a height more than two standard deviations above the mean for age (greater than the 97th percentile). The initial evaluation of short and tall stature should include : a history and physical examination, accurate serial measurements, and determination of growth velocity, midparental height, and bone age. Common normal variants of short stature are familial short stature, constitutional delay of growth and puberty, and idiopathic short stature. Pathologic causes of short stature include chronic diseases; growth hormone deficiency; and genetic disorders, such as Turner syndrome. The most common causes of short stature beyond the first year or two of life : 1- Familial (Genetic, intrinsic) short stature 2- Delayed (Constitutional) growth

27. Short stature key points By definition, normal growth encompasses the 95% confidence interval (CI) for a specific population 1. Most children who have a normal growth pattern but remain below the lower 2.5 percentile (approximately −2.0 standard deviations [SD]) are otherwise normal. The further below −2.0 SD (2.5 percentile) an individual’s growth falls, the more likely it is that there is a pathological condition keeping him or her from achieving their genetically determined height potential. Growth retardation refers to a downward deflection of the growth velocity with the resultant growth curve crossing the SD lines or percentiles. It is important to remember that only about 3% of short stature patients have an actual endocrinologic problem that will need further treatment, which is why it is important to take a good history. If there is a concern in growth delay after proper height documentation, the patient needs to be sent for growth hormone (GH) levels, IGF-1 and bone age. If this results within normal limits including a delay in bone age that correlates with the height of the patient, most likely it is safe to continue to monitor the patient. If taking this approach, and any of the laboratory workup or bone age are uncertain, or this type of lab workup cannot be done or properly interpreted, a specialist referral is in order. These are other recommendations on when to refer a patient : Any patient who is below two standard deviations on their height Any patient whos growth velocity is below the expected one in a 6 to 12 months period follow up. (please see up for normal growth velocities by age) Any patient that crosses two percentile lines for their height (even if still within “normal” standard deviations) Patient with known or suspected comorbidities (thyroid disorder, turner, septo -optic dysplasia, etc.) – this type of population will need a full workup

28. Familial Short Stature Vs Constitutional Short Stature Sex Both equally affected More common in boys Length at Birth Normal (starts falling <5 th centile in 1 st 3 yrs of life) Family History Of short stature Of delayed puberty Parents Stature Short (one or both) Average Height Velocity Normal Puberty Normal Delayed Bone Age & Chronological Age BA = CA > Height Age CA > BA = Height Age 8) Final Height Short, but normal for target height Normal .

29. Approach to Short Stature 1- HT = Height 2- MPH = Mid Parental Height 3- BA = Bone Age 4- CA = Chronological Age 5- HA = Height Age

30. Familial Short Stature = Genetic Short Stature Familial short stature (FSS) is a condition in which the final adult height achieved is less than the third percentile for the patient's age, gender, and population. Nevertheless, it is consistent with parental height in the absence of nutritional, hormonal, acquired, genetic, and iatrogenic causes. It is considered one of the most common causes of short stature, along with the constitutional delay in growth and puberty (CDGP), from which it can easily be distinguished. FSS also called genetic short stature (GSS) is considered a normal variant of growth (along with CDGP). It is believed to be caused by small contributions of multiple genes (polygenic inheritance) although this has not been firmly established. FSS may also be caused by maternal constraint or short stature of the mother . When short stature that runs in families is very severe, namely, less than three standard deviations below the mean for age, gender, and study population, then monogenic defects should be strongly considered and investigated.

31. Familial (Genetic) Short Stature : The hallmarks of familial short stature (also referred to as genetic short stature) include bone age appropriate for chronologic age, normal growth velocity, and predicted adult height appropriate to the familial pattern. A child's genetic height potential can be estimated by calculating the mid-parental height, which is based upon the heights of both parents and adjusted for the sex of the child. Individuals with familial short stature usually have low-normal height velocity throughout life. The otherwise normal height velocity generally distinguishes these children from those with pathologic causes of short stature.

32. Constitutional Short Stature : The term constitutional short stature is used to describe clinical situations characterized by low stature, assessed using special growth nomograms, but which are not due to specific endocrine alterations, nor to genetic causes or skeletal dysmorphisms , nor secondary to specific organ pathologies or chronic diseases. Clinical features • This condition often presents in adolescence but may also be recognized in earlier childhood, although it is more prevalent in ♂. • Characteristic features include short stature and delay in pubertal development by >2 standard deviations (SD), and/or bone age delay in an otherwise healthy child. In the adolescent years, short sitting height percentile, compared to leg length, is typical. • There is often a family history of delayed puberty. • Bone age delay may also develop in a number of other conditions, but, in constitutional delay, bone age delay usually remains consistent over time and height velocity is normal for the bone age. Final height may not reach target height. • GH secretion is usually normal, although provocation tests should be primed by prior administration of exogenous sex hormones if bone age is >10 years .

33. Constitutional Delay of Growth and Development By contrast, constitutional growth delay is characterized by delayed bone age, normal growth velocity, and predicted adult height appropriate to the familial pattern It results in childhood short stature but relatively normal adult height. The result is a growth curve that remains below, but parallel to, the third percentile for height. In addition to a low preadolescent height velocity, they tend to have delayed pubertal maturation. This leads to a marked height discrepancy during the early teenage years compared with their peers but is followed by catch-up growth when they do enter puberty . Patients with constitutional growth delay typically have a first-degree or second-degree relative with constitutional growth delay ( eg , menarche reached when older than 15 y, adult height attained in male relatives when older than 18 y). Familial Short stature and constitutional growth delay are diagnoses of exclusion. Most short children evaluated by clinicians in developed countries have familial short stature, constitutional growth delay, or both.

34. Constitutional Growth Delay Differential Diagnosis Differential diagnosis will vary depending on the clinical presentation as well as age; the most common differential diagnosis in infancy is the failure to thrive followed by cardiac abnormalities. As children grow the diagnosis becomes broader. Delayed puberty : Patient will have short stature, but will also have other features that point towards a delay in puberty. Hypothyroidism : Most often this condition is diagnosed in the first week of life, for some cases that are either mild at birth or go unrecognized, growth is very slow compared to growth hormone deficiency, having a very low percentile in their growth height. Growth hormone (GH) insensitivity : there are reports of rare cases of patients who have malfunctioned GH receptors. Turner syndrome : growth failure is universal in individuals with Turner syndrome, which results from haploinsufficiency of SHOX. Some times this disease has no evidence of skeletal dysplasia or other clinical anomalies but just the short stature . There is also a mass effect that results in comorbidities such as diabetes insipidus, hypopituitarism, growth hormone deficiency

35. Constitutional delay in growth and puberty Constitutional delay in growth and puberty is a condition in which children experience delayed puberty compared to their peers of similar age associated with a delay in the pubertal growth spurt (‘late bloomers’). These children have short stature relative to their parents’ heights, and a delayed bone age. The bone age is typically determined by examining the maturity of the individual’s bones relative to what is expected for their age in years since birth. These children typically have a family history of ‘late bloomers’. Once puberty begins, it progresses as expected, followed by the pubertal growth spurt. These children will typically have an adult height that is within range of what is expected for their genetic potential. The following conditions need to be considered and ruled out in making a diagnosis of constitutional delay in growth and puberty: 1-Familial short stature : This is a condition in which the child is short because the parents are short. There is no pathological cause of short stature in the parents or the child 2-Achondroplasia and other skeletal dysplasias : These are genetic conditions in which there are abnormalities in how bones develop and grow. These children usually have abnormal body proportions. 3-Growth hormone deficiency (GHD): These children are short because their pituitary gland makes insufficient amounts of growth hormone (GH) 4-Hypothyroidism : These children are deficient in thyroid hormone, another hormone that is very important for growth 5-Cushing syndrome : In this condition, the adrenal glands make excessive amounts of cortisol (the hormone involved in the body’s response to stress), resulting in marked weight gain and a decrease in growth rate (in height), resulting in short stature 6-Early onset of puberty : Going through puberty too early may result in short stature because the children have an early growth spurt and also stop growing early 7-Nutritional disorders : In certain nutritional disorders, children are short because of associated inflammation and an inability to absorb nutrients appropriately 8-Small for Gestational Age (SGA): Some infants who are smaller than average for gestational age at birth fail to demonstrate sufficient “catch-up” growth after birth, and remain short relative to their genetic potential 9-Idiopathic short stature (ISS): This refers to children who are short relative to their genetic potential with no identifiable cause

36. Management of Constitutional Short Stature : Often only reassurance is necessary. Treatment is sometimes indicated in adolescent boys who have difficulty coping with their short stature or delayed sexual maturation. • For the younger child with concerns about growth: low-dose Oxandrolone (1.25mg/day for up to 12 months, oral). A synthetic derivative of testosterone which has significant growth-promoting, but minimal virilizing , actions and does not affect final height. • For the older boy (>14 years) with concerns about puberty: Testosterone (50–100mg IM, monthly for 3–6 months). • For the older girl (>13 years) with concerns about puberty: ethinyl estradiol (2 micrograms/day for 3–6 months).

37. Idiopathic Short Stature Idiopathic short stature is a condition in which the height of the individual is more than 2 SD below the corresponding mean height for a given age, sex and population, in whom no identifiable disorder is present. It can be subcategorized into familial and non-familial ISS, and according to pubertal delay. It should be differentiated from dysmorphic syndromes, skeletal dysplasias , short stature secondary to a small birth size (small for gestational age, SGA), and systemic and endocrine diseases. ISS is the diagnostic group that remains after excluding known conditions in short children. Idiopathic Short Stature ttt : For children with a height SD <-3 and normal GH provocation test, if a growth velocity calculated over a 6 months period is subnormal (< -1SD), a trial of GH treatment for 6 months is started. If the child demonstrates a good response i.e. improvement of GV and height SDS, then therapy is continued. If no improvement is documented after 6 months, therapy is terminated .

38. Idiopathic short stature (ISS) is a term used to encompass children who are short with no abnormal growth pattern, normal growth velocity, no significant skeletal delay, and no evidence of pathology who generally go through puberty at a normal age and progress normally but who achieve or have a predicted final height below what is expected given their parental height. Many of these children undergo extensive investigations, including provocative GH testing, with no abnormalities detected. Some argue that these are children with genetic problems that are yet unknown to modern medicine, and some studies have shown novel genetic defects in a small proportion of children with ISS. GH therapy has been shown to increase final height in children with ISS; however, recently insurance carriers in the United States have not been reimbursing GH therapy for this condition, and the yearly cost of therapy is generally prohibitive.

39. Prediction of Adult Height Ultimate adult height can be predicted from the bone age, as there is a direct correlation in a normal individual between the degree of skeletal maturation and the time of epiphyseal closure, the event that ends skeletal growth. Predictions of ultimate height are based on the fact that the more delayed the bone age is for the chronological age, the longer the time before epiphyseal fusion ends further growth. The growth potential of an individual must be evaluated according to the parents' and siblings' heights, as genetic influences play a crucial role in determining the final height. An approximation of the ultimate adult height is obtained by calculating the mid-parental height. For girls, mid-parental height is (mother's height + father's height - 13 cm) /2; for boys, (mother's height + father's height + 13 em ) / 2. The child's target height is the mid-parental height +1- 2 SO (10 em or 4 in) . When the growth pattern deviates from the parental target height, an underlying pathology must be ruled out. Three methods to estimate the final adult height are available: I) Bayley- Pinneau (B-P) which is based on current stature, chronological age (CA), and bone age (BA) obtained by the Greulich and Pyle method . This method probably under predicts growth potential . The TW2 method considers current height, chronologie age, TW2 assessment of bone age, mid-parental stature, and pubertal status . The Roche- Wainer - Thissen (R-W -T) method requires recumbent length, weight, chronological age, mid-parental stature, and Greulich and Pyle bone age assessment. Predictions of the ultimate adult height are not totally accurate and are of limited value in children with growth disorders.

40. Mid-Parental Height (MPH) calculation of mid-parental height (MPH) has been recommended for assessing growth in individual children since it was first described in 1970. Formulae (in cm) for calculating gender adjusted MPH are the following: for girls (father’s height − 13 + mother’s height)/2; and for boys (father’s height + mother’s height + 13)/2. Results of both formulae are reported ±10 cm ( ie , ±2 SD). Using MPH to guide clinical decisions requires obtaining parental heights, making the calculation, and considering the results for the individual patient. It can be used to estimate a child’s expected final height, but there is a wide target range (MPH ± 10cm for boys and ± 8.5cm for girls), and it is more commonly used to assess whether the child’s current height centile is consistent with genetic expectation.

41. Mid Parental Height

42. Mid Parental Height Calculating the midparental height is an important part of the evaluation because most short or tall children have short or tall parents. Projected height can be estimated by projecting the current growth curve to adulthood in children with normal bone age, or by using a bone age atlas in those with delayed bone age. Most children will have a projected adult height within 10 cm (4 in), or two standard deviations, of their midparental height. A projected height that differs from the midparental height by more than 10 cm suggests a possible pathologic condition. Short or tall parents may themselves have a pathologic reason for their height, especially if they are more than two standard deviations from the adult norm.

43. Mid-parental centile (MPC) The child’s growth is assessed in the context of his/her family. Heights from both biological parents should be used to calculate the MPC and the child’s current centile can be compared to this. There are two main methods: • Plotting mother’s and father’s height on a parent height comparator which are included on growth charts , with a line drawn between the two points, crossing the MPC line. • Calculating the mean of the father’s and mother’s height, with 7 cm added to the mid-parental height for a boy and 7 cm subtracted for a girl. Then the centile closest to this on the child’s growth chart at age 18 years is identified to give the MPC. Details are described on growth charts. Most children have a height centile within two centile spaces of the MPC and the further the child is away from the MPC, the more likely they are to have a pathological explanation for their growth pattern.

44. The Genetic Potential The genetic makeup of an individual is a large contributor to final adult height. Children from tall families generally end up tall and vice versa. Crucial to the assessment of genetic potential is the accurate measurement of both parents. Once the parental heights are known, one can calculate a mid-parental height (MPH) according to the following formula: Boys (inches): MPH = (father’s height + mother’s height + 5)/2 Boys (centimeters): MPH = (father’s height + mother’s height + 13)/2 Girls (inches): MPH = (father’s height + mother’s height – 5)/2 Girls (centimeters): MPH = (father’s height + mother’s height – 13)/2 The number obtained should be plotted on the sex-appropriate height percentile chart at age 18 years. James Tanner originally suggested that the expected final height of a child should fall within ± 8.5 cm of the MPH based on the fact that the third to 97th percentile range for parental height is 17 cm, although the basis for that number or what proportion of the distribution this range includes was not given. When reporting an MPH, one is indicating that the child’s final height is expected to fall within a distribution, with the mean being the MPH and the range being 8.5 cm.

45. Growth Velocity is a measurement of growth rate. Children with normal variants of height tend to have a normal growth velocity (5 cm [2 inchs ] per year for children between five years of age and puberty) after catch-up or catch-down growth. A growth velocity that is less than normal should prompt further investigation. 1 inch = 2.54 cm

46. Growth Velocity While many practitioners mostly use the height curve, the growth velocity curve is the most crucial and telling measure. At the onset of any disease affecting growth, the growth velocity is the first thing that changes. A persistent change of the growth velocity over time will eventually lead to a crossing of percentiles on the height curve. Therefore, the most important measure one should look at when evaluating growth is the growth velocity because it is the most sensitive indicator of a problem. Because of its sensitivity, the growth velocity is also more prone to errors in measurement. The yearly growth velocity is ideally calculated by measuring the difference in height from 2 different clinic visits 1 year apart. In real life, one may not have the luxury of waiting a full year before remeasuring growth, particularly when there are concerns about short stature. In that case, the measurements are done several months apart, and difference in height is divided by the time elapsed expressed in fraction of 1 year. This introduces errors into the measurement of growth velocity.

47. A child growing at a growth velocity of 6 cm/year adds, on average, 0.5 cm of height per month. A 0.5-cm error in the measurement made up or down would significantly impact the calculated growth velocity if the measurements were made 1 month apart. Therefore, because growth is a slow process, growth velocity should be calculated by using 2 different measurements at least 4 months apart to minimize the impact of measurement errors. In addition, growth in children is episodic, occurring in bursts with intervening periods of low growth. Using the above example, a yearly growth velocity of 6 cm does not mean that the child grew 0.5 cm each month of the year. This is another reason why measurements of growth velocity should be done over a period of at least 4 months. When one combines the potential error in measurement, the episodic nature of linear growth, and the small increment in height when the 2 measurements are made over a short period of time, the error in growth velocity will be amplified. It is my experience that a much more accurate assessment of growth velocity can be made using 2 points 6 to 12 months apart.

48. Normal Growth velocities at different ages Average Growth Velocity / Year 1- 1st year -----25cm 2- 2nd year------12-13cm 3- 3rd & 4th year-----6-7 cm 4- 5 years- till onset of puberty------5cm/year The Growth Velocity may fall to as low as 4cm/year just before the pubertal spurt

49. Classification of Dwarfism : In men and women, the sole requirement for being considered a dwarf is having an adult height under 147 cm (4 ft 10 in) and it is almost always sub-classified with respect to the underlying condition that is the cause of the short stature. Dwarfism is usually caused by a genetic variant; achondroplasia is caused by a mutation on chromosome 4. If dwarfism is caused by a medical disorder, the person is referred to by the underlying diagnosed disorder. Disorders causing dwarfism are often classified by proportionality. Disproportionate dwarfism describes disorders that cause unusual proportions of the body parts, while proportionate dwarfism results in a generally uniform stunting of the body. Disorders that cause dwarfism may be classified according to one of hundreds of names, which are usually permutations of the following roots: location 1. rhizomelic = root, i.e., bones of the upper arm or thigh 2. mesomelic = middle, i.e., bones of the forearm or lower leg 3. acromelic = end, i.e., bones of hands and feet. 4. micromelic = entire limbs are shortened source 1. chondro = of cartilage 2. osteo = of bone 3. spondylo = of the vertebrae 4. plasia = form 5. trophy = growth Examples include achondroplasia and chondrodystrophy .

50. Length : Children 2 years and younger should be measured in a supine position using a Harpenden infant measuring table . Height : Children older than 2 years of age and adolescents should be measured using a Harpenden stadiometer .

51. Body Proportions Documenting body proportions is an important part of evaluating growth. Short stature can be categorized as proportionate (the ratio of upper to lower body proportions is maintained) or disproportionate (the ratio is abnormal). Measuring body proportions can be achieved in 1 of 2 ways—measuring a sitting height or measurement of upper and lower segments. Sitting height is obtained by measuring height with the subject sitting in a chair and then subtracting the height of the seat from the sitting height to calculate the height of the trunk. Subtract the height of the trunk from the standing height to calculate the leg height. Upper and lower segments can be measured from the vertex of the skull to the top of the symphysis pubis. The lower segment can be measured from the top of the symphysis pubis to the floor. It is my experience that measuring the lower segment is easier and more accurate. The upper segment can be calculated by subtracting the lower segment from the standing height.

52. Short stature = Height below 3 rd centile or less than 2 standard deviations below the median height for that age & sex according to the population standard or Even if the height is within the normal percentiles but growth velocity is consistently below 25 th percentile over 6 -12 months of observation The term ‘Dwarfism’ is no longer used for short stature . Essential Pediatrics, 7 th Edition, OP Ghai ; Fima Lifschitz - Pediatric Endocrinology

53. Syndromes with Short Stature

54. Silver Russell Syndrome

55. Turner Syndrome

56. Prader Willi Syndrome

57. Noonan Syndrome

58. Dubowitz syndrome

59. Seckel Syndrome

60. Laron’s Syndrome

61. Laron’s Syndrome - Metabolic disorder, AR inheritence - Clinically resembles h. GH deficiency, but blood h. GH levels are high - Somatomedin levels are low Laron syndrome is a rare form of short stature that results from the body's inability to use growth hormone, a substance produced by the brain's pituitary gland that helps promote growth. Affected individuals are close to normal size at birth, but they experience slow growth from early childhood that results in very short stature. If the condition is not treated, adult males typically reach a maximum height of about 4.5 feet; adult females may be just over 4 feet tall. Other features of untreated Laron syndrome include reduced muscle strength and endurance, low blood sugar levels (hypoglycemia) in infancy, small genitals and delayed puberty, hair that is thin and fragile, and dental abnormalities. Many affected individuals have a distinctive facial appearance, including a protruding forehead, a sunken bridge of the nose (saddle nose), and a blue tint to the whites of the eyes (blue sclerae). Affected individuals have short limbs compared to the size of their torso, as well as small hands and feet. Adults with this condition tend to develop obesity. However, the signs and symptoms of Laron syndrome vary, even among affected members of the same family. Studies suggest that people with Laron syndrome have a significantly reduced risk of cancer and type 2 diabetes. Affected individuals appear to develop these common diseases much less frequently than their unaffected relatives, despite having obesity (a risk factor for both cancer and type 2 diabetes). However, people with Laron syndrome do not seem to have an increased lifespan compared with their unaffected relatives.

62. Achondroplasia

63. Achondroplasia

64. Common Types of Dwarfism (Skeletal Dysplasia) Hundreds of types of dwarfism (skeletal dysplasia) affect bone growth. Some of the most common types include : 1- Achondroplastic dwarfism: The most common form of dwarfism is characterized by short limbs and a prominent forehead. 2- Hypochondroplasia dwarfism: A mild type of short-limbed dwarfism with characteristics not noticeable during infancy. 3- Pituitary dwarfism: Dwarfism caused by a growth hormone deficiency. 4- Primordial dwarfism: A form of dwarfism where a small body size occurs during all stages of life, even before birth. 5- Thanatophoric dysplasia: A less common, very severe form of dwarfism that causes very short limbs along with a narrow chest. It usually causes infants to die shortly after birth due to breathing difficulties.

65. Rubinstein Ta yb i Syndrome

66. Thanatophoric dysplasia

67. Brachman de Lange syndrome = Cornelia de Lange syndrome

68. Skeletal dysplasias Skeletal dysplasias are a group of genetic disorders that affect the development of bone and cartilage . The disorders may be inherited in an autosomal dominant , autosomal recessive or X-linked manner. Some skeletal dysplasias can be detected as early as the prenatal period, while others manifest later in life, typically during childhood or adolescence . Achondroplasia, characterized by disproportionate short stature and craniofacial abnormalities, is the most common type of skeletal dysplasia. Osteogenesis imperfecta is a bone disease characterized by impaired osteogenesis that results in brittle bones that fracture easily, while osteopetrosis is a high-density bone disease that results in increased sclerotic thickening of the skeleton on radiological examination. Campomelic syndrome is a life-threatening disorder characterized by skeletal dysplasia , abnormal sex development, and other congenital defects due to SOX9 gene mutations. The Skeletal Dysplasias or Osteochondrodysplasias are a heritable group of more than 450 well delineated disorders that affect primarily bone and cartilage, but can also have significant effects on muscle, tendons and ligaments.1 By definition, skeletal dysplasias are heritable diseases that have generalized abnormalities in cartilage and bone, while dysostoses are genetic disorders characterized by abnormalities in a single or group of bones. Over time, the distinction between these disorders has become blurred, as the field has recognized that there is radiographic, clinical and molecular overlap. Recent advances in genetic technologies have identified the molecular basis in more than 350 of these disorders, providing us with the opportunity to translate research findings into clinical service. Understanding the genes that produce these disorders allows us to delineate the extent of spectrum of disease associated with a particular disorder, provides diagnostic service for families at risk for recurrence based on mode of inheritance, as well as furthering our understanding of pathways involved in the development and maintenance of the skeleton.

69. Growth Hormone Deficiency = GHD Acquired GHD Congenital GHD idiopathic GHD

70. The initial evaluation of short stature should include a history and physical examination, accurate growth assessment, calculation of the growth velocity and midparental height, and radiography to evaluate bone age. Drugs known to cause short stature include steroids (chronic use), attention-deficit/hyperactivity disorder medications, and anticonvulsants. Dysmorphic characteristics suggest a genetic disorder, whereas midline defects suggest an abnormality of the growth hormone axis.

71. Examination : Anthropometric assessment (weight, height, weight for height and head circumference) provides crucial inputs for the diagnosis. Body proportions help in identifying skeletal dysplasia. Increased upper to lower segment (US: LS) ratio is observed in hypothyroidism, achondroplasia or Turner syndrome while reduced US: LS ratio is seen in disorders such as Morquio syndrome and spondyloepiphyseal dysplasia. Body proportions are normal in GHD. The clinician should also look for specific clinical features of an underlying etiology such as GHD, hypothyroidism, Turner syndrome and rickets Evaluation for dysmorphism , skeletal deformities and pubertal staging (sexual maturity rating) is essential for diagnosis.

72. Hormones act as chemical messengers that are released into the blood stream to act on an organ in another part of the body. Although hormones reach all parts of the body, only target cells with compatible receptors are equipped to respond. Over 50 Hormones have been identified in humans and other vertebrates. Hormones control or regulate many biological processes and are often produced in exceptionally low amounts within the body.

73. Thyroid Hormone and GH Thyroid hormone plays a permissive effect on GH secretion by increasing responsiveness to GHRH. T3 at the level of the pituitary increases GH gene expression as well as GH secretion. Hypothyroidism is associated with decreased GHRH stores and decreased responsiveness to GHRH as well as depleted somatotroph GH stores. Hypothyroidism is associated with poor GH responsiveness to provocative testing and low serum IGF-1 concentrations. In addition to its action at the pituitary and hypothalamic level, T3 also plays a permissive role for GH action at the growth plate.

74. Etiology of Growth Hormone Deficiency : Congenital 1- Genetic defects Isolated GH deficiency Type 1: Autosomal recessive Type 2: Autosomal dominant Type 3: X-linked recessive Multiple pituitary deficiencies Type I: Autosomal recessive Type II: X-linked 2- Idiopathic GH releasing hormone deficiency 3- Developmental defects: Pituitary aplasia or hypoplasia anencephaly, holoprosencephaly , midfacial anomalies septo-optic dysplasia . Acquired 1- Tumors: Hypothalamic, pituitary or other intracranial tumors 2- Irradiation 3- lnfectious : Encephalitis, meningitis, tuberculosis, toxoplasmosis 4- lnfiltration : Histiocytosis , hemochromatosis sarcoidosis 5- Injury: Perinatal insult (breech), head injury. surgery 6- Vascular: Aneurysm, infarction

75. Approximately 3% children in any population will be short Approximately half will be physiological ( familial or constitutional ) & half will be pathological short stature .

76. Causes Of Short Stature : Proportionate Short Stature 1- Normal Variants: -Familial -Constitutional Growth Delay 2- Prenatal Causes: -Intra-uterine Growth Restriction. Placental causes, Infections, Teratogens -Intra-uterine Infections -Genetic Disorders (Chromosomal & Metabolic Disorders)

77. 3) Postnatal Causes : i ) Undernutrition ii) Chronic Systemic Illness : Cardiopulmonary: CHD, Chronic Asthma, Cystic Fibrosis Renal: RTA, CRF, Steroid dependent Nephrotic Syndrome GI and Hepatic: Malabsorption, IBD, chronic liver disease Chronic Severe Infections Hematological : Thalassemia, Sickle cell anemia

78. iii) Psychosocial Short Stature (emotional deprivation) iv) Endocrine Causes : - Growth Hormone Deficiency/ insensitivity - Hypothyroidism - Juvenile Diabetes Mellitus - Cushing Syndrome - Pseudohypoparathyroidism - Precocious/ delayed puberty

79. B) Disproportionate Short Stature 1) With Short Limbs: - Achondroplasia, Hypochondroplasia , Chondrodysplasia punctata , Chondroectodermal Dysplasia, Diastrophic dysplasia, Metaphyseal Chondrodysplasia - Deformities due to Osteogenesis Imperfecta , Refractory Rickets 2) With Short Trunk: - Spondyloepiphyseal dysplasia, Mucolipidosis , Mucopolysaccharidosis - Caries Spine, Hemivertebrae

80. Intra-uterine Growth Restriction Arrest of fetal growth in early embryonic life causes reduction in total number of cells, leading to diminished growth potential in postnatal life BW <10 th centile for gestational age Most of these babies show catch-up growth by 2 yrs of age, but 20 -30% may remain short Subtle defects in the GH-IGF axis are considered to be responsible Growth Velocity is normal • BA = CA • Learning disabilities could be present .

81. Genetic Syndromes: A) Chromosomal Disorders - Turner syndrome ( XO) : an incidence of 1 in 2000 live births - should be ruled out even if typical phenotypic features are absent - Other e. g. : Down, Noonan, Prader -Willi, Silver- Russel, Seckle syndrome B) Inborn Errors of Metabolism - eg . Galactosemia , Aminoaciduria

82. Under nutrition: One of the commonest cause of short stature in Developing countries Protein Energy Malnutrition, anemia and trace element deficiency such as Zinc deficiency are common causes Weight gain is slow and muscles are wasted. Long standing malnutrition leads to Stunting BA < CA Diagnosis: good dietary history, anthropometric measurements.

83. Chronic Systemic Illness: Chronic Infections - eg : TB, Malaria, Leishmaniasis , Chronic pyelonephiritis - Growth retardation is due to impaired appetite, decreased food intake, increased catabolism, poor utilization of food, vomiting & diarrhoea 2) Malabsorbtion Syndromes - eg : chronic recurrent infective diarrhoea , lactose intolerance, cystic fibrosis, celiac disease, giardiasis, cow’s milk allergy, abeta lipoproteinemia

84. 3) Birth defects: CHD, urinary tract & nervous system anomalies 4) Miscellaneous: Cirrhosis of liver, bronchiectasis, acquired heart diseases, cardiomyopathies, SDH .

85. Endocrine causes: 1) Human growth hormone deficiency - Normal length & weight at birth - Growth delay seen >1 yr of age, growth velocity < 4 cm/year - BA < CA by at least 2 yrs - Infantile gonadal devlopment , - Delay in SSC - Normal intelligence - Diagnosis: h. GH levels in sleep & after provocation with clonidine, insulin, propranolol - h. GH>10 ng/ml excludes h. GH deficiency

86. 3) Type 1 Diabetes Mellitus - significant growth retardation - insulin has chondrotropic effect

87. 4) Hypothyroidism - Short, stocky child; dull looking, puffy face - Thickened skin & subcutaneous tissue with myxematous appearance, cold intolerance - Protuberant abdomen with umbilical hernia - Infantile sexual development & delayed puberty - Bone age markedly delayed - Diagnosis- Low T 4 levels, high TSH levels .

88. 5) Cushing syndrome : Growth retardation ( early feature) Other features: Obesity, plethoric moon facies , abdominal striae , hypertension, decreased glucose tolerance 6) Gonadal disorders: - Adiposogenital dystrophy ( Frohlich syndrome) moderate growth retardation, bone age normal or slightly delayed - Precocious puberty: early fusion of epiphyseal centres

89. Psychosocial Short Stature = emotional deprivation dwarfism, maternal deprivation dwarfism, hyperphagic short stature Functional hypopituitarism- low IGF-1 levels & inadequate response to GH stimulation . Type 1 - below 2 yrs , failure to thrive, no Gh deficiency Type 2 - in > 3 yrs Other behavioural disorders: enuresis, encorpresis , sleep & appetite disturbances, crying spasms, tantrums Dental eruptions & sexual development delayed .

90. Skeletal dysplasias = chondrodysplasias Inborn error in formation of components of skeletal system causing disturbance of cartilage & bone Abnormal skeletal proportions & severe short stature Diagnosisfamily history, measurement of body proportions, examination of limbs & skulls, skeletal survey .

91. Assessment of a child with short stature 1) Accurate height measurement Below 2 yrs - supine length with infantometer For older children- Stadiometer 2) Assessment of body proportion Upper segment: Lower segment ratio Increase: rickets, achondroplasia, untreated hypothyroidism Decrease: spondyloepiphyseal dysplasia, vertebral anomalies Comparison of arm span with height

92. 3) Assessment of height velocity Rate of increase in height over a period of time, expressed as cm/year If low – pathological cause of short stature 4) Comparison with population norms Height plotted on appropriate growth charts & expressed as centile or SD score 5) Comparison with child’s own genetic potential Mid parental height for boys = mother's height + father's height /2 + 6. 5 cm Mid parental height for girls = mother's height + father's height /2 – 6. 5 cm 6) Sexual maturity rating ( SMR): Also known as Tanners stages Used in older children Total 5 stages included in each gender

93. Tanner puberty scale Below are the Tanner 5 Stages described in detail for clinical reference. For all three sites of development, Tanner Stage 1 corresponds to the pre-pubertal form with progression to Tanner Stage 5, the final adult form. Breast and genital staging, as well as other physical markers of puberty such as height velocity, should be relied on more than pubic hair staging to assess pubertal development because of the independent maturation of adrenal axis.

94. Tanner puberty scale Pubic hair scale (both males and females) Stage 1: No hair Stage 2: Downy hair Stage 3: Scant terminal hair Stage 4: Terminal hair that fills the entire triangle overlying the pubic region Stage 5: Terminal hair that extends beyond the inguinal crease onto the thigh Female breast development scale Stage 1: No glandular breast tissue palpable Stage 2: Breast bud palpable under areola (1st pubertal sign in females) Stage 3: Breast tissue palpable outside areola; no areolar development Stage 4: Areola elevated above contour of the breast, forming “double scoop” appearance Stage 5: Areolar mound recedes back into single breast contour with areolar hyperpigmentation, papillae development and nipple protrusion Male external genitalia scale Stage 1: Testicular volume < 4 ml or long axis < 2.5 cm Stage 2: 4 ml-8 ml (or 2.5-3.3 cm long), 1st pubertal sign in males Stage 3: 9 ml-12 ml (or 3.4-4.0 cm long) Stage 4: 15-20 ml (or 4.1-4.5 cm long) Stage 5: > 20 ml (or > 4.5 cm long)

95. Normal Pubertal Growth : Pubertal growth accounts for approximately 20 percent of final adult height The pubertal growth spurt is immediately preceded by a decrease in height velocity The pubertal growth spurt in girls: Tanner stage II and III 23 to 28 cm during puberty average peak height velocity of 9 cm/year The pubertal growth spurt in boys : Tanner stage III and IV 18 to 24 months after the spurt in girls 26 to 28 cm during puberty average peak height velocity of 10.3 cm per year The later onset, longer duration, and increased velocity of the pubertal growth spurt in boys accounts for their taller stature (an average of 12 to 13 cm greater than that of girls )

96. Bone age Skeletal maturation proceeds in an orderly manner from the first appearance of each epiphyseal centre to the fusion of the long bones. From chronological age 3–4 years, bone age may be quantified from radiographs of the left hand and wrist by comparison with standard photographs (e.g. Greulich and Pyle method) or by an individual bone scoring system (e.g. Tanner–Whitehouse method). The difference between bone age and chronological age is an estimation of tempo of growth. The initiation of puberty usually coincides with a bone age around 10.5–11 years in girls and 11–11.5 years in boys, although the correlation between bone age and pubertal timing is approximate. Girls reach skeletal maturity at a bone age of 15 years and boys when bone age is 17 years. Thus, bone age allows an estimation of remaining growth potential and can be used to aid in the prediction of final adult height.

97. Bone age should be compared with chronologic age to narrow the differential diagnosis of short stature. The traditional method compares a plain radiograph of the left wrist and hand to a database of norms, although various methods are now available. Children with normal variations of growth may have advanced or delayed bone age, but a bone age that is more than two standard deviations from the mean for age is likely due to a pathologic condition. A bone age that is more or less than two standard deviations from the mean is considered abnormal One standard deviation is approximately 10 percent of the child's chronologic age Bone age is delayed in children with constitutional growth delay, hypothyroidism, GH deficiency, or chronic disease, particularly gastrointestinal disease.

98. Tanner-Whitehouse method The Tanner-Whitehouse (TW) technique of estimating bone is a "single-bone method" based on an x-ray image of a patient's left hand and wrist. There have been two updates since the first publication of the TW method in 1962: the TW2 method in 1975 and the TW3 method in 2001.The TW methods consist of evaluating individual bones and assigning a letter grade to each bone based on its degree of maturation. Next, the scores for all evaluated bones are compiled into a sum, and that sum is correlated to bone age through a lookup table for males or females depending on the sex of the patient. The bones considered in the TW3 method include the distal radius and ulna, the metacarpals and phalanges of the 1st, 3rd, and 5th fingers, and all of the carpal bones except the pisiform.

99. Bone age Hand Bone Age: A Digital Atlas of Skeletal Maturity 2nd Edition 2011

100. Bone age is the degree of maturation of a child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray techniques. The "bone age" of a child is the average age at which children reach various stages of bone maturation. A child's current height and bone age can be used to predict adult height. For most people, their bone age is the same as their biological age but for some individuals, their bone age is a couple of years older or younger. Those with advanced bone ages typically hit a growth spurt early on but stop growing sooner, while those with delayed bone ages hit their growth spurt later than normal. Children who are below average height do not necessarily have a delayed bone age; in fact their bone age could actually be advanced which if left untreated, will stunt their growth. At birth, only the metaphyses of the "long bones" are present. The long bones are those that grow primarily by elongation at an epiphysis at one end of the growing bone. The long bones include the femurs, tibias, and fibulas of the lower limb, the humeri , radii, and ulnas of the upper limb (arm + forearm), and the phalanges of the fingers and toes. The long bones of the leg comprise nearly half of adult height. The other primary skeletal component of height is the spine and skull. As a child grows the epiphyses become calcified and appear on the x-rays, as do the carpal and tarsal bones of the hands and feet, separated on the x-rays by a layer of invisible cartilage where most of the growth is occurring. As sex steroid levels rise during puberty, bone maturation accelerates. As growth nears conclusion and attainment of adult height, bones begin to approach the size and shape of adult bones. The remaining cartilaginous portions of the epiphyses become thinner. As these cartilaginous zones become obliterated, the epiphyses are said to be "closed" and no further lengthening of the bones will occur. A small amount of spinal growth concludes an adolescent's growth. Pediatric endocrinologists frequently order bone age x-rays to evaluate children for advanced or delayed growth and physical development. These are interpreted by pediatric radiologists, physicians who are experts in using medical imaging for pediatric diagnosis and therapy.

101. The most commonly used bone age assessment methods are the Greulich-Pyle (GP) and Tanner-Whitehouse 2 (TW2) methods, both of which involve left hand and wrist radiographs. Radiographs of the hand and wrist are suitable for bone age assessment because the hand and wrist possess many bones and taking radiographs of the hand and wrist is easy. There are several reasons for using left hand and wrist radiographs for bone age assessment rather than right hand and wrist radiographs. One reason is that most people are right-handed, and therefore, the right hand is more likely to be injured than the left hand .Another reason is that it was determined that physical measurements should be performed on the left side rather than the right side of the body at the conferences of physical anthropologists in the early 1900s . The hand and wrist bones consist of the radius, ulna, 19 short bones (5 metacarpals and 14 phalanges) and 7 carpals. Bones are formed by endochondral ossification in the radius, ulna and short bones and by intramembranous ossification in the carpal bones. The maturation rates of the carpals vary among individuals. The completion of maturation occurs earlier in the carpals compared with the long and short bones, and intramembranous ossification is less dependent on GH than endochondral ossification. Therefore, the carpals are not suitable for bone age assessment. Although the bone maturation process itself is similar among all people, the rate of bone maturation differs among ethnic groups. The main cause of the difference in bone maturation rate among ethnic groups is the difference in the timing of pubertal onset .

102. Clinical application of bone age readings : For the average person with average puberty, the bone age would match the person's chronological age. In terms of height growth and height growth related to bone age, average females stop growing taller two years earlier than average males. Peak height velocity(PHV) occurs at the average age of 11 years for girls and at the average age of 13 years for boys . A girl has reached 99% of her adult height at a bone age of 15 years and has a small amount of height growth left from this point on. A boy has reached 99% of his adult height at a bone age of 17 years and has a small amount of height growth left from this point on. When the bone age reaches 16 years in females and 18 years in males, growth in height is over and they have reached their full adult height. There are exceptions with people who have an advanced bone age (bone age is older than chronological age) due to being an early bloomer (someone starting puberty and hitting PHV earlier than average), being an early bloomer with precocious puberty, or having another condition. There are also exceptions with people who have a delayed bone age (bone age is younger than chronological age) due to being a late bloomer (someone starting puberty and hitting PHV later than average), being a late bloomer with delayed puberty, or having another condition.

103. An advanced or delayed bone age does not always indicate disease or "pathologic" growth. Conversely, the bone age may be normal in some conditions of abnormal growth. Children do not mature at exactly the same time. Just as there is wide variation among the normal population in age of losing teeth or experiencing the first menstrual period, the bone age of a healthy child may be a year or two advanced or delayed. Those with an advanced bone age typically hit a growth spurt early on but stop growing at an earlier age. Consequently, when a naturally short child has an advanced bone age, it stunts their growth at an early age leaving them even shorter than they would have been. Because of this, those who are short with an advanced bone age, need medical attention before their bones fully fuse. An advanced bone age is common when a child has had prolonged elevation of sex steroid levels, as in precocious puberty or congenital adrenal hyperplasia. The bone age is often marginally advanced with premature adrenarche , when a child is overweight from a young age or when a child has lipodystrophy. Those with an advanced bone age typically hit a growth spurt early on but stop growing at an earlier age. Bone age may be significantly advanced in genetic overgrowth syndromes, such as Sotos syndrome, Beckwith- Wiedemann syndrome and Marshall-Smith syndrome. Bone maturation is delayed with the variation of normal development termed Constitutional delay of growth and puberty, but delay also accompanies growth failure due to growth hormone deficiency and hypothyroidism. Recent studies show that organs like liver can also be used to estimate age and sex, because of the unique feature of liver. Liver weight increases with age and is different between males and females. Thus, liver can be employed in special medico-legal cases of skeletal deformities or mutilation.

104. Bone age

105. Source : en.wikipedia.org

106. According to the Greulich and Pyle radiographic atlas of skeletal development of the hand and wrist, approximate bone age is 2 years with a standard deviation of +/- 4 months. (Patient's exact chronological age = 5 years).

107. Advanced bone age congenital adrenal hyperplasia

108. advanced bone age A generalized acceleration in bone maturation can result from a number of etiological factors. They include: 1-endocrine disorders -idiopathic isosexual precocious puberty -hypothalamic or parathalamic lesion with sexual precocity: e.g. craniopharyngioma astrocytoma hypothalamic hamartoma hypothlamic -optic chiasmatic glioma tuberculosis -adrenogenital syndrome (adrenocortical tumor or hyperplasia) -excessive androgen, estrogen or steroid administration or production: e.g. virilizing adrenal or gonadal neoplasm or hyperplasia Cushing syndrome pituitary gigantism: hyperpituitarism hyperthyroidism (maternal or acquired): uncommon 2-congenital disorders -McCune-Albright syndrome: polyostotic fibrous dysplasia with precocious puberty -cerebral gigantism: Sotos syndrome -lipodystrophy - acrodysostosis : uncommon -pseudohypoparathyroidism: uncommon -Weaver syndrome: uncommon -Marshall-Smith syndrome: uncommon -asphyxiating thoracic dysplasia: Jeune syndrome: uncommon -Beckwith-Wiedemann syndrome: uncommon others constitutional or familial tall stature

109. Diagnosis of Short Stature Detailed history Careful examination Laboratory evaluation

110. Clues to etiology from history History Etiology History of delay of puberty in parents Constitutional delay of growth Low Birth Weight SGA Neonatal hypoglycemia, jaundice, micropenis GH deficiency Dietary intake Under nutrition Headache, vomiting, visual problem Pituitary/ hypothalamic SOL Lethargy, constipation, weight gain Hypothyroidism Polyuria CRF, RTA Social history Psychosocial dwarfism Diarrhea, greasy stools Malabsorption

111. Pointers to etiology of short stature Pointer Etiology Midline defects, micropenis , Frontal bossing, depressed nasal bridge, crowded teeth, GH deficiency Rickets Renal failure, RTA, malabsorption Pallor Renal failure, malabsorption, nutritional anemia Malnutrition PEM, malabsorption, celiac disease, cystic fibrosis Obesity Hypothyroidism, Cushing syndrome, Prader Willi syndrome Metacarpal shortening Turner syndrome, pseudohypoparathyroidism Cardiac murmur Congenital heart disease, Turner syndrome Mental retardation Hypothyroidism, Down/ Turner syndrome, pseudohypoparathyroidism

112. Examination • Assess height and height velocity over at least 6 months. • Measure sitting height, and derive subischial leg length (standing height – sitting height (cm)) if skeletal disproportion suspected. • Assess for the presence and severity of chronic disease. Low weight for height suggests a nutritional diagnosis, GI cause, or other significant systemic disease. • Pubertal stage using Tanner’s criteria • Observe for dysmorphic features and signs of endocrinolopathy , presence and severity of chronic disease. • Measure parents’ heights, and calculate MPH.

113. Clues to etiology from examination Examination finding Etiology Disproportion Skeletal dysplasia, rickets, hypothyroidism Dysmorphism Congenital syndromes Hypertension CRF Goitre , coarse skin Hypothyroidism Central obesity, striae Cushing syndrome. Clinical features of Primary GH deficiency : 1- Infancy GH deficiency may present with hypoglycaemia . Coexisting ACTH, TSH, and gonadotrophin deficiencies may cause prolonged hyperbilirubinaemia and micropenis . Size may be normal, as fetal and infancy growth is more dependent on nutrition and other growth factors than on GH. 2- Childhood Typical features include slow growth velocity, short stature, d muscle mass, and i SC fat. Underdevelopment of the mid-facial bones, relative protrusion of the frontal bones because of mid-facial hypoplasia, delayed dental eruption, and delayed closure of the anterior fontanelle may be seen. These children have delayed bone age and delayed puberty.

114. Investigation : Level 1 ( essential investigations): Complete hemogram with ESR BONE AGE Urinalysis ( Microscopy, p. H, Osmolality) Stool ( parasites, steatorrhea, occult blood) Blood ( RFT, Calcium, Phosphate, alkaline phosphatase, venous gas, fasting sugar, albumin, transaminases) BONE AGE ( BA ): Bone age assessment should be done in all children with short stature Appearance of various epiphyseal centers & fusion of epiphyses with metaphyses tells about the skeletal maturity of the child Conventionally read from Xray of hand & wrist using Gruelich -Pyle atlas or Tanner- Whitehouse method Bone age gives an idea as to what proportion of adult height has been achieved by the child & what is remaining potential for height gain BA is delayed compared to chronological age in almost all causes of short stature Exceptions: Familial short stature, Precocious puberty

115. Level 2 : Serum thyroxine, TSH Karyotype to rule out Turner syndrome in girls If above investigations are normal and height between -2 to -3 SD Observe height velocity for 6 -12 months If height < 3 SD level 3 investigations Level 3 : Celiac serology ( anti- endomysial or anti- tissue transglutaminase antibodies) Duodenal biopsy GH stimulation test with Clonidine or insulin & serum insulin like GF-1 levels

116. Management: Counselling of parents ( for physiological causes) Dietary advice ( Undernutrition, Celiac disease, RTA ) Limb lengthening procedures ( skeletal dysplasias ) Levothyroxine ( In Hypothyroidism) GH s/c injections ( GH deficiency, Turner syndrome, SGA, CRF prior to transplant) Monitoring with regular & accurate recording of height is mandatory for a good outcome in any form of therapy .

117. Representation of the three-sigma rule. The dark blue zone represents observations within one standard deviation (σ) to either side of the mean (μ), which accounts for about 68.3% of the population. Two standard deviations from the mean (dark and medium blue) account for about 95.4%, and three standard deviations (dark, medium, and light blue) for about 99.7%.

118. Percentile In statistics, a k- th percentile (percentile score or centile) is a score below which a given percentage k of scores in its frequency distribution falls (exclusive definition) or a score at or below which a given percentage falls (inclusive definition). For example, the 50th percentile (the median) is the score below which (exclusive) or at or below which (inclusive) 50% of the scores in the distribution may be found. Percentiles are expressed in the same unit of measurement as the input scores; for example, if the scores refer to human weight, the corresponding percentiles will be expressed in kilograms or pounds. The percentile score and the percentile rank are related terms. The percentile rank of a score is the percentage of scores in its distribution that are less than it, an exclusive definition, and one that can be expressed with a single, simple formula. Percentile scores and percentile ranks are often used in the reporting of test scores from norm-referenced tests, but, as just noted, they are not the same. For percentile rank, a score is given and a percentage is computed. Percentile ranks are exclusive. If the percentile rank for a specified score is 90%, then 90% of the scores were lower. In contrast, for percentiles a percentage is given and a corresponding score is determined, which can be either exclusive or inclusive. The score for a specified percentage (e.g., 90th) indicates a score below which (exclusive definition) or at or below which (inclusive definition) other scores in the distribution fall. The 25th percentile is also known as the first quartile (Q1), the 50th percentile as the median or second quartile (Q2), and the 75th percentile as the third quartile (Q3).

119. Growth Charts 1- WHO ----www.who.int 2- CDC ----www.cdc.gov 3- Egyptian Growth Chart ---www. www.researchgate.net

120. Growth Charts Babies and CDC Growth Charts Growth charts consist of a series of percentile curves that illustrate the distribution of selected body measurements in children. Pediatric growth charts have been used by pediatricians, nurses, and parents to track the growth of infants, children, and adolescents in the United States since 1977. CDC recommends that health care providers: Use the WHO growth standards to monitor growth for infants and children ages 0 to 2 years of age in the U.S. Use the CDC growth charts for children age 2 years and older in the U.S. Growth charts are not intended to be used as a sole diagnostic instrument. Instead, growth charts are tools that contribute to forming an overall clinical impression for the child being measured.

121. The normal distribution and percentile s The methods given in the definitions section (below) are approximations for use in small-sample statistics. In general terms, for very large populations following a normal distribution, percentiles may often be represented by reference to a normal curve plot. The normal distribution is plotted along an axis scaled to standard deviations, or sigma ({\ displaystyle \sigma }\sigma ) units. Mathematically, the normal distribution extends to negative infinity on the left and positive infinity on the right. Note, however, that only a very small proportion of individuals in a population will fall outside the −3σ to +3σ range. For example, with human heights very few people are above the +3σ height level. Percentiles represent the area under the normal curve, increasing from left to right. Each standard deviation represents a fixed percentile. Thus, rounding to two decimal places, −3σ is the 0.13th percentile, −2σ the 2.28th percentile, −1σ the 15.87th percentile, 0σ the 50th percentile (both the mean and median of the distribution), +1σ the 84.13th percentile, +2σ the 97.72nd percentile, and +3σ the 99.87th percentile. This is related to the 68–95–99.7 rule or the three-sigma rule. Note that in theory the 0th percentile falls at negative infinity and the 100th percentile at positive infinity, although in many practical applications, such as test results, natural lower and/or upper limits are enforced.

122. Z-Scores vs. Standard Deviation Standard a. Standard deviation is calculated by first determining the difference between each data point and the mean. The differences are then squared, summed, and averaged. This produces the variance. The standard deviation is the square root of the variance. The Z-score, by contrast, is the number of standard deviations a given data point lies from the mean. For data points that are below the mean, the Z-score is negative. In most large data sets, 99% of values have a Z-score between -3 and 3, meaning they lie within three standard deviations above and below the mean.

123. Average Height Velocity at different phases: • Prenatal growth : 1.2 -1.5 cm / week • Infancy :23 - 28 cm / year • Childhood : 5 - 6.5 cm / year • Puberty : 8.3 cm / year (girls), 9.5 cm / year (boys)

124. Egyptian Growth Charts

125. WHO Growth Charts

126. CDC Growth Charts

127. Growth velocity charts are important to evaluate the growth of a subject and are available for height and weight, in both boys and girls. Height or weight velocity is a variable derived from the measurement of height or weight at different times and represents the increase in height or weight during a fixed period. Height or weight velocity charts depict the age-dependent changes in velocity that characterize human postnatal growth. Height velocity (HV) is characterized by rapid progress from birth up to the end of the first year of life, followed by decreases through the second year. The male neonate grows slightly faster than the female, but the velocities equilibrate at 7 months of age. Then, up to adolescence there are no significant differences in growth rates.

128. The adolescent height spurt in females begins at 10.5 years and reaches a peak at about 12 years. Males instead exhibit the pubertal spurt later at 12.5 years and reach a peak HV at 14 years. The curves for weight velocity (WV) show a peak before the first year of age for both boys and girls. The male WV is greater at birth, but reaches an equilibrium with female WV at about 8 months and then gradually lags behind the female WV until adolescence. During pubertal development WV peaks at about 12.9 years in girls and 14.3 years in boys; peak WV generally occurs at a slightly older age than peak HV. Growth velocity is central to the diagnosis of growth retardation. In the presence of a very low single value for HV (3rd centile), the paediatrician should start a prompt endocrinological evaluation. When height is >3rd centile and more than one HV value is available, an endocrinological evaluation is warranted when the values are persistently under the 25th centile. An HV value consistently above the 75th centile should be checked and correlated to signs of precocious puberty and elevated body weight. In conclusion, growth velocity charts are valuable tools for the paediatrician and can be used by clinicians in the screening and assessment of metabolic/ endocrinological disorders.

129. Formulas for Calculating Midparental Height in Children : Girls 1- [Paternal height (cm) – 13 cm + maternal height (cm)] ÷ 2 or 2- [Paternal height (in) – 5 in + maternal height (in)] ÷ 2 Boys 1- [Paternal height (cm) + 13 cm + maternal height (cm)] ÷ 2 or 2- [Paternal height (in) + 5 in + maternal height (in)] ÷ 2

130. Growth Hormone Deficiency Hypopituitarism can be caused by anything that damages the hypothalamus, pituitary stalk, or pituitary gland. The incidence of congenital GH deficiency has been reported as between 1 :4000 and 1: 10,000 live births . Growth failure is the most common sign of GH deficiency presenting in infancy and childhood. Children with mild GH deficiency usually present after 6 mo of age, when the influences of maternal hormones wane . They generally have normal birth weights, with slightly below average lengths . The growth rate of a child with GH deficiency will progressively decline, and typically the bone age will be delayed. They develop increased peri -abdominal fat and decreased muscle mass, and may also have delayed dentition, thin hair, poor nail growth, and a high-pitched voice . Severe GH deficiency in the newborn period may be characterized by hypoglycemia and conjugated hyperbilirubinemia, as well as a small phallus in boys, consistent with multiple anterior pituitary hormone deficiencies .

131. Primary GH deficiency p GH deficiency is usually sporadic, but rarely it may be inherited as autosomal dominant, recessive, or X-linked recessive and may be associated with other pituitary hormone deficiencies. It may represent a defect in homeobox genes (e.g. Pit1 (leading to GH, TSH, and PRL deficiency), Prop1 (leading to GH, TSH, PRL, gonadotrophin, and later ACTH deficiencies), or Hesx1) which control HP development. Mutation in Hesx1 has been associated with midline defects, such as optic nerve hypoplasia and corpus callosum defects (i.e. ‘ septo -optic dysplasia’). GH deficiency usually arises because of failure of release of GHRH from the hypothalamus. Clinical features • Infancy GH deficiency may present with hypoglycaemia . Coexisting ACTH, TSH, and gonadotrophin deficiencies may cause prolonged hyperbilirubinaemia and micropenis . Size may be normal, as fetal and infancy growth is more dependent on nutrition and other growth factors than on GH. • Childhood Typical features include slow growth velocity, short stature, d muscle mass, and i SC fat. Underdevelopment of the mid-facial bones, relative protrusion of the frontal bones because of mid-facial hypoplasia, delayed dental eruption, and delayed closure of the anterior fontanelle may be seen. These children have delayed bone age and delayed puberty.

132. Secondary GH deficiency Brain tumours and cranial irradiation Pituitary or hypothalamic tumours may impair GH secretion, and deficiencies of other pituitary hormones may coexist. Cranial irradiation, used to treat intracranial tumours , facial tumours , and acute leukaemia , may also cause GH deficiency. Risk of HP damage is related to total dose administered, fractionation (single dose more toxic than divided), location of the irradiated tissue, and age (younger children are more sensitive to radiation damage). GH secretion is most sensitive to radiation damage, followed by gonadotrophins, TSH, and ACTH. Central precocious puberty may also occur and may mask GH deficiency by promoting growth but will compromise final height if untreated. At-risk children should, therefore, be screened regularly by careful examination and multiple pituitary hormone testing. These survivors of childhood cancer may also have other endocrine problems, including gonadal damage related to concomitant chemotherapy or radiation scatter, hypothyroidism related to spinal radiation, or glucose intolerance related to total body irradiation. It is recommended that all such patients should undergo endocrine surveillance.

133. Growth Hormone Physiology

134. Diagnostic Criteria for GH deficiency (GHD): 1. Short stature (height <-2.5SD) that is inappropriate for the target centile range 2. Subnormal growth-rate; as a rough guide < 5cm per year in a prepubertal child over 2 years of age, to be calculated over a period of NOT less than 6 months unless height is <-3 SD 3. Exclusion of other genetic e.g. skeletal dysplasia and systemic causes of growth failure 4. Normal karyotype in girls 5. Bone age delay <2SD 6. Normal thyroid functions. If abnormal, thyroid functions must be normalized with treatment before performing GH provocation 7. Celiac screening 8. Subnormal GH response to 2 provocation tests (insulin and clonidine). Peak GH < 7 ng/ml. Cortisol is to be measured in the 60-minute sample of an insulin tolerance test . 9. For the following categories one test is sufficient: a. Defined CNS pathology b. History of irradiation c. Multiple pituitary hormone deficiency (MPHD) 9. MRI sella turcica to be done on individual basis 10. No provocation tests are needed for Turner Syndrome

135. The Diagnostic Evaluation of a Child with Short Stature Growth is an integral part of the medical evaluation of any child. Medical professionals caring for children should be aware of the following: 1. A very careful history should be obtained, including the circumstances of pregnancy and those surrounding delivery. Particular attention should be paid to the period when growth deceleration occurred. Previous medical records should be evaluated, in particular growth charts. 2. A careful physical examination should be done to detect abnormal physical findings, signs of disease, and features of known genetic syndromes. Particular attention should be paid to measuring body proportions as well carefully documenting the stage of puberty. 3. Children should be measured using appropriate techniques and standard instruments. Supine length should be measured for children under 2, and standing height should be measured in older children using a stadiometer. 4. The appropriate growth chart should be used to plot the measured height. The WHO charts are the standard for growth from 0 to 2 years of age, and the CDC charts are the standard for children older than age 2 years. 5. Children often cross percentiles during the first 2 to 3 years of life depending on their prenatal condition and genetic potential. 6. The rate of growth from 2 years of age until the onset of puberty is almost constant, and children do not cross percentiles in either direction during this period. Any clear crossing of percentiles requires immediate attention. 7. The age of onset of puberty varies considerably between the sexes as well as between different individuals from the same sex. Because of this variability, the use of longitudinal charts is preferable during pubertal years, particularly in children who deviate from the norms (early or late bloomer). 8. The assessment of the genetic potential should be performed for every child by measuring parents, if possible, or by report otherwise and calculating an MPH. 9. A growth velocity should always be calculated and plotted on a growth velocity chart. The measurements chosen to calculate growth velocity should be at least 4 months apart and preferably 1 year apart. If enough data are available, the yearly growth velocity should be calculated going back several years to establish a pattern.

136. Children with short stature should undergo a diagnostic evaluation if any of the following is true: 1. The calculated growth velocity is below the expected normal range for age and pubertal stage 2. There is significant discrepancy between the MPH percentile and the percentile the child is growing at 3. The child is growing at more than 3 standard deviations below the mean, even if there is short stature in the family (conditions causing short stature can be familial)

137. GH Resistance GH resistance may arise because of p GH receptor defects or post-receptor defects s to malnutrition, liver disease, type 1 diabetes, or, very rarely, circulating GH antibodies. Laron syndrome is a rare autosomal recessive condition caused by a genetic defect of the GH receptor. Affected individuals have extreme short stature, high levels of GH, low levels of IGF-I, and impaired GH-induced IGF-I generation .

138. IGF-1 and IGFBP-3 - IGF-1 = insulin-like growth factor-1 - IGFBP-3 = Insulin-like growth factor binding protein 3 Insulin-like growth factor binding protein 3 (IGFBP-3) is the main carrier of somatomedin C (also called insulin-like growth factor-1, or IGF-1) in the body. Blood levels of both these proteins are controlled by human growth hormone ( hGH ), a hormone made by the pituitary gland. IGFBP-3 also helps extend the life of somatomedin C in the blood and helps control its effects on body tissues. IGFBP-3 levels are highest during childhood and puberty. They decrease during adulthood. Levels also may be affected by sexual maturation and nutritional status. Why Are IGFBP-3 Tests Done? The IGFBP-3 test can help doctors see if the body is making a normal amount of human growth hormone. They’ll order it to check for pituitary gland disorders and problems in growth hormone production (for instance, if a child has short stature or excessive growth, known as gigantism). The test also can help them monitor treatment of growth disorders.

139. Drugs used in Growth Hormone Stimulation Test = Growth Hormone Provocation Test : 1. Insulin 2. Clonidine 3. Glucagon 4. Arginine 5. Levodopa

140. Clonidine GH Provocation Test Dose of Clonidine in GH Provocation test : Clonidine tablet 0.1 mg = 100 micrograms Clonidine tablet 0.15 mg = 150 micrograms Dose = 5 microgram / kg or = 0.15 mg / m2

141. Measurement of serum levels of GH Beyond the first months of life, endogenous GH is secreted in a pulsatile fashion. These intermittent peaks are greatest after exercise, after meals (as blood glucose levels decrease), and during deep sleep. Therefore, measuring a single random serum GH value is of no use in the evaluation of the short child. Beyond the neonatal period, values obtained during the daytime are unlikely to be detectable. Although a random serum GH value of more than 10 mg/ dL generally excludes GHD, a random low serum GH concentration does not confirm the diagnosis of GHD.

142. Procedures of Growth Hormone Provocation Test : Several provocative tests have been developed for the evaluation of suspected GHD, including the following: Insulin-induced hypoglycemia is the most powerful stimulus for GH secretion; however, this test also carries the greatest potential for harm and is the only GH provocative test that has been associated with fatalities. Alternate GH secretagogues used successfully in combination as 2 serial tests include arginine, levodopa, propranolol with glucagon, exercise, clonidine, or epinephrine. Peak GH level is higher if the patient has been recently exposed to sex steroids, but controversy among pediatric endocrinologists persists regarding the use of sex steroid priming prior to stimulation testing. Perform all GH provocative testing under the supervision of a pediatric endocrinologist. Please refer to Hyposomatotropism for further details of these tests.

143. Growth Hormone assessment : GH is normally secreted overnight in regular pulses (pulse frequency 180min). Frequently sampled overnight GH profiles are costly and laborious, and therefore standardized stimulation tests are more commonly useful. Peak GH <10 micrograms/L indicates GH deficiency (values >5 and <10 micrograms/L indicate partial GH deficiency). However, there can be large variation between different assay methods, and exact cut-offs must be locally validated. In late prepuberty , there is a physiological blunting of GH secretion, and when bone age is >10 years, sex steroid priming (testosterone 100mg IM in boys or oral ethinylestradiol 20 micrograms daily for 3 days in either sex) is necessary before GH testing. A number of different agents may be used to stimulate GH secretion (arginine, insulin, or glucagon; see Table 7.1). All tests should be performed in the morning following an overnight fast, and serial blood samples are collected over 90–180min. An IGF-1 level should also be measured in the baseline sample, as an additional marker of GH status. IGF-I generation test In those with high basal and stimulated GH levels, measurement of IGF-I levels before and following administration of GH (30 micrograms/kg/day) SC for 4 days allows an assessment of GH sensitivity/resistance. This test is rarely necessary.

144. Growth Hormone Provocation Test

145. Body Surface Area (BSA) Formula The Mosteller formula takes the square root of the height (cm) multiplied by the weight (kg) divided by 3600.

146. Insulin provocative test : Type of insulin : Regular insulin as actrapid Dose : 0.15 u / kg / iv/ after fasting 8- 12 houres Takes 6 blood samples at 0 , 20 , 30 , 60 , 90 , 120 minutes for cortisol and glucose , GH Containdicated in : - Epilepsy or history of seizure - less than 5 years or over 55 years - coronary artery disease - hypoglycemia

147. FDA approved indications for the administration of Growth Hormone in children 1. Growth failure associated with growth hormone deficiency (GHD) 2. Chronic renal failure Turner syndrome Prader -Willi syndrome 5. Small size for gestational age, with failure to catch up 6. Idiopathic short stature 7. SHOX gene deficiency 8. Noonan syndrome

148. Short Stature Cases NOT Takes Growth Hormone : 1- Dysmorphic Syndromes associted with short stature 2- Skeletal Dysplasia 3- Systemic Diseases causing Growth Failure 4- Children under Corticosteroid Therapy 5- Familial Short Stature Males with a bone age 15.5 years or more And females with a bone age 13.5 years or more 6- Children with known risk of malignancy e.g. chromosomal abnormality such as Down and Bloom Syndromes 7- Evidence of Brain atrophy 8- Growth failure due to diabetes 9- I.Q. less than 75% .

149. Growth Hormone Dosage : 1- Dose for GHD: 0.03 mg/kg/day or 0.09 IU/kg/day . GH should be given 7days per week by subcutaneous injection. Results may worsen if frequency is reduced. 2- Dose for ISS: 0.04mg /kg/day or 0.12 IU/kg/day 3- Dose for chronic renal failure: 0.045-0.05 mg/kg per day Method of administration 1. Regular syringe 2. Pen when dose is less than 1 IU/day or more than 4 IU /day

150. Treatment of a Child with Growth Hormone Deficiency A child with documented growth hormone deficiency should be treated with rhGH in a dose of 0.18–0.35 mg/Kg/week (1 mg = 3 IU). The rhGH is administered subcutaneously, daily between 8 and 9 pm to mimic the physiology of GH secretion. Optimal response to GH requires adequate nutrition and regular physical activity. In addition, regular surveillance for the development of thyroid hormone and cortisol deficiency is required to optimize the response to rhGH therapy Treatment with rhGH results in a brisk growth response of 10–12 cm in the first year and 7–9 cm in the second and third years, followed by 5 cm/year thereafter. Suboptimal response to rhGH therapy should raise a suspicion of poor compliance, malnutrition, coexisting celiac disease, and hypothyroidism.

151. Management options for non-GH deficient short stature The FDA-approved indications of rhGH therapy in children with short stature without GHD include Turner syndrome, Noonan syndrome, chronic kidney disease, Prader–Willi syndrome, idiopathic short stature (height <−2.25 SD), small for gestational age, and SHOX haploinsufficiency (Leri–Weill syndrome). Léri-Weill dyschondrosteosis is a disorder of bone growth. Affected individuals typically have shortening of the long bones in the arms and legs ( mesomelia ). As a result of the shortened leg bones, people with Leri-Weill dyschondrosteosis typically have short stature. In addition, rhGH therapy is also approved in patients with AIDS- associated cachexia and short bowel syndrome on total parenteral nutrition. The dose of rhGH used in children with non-GHD short stature is higher (0.375 mg/Kg/week) as compared to that used in children with GHD (0.3 mg/ Kg/week). This is because these disorders are GH-resistant states and need supraphysiological doses for optimal growth.

152. Somatropin vial 4 iu in 2 ml 3 IU = 1 mg = 1000 micrograms

153. Response Criteria and Termination of Therapy : 1. Minimum height velocity of 5cm/year 2. IGF1 level follow up shows no improvement with a subnormal GV 3. In cases where the above criteria are not met, an increased dose of GH may be approved to a maximum of 0.04 mg/ kg/day or 0.12 IU/kg/day. If response is inadequate after a 6 months period at the maximum dose, treatment should cease. 4. No improvement of the standard deviation score after 1 year of treatment in prepubertal children. 5. Growth hormone treatment should be discontinued once growth velocity declined to ≤ 2 cm/year (the bone age has reached 15.5 years in males and 13.5 years in females. 6. In general, treatment with human growth hormone will cease once the patient has reached the 10th adult height centile (females 155cm; males 165cm)

154. Turner Syndrome Girls with Turner Syndrome will be considered for therapy, if their height is at or below the 75th centile on the Turner specific chart. 1. Karyotype 2. Bone age Treatment: GH: 0.05 mg/kg/day (0.15 IU/kg/day). GH should be given at least 6 days per week by subcutaneous injection. Results may worsen if frequency is reduced.  Estrogen replacement: Started at a chronological age of 13 years. The starting dose of depot estradiol ( Folone ) IM is 0.2 mg; the dose is then increased at successive 6-month intervals by 0.2 mg initially and by 0.5 mg after a dose of 1.0 mg is reached, to a maximum of 3.0 mg monthly. Progestin is not prescribed until after 4 yr of estradiol therapy unless irregular menstrual bleeding occurs.

155. Management of Turner Syndrome • High-dose GH therapy (45 micrograms/kg/day) increases final height, although individual responses are variable. The height gained is related to time on GH treatment, and thus GH therapy should be commenced early; if the diagnosis has been made in early life, treatment is usually started from 3–5 years of age. • The anabolic steroid oxandrolone can be used, in addition to GH, to promote growth from the age of 9 years. It has a positive effect on final height at a dose of 0.05mg/kg/day, max 2.5mg/day. • Oral oestrogen is commenced between 12–14 years to promote s sexual development and pubertal growth. It should be started in low dose ( ethinylestradiol 2 micrograms/day) and gradually i with age. Progesterone should be added if breakthrough bleeding occurs or when oestrogen dose reaches 10 micrograms/day.

156. Hormones Classification : Hormones are categorized based on their molecular structure. Most are peptide hormones , made of amino acid chains. Small neuropeptide hormones include antidiuretic hormone (ADH), gonadotropin-releasing hormone ( GnRH ), and thyrotropin-releasing hormone (TRH). Larger peptide hormones, known as protein hormones , include insulin and GH. Glycoprotein hormones have carbohydrate side chains attached; these include human chorionic gonadotropin ( hCG ), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). Amino acid–derived peptide hormones have an NH2 group at the end of the molecule and arise from the amino acids tyrosine and tryptophan. These include thyroxine, dopamine, catecholamines , and melatonin. In general, peptide hormones work through cell surface receptors. In contrast, steroid hormones are lipid and phospholipid derivatives. These hormones are synthesized from cholesterol ( eg , testosterone, cortisol) or the eicosanoids (prostaglandins) by a series of enzymatic steps. Other hormones are vitamin derivatives , including the retinoids (vitamin A) and vitamin D. In general, thyroid hormones, steroid hormones, retinoids , and vitamin D are lipidsoluble and work through intracellular receptors.

157. History of Growth Hormone Therapy : The first human to receive GH therapy was in 1956 ; it was of bovine origin and was given for 3 wk for metabolic balance studies revealing no effects. By 1958, three separate laboratories utilizing different extraction methods retrieved hGH from human pituitaries, purified it and used for clinical investigation. By 1959 presumed GHD patients were being given native hGH collected and extracted by various methods. Since 1 mg of hGH was needed to treat one patient per day, >360 human pituitaries were needed per patient per year. Thus, the availability of hGH was limited and was awarded on the basis of clinical research protocols approved by the National Pituitary Agency (NPA) established in 1961. hGH was dispensed and injected on a milligram weight basis with varied concentrations between batches from 0.5 units/mg to 2.0 units/mg of hGH . By 1977 a centralized laboratory was established to extract all human pituitaries in the US, this markedly improved the yield of hGH obtained and most remarkably, hGH of this laboratory was never associated with Creutzfeld -Jacob disease (CJD) resulting from the injection of apparently prior- contaminated hGH produced years earlier. However, widespread rhGH use was not possible even if a pituitary from each autopsy performed in the US was collected, this would only permit therapy for about 4,000 patients. Thus, the mass production of rhGH required the identification of the gene structure of the hormone, methodology that began in 1976 to make insulin by recombinant technology. Serendipity was manifest in 1985 when patients who had received hGH years previously were reported to have died of CJD. This led to the discontinuation of the distribution and use of hGH , at a time when a synthetic rhGH became available for clinical use. The creation of a synthetic rhGH was accompanied by unlimited supplies of hGH for investigation and therapy. However, the appropriate use and the potential abuse of this hormone are to be dealt with. The illegitimate use of rhGH , unequivocally the abuse by athletes is, and should be, of primary concern to society and should be halted. The abuse of prescribing rhGH in an attempt to retard the aging process also should receive attention.

158. The availability of somatropin [recombinant human growth hormone (GH)] has revolutionized the treatment of short stature resulting from GH deficiency. It is also widely used as an adjunct in the treatment of other disorders which do not fit the definition of classic GH deficiency, such as intrauterine growth restriction, Turner syndrome, healthy children with short stature and skeletal dysplasias . The widespread use and ready availability of GH treatment has prompted questions about its tolerability, rationality, and the psychological effects of long-term treatment, leading to several trials. Early treatment of GH deficiency will allow the child to reach his or her genetic potential, although there continues to be marked variability in the criteria used to diagnose the deficiency, and in the treatment schedule, especially during puberty. Treatment has also been shown to have a beneficial effect on growth in children with chronic renal failure, with no adverse effects on the renal function. There are, however, no long-term data to determine final height, or randomized controlled studies to justify routine use of GH in conditions such as intrauterine growth restriction. It remains controversial in conditions such as Turner syndrome and achondroplasia, where the response to treatment is only moderate. Healthy children with short stature have not been shown to have a psychological disadvantage, again proving difficult to justify prolonged GH treatment for idiopathic short stature. Meticulous monitoring, long-term follow-up to adult or near-adult final height, and well-defined endpoints of treatment need to be better clarified. The metabolic effects of treatment on the patient's lipid profile, bone mineral density, and muscle mass need careful documentation, especially with the high doses used in an already susceptible population such as low birthweight children and those with Turner syndrome. Lastly, the psychosocial impact of GH treatment, financial implications, and cost efficacy of treatment in an ever-increasing list of indications should be taken into consideration for rationalizing its use in future.

159. Treatment of Short Stature : Recombinant growth hormone is approved for a variety of conditions that cause short stature, including Turner syndrome, chronic renal failure, Prader -Willi syndrome, small for gestational age, Noonan syndrome, short stature homeobox -containing gene deficiency, and idiopathic short stature. It is administered through daily injections over several years. The injections are generally well tolerated, but rare adverse reactions have been reported. For children with idiopathic short stature, four years of treatment results in an increased height of 3.7 cm (1.46 in) and costs between $100,000 and $120,000.25,26 Oxandrolone ( Oxandrin ) is an oral anabolic steroid that has been shown to increase height velocity but has little effect on final height. Insulinlike growth factor has been used in children with insulinlike growth factor deficiency. Although aromatase inhibitors have been used in children with idiopathic short stature, long-term effectiveness and safety data are not available.

160. A 2016 update to 2003 guidelines for GH and insulinlike growth factor-I treatment in children and adolescents with GH deficiency, idiopathic short stature, or primary insulinlike growth factor-I deficiency, from the Pediatric Endocrine Society, suggests the use of “a shared decision-making approach to pursuing GH treatment for a child with” idiopathic short stature. The update also states that the “decision can be made on a case-by-case basis after assessment of physical and psychological burdens, and discussion of risks and benefits,” and recommends that GH therapy not be used routinely in every child with a height standard deviation score at or below -2.25. It also suggests that, due to response overlap between dosing groups, the GH dose be initiated at 0.24 mg/kg/ wk , “with some patients requiring up to 0.47 mg/kg/week.” hGH produced via recombinant DNA technology in Escherichia coli; widely available since 1985. Currently, only 1 of the 10 largest reported clinical studies has demonstrated that therapy can increase final adult height in patients with normal variant short stature. This most recent NIH-funded study was randomized, placebo controlled, and took place over 14 y. Investigators demonstrated average gain in height did not exceed 4 cm when rhGH treatment of normal variant short stature began prior to puberty and continued through completion of puberty. They did not identify any clinical feature that, prior to start of therapy, could predict whether an individual patient would respond to rhGH and to what degree. Whether several years of daily injections are worth the potential, but not promised, relatively small increase in final adult height remains a personal and individual decision involving the patient, patient's family, and physician.

161. Growth Hormone Medications : 1. Genotropin 2. Humatrope 3. Norditropin 4. Nutropin/Nutropin AQ 5. Saizen 6. Serostim 7. Zomacton Somatropin Omnitrope

162. Growth Hormone Medications

163. Idiopathic short stature: For children with a height SD <-3 and normal GH provocation test, if a growth velocity calculated over a 6 months period is subnormal (< -1SD), a trial of GH treatment for 6 months is started. If the child demonstrates a good response i.e. improvement of GV and height SDS, then therapy is continued. If no improvement is documented after 6 months, therapy is terminated.

164. Response Criteria and Termination of Therapy for Turner Syndrome : In girls with Turner Syndrome, the growth velocity should exceed that normally expected in untreated Turner girls with reference to the Turner specific chart (at least 3 cm/year) Therapy may be continued until a satisfactory height has been attained or until the growth rate falls to (bone age is more than 14 years ) . Dose : 45 – 50 Microgram / kg / day / SC N.B. Growth Hormone Therapy is a daily injection, started at around 5 or 6 years of age or later. It's usually continued until 15 or 16, helping the girl gain on average around 5cm (about 2in) in height.

165. Growth Hormone Therapy in Chronic Renal Failure : The indications for the growth hormone therapy in CRF are: • Continuing growth retardation despite the correction of insufficient nutrition, metabolic acidosis, fluid and electrolyte disorders, anemia and renal osteodystrophy • Glomerular filtration rate less than 75 mL/min per 1.73 m2 Follow up of a child with CRF started on growth hormone • Nutritional status • Stage of puberty • Serum glucose, electrolytes, creatinine, calcium phosphorus and parathyroid hormone levels (intact PTH should be <500 pg /ml prior to starting rGH ) • Bone age • Fundus examination (raised intracranial pressure) • Knee and hip imaging only if persistent hip or leg pain is present (avascular necrosis, slipped capital femoral epiphysis) N.B. Nutritional status can be measured by clinical, anthropometric, and biochemical parameters such as height, weight, BMI (weight/height2; kg/m2), and serum albumin and prealbumin .

166. Growth Hormone Safety The main concerns include the following: 1. Skeletal abnormalities (slipped capital femoral epiphysis, avascular necrosis of hip, scoliosis). 2. Progression of renal failure. 3. Glucose intolerance 4. Hypothyroidism. 5. Raised intracranial pressure. 6. Hypertension. Existing clinical data have shown that rhGH therapy does not accelerate the residual renal function loss in patients with CRF. However, individual rises in the plasma creatinine concentrations have been observed. In the absence of any other reason for a decrease in renal functions, rhGH therapy should be revised.

167. Mecasermin (Increlex) Insulin-like growth factor-I Indicated for long-term treatment of severe, primary insulin-like growth factor-I (IGF-I) due to mutations of the growth hormone receptor (GH-R) or GH-R downstream signaling pathways. Recombinant human insulinlike growth factor-1 (rhIGF-1) indicated for long-term treatment of GF in children with severe primary IGFD (primary IGFD defined as basal serum IGF-I level and height SD scores ≤ -3, normal or elevated serum GH level). IGF-I is essential for normal growth of children's bones, cartilage, and organs by stimulating uptake of glucose, fatty acids, and amino acids into tissues. IGF-I is the principal hormone for linear growth and directly mediates GH actions. Primary IGFD is characterized by absent IGF-I production despite normal or elevated GH release.

168. Side effects of Growth Hormone Therapy : Local lipoatrophy and benign intracranial hypertension occur rarely. Slipped upper femoral epiphyses are associated with GH deficiency, but the incidence is similar before or after GH treatment. Other pituitary hormone deficiencies may be unmasked by GH therapy, and thyroid function should be checked within 4–6 weeks of commencing therapy.

169. Retesting in adulthood Once final height is achieved, GH secretion should be retested, as a significant percentage of subjects (25–80%) with GH deficiency in childhood subsequently have normal GH secretion in adulthood. In those with confirmed GH deficiency, continuation of GH treatment (at a dose of 0.2–0.5mg/day) through the late adolescent years into early adulthood (the transition phase) is recommended in order to complete somatic development (increasing lean body mass and muscular strength, reducing fat mass, improving bone density, and maintaining a healthy lipid profile). GH treatment may need to be continued beyond this phase as adult GH replacement. The transition from paediatric to adult care is an important time, not only to re-evaluate GH status but also to reassess other pituitary function and management of any underlying disorder. It is also recommended that assessment of bone mineral density, body composition, fasting lipid profile, and QoL by questionnaire should be undertaken at this time and repeated at 3–5-yearly intervals for those restarting GH treatment.

170. Skytrofa = lonapegsomatropin-tcgd for injection Skytrofa is a prescription medicine used to treat the symptoms of Growth Hormone Deficiency in children. Skytrofa may be used alone or with other medications. Skytrofa belongs to a class of drugs called Growth Hormone Analogs. SKYTROFA (lonapegsomatropin-tcgd) is a human growth hormone indicated for the treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH). Skytrofa For subcutaneous injection, once-weekly. The recommended dose of SKYTROFA for treatment of short stature and patients and patients switching from daily somatropin therapy is 0.24 mg/kg body weight, given once-weekly. www.rxlist.com/skytrofa-drug.htm#medguide Price : tcgd 3 mg Skytrofa subcutaneous injection = $ 2,894.71 for 4 injection

171. Sogroya = Somapacitan-beco Sogroya is used as replacement therapy in adults with growth hormone deficiency SOGROYA is indicated for the replacement of endogenous growth hormone (GH) in adults with growth hormone deficiency (GHD). Patients Aged 65 Years And Older Initiate SOGROYA with a dosage of 1 mg once weekly and use smaller dose increment increases when titrating the dosage . Women Receiving Oral Estrogen Initiate SOGROYA with a dosage of 2 mg once weekly. Missed Doses Administer a missed dose as soon as possible and not more than 3 days after the missed dose (72 hours). If more than 3 days have passed since the missed dose, skip the dose and administer the next dose on the regular dosing day. www.ema.europa.eu/en/medicines/human/EPAR/sogroya Price : Sogroya 10 Mg/1.5 Ml Pre-Filled Pen = 2,048.00 SAR

172. Prognosis Individuals with normal variant short stature have an excellent prognosis. Treatment of patients with classic growth hormone deficiency (GHD) with rhGH can be expected to yield a height consistent with genetic potential, provided that therapy is initiated at least 5 years prior to the onset of puberty. Whether cotreatment with rhGH and a gonadotropin-releasing hormone analog ( eg , leuprolide) to inhibit puberty results in greater adult height in patients with classic GHD remains controversial. Treatment of hypothyroidism at least 5 years before the onset of puberty is essential to attain a height consistent with the genetic potential. Any chronic illness can reduce the adult height achieved if treatment of the condition is initiated late.

173. Adult Growth Hormone Deficiency Syndrome

174. Typical Symptoms and Signs of the Adult Growth Hormone Deficiency Syndrome Body composition increased body fat, particularly central adiposity decreased muscle mass decreased muscle function Cardiovascular and metabolism decreased sweating and poor thermoregulation decreased insulin sensitivity and increased prevalence of impaired glucose tolerance increased total and LDL cholesterol and Apo B. Decreased HDL cholesterol accelerated atherogenesis a variable decrease in cardiac muscle mass impaired cardiac function decreased exercise capacity decreased total and extracellular fluid volume increased concentration of plasma fibrinogen and plasminogen activator inhibitor type I Bones decreased bone mineral density, associated with an increased risk of fracture Quality of Life depressed mood reduced concentration increased anxiety fatigue lack of energy levels low self-esteem increased sick days social isolation lack of positive well being

175. Usual Adult Dose for Adult Human Growth Hormone Deficiency Weight Based Regimen: Initial dose: Not more than 0.004 mg/kg subcutaneously once a day (or a total of 0.04 mg/kg per week in divided doses). Maximum dose: 0.016 mg/kg once a day (0.08 mg/kg per week in divided doses) Non-Weight Based Regimen: Approximately 0.2 mg subcutaneously once a day (range: 0.15 to 0.3 mg once a day) Comments: The weekly dose should be divided over 6 or 7 days of subcutaneous injections. May increase dose (weight or non-weight based) at 4 to 8 week intervals, by increments of approximately 0.1 to 0.2 mg per day (not more than 0.004 mg/kg per day), based on clinical response and serum IGF-I concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and between male and female patients. Obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. -To reach the defined treatment goal, estrogen-replete women may need higher doses than men.

176. Uses : Replacement of endogenous growth hormone (GH) in adults with growth hormone deficiency (GHD) who meet either of the following two criteria: Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Reevaluate patients treated for childhood GHD whose epiphyses are closed before continuing therapy at the reduced dose level recommended for adults. Confirmation of the diagnosis of adult GHD in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.

177. Usual Adult Dose for Cachexia 0.1 mg/kg subcutaneously once a day at bedtime Under 35 kg/ 75 lbs : 0.1 mg/kg subcutaneously once a day at bedtime 35 to 45 kg/ 75 to 99 lbs : 4 mg subcutaneously once a day at bedtime 45 to 55 kg/ 99 to 121 lbs : 5 mg subcutaneously once a day at bedtime Over 55 kg/ 121 lbs : 6 mg subcutaneously once a day at bedtime Maximum dose: 6 mg once a day Comments: Most of the effect on work output and lean body mass were seen after 12 weeks of treatment. There are no data on safety or efficacy with use beyond 48 weeks. There are no data on safety or efficacy of intermittent treatment. Use: Treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance.

178. Usual Adult Dose for Short Bowel Syndrome Approximately 0.1 mg/kg subcutaneously once a day Maximum dose: 8 mg once a day Duration of therapy: 4 weeks Comments: Administration for more than 4 weeks has not been adequately studied. Use in conjunction with optimal management of Short Bowel Syndrome (SBS). Optimal management of SBS may include dietary adjustments, enteral feedings, parenteral nutrition, fluid, and micronutrient supplements, as needed. Specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for patient requirements and preferences. Nutritional supplements may be added at the discretion of the treating physician. Changes to concomitant medications should be avoided. Patients and physicians should monitor for adverse events. Use: Treatment of Short Bowel Syndrome in patients receiving specialized nutritional support.

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183. Thank You