Approach to Cafe au lait spots in children

Lecture for MBBS student, for approach to cafe au lait spots, short case

1. Approach to child with Neurocutaneous syndrome & CAFÉ AU LAIT SPOTS Dr Varsha Atul Shah, Senior Consultant, Singapore General Hospital

2. INTRODUCTION Heterogeneous group of disorders characterized by the abnormalities of integument(skin) and CNS Mostly familial Defect in differentiation in primitive ectoderm (nervous system, eyeball, retina, and skin)

3. INTRODUCTION Various syndromes include: Neurofibromatosis Tuberous Sclerosis Sturge Weber Syndrome Von Hippel Lindau Syndrome Ataxia-telangiectasia Hereditary Hemorrhagic Telangiectasia Epidermal nevus Syndrome

4. OTHERS: AD Hemorrhagic telangiectasia (Osler- Rendu -Weber) Incontinentia Pigmenti Achromians (Hypomelanosis of Ito) AR Chediak -Higashi Divry -Van Boegart Meckel-Gruber Xeroderma pigmentosa X-linked Albright syndrome (polyostotic fibrous dysplasia) Dyskeratosis congenita (Zinsser-Cole- Engman syndrome) Incontinentia Pigmenti (Bloch-Sulzberger) No inheritance Cobb syndrome (cutaneous meningeal angiomatosis) Linear Sebaceous Naevus of Jadassohn

5. NEUROCUTANEOUS DISORDERS INCIDENCES Neurofibromatosis Type 1: 1/1,000 -1/7,800 (COMMONEST) Tuberous Sclerosis: 10.6/100,000 Ataxia Telangiectasia: 1.7/100,000 Xeroderma Pigmentosum: 1/100,000 - 1/250,000 Neurofibromatosis type 2: 1/200,000

6. Commonest presentation of NF1 is CALM Café au lait spots, or café au lait (CAL) macules (CALMs)

7. Background-CALMS Café au lait spots, or café au lait (CAL) macules (CALMs),Giraffe’s spots, are hyperpigmented lesions that may vary in color from light brown to dark brown In French, which means "coffee with milk." Borders may be smooth or irregular The size and number of café au lait skin lesions widely vary Usually, the earliest manifestations of neurofibromatosis

8. Pathogenesis Arise from increased melanin production by melanocytes in the basal layer (stratum basale ) of the epidermis. Dendritic pigment-producing cells are simply more active and thus manufacture more melanin, resulting in darker pigment No increase in the number of melanocytes in the area;

9. Differential Diagnosis 1. Large, solitary café au lait macules: Are larger than 0.5 cm. Found more commonly on the buttocks than any other anatomical location. No other physical findings or syndromes are usually related to solitary CAL spots. Most of the CALMs are present at birth or may appear early in life  (0.3%) CALMs present at birth may be difficult to visualize (Wood's lamp may improve visibility Solitary CALMs are common in the general population and are familial and inherited as autosomal dominant, typically very light in infants May enlarge in size and become obvious after age 2 years

10. NF 1. NF1 :Incidence: 1 in 3,500 Due to mutations in the NF1 tumor suppressor gene located on chromosome 17, (17q11.2) 2. NF2 : 1 in 40,000 births Due to mutations in the NF2 tumor suppressor gene located on chromosome 22 Clinical features of NF2 include bilateral acoustic schwannomas, cataracts, meningiomas, and ependymomas, hearing problem, ringing in the ears (tinnitus), and dizziness 3. McCune-Albright Syndrome : Due to a mutation in the GNAS gene 4. Legius syndrome: Due to a mutation in the SPRED-1 gene

11. Neurofibromatosis Type 1 Classical NF NF1 Von Recklinghausen’s disease CALM are observed in 95% of patients with neurofibromatosis type 1 (NF1), NF1 is the most frequently occurring neurocutaneous syndrome CALM should raise the suspicion of a genetic disorder, (NF1). Most prevalent type Incidence of 1/3,000 Autosomal dominant disorder Over half the cases are sporadic, representing De novo mutations. Chromosome region 17q11.2 Encodes a protein also known as Neurofibromin.

12. The diagnostic criteria for NF1 ( Von Recklinghausen’s disease): NIH Diagnostic Criteria for NF 1 (1988) Are met if 2 or more of the following are present: 1. A first-degree relative with NF1 2. Six or more café au lait spots: larger than 5 mm in prepubertal larger than 15 mm in post pubertal 3. Two or more neurofibromas of any type or 1 plexiform neurofibroma 4. Freckling in the axillary or inguinal regions, Ephelides (Crowe’s sign), 5. Optic glioma 6. Two or more Lisch nodules (iris hamartomas) 7. Osseous lesion, such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis

13. Neurofibromatosis Type 1 Children born into a family with affected individuals can usually be diagnosed by 1 year Without FH, surveillance is needed by pediatricians, dermatologist CALM spots can increase in size and number throughout childhood Axillary freckling by 2 years Neurofibromas usually appear after 5 years of age, at least 90% of patients develop the lesions by 20 years of age.

14. Neurofibromatosis Type 1: Surveillance after diagnosis 5. Evaluate the child for skeletal changes. Look for scoliosis, vertebral angulation, and limb abnormalities, particularly tibial dysplasia. Sometimes localized hypertrophy of a leg, arm, or other part of the body results from plexiform neurofibromata . Nonossifying fibromas of the long bones infrequently occur in adolescence or adulthood and have been associated with fracture; although a screening radiograph of the knees in adolescence has been suggested as a routine study, evidence is not sufficient to support routine screening at this time. 6. If any unexplained complications occur or if cutaneous lesions appear to be growing rapidly, refer the patient to the appropriate subspecialist for further evaluation.

15. HEALTH SUPERVISION FROM BIRTH TO 1 MONTH: NEWBORN INFANTS CLSs may be present, and in 10% to 15% of neonates All first-degree relatives should be advised to have a physical examination, including a slit-lamp examination to look for Lisch nodules, which are found in >90% of adults with this disorder but are uncommon in children younger than 5 years.

16. HEALTH SUPERVISION FROM 1 MONTH TO 1 YEAR: INFANCY Compare the infant's growth and development with figures on growth charts.As a group, children with NF1 are shorter than average but have a larger head size. Rarely, aqueductal stenosis can cause obstructive hydrocephalus, but in most children with NF1, the basis for macrocephaly is likely to be increased brain volume. Examine the patient for the presence of CLSs. Inform the family that new ones may appear, and preexisting CLSs often increase in size. Reassure the family that CLSs have no functional significance. Check for proptosis, a rapidly increasing head size, and focal neurologic signs.

17. HEALTH SUPERVISION FROM 1 MONTH TO 1 YEAR: INFANCY Perform a careful physical examination and look for skeletal abnormalities, especially in the spine and legs. This is particularly important before the child begins to bear weight because of the risk of cortical thinning of the long bones, which increases the likelihood of fracture. Refer the infant for formal ophthalmologic evaluation and to other appropriate specialists and subspecialists, as indicated. Check the infant's neurodevelopmental progress at each visit..

18. HEALTH SUPERVISION FROM 1 TO 5 YEARS: EARLY CHILDHOOD Examine the child for neurofibromata and the presence of skinfold freckling, which can appear in any intertriginous area. Assure parents that CLSs and freckling only have cosmetic significance. Consider taking photographs to document lesion size for future reference. Evaluate the child's vision and recommend that the child undergo an ophthalmologic examination annually throughout childhood.

19. HEALTH SUPERVISION FROM 1 TO 5 YEARS: EARLY CHILDHOOD If there are visual changes, persistent headaches, seizures, marked increase in head size, or a plexiform neurofibroma of the head, obtain a brain MRI. Assess the child's speech and motor skills for deficits that require further assessment. Hypernasal speech attributable to velopharyngeal insufficiency can be present, and there may be delayed expressive language development. Monitor blood pressure yearly..

20. HEALTH SUPERVISION FROM 5 TO 13 YEARS: LATE CHILDHOOD Examine the child for skin tumors causing disfigurement and obtain a consultation with a specialist if surgery is desired to improve appearance or function. Severe cosmetic disfigurement is seen more often in adults than in children. Evaluate the child for signs of puberty. Premature onset of sexual maturation or delayed puberty may occur. If sexual precocity is present, evaluate the child for the presence of an optic glioma or hypothalamic lesion.

21. HEALTH SUPERVISION FROM 5 TO 13 YEARS: LATE CHILDHOOD Check for signs of learning disabilities and attention-deficit/hyperactivity disorder. Review the child's social adjustment. Monitor the child's ophthalmologic status yearly under 8 years of age, followed by complete eye examination every 2 years.23 Monitor blood pressure yearly.

22. HEALTH SUPERVISION FROM 13 TO 21 YEARS OR OLDER: ADOLESCENCE TO EARLY ADULTHOOD Examine the adolescent for signs of abnormal pubertal development. Perform a thorough skin examination to evaluate for and determine the status of plexiform neurofibromas and a complete neurologic examination to check for findings that might suggest the presence of deep plexiform neurofibromata . Obtain a surgical consultation with a specialist if signs of pressure on deep structures are found. Continue monitoring blood pressure yearly. Continue ophthalmological examination every 2 years until 18 years of age

23. Neurofibromatosis Type 1: Surveillance after diagnosis Evaluate the child for new neurofibromas and progression of lesions. Examine the skin carefully for signs of plexiform neurofibromas that may impinge on or infiltrate underlying structures. Check the child's blood pressure yearly to determine if there is evidence of hypertension, which occurs more frequently with NF1 and could be secondary to renal artery stenosis, aortic stenosis, and pheochromocytoma, the latter being more common in adults. A variety of vascular hypertrophic lesions may be found. Evaluate neurodevelopmental progress of an affected child. Obtain a formal ophthalmologic evaluation yearly.

24. DD: Other syndromes associated with café au lait spots include the following: McCune-Albright syndrome : this syndrome often has one large, asymmetric café au lait macule with irregular borders, which is often described as being like the "coast of Maine." -is a rare genetic condition resulting from a mutation in the GNAS gene affecting G-protein signaling. The classical presentation is a triad of CALMs, fibrous dysplasia of the bone, which leads to pathologic fractures and precocious puberty. Other endocrinopathies may be present in some patients like hyperthyroidism, hypercortisolism, and hypophosphatemic rickets Early in life, it may present with a single, large irregular café au lait spot. Follow-up observations reveal the endocrine abnormalities. Fanconi anaemia: Café au lait macules are present along with mental retardation, aplastic anaemia, and risk for malignancy. Tuberous sclerosis: Café au lait spots are present along with Ash leaf spots, facial angiofibroma's, haemangiomas, cardiac rhabdomyomas, and shagreen patches.

25. CALMs associated with RASopathies : Legius syndrome Watson syndrome Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome)

26. Mcune Albright

27. Differential Diagnosis multiple CALMS Silver-Russell syndrome Ataxia telangiectasia Bloom syndrome Basal cell nevus syndrome Gaucher disease Chediack -Higashi syndrome Hunter syndrome Maffucci syndrome Multiple mucosal neuroma syndrome Watson syndrome Legius syndrome

28. Characteristics of NF1 in the newborn period Pseudarthroses Congenital glaucoma Sphenoid wing dysplasia

29. Characteristics of NF1 in the early childhood period include the following: Embryonal tumors Compression injuries: Plexiform neurofibromas in the mediastinal cavity may cause compression. Back pain in a patient with café au lait lesions should always be taken seriously because this symptom may be a sign of a radiculopathy. Optic pathway gliomas: These occur by the time the patient is aged 3 years

30. NF1 differentiation from (NF2). NF2 referred to as central neurofibromatosis It is associated with acoustic neuroma. Patients with NF2 may also have café au lait macules. NF2 is more likely to be diagnosed in middle-aged persons , unlike NF1, which is typically diagnosed in children. The genes that are responsible for these 2 disorders are on different chromosomes: In NF 1 chromosome (nf1) 1 7 in (encoding neurofibromin) and in NF 2 is chromosome (nf2) 2 2 in.

31. Investigations Family History Developmental history and progression of the child in school  Refer genetics specialist for Genetic testing  Ophthalmological examination with a slit lamp is equally important to identify Lisch nodules and signs of optic glioma NF2 should be further evaluated with magnetic resonance imaging (MRI)  A skin biopsy is usually not needed to confirm the diagnosis. On biopsy, an increased amount of melanin in the basal layer along with giant melanosomes can be seen in NF1

32. Treatment: Interprofessional team approach. There has no medical treatment for CALMs Other therapy tried are cryotherapy, electrofulguration, chemical peeling, mechanical grinding, and surgical operations Laser therapy is the mainstay of treatment for these lesions. Q‐switched Alexandrite laser treatments Pediatric neurologist, dermatologist, ophthalmologist, geneticist, a specialized nurse, and an orthopedic surgeon.  Genetic counseling for the family members 

33. Prognosis Cafe-au-lait macules are difficult to treat. Partial clearance may be achieved with laser treatment, but recurrence is common. CALMs are benign lesions with no reported morbidity or mortality, Associated genetic syndromes may lead to the development of malignant tumor CALMs that are multiple and segmental may be a marker for many genetic syndromes. NF1 may lead to the development of malignancy like nerve sheath tumors, optic gliomas, and leukemias

34. Schooling and education Most children diagnosed with NF1 may suffer from learning difficulties, writing problems, and attention difficulties. Parents should be given education about these problems and ways to handle them. Rehabilitation programs should be considered for more serious ones. For a patient diagnosed with NF2, annual history and physical examination should be done that includes cutaneous, ophthalmology, and audiology examination . Beginning at 10 years of age, annual brain MRI should be done for early detection of tumors associated with NF2.

35. MCQ/QUIZ on CALMS

36. Q 1. Which of the following statements about cafe au lait macules is true? They are caused by an increased number of melanocytes They are caused by more active melanocytes Their size denotes their clinical significance Their shape is diagnostic

37. Q.2:-Faintly colored cafe au lait macules may be better appreciated using which of the following? Magnifying glass Microscope Wood’s lamp Penlight

38. Q.3: Where is the NF1 gene located? Chromosome 27 Chromosome 22 Chromosome 16 Chromosome 17

39. Q.4: It is a priority for the pediatric primary care provider, caring for a 3-year-old, with four cafe au lait macules ranging in size from 2 to 5 mm noted on physical examination to do which of the following? Ask about other family members with cafe au lait macules Order genetic consultation and genetic testing Recommend follow-up in 6 months Refer to cardiology for echocardiography and electrocardiography

40. Q.6: After cafe au lait macules, which of the following is another early symptom suggestive of neurofibromatosis type 1? Peripheral nerve sheath tumors Axillary and inguinal freckling Thoracolumbar scoliosis Intellectual disability

41. Q.7: It is incorrect to state the following about café au lait spots in NF1: When they occur in the axilla, they are called ephelides and are pathognomonic of NF1 Presence of more than six spots greater than 0.5 cm in diameter before puberty or greater than 1.5 cm in diameter after puberty is suggestive of NF They are present at birth and do not increase in number - only in size- - over the years They occur in approximately 95% of patients

42. Q.9: . Children with neurofibromatosis type 1 should have annual slit-lamp eye examinations until what age? 2 years 4 years 6 years 8 years

43. Q.9: Children with a known or suspected diagnosis of neurofibromatosis type 1 require ophthalmology examinations to assess for which of the following? Optic gliomas Strabismus Retinoblastoma Cataract

44. Q.10: Which of the following diagnoses should be considered in older individuals who present with multiple cafe au lait macules and no neurofibromas or Lisch nodules? Neurofibromatosis type 2 Legius syndrome Noonan syndrome with multiple lentigines McCune−Albright syndrome

45. Q 11: It is correct to state the following about NF1: All cases of NF1 have a family history. The NF1 gene is located on the long arm of chromosome 17. Clinical manifestations are very similar in a single family affected. There is increased production of neurofibromin.