embryology of head and face 2 ,pediatric and preventive dentistry

embryology of head and face

1. EMBRYOLOGY OF HEAD AND FACE PART 2 PRESENTED BY SHRADHA AKOLKAR MDS 1 ST YEAR

2. CONTENTS GENETICS AND MOLECULAR BIOLOGY IN EMBRYOLOGY CONTROL OF DEVELOPMENT OF EMBRYO MOLECULAR (GENETIC) CONTROL OF GROWTH, DIFFERENTIATION AND DEVELOPMENT COMPONENTS REQUIRED FOR EXPRESSION OF GENE GENES CONTROLLING DEVELOPMENT OF VARIOUS PARTS OF DEVELOPING EMBRYO PEDIGREE CHARTS CONTROL OF FETAL GROWTH CAUSATION OF CONGENITAL ANOMALIES (TERATOGENESIS) PRENATAL DIAGNOSIS OF FETAL DISEASES AND MALFORMATIONS CLINICAL CORRELATION CONCLUSION REFERENCES

3. GENETICS AND MOLECULAR BIOLOGY IN EMBRYOLOGY Genetics is a branch of biology that deals with transmission of inherited characters (traits) from parent to offspring at the time of fertilization. Some of the characters/traits are dominant and some are recessive. Embryology includes development, differentiation, morphogenetic processes (cell migration transformation, folding, invagination, evagination, apoptosis, etc.) and controlled growth. These processes are controlled by genes. Most of these genes produce transcription factors that control transcription of RNA.

4. CONTROL OF DEVELOPMENT OF EMBRYO Certain regions of the embryo have the ability to influence the differentiation of neighboring regions. The influence exerted by an area is called induction whereas the area exerting induction is called organizer. In interactions between tissues, one is inductor and the other is responder. Capacity to respond to the inductor is called competence . The factors that influence the competence to respond are called competence factors. It is now known that the organizers exert their influence by elaborating chemical substances, which are probably complex proteins, including enzymes. The chemical substances elaborated by the organizer may be inductors that stimulate tissue differentiation or inhibitors that have a restraining influence on differentiation With the advent of molecular biology, the production of organizers, inductors and inhibitors are controlled by genes. A study of controlling mechanisms can be termed as “Genetic control of development” or “Molecular control of development”.

5. MOLECULAR (GENETIC) CONTROL OF GROWTH, DIFFERENTIATION AND DEVELOPMENT Several genes and gene families play important roles in the development of embryo. Most of these genes produce transcription factors that control transcription of RNA Transcription factors play an important role in gene expression as they can switch genes on and off by activating or repressing them. Many transcription factors control other genes , which regulate fundamental embryological processes of induction, segmentation, migration, differentiation and apoptosis (programmed cell death). These fundamental differentiation factors are mediated by growth and differentiation factors, growth factor receptors and various cytoplasmic proteins.

6. COMPONENTS REQUIRED FOR EXPRESSION OF GENE Several components are required for gene expression. These are 1. Growth factors —act as cell signaling molecules for induction of cellular differentiation. 2. Receptors —present on cell membrane and they recognize and respond to growth factors. 3. Activation of signal transducing proteins that is present within the cell cytoplasm. 4. Activation of transcription factor, which binds to DNA in the nucleus and finally leads to transcription (gene expression). Thus two different categories of molecules play an important role in embryonic development . They are signaling molecules and transcription factors. The signaling molecules like growth factors are present outside the cell and exert their effects on neighboring cells, or on cells located at a distance. They act by binding to the receptors on the plasma membrane of the cell and ultimately activate the transcription factors. The transcription factors are gene regulatory proteins, which are present in the nucleus and are responsible for gene expression and are therefore important molecules for control of embryonic development.

7. Molecular and genetic basis of gametogenesis During oogenesis the number of layers of granulosal cells increase leading to the formation of theca interna. The oocyte accumulates mRNA molecules that are important for embryogenesis and for formation of zona pellucida. • Proliferation of granulosa cells is mediated by growth differentiation factor 9, a member of TGF family Molecular regulation and genetic basis of pharyngeal arch development The formation of pharyngeal arches is controlled by pharyngeal arch endoderm. Lateral migration of pharyngeal endodermal cells forms the pharyngeal pouches. This migration is controlled by fibroblast growth factor (FGF-8), bone mineral protein (BMP7), paired box gene (PAX-1), and sonic hedgehog (SHH) gene.

8. Molecular and genetic basis of neural tube formation • Varieties of signals are required for induction of surface ectodermal cells to differentiate into neurectoderm. • Signalling molecules of transforming growth factor B (TGF-B) family and inactivation of morphogenetic protein BMP4 (forms surface ectoderm) is required for formation of neuroectoderm. • Certain genes, such as PAX3, sonic hedgehog are responsible for the closure of neural tube along with dietary cholesterol and folic acid (Vitamin B12). • Change in the expression of cell adhesion molecules by cells that are destined to become neurectodermal cells which start producing N-cadherin and N-CAM adhesion molecules instead of E-cadherin cause separation of neural tube form the surface ectoderm Molecular regulation of primitive streak Migration of primitive streak cells and their specification to form various derivatives are controlled by fibroblast growth factor 8 (FGF8 ) produced by primitive streak cells

9. Genes controlling development of various parts of developing embryo

10. Pedigree Chart Pedigree Chart It is a pictorial representation of generations of a family showing the information of family members and their relationship to one another, marriages among cousins (consanguineous) including details of live births, stillbirths and abortions, etc. A pedigree chart shows genetic connections among individuals using standardized symbols. For drawing pedigree charts certain standard symbols are used Knowledge of probability and Mendelian patterns are required for understanding the basis for a trait. Conclusions are most accurate if they are drawn using large number of pedigrees (generations ).

11. According to the mode of transmission the genetic disorders can be classified as follows: 1. Autosomal dominant inheritance 2. Autosomal recessive inheritance 3. X-linked dominant inheritance 4. X-linked recessive inheritance 5. Y-linked inheritance 6. Multifactorial inheritance.

12. Autosomal Dominant Inheritance • The mode of transmission is vertical. An affected person has an affected parent. • There is 50% of chance of dominant trait being transmitted to offsprings . • Both males and females are equally affected. • Dominant gene is expressed in heterozygotes. • Delayed age of onset. • The trait appears in every generation without skipping. • An unaffected offspring does not transmit the disease. • Examples : Achondroplasia – Angioneurotic edema – Huntington’s chorea – Multiple neurofibromatosis – Osteogenesis imperfecta .

13. Autosomal Recessive Inheritance • Horizontal transmission. The trait appears in sibs and parents are normal. • History of consanguineous marriage. The parents are blood related. Both the couple are carriers of abnormal gene. • 25% chance of having an affected child (double dose of abnormal gene) in a carrier couple. • Early age of onset. • Both males and females have an equal chance of getting affected. Examples: – Cystic fibrosis – Inborn errors of metabolism—albinism, phenylketonuria – Hemoglobinopathies—sickle-cell anemia , thalassemia.

14. X-linked Dominant Inheritance • Trait is more frequent in females than in males. • Affected male transmit the trait to all his daughters not to his sons. • Affected females if homozygote, transmit to all of her children. • If affected females are heterozygote, transmit the trait to half her children of either sex. • Example: – Vitamin D-resistant rickets – Xg blood groups

15. X-linked Recessive Inheritance • Females (XX) are the carriers. One X chromosome contains abnormal gene. Allelic gene on other X chromosome is normal. • Males are the victims. When abnormal gene involves nonhomologous part of single X chromosome of male (XY) disease is expressed. Defective gene has no corresponding allele in Y chromosome to counteract. • If mother is carrier and father is healthy, 50% of her sons are affected by the disease and 50% of her daughters are carrier Examples: – Hemophilia – Partial color blindness – Glucose-6-phosphate dehydrogenase (G6PD) deficiency – Duchenne muscular dystrophy .

16. Y-linked Inheritance • Y-linked traits are present in all male descendants of affected male. • The genes that are carried on the Y-chromosome are called holandric genes. • Dominant and recessive pattern will not apply as only one allele is present. • Example: – Hairy pinna.

17. Multifactorial Inheritance • It includes genetic and environmental factors like: – Drugs—thalidomide, anticancer drugs, antiepileptic drugs and antimalarial drugs. – Viral infections—rubella virus, papilloma virus – Ionizing radiation—X-rays and radioactive substances like I131. • Examples: – Cleft lip and cleft palate – Clubfoot – Congenital heart disease – Neural tube defects—anencephaly and spina bifida.

18. CONTROL OF FETAL GROWTH Intrauterine growth of the fetus is influenced by maternal factors, placental factors and fetal factors. Maternal Factors : Adequate availability of nutrition in maternal blood and its transfer across the placenta are essential for normal growth of the fetus. Malnutrition in the mother affects fetal growth and can possibly cause fetal malformations. As a rule, maternal hormones do not pass through the placenta and hence they cannot affect fetal growth. However, they can influence the fetus indirectly by controlling maternal metabolic processes. Placental Factors Hormones secreted by the placenta can influence the fetus indirectly by influencing maternal metabolism. For example, somatomammotropin secreted by the placenta has an anti-insulin effect leading to increased plasma levels of glucose and amino acids in maternal blood. The availability of these to the fetus is, thereby, increased. Placental hormones also have a direct influence on fetal growth. Somatomammotropin increases fetal growth. Human chorionic gonadotropin ( hCG ) stimulates growth of the fetal testis.

19. Fetal Factors Fetal growth is influenced by genetic factors. However, genetic factors that determine the height of the individual operate mainly in postnatal life (through the action of the growth hormone and of the thyroid hormone). Fetal endocrine glands start functioning near the middle of intrauterine life. The effects of hormones produced by them may be different from those seen in postnatal life, the modifications being necessary for requirements of the fetus. For example, the fetal adrenal gland starts producing cortisol in the 9th week. In an adult, cortisol has a catabolic effect. To prevent this, cortisol secreted by the fetus is converted to cortisone (which does not have this effect). Growth hormone (produced by the hypophysis cerebri) and thyroid hormones have very little effect on fetal growth. Infants in whom these hormones are deficient do not show growth retardation. However, sex hormones produced by developing gonads greatly influence differentiation of genital organs in both sexes.

20. Fetal Growth Retardation When the growth of a fetus is less than that seen in 90% of fetuses (i.e. it is below the 90th percentile), the phenomenon is described as intrauterine growth retardation (IUGR). Such infants are also described as small for gestational age. Such fetuses have an increased risk of congenital malformations, Apart from genetic factors like chromosomal abnormalities, growth retardation can also be caused by infections, poor nutrition, cigarette smoking, alcohol and use of harmful drugs by the mother.

21. CAUSATION OF CONGENITAL ANOMALIES (TERATOGENESIS) If a growing embryo is exposed to certain agents (chemical or physical), abnormalities in development can result. Such agents are called teratogens. The study of congenital malformations constitutes the science of teratology. congenital anomalies may occur either as a result of genetic or environmental defects, or by a combination of both. Mode of action of teratogens—some general principles may be stated as follows: 1. Stage of action of embryonic development 2. Period of organogenesis and critical period of development 3. Genetic and metabolic influences 4. Dose and duration of exposure

22. Hereditary Causes Anomalies may be caused by defects in a specific chromosome or in a specific gene. Chromosomal defects owe their effects to the absence of certain genes, or presence of extraneous ones on them. Hence, all hereditary defects are ultimately caused by failure of the cells to synthesize the right proteins (especially enzymes) at the right time. In producing an anomaly, the genetic defect may directly affect the organ, or may have an indirect effect. For example, a genetic defect that leads to agenesis of the testis may indirectly influence the developing external genitalia by interfering with the production of hormones necessary for their development.

23. Environmental Causes (Teratogens) Infections Syphilis, chickenpox, human immunodeficiency virus (HIV), measles and toxoplasmosis Malnutrition Deficiencies of vitamins, minerals (like calcium or phosphorus), certain trace elements, and of some amino acids have been shown to cause anomalies. Antigenic Reactions: Hemolytic disease of the newborn . Drugs and Chemicals : Thalidomide, aminopterin (a folic acid antagonist); diphenylhydantoin and trimethadione (used for epilepsy); phenothiazine, lithium, meprobamate, chlordiazepoxide and diazepam (which are used as tranquilizers). Alcohol in fetal blood produces the fetal alcohol syndrome. Hormones: Administration of synthetic estrogens or progestins can cause malformations of external genitalia. Fetuses exposed to diethylstilbestrol (a synthetic estrogen ) in intrauterine life, show increased incidence of carcinoma of the vagina and cervix in later life. Maternal diabetes can also cause congenital malformations.

24. Physical Factors Abnormal intrauterine environment due to an abnormal site of implantation, due to the presence of twins, because of an abnormal position of the fetus within the uterus, because of too much amniotic fluid (hydramnios) or because of too little fluid ( oligoamnios ). Insufficient or excessive availability of oxygen. Too much oxygen leads to a condition called retrolental fibroplasia. Hyperthermia or increased body temperature is teratogenic. Increase in temperature may be due to fever secondary to infection, or due to bathing with hot water for long duration. Hyperthermia leads to mental retardation, cleft lip and cleft palate, limb deficiency, spina bifida and anencephaly.

25. PRENATAL DIAGNOSIS OF FETAL DISEASES AND MALFORMATIONS Ultrasonography Alpha-fetoprotein Assay Amniocentesis Chorionic Villus Sampling Fetoscopy Magnetic Resonance Imaging Percutaneous Umbilical Cord Blood Sampling

26. Clinical correlation with gamete formation Abnormalities in formation of gametes Abnormalities of form Spermatozoa may be too large (giant) or too small (dwarf ). The head, body or tail may be duplicated. The ovum may have an unusually large nucleus or two nuclei. Two oocytes may be seen in one follicle. Chromosomal abnormalities Nondisjunction: – During the first meiotic division, the two chromosomes of a pair, instead of separating at anaphase, may both go to the same pole. This is called nondisjunction. The resulting gamete then has 24 chromosomes instead of the normal 23 At fertilization by this gamete, the zygote will, therefore, have 47 chromosomes; there being three identical chromosomes instead of one of the normal pairs. This is called trisomy. Down’s syndrome: Trisomy of chromosome 21 Extra sex chromosome: XXY (Klinefelter’s syndrome) Super females: Patients with XXX chromosomes show two masses of sex chromatin in their cells and are sometimes referred to as “super females”. Monosomy: When both chromosomes of a pair go to one gamete (as described above), the other gamete resulting from the division has only 22 chromosomes (instead of the normal 23); and at fertilization, the zygote has only 45 chromosomes. Hence one pair is represented by a single chromosome. This is called monosomy Turner’s syndrome

27. Clinical correlation with blastulation Hydatidiform mole It is a form of abnormal blastocyst that resulted from development of trophoblast/outer cell mass that forms the placenta. There will be little or no embryonic tissue. The moles secrete high levels of HCG and can produce benign (invasive mole) or malignant (Choriocarcinoma) tumors. Genetic analysis of moles indicates diploid chromosomes of paternal origin. This results from fertilization of an oocyte without nucleus and duplication of paternal chromosomes to maintain diploid state. Paternal genes regulate the development of trophoblast.

28. Clinical correlation with Formation of germ layers Use of stem cells in the treatment of diseases Embryonic stem cells (ESCs) Pluripotent cells Embryonic stem cells therapy Therapeutic stem cell cloning Adult stem cells

29. Clinical correlation with development of embryonic disc Teratogenic effects on primitive streak: Holoprosencephaly: In this condition, the forebrain is small and the two lateral ventricles fuse into a single cavity. The eyes are closely placed (hypertelorism). High doses of alcohol in the mother can cause this condition. Caudal dysgenesis ( Sirenomelia ): Deficiency of mesoderm in the caudal part of the embryo that normally contributes for the formation of lower limbs, urogenital system and lumbosacral vertebrae will result in abnormalities in these structures. The child is born with fused lower limbs and presents renal, genital and vertebral anomalies including imperforate anus. This condition is more common in mother with diabetes. Sacrococcygeal teratoma: Persistence of pluripotent cells of primitive streak at the caudal end of embryonic disc after 4th week of gestation gives rise to a large tumor called sacrococcygeal teratoma. It can cause obstruction during labor and is usually malignant. It has to be removed within 6 months after birth. Chordoma : Malignant tumor arising from remnants of notochord. It can be seen at cranial or caudal end of notochord.

30. Clinical correlation with neural tube Neural tube defects ( ntds ) These are a group of conditions where due to non-approximation of neural folds, they result in an opening in the spinal cord or brain or both from the early human development. There are two types of NTDs: open and closed. Open NTDs are more common . It results when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae. Examples are anencephaly and spina bifida ,When this happens in the region of the brain, the condition is called encephalocele , and when it occurs in the spinal region, it is called myelocele. Closed NTDs are rare and occur when the spinal defect is covered by skin. It is due to malformation of fat/bone/membranes

31. Clinical importance of amniotic fluid Amniocentesis It is a technique to collect amniotic fluid. The fluid is collected either through cervix or anterior abdominal wall. This procedure is usually done during 15–20 weeks of pregnancy. There is risk of fetal injury or preterm delivery in performing this procedure The indications for this procedure are: • Maternal age • Bad obstetric history • Cytogenetic analysis: Diagnosis of trisomy’s, sex-linked disorders • Biochemical analysis : Enzyme estimations—gross fetal anomalies—alpha-fetoproteins, surfactant • Metabolic disorders: – Lipid—Tay-Sachs disease – Mucopolysacharides —Hurler’s syndrome – Carbohydrate— Pompe’s disease – Purine— Lesch-Nyhan syndrome • Amniotic stem cells : Production of embryonic cells in stem cell therapy for defects of mesenchymal, hematopoietic, neural, epithelial or endothelial cell origin.

32. Multiple births: If more than one fetus is carried to term in a single pregnancy. When a mother gives birth to two infants at the same time, they are called twins. Three ( triplets), four ( quadruplets) or even more infants are sometimes born simultaneously Types of twinning: Twins can be produced in two ways Dizygotic twins: Two ova may be shed simultaneously from the ovary. Each of them may be fertilized and may develop in the usual manner. This results in twins that are called dizygotic or fraternal twins. Monozygotic twins: Twins can also arise from a single fertilized ovum. These are called monozygotic or maternal twins

33. Clinical correlation with Pharyngeal arches First-arch syndrome: These are congenital defects caused by a failure of migration of neural crest cells into the first pharyngeal arch. They usually produce facial anomalies. • Treacher Collins syndrome ( Mandibulo -facial dysostosis): – It is a rare autosomal dominant disorder. Genetic defect: Mutation of TCOF1 (Treacle) gene located on chromosome 5 • Pierre Robin syndrome: – Genetic cause—anomalies in chromosomes 2, 11 or 17. Genetic dysregulation of SOX9 gene that controls development of face. The incidence of this condition is 1:8,500.

34. Clinical correlation with development of face Harelip : The upper lip of the hare normally has a cleft. Hence, the term harelip is used for defects of the lips. Unilateral harelip : failure of fusion of maxillary process with medial nasal process on one side (A to C). Bilateral harelip: failure of fusion of both maxillary processes with the medial nasal process (D). Midline cleft of upper lip: Defective development of the lowermost part of the frontonasal process may give rise to a midline defect of the upper lip (E). Cleft of lower lip: When the two mandibular processes do not fuse with each other the lower lip shows a defect in the midline. The defect usually extends into the jaw (F)

35. Oblique facial cleft: Nonfusion of the maxillary and lateral nasal process gives rise to a cleft running from the medial angle of the eye to the mouth (Fig.11.12A). Inadequate fusion of the mandibular and maxillary processes with each other may lead to an abnormally wide mouth ( macrostomia ) Too much fusion may result in a small mouth ( microstomia)

36. Clinical correlation with development of palate Cleft palate Defective fusion of the various components of the palate gives rise to clefts in the palate. Complete cleft palate: • Bilateral complete cleft: Failure of fusion of both palatine processes of maxilla with premaxilla. A y-shaped cleft will be present between primary and secondary palate and between the two halves of secondary palate. It presents bilateral cleft of upper lip also • Unilateral complete cleft: Nonfusion of one side palatine process of maxilla with premaxilla. It presents unilateral cleft of upper lip ( Fig.B ). Incomplete cleft palate: • Cleft of hard and soft palate: Cleft limited to hard palate ( Fig.C ). • Cleft of soft palate ( D). • Bifid uvula: Cleft limited to uvula (Fig E).

37. Clinical correlation with development of tongue Anomalies of the tongue macroglossia microglossia aglossia Bifid tongue ankyloglossia or tongue-tie. Occasionally, the tongue may be adherent, to the palate ( ankyloglossia superior). • A red, rhomboid-shaped smooth zone may be present on the tongue in front of the foramen cecum. It is considered to be the result of persistence of the tuberculum impar . • Thyroid tissue may be present in the tongue either under the mucosa or within the muscles. • Remnants of the thyroglossal duct may form cysts at the base of the tongue. • The surface of the tongue may show fissures

38. CONCLUSION

39. REFERENCES Inderbir Singh, Inderbir Singh’s human embryology 12th edition, Jaypee Brothers Medical Publishers (P) Ltd . TW Saddler, Langman’s Medical Embryology,9th edition, Wolters Kluwer India Pvt. Ltd Mark Hill, UNSW embryology (online), Available from: https://embryology.med.unsw.edu.au