Genetic Syndromes Part 1 and 2 Dr Tabrez

Genetic Syndromes Part- 1 and 2 Dr. Tabrez Associate Professor Dept. of Anatomy MBBS Batch : 2019 -20 13/7/2020

CLASSIFICATION OF GENETIC DISORDERS A. Disorders of the autosomes: 1) Chromosomal deletion syndromes 2) Trisomy syndromes B. Disorders of sex chromosomes : A. Disorders of the autosomes: 1) Chromosomal deletion syndromes a) Cri-du-chat syndrome b) Wolf Hirschonn Syndrome c) Prader – Willi Syndrome d) Angelmans syndrome e) WAGR Syndrome f) Retinoblastoma g) Digeorge syndrome h) Philadelphia chromosome

a) CRI-DU-CHAT SYNDROME • Introduction : It is derived from a French word means cat’s cry. It occurs in 1 in 50, 000 births. It is more common in females, ratio being 4 : 3. • CAUSE : It is due to deletion of the terminal portion of short arm of chromosome 5 (5 p-). • MANIFESTATION: • Round face • Hypertelorism • Micrognathia

Mental retardation Downward slant to the eyes Low birth weight & slow growth Microcephaly Hypotonia Partial webbing of fingers and toes • Single palmar crease • Inguinal Hernia, Diastasis recti, epicanthal folds and congenital heart defects are common VSD, ASD etc. • Due to underdevelopment of the larynx, the child cries like a cat. • • •

b)WOLF–HIRSCHONN SYNDROME: • It was first documented by cooper & Hirschonn in 1961. • It occurs in 1 in 50, 000 birth, females are more affected, ratio being 2 : 1. • CAUSE: It is due to deletion of short arm of chromosome 4 (4 P-).

• MANIFESTATIONS : a) Growth retardation b) Micrognathia c) Microcephaly with hypoplasia of cerebellum, absence of septum pellucidum, agenesis of Corpus callosum, absence of olfactory bulbs & tracts, hydrocephalus. d) Seizures are common between 5 months to 2 years of age e) Greek Helmet facies – Microcephaly Eyes widely spaced Downturned mouth Bilateral cleft lip Micrognathia

c) PRADER – WILLI SYNDROME : • Introduction: It occurs in 1 in 30, 000 births • CAUSE: It is due to microdeletion of the proximal part of long arm of chromosome 15 that is paternally inherited.

• MANIFESTATIONS: • • Hypotonia Feeding difficulties Poor growth and development Voracious appetite & obesity Type II DM Learning disabilities Temper tantrums Puberty is delayed & males & females are infertile

d) ANGELMAN’S SYNDROME: • It was first described by Harry Angelman in 1965. • CAUSE : It is due to microdeletion of the proximal part of the long arm of chromosome 15 that is maternally derived(15 q-).

• MANIFESTATIONS: • • • Mental retardation Ataxia Convulsions Speech impairment Development is delayed Intellectual disability

e) WAGR SYNDROME: • Introduction: Combination of Wilm’s tumour, Aniridia, Genital abnormalities & Growth retardation. • CAUSE: It is due to interstitial deletion of a particular region of the short arm of chromosome 11(11 p-).

• MANIFESTATIONS: a) Hypernephroma b) Aniridia - Absence of Iris results in decrease in Visual acuity, glaucoma, cataracts, optic nerve hypoplasia, nystagmus in infants. c) Genito-Urinary abnormalities- Cryptorchidism, hypospadias, renal and ureteral malformations, streak ovaries and bicornuate uterus. d) Growth retardation

f) RETINOBLASTOMA: Introduction: • It is a highly malignant cancer of developing retinal cells (retinoblasts), hence the name. It usually affects children below the age of 5 years. It may be hereditary also and in such cases it is bilateral and is expressed as autosomal dominant inheritance. • Verhoff first coined the term retinoblastoma which was later adopted by the American ophthalmological society in 1926 as a general term for this entity. • CAUSE: It is due to interstitial deletion of long arm of chromosome 13(13 q-).

• • • MANIFESTATIONS: Abnormal appearance of pupil. Leukocoria also known as amaurotic cat’s eye reflex Squint Glaucoma

f) DIGEORGE SYNDROME: Introduction • In these individuals there is congenital absence of the thymus in which cellular immunity imparted by T Cells is absent but humoral immunity offered by B cells is intact. • CAUSE: This is due to microdeletion of proximal long arm of chromosome 22(22 q-).

• • MANIFESTATIONS: Thymic hypoplasia - (due to defect in 3 rd & 4 th Hypoparathyroidism pharyngeal pouches Recurrent infections during embryogenesis) Cardiac anomalies Craniofacial dysmorphology Learning dysfunctions.

g) PHILADELPHIA CHROMOSOME: • Introduction • This abnormality found in some cases of CML (95%), ALL (25 -30%) & AML occasionally was first read in Philadelphia conference in 1960, hence the name.

• CAUSE: • This is due to translocation and deletion. Long arm of chromosome 22 is deleted and the deleted arm is then translocated to the long arm of chromosome 9. This altered karyotype is found in blood or bone narrow cells but other tissues show normal chromosome complement.

2. TRISOMY SYNDROMES a) PATAU’S SYNDROME: • Introduction : It occurs in 10, 000 births. • Karyotype : trisomy 13

MANIFESTATIONS • Gross brain malformations, seizures, mental retardation • Microphthalmia • Harelip or cleft palate • Polydactyly associated with congenital heart disease • Hypotonia • Umbilical Hernias • Child will not survive for more then few weeks

b) EDWARDS SYNDROME: • Introduction: It occurs in 1: 6000 births. Females are more affected. • Karyotype : trisomy 18

MANIFESTATIONS: • • Elongated head, broad and flat nose Contraction of fingers Rocker bottom foot Congenital Heart disease Spina bifida Kidney problems Feeding problems The child will not survive for more then few months.

c) DOWN’S SYNDROME • Introduction : It occurs in 1 in 700 births • Karyotype: Trisomy 21, Translocation 21/22. • Majority of the babies with Down's syndrome have 47 chromosomes with trisomy 21, but 3% have normal 46 chromosomes with translocation. Increased maternal age predisposes to nondisjunction carrying two 21 chromasomes instead of one in gametogenesis. Paternal age is also significant. When a mother carries translocation between two 21 chromosomes, she will have repeated translocated Down's babies.

MANIFESTATIONS: • Moon shaped face with epicanthic fold (Mongolism) • Mental retardation • Hypotonia • Single palmar crease/simian crease • Wide gap between first and second toes.

• Long protruding tongue • Flat occiput with excess nuchal skin • Short in stature, short and stocky hands and feet • Have congenital Heart diseases • Easy to manage and love music. • Most affected adults develop Alzheimer’s disease. • Brush field spots in Iris, Cataracts

DISORDERS OF SEX CHROMOSOMES 1. KLINEFELTER’S SYNDROME: • Karyotype : 47 XXY in most cases ; 48 XXXY, 49 XXXXY occasionally. • Incidence : 1 in 1000 male live births. • Barr body present in phenotypic male

Discussion: • This chromosomal abnormality is due to nondisjunction in gametogenesis. In about 75% of Klinefelter's patients, the two X-chromosomes are of maternal origin. When the sex chromosome numbers is more it means that the non-disjunctional events have occurred during meiosis I and II. Increased number of X chromosomes makes the individual more mentally retarded. ‘Y’ chromosome contains in the short arm TDF(testes determining factor) on SRY gene i. e. sex determining region of Y chromosome. So affected people are male.

MANIFESTATIONS: 1. Subject is taller than normal males 2. Testes are small, dysgensis of seminiferous tubules with azoospermia, occasional gynaeco mastia 3. Mental retardarion • Usually attends the clinic along with his wife for infertiliy.

2. TURNER’S SYNDROME: • Karyotype : 45, XO with complete deletion of one X chromosome • 46, XXq i, with Iso– chromosome of long arm of one X chromosome. Barr body is absent in phenotypic female. • Incidence : In live born female infants is approximately 1 in 5000.

Discussion : • The primary cause for this syndrome is nondisjunction in gametogenesis. In 75% of turner’s patient the Xchromosome is maternal in original. The presence of two active xchromosomes is essential for the development of ovaries and their maintenance.

MANIFESTATIONS: • Female phenotype • Short stature with webbed neck. • Bilateral cubital valgus • Shield chest with widely shapped nipples • Low set ears • Ovaries are represented by streaks of fibrous tissue; gonadal dysgenesis is associated with primary amenorhoea. • Lymphoedema & coarctation of aorta.

3. TRIPLE X – SYNDROME: • Karyotype : 47, XXX (trisomy) • Barr bodies are two. • Discussion : Females with triple X syndrome may have normal children.

MANIFESTATIONS: • Female in phenotype. • There are no marked abnormalities, because two X – chromosomes are heterochromatic and genetically inert and only one X – chromosome is active throughout life. • She may be mentally retarded.

4. XYY SYNDROME: • Karyotype – XYY • Discussion: XYY individual results from non-disjunction in gametogenesis of his father, and non-disjunction takes place in meiosis II where the Y chromosomes fail to separate.

MANIFESTATIONS: • Affected male is taller than average(above 8 ft). • Immature mind aggressive antisocial behaviour. • XYY individuals usually give birth to normal individual.

5. FRAGILE X SYNDROME: • Karyotype : The distal end of long arm of Xchromosome shows of gap as a ‘fragile site’ at the level of Xq 27. 3. With the application of molecular technique the gap region posseses tandemly repeats of ‘CGG’ triplet DNA sequence of about 200 repeats or more, which makes the DNA unstable and non functional. Fragile X syndrome might be expressed in boys transmitted from carrier mother.

MANIFESTATIONS: Male in phenotype. Mental retardation Large ears Elongated face with prominence of lower jaw • Enlarged testes • •

6. XX MALE: • This is due to abnormal X-Y cross over in male gametogenesis. • The physical appearance corresponds with klinefelter’s male.

Discussion: • In Meiosis I of male, pairing of X and Y chromosomes occurs between homologous segments at the tip of their short arms, this region of each chromosome is known as the pseudo autosomal region, close to which TDF of SRY gene is located. This region of homologous segments in male meiosis does not exchange in crossing over. Occasionally SRY gene can be caught in crossing over event and give rise to XX male.

7. XY FEMALE: • Karyotype - XYqi. This is due to SRY gene located in the short arm of Y regulating the development of testis. • Discussion: The individual is female in appearance with normal growth, but without testis or with streak gonads.