AUTOSOMAL & SEX CHROMOSOMAL DISORDERS

Autosomal Disorders Cytogenetics- study of chromosomes and their abnormalities Abnormalities of autosomes: Alteration in number (Aneuploidy) Alteration in structure Deletion Translocation Ring chromosome Shift Inversion

Autosomal Chromosomal Disorders Approximately 1 of every 160 liveborn infants has a demontrable chromosomal abnormality Associated with 50% – 60% of first trimester spontaneous abortions 5% of stillbirths

Chromosomal Syndromes Diagnosis based solely on clinical characteristic possible but not reliable because: 1. No single anomaly is pathognomonic for a given syndrome 2. Patterns of anomalies for different chromosomal syndromes share common features 3. Phenotypic variation exists among people with apparently identical abnormal karyotypes 4. Malformations associated with chromosomal aberrations also can be associated with normal karyotypes (etiologic heterogenecity)

Chromosomal Syndromes Characteristics Multiple malformations (craniofacial, skeletal, cardiac and genitourinary) Abnormal facies, low set or malform ears, and certain digital anomalies (eg. Clinodactyly, polydactyly, syndactyly and single palmar creases) Mental retardation Intrauterine and postnatal growth retardation

Autosomal Disorders A. Alteration in number (Aneuploidy) 1. Down’s syndrome (Trisomy 21) 2. Pataus syndrome (Trisomy 13) 3. Edwards syndrome (Trisomy 18) B. Alteration in structure 1. Cri-du-chat syndrome (Deletion of chr.5) 2. Wolf’s syndrome (Deletion of chr.4)

Down syndrome (Trisomy 21) Most frequent Characteristics craniofacial features: Brachycepaly, oblique palpebral fissures, epicathal folds, broad nasal bridge, a protruding tongue, and small low-set ears with overlapping helix and prominent antihelix At birth infants are hypotonic Other features: Iridial Brushfield spots, broad short fingers, clinodactyly, wide space between first two toes Simian Line-Present in only 30%

Down syndrome (Trisomy 21) Common internal anomalies (cardiac lesions and duodenal atresia) Mental retardation-mean IQ 50 (range 25-70) if IQ is 70-80 mosaicism is suspected Growth retardation and hypotonia persist and older patients opened become obese Females are fertile male are not

Down syndrome (Trisomy 21)

Down Syndrome

Down syndrome (Trisomy 21) Mechanism of chromosomal abnormalities: Nondisjunction – 93% - 95% Related to late maternal age; paternal effect does not occur until the 5th - 6th decade Mosaicism (46/47 + 21) – 2% - 3% Translocations 3% - 5% Translocations show no definite relationship to parental age and maybe either sporadic or familial: Involves chromosome nos. 13-15 usually nos. 14 The recurrence risk is approximately 10% if mom is translocation carrier but only 2% - 3% if dad is carrier

Edwards syndrome (Trisomy 18) Frequency of 1/8000 live births Characteristics facial features: Microcephaly prominent occiput; low-set abnormal, somewhat pointed (Fawn like) ears and micrognathia Skeletal anomalies: Overlapping fingers short sternum, shield chest, narrow pelvis, “rocker bottom” feet with protrusion of calceneum, great hallux is short and dorsiflexed (hammertoe) Cardiac and renal anomalies At birth fetal movement if feeble Mean survival time few months only Severe mental retardation for those who survives

Pataus syndrome Trisomy 13 1/20,000 live births 50% affected children died in the first month Fewer than 5% survives past three years of age Characteristic features: holoprosencephaly, eye anomalies (microphthalmia, anopthalmia or coloboma), cleaf lip and palate, polydactyly and cardiac defects Other features: cutaneous scalp defects, hemangiomata on face and forehead, low-set ears with abnormal helix, and rocker botton feet (convex soles and protruding heels)

Pataus syndrome Trisomy 13 80% associated with nondisjunction (47,+13) Translocation occurs in 20% and involves chromosomes nos. 13-15 If either parent is carrier recurrence risk of an affected offspring increases but less than for Down syndrome

Cri-du-chat syndrome Deletion of short arm of chromosome 5 (5p) Peculiar cry (meowing of a cat) due to softening of larynx During infancy facies become rounded (“moonlike”) because of microcephaly hypertelorism broad nasal bridge downward slanting of palpebral fissures, micrognathia and low-set ears

As patients ages facies become elongated and philtrum shorter Hypertonicity Severe mental and growth retardation Can reach adulthood

Deletion of chr.4 (Wolf’s Syndrome) Results from absence of distal portion of 4p Distinctive facial appearance: forehead high characterized by facial bossing (glabella is prominent), hypertelorism, bilateral epicantus, downward slanting palpebral fissures and protruding eyes, nose has a square apex and length of bridge is equal to each width-resemble helmets Microcephaly and micrognathia common Other malformations include: cardiac defects, hypospadias, umbilical hernias Hypotonia and seizures are regular features in neonates Severe mental retardation

Sex Chromosome Disorders Turner’s Syndrome - XO Klinefelter’s Syndrome - XXY Triple X female - XXX Double Y Male - XYY

Non-disjunction of Sex Chromosomes Failure of sex chromosomes to separate during cell division

Turner’s Syndrome Monosomy X Somatic anomalies Short stature – less than 4’10” Webbing of neck Shield chest CVS (coarctation of aorta/VSD) Renal (horseshoe kidneys) Bilateral lymphedema of feet due to hypoplasia of superficial vessels Skeletal – Cubitus valgus (54%) At birth: decreased birth weight, birth length close to 50th percentile Normal intelligence

Turner’s Syndrome

Turner’s Syndrome ( Monosomy X ) Chromatin negative Absent Barr body Streak gonads – normal gonads replaced by white fibrous streak, Oocytes are usually completely absent Lack of normal ovarian development leads to deficient secretion of sex steroids; estrogen and androgen levels ; FSH and LH levels  At puberty, pubic and axillary hair failed to develop in normal amount; breasts contain little parenchymal tissue; external genitalia, vagina and uterus small

Klinefelter’s Syndrome 1/1000 live born males Testicular feminization syndrome Androgen deficiency (lack of normal secondary sexual development) increased gonadotropin levels (FSH LH) gynecomastia Hyalinization of seminiferous tubules Infertility External genitalia well differentiated although in neonates, may show micro-penis Scrotum well developed, vas deferens normal, prostate small Slightly taller than normal, legs are relatively long compared with their trunk and arms More likely to be retarded (IQ 50-85) or socially maladjusted, often passive poorly motivated because of poor self-image

Klinefelter’s syndrome

Klinefelter’s Syndrome ( 47XXY )

Triple X syndrome 1/1000 live born females Maybe associated with subnormal intelligence – IQ is 16 points below those of their sibs, IQ is 45-70 (5%) 1/3 show some mental or behavioral problems Suboptimal fertility Delayed menarche or premature ovarian failure

Trisomy X

XYY syndrome Approximately 1/1000 liveborn males Tall stature Increased tendency to psychiatric problems Antisocial behavior and mental retardation Usually have grossly normal testis and normal external genitalia; Spermatogenic arrest is seen in approximately half the cases

XYY syndrome

46 XYY

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