Chromosomal Disorders Dr Mubarak Abdelrahman Assistant Professor Jazan University

OBJECTIVES To be able: To discuss the basis of chromosomal disorders. To differentiate between the main types of chromosomal syndromes.

Chromosomal Disorders Chromosomal abnormalities occur: - in approximately 8% of fertilized ova. - in 0.6% of live born infants. in 50% of abortions (the most common: Turner). Cell division problems can lead to abnormalities of chromosome structure and/or number.

Chromosomal Disorders Features suggestive: - Low birth weight (small for gestational age). Failure to thrive. Developmental delay. Presence of 3 or more congenital malformations. Syndromes include trisomies, monosomy, duplications and chromosomal deletions.

ABNORMALITIES IN NUMBER (ANEUPLOIDY) Nondisjunction: failure of a chromosomal pair to separate during meiosis or mitosis. Aneuploidy: change in number of chromosomes. A cell may have: one chromosome (monosomy) three (trisomy) copies of a particular chromosome.

Trisomy 21 (Down Syndrome) Most common abnormality of chromosomal number. 1 in 800 births. Nondisjunction (92–94%): 3copies of chromo 21. Translocation (4 %): extra chromos 21 is part of 14. Mosaicism (2-3%): nondisjunctional after few cell divisions.

Trisomy 21 (Down Syndrome) The risk increases with increasing maternal age. But 75% born to women younger than 35 years. The recurrence risk depends on cytogenetic findings: In nondisjunction recurrence is 1% + age specific risk. In translocation, the recurrence risk is: 10% to 15% if the mother is the carrier 2% to 5% if the father is the carrier.

Trisomy 21 (clinical manifestations) Most likely diagnosed in the newborn period. Hypotonic and had characteristic dysmorphic features. 40% have congenital heart disease (AVSD, VSD, ASD, TOF,..). 10% have gastrointestinal tract anomalies (duodenal atresia, annular pancreas, and imperforate anus). 1% have congenital hypothyroidism. Polycythemia at birth is common. Increased risk of infection, cataracts, leukemia & Alzheimer 10% have atlantoaxial instability.

Down syndrome

Trisomy 18 (Edward`s syndrome) The second most common autosomal trisomy. 1 in 7500 live births. >95% spontaneously aborted in the first trimester.

Trisomy 18 ( Edward syndrome) Head and Face: Prominent occiput, micrognathia, microcephaly, cleft lip and palate, … Precordium: Congenital Heart Disease. Extremities: Limited hip abduction, overlapping fingers, rocker bottom feet, .. General: Severe developmental delay and growth retardation. Only 5% live beyond 1 year.

Edward Syndrome

Edward Syndrome

Trisomy 13 (Patau syndrome) The third of the trisomies. 1 in 12,000 live births.

Trisomy 13 (clinical manifestations) Head and Face: Scalp defects, microphthalmia, microcephaly, Midline facial defects such as: - cyclopia (single orbit). - cebocephaly (single nostril). - cleft lip and palate (60-80%). Midline CNS anomalies e.g. holoprosencephaly.

Trisomy 13 (clinical manifestations) Precordium: Congenital HD 80% (VSD, PDA, ASD) Extremites: Overlapping fingers & toes, polydactyly General: Severe developmental delay and growth retardation. Only 5% live longer than 6 months.

Klinefelter Syndrome (47,XXY) The most common genetic cause of hypogonadism and infertility in men. 1 in 500 male births. The extra X chromo: non-disjunction in sperm/Ova. About 15% are mosaic, with 46,XY/47,XXY. The diagnosis is most often made at 15-16 yrs.

Klinefelter Syndrome (47,XXY) Hypogonadism at puberty Retardation if more X’s Gynaecomastia in 30% LONG legs Atrophic testes Small penis

Monosomy: Turner Syndrome (45,X) The only condition in which a monosomic survives to term. 1 in 3200 liveborn females. Short stature is a cardinal feature (GH hormone therapy). Hypothyroidism: five times more frequently than in the general population. GH: Turner syndrome, end-stage renal failure before kidney transplantation, Prader-Willi syndrome, intrauterine growth retardation, and idiopathic short stature.

TURNER (45 XO) SHORT (needs GH) but normal IQ. NECK “WEBBING” EDEMA of HAND DORSUM CONGENITAL HEART DEFECTS IN 45%: most serious is aortic coarctation. RENAL (horseshoe kidney). Streak gonads in most (needs estrogen) GH: Turner syndrome, end-stage renal failure before kidney transplantation, Prader-Willi syndrome, intrauterine growth retardation, and idiopathic short stature.

“STREAK” ovaries are the rule, neck webbing and cardiac structural abnormalities are also at the top of the list. TURNER SYNDROME (45 XO)

CHROMOSOMAL DELETIONS 1. Williams Syndrome: Due to a small deletion of chromosome 7. Congenital heart disease is seen in 80% of affected children (supravalvular aortic and pulmonic stenosis). Short stature, ("elfin faces"), moderate mental retardation, cocktail party personality and hypocalcaemia.

Williams Syndrome ("elfin facies") with: - median flare of the eyebrows. - fullness of the perioral and peri-orbital region. - blue iris. - depressed nasal bridge with ante version of the nares.

CHROMOSOMAL DELETIONS 2. DiGeorge syndrome (CATCH 22) Deletions of chromosome 22. Cardiac defects ( aortic coarctation, VSD, TOF). Abnormal facial features (a prominent nose). Thymic hypoplasia (70% has immunodeficiencies). Cleft palate. Hypocalcemia.

DiGeorge syndrome (CATCH 22)

CHROMOSOMAL DELETIONS 3. Prader-Willi syndrome (PWS) Occurs in 1 in 10,000 infants. A small deletion of chromosome 15. ## In 20% have uni-parental diosomy: (maternal UPD: missing the paternal chromosome 15).

Prader-Willi syndrome Characterized by: Hypotonia with postnatal growth delay. Obesity after infancy. Almond-shaped eyes. Small hands and feet. Developmental disability. Hypogonadotrophic hypogonadism.

Reference: Nelson essential 7th edition