(ILA1)

Clinical diseases with chromosomal abnormalities

By Dr Iman Marzouk Professor of Pediatrics Head of clinical genetics unit

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Diseases with chromosomal abnormalities

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Case (1):
A nine month old infant of a mother aged 38 years from Alexandria. He was admitted to the hospital since 2 days, C/O : Fever, cough, vomiting and tachypnea since 4 days. Present history: The infant was suffering from repeated attacks of pulmonary infection, which might be preceded by an upper respiratory tract infection. He was admitted to the hospital for three times due to pulmonary infections and inability to feed properly.

Examination of the infant revealed: Delayed mile stones, Facial features of Down syndrome, Hypotonia, Congenital heart disease. The following investigations were done: X ray chest: Patches of consolidations (Bronchopneumonia).

Down Syndrome (Trisomy 21)

It is the most common pattern of malformation in man due to trisomy for all or a large part of chromosome 21.

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Clinical presentation
During neonatal period (1st month of life) Abnormal facial features. Simian crease. Hypotonia, hyper flexibility of the joints. Congenital malformation (Congenital heart disease, duodenal atresia).

During infancy (1 month to 2 years): Characteristic facial features Delayed mile stones (motor, language and mental deficiency). Repeated upper and lower respiratory tract infections. During childhood: Characteristic facial features

Clinical abnormalities
General Hypotonia: delayed motor mile stones Opened mouth with frequent protrusion of the tongue. Acrobatic movements. Central nervous system (CNS): Mental deficiency.

Craniofacial: Brachycephaly with relatively flat occiput. Upslanting of palpebral fissures. High arched hard palate and small nose with low nasal bridge. Inner epicanthic folds.

Prominent forehead, flat face, short nose with flat nasal bridge, Up slanting palpebral fissures , epicanthic folds and protruded tongue.

Eyes: Brush field spots in the iris. Lens opacities ------- cataract. Refractive errors mainly myopia. Nystagmus Strabismus.

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Adult patient with Down syndrome. Note bilateral cataract.

Ears: Small over folding of angulated upper helix Hearing defects (conductive and/or sensorineural ). Hair: Fine, soft and sparse. Dentition: Hypoplasia

Simian crease.

Feet: Wide gap between 1st and 2nd toes with planter crease in between. Cardiac: Many cardiac defects like ventricular septal defect (VSD), atrial septal defect (ASD). Genitalia: Primary gonadal deficiency.

wide furrow between the big toe and other toes

Natural History
Muscle tone tends to improve with age. The rate of developmental progress slows with age. Early developmental intervention programs for DS children have resulted in improved rate of progress during the first five years of life.

The median age of death is about 50 years. The major causes of early mortality: Congenital heart defects Low immunity leads to frequent respiratory infections and high incidence of hepatitis B. Leukemia.

Etiology of Down Syndrome (DS)

It is a trisomy for all or a large part of chromosome number 21.

Type Non disjunction Mosaicism Translocation

Percent (%) 94% 2.5% 3.5%

Incidence of DS:
About 70% of trisomy 21 fetuses abort spontaneously. The incidence is generally: 1:700 newborn. According to the maternal age:

Maternal age 15-29 years 30-34 years 35-39 years 40-44 45 years

Incidence 1:1500 1:800 1:270 1:100 1:50

Recurrence rate:
It is about 1% in case of non disjunction DS. In case of translocation DS : The translocation is de novo in 70% of cases; with recurrence rate 1%. If one of the parents is a carrier for translocation (30% of cases), the recurrence rate is about 10-15%; except if the carrier has t(21,21) or isochromosome 21, where the

Case (2):
A fourteen year old girl C/O: Short stature and delayed menarche There was past history of edema of the dorsum of the hands and feet. Examination revealed: Proportional short stature Neck webbing

Turner Syndrome (TS) (X0 Syndrome)

It is a chromosomal syndrome of short female with sexual infantilism and certain physical abnormalities.

Incidence of TS:
About 99% of 45X fetuses abort

spontaneously and only 1% of these fetuses survive to term. Despite this TS incidence is 1: 2500 live births.

Clinical presentations:
During neonatal period: Edema of the dorsum of the hands and feet. Webbed neck. Wide spaced nipples. During the childhood: Short stature.

Short webbed neck in the previous neonate wide spaced nipples

Edema of the dorsum of the hands and feet in a neonate with turner syndrome

Clinical Abnormalities
Growth: Short stature. Performance: Low school performance (mild). Although early development is usually normal, delayed motor skills are common. Gonadal hypoplasia (estrogen therapy).

Mild facial dysmorphism: Narrow maxilla Micrognathia Downturned mouth angles Prominent ears. Neck: Low posterior hair line. Short webbed neck.

A girl with turner syndrome Note: webbing of the neck , wide-spaced nipples and an increased carrying angle at the elbows.

Short webbed neck from the front

Short webbed neck from the back

Etiology of TS:
Fault chromosomal distribution leading to 45,X0 (monosomy X) individual. Paternal X or Y chromosome is one more likely to be missing. Other chromosomal anomalies: 46XX/45X0, isochromosome X, partial deletion of one of the X chromosomes.

Case (3):
A five month old infant C/O: Low birth weight, delayed mile stones, failure to thrive and a cat like cry specially in the early months of life. Her examination revealed rounded face,

inappropriate growth and delayed development. Karyotype: 46, XX, 5p-

Cri du Chat syndrome Microdeletion (5psyndrome) There is partial deletion of the short arm of
chromosome number 5. 85% of the cases occurs de novo and from unbalanced translocation from one of the parents in 15% of the cases.

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Flat occiput, microcephaly and low set ears in an infant with cri du chat.

Girl with cri du chat: note the rounded face and hypertelorism.

Hand of the same girl showing simian crease.

The risk of recurrence: 1% if the parents are normal. 15-25% in case of parental translocation. Incidence: 1:20000 live births.

Clinical presentation
Abnormal cat like cry in early neonatal period (disappear later) Low birth weight. Slow growth (failure to thrive)

Clinical Mental deficiency. Abnormalities:

Hypotonia Microcephaly Round face (become elongated later) Hypertelorism Epicanthic folds Downward slanting of palpebral fissure

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