أسئلة الأولى أطفال الجديدة - Down Syndrome

• Down syndrome (DS) features a consistent and specific phenotype and genotype.
• The phenotype includes mental retardation and characteristic facial features (mongoloid facies).
• The genotype involves the presence of three copies of chromosome 21.

Down Syndrome Karyotype

• The karyotype shows the presence of three copies of chromosome 21.

Epidemiology

• Down syndrome occurs in approximately 1 in 600 births.
• The male to female ratio at birth is 1.24:1.0.

Genotypes

• Meiotic non-disjunction Trisomy 21 accounts for 95% of cases.
• Translocation Trisomy accounts for 4% of cases.
• Mosaic type accounts for 1% of cases.

Meiotic Non-disjunction (Maternal Age Dependent DS)

• All cells show an additional No. 21 chromosome, i.e. 47, XX, +21.
• This type results from meiotic non-disjunction.
• Approximately 95% of all Down syndrome cases are this type.
• About 70% of trisomy 21 cases are born to mothers older than 30 years.
• Karyotyping of both parents is usually normal.

Translocation Trisomy 21

• All cells show a normal number of chromosomes (46).
• An extra chromosome 21 is attached to another one (13, 14, 15, or 21), i.e., 46, XX, +t (14q 21q).
• Approximately 4% of Down syndrome cases are this type.

Mechanisms of Underlying Translocation

• In the sporadic type, half of translocated Down syndrome cases arise de novo in the affected individual, and both parents are usually normal.
• In the inherited type, the disease is inherited from a balanced translocation carrier parent, i.e., 45, XX, t (14q 21q).

Mosiacism: (Mitotic Non-disjunction)

• Individuals have various proportions of trisomy 21 (47, XX, + 21) and normal cells (46, XX).
• This group may have normal intelligence, depending on the number of trisomic cells present.
• Represents 1% of Down syndrome cases.
• Parents are usually normal.

Clinical Manifestations: Early Presentations

• Prematurity can occur.
• Low birth weight is common.
• Prolonged physiological jaundice may be present.

Dysmorphic Features: Head & Neck

• Brachycephaly (occipital flattening) is typical.
• Microcephaly may be present.
• Delayed closure of fontanels is common.
• Hair is often fine & soft and may be sparse.
• Rounded face with a flat profile.
• Short neck with excessive nuchal skin.

Eyes

• The palpebral fissures slant upward and outward.
• Epicanthic folds are often present.
• Flat nasal bridge may give the appearance of hypertelorism, but the interorbital distance is usually not increased.
• Brushfield spots (small white spots) may be visible on the iris.

Ears

• Tend to be small and low set.
• Ear canals may be atretic.

Mouth Cavity

• High arched palate is common.
• In older children, the tongue is often protuberant.
• Delayed & irregular eruption of the teeth.

Hands

• Short, brachydactyly (short fingers).
• Often a single transverse palmar crease (simian crease).
• Incurved fifth finger (clinodactyly).
• Single fifth finger crease is common.
• Wide gap between the first and second toes (wide sandal gap).

CNS

• Profound hypotonia (cerebral hypotonia).
• Laxity of joints is often evident, lessening as the child grows older.
• Varying degrees of mental retardation is the most significant feature.
• Decayed milestones, including speech, locomotion, and social behavior.
• Intelligent quotient (I.Q.) ranges from 20 to 75, with a mean of 50.
• Individuals with mild mosaicism may have relatively higher IQ.

Complications: CVS

• Congenital heart diseases (CHD) are present in at least 40% of cases.
• The most characteristic are endocardial cushion defects, followed by VSD & ASD.

GIT

• Gastrointestinal malformations include duodenal stenosis or atresia, esophageal atresia, anal atresia, and Hirshsprung disease.

Immunity

• Intercurrent infection: Frequent respiratory, eyes, and skin infections.
• Serous otitis media may lead to hearing loss.
• Decreased immune defense mechanism (cellular & humoral).

Hematologic

• Acute lymphoblastic leukemia: There is a 10 to 30 fold increased risk compared with the general population.
• Polycythemia
• Leukemoid reaction that resolves by age 5 months.

Sexual Development

• Males may be infertile due to interstitial fibrosis of the testes and hypoplasia of the seminiferous tubules.

CNS

• Unstable atlanto-axial joint with subsequent dislocation and neurological complications in about 10-15% of Down syndrome cases.

Endocrine

• Congenital hypothyroidism may coexist.
• Requires thyroid replacement therapy (eltroxin).

Ophthalmic

• Refractive errors
• Keratoconus
• Cataract

Investigations: Cytogenetic Studies

• Although the clinical picture of DS is often straightforward, cytogenetic analysis should always be obtained. Provide confirmation of the diagnosis and determine the genotypes of DS for accurate genetic counseling.
• Chromosomal studies can be obtained from any dividing nucleated cell.
• blood is easy to obtain, cytogenetic studies are usually done on lymphocytes.
• If there is a suspicion of mosaicism, fibroblast cytogenetic studies must be considered.

Laboratory Findings

• Complete blood pictures & bone marrow examinations are mandatory when leukemia is suspected.
• Polycythemia in the first days of life & transient congenital leukemoid reaction.

Imaging Studies

• Echo-Doppler evaluation is mandatory for all cases, even if there are no clinical cardiac abnormalities.
• Screening lateral cervical radiograph is recommended at about age 6 years to diagnose an unstable atlanto-axial joint.

Genetic Counseling: Preconception

• Advise mothers of advanced maternal age about the risk of trisomy.
• If pregnant, ensure appropriate follow-up.

Prenatal

• Pregnant women with a high risk of having DS (advanced age, translocated carrier) may benefit from prenatal diagnosis.
• Prenatal diagnosis can be achieved by screening tests, maternal serum alpha, fetoprotein unconjugated estriol, and confirmation tests like amniocentesis or chorionic villus sampling for chromosomal analysis.

Postnatal

• Families with DS children must be aware of the nature of the disease and the recurrence risk.
• The recurrence risk depends on the cytogenetic analysis of the infant & parents.

Recurrence Risk

• Trisomy 21 and normal parents have a 1-2% recurrence risk.
• Trisomy 21 with a Mosaic parent (M or F) depends upon the degree of mosaicism.
• Translocation with normal parents has a slightly increased recurrence risk.
• Translocation with carrier mother: 10-15% recurrence risk.
• 21/21: 100%
• Mosaic: slightly increased, depending upon degree of mosaicism