Down syndrome

Place in the structure of congenital anomalies

Congenital malformations develop as a consequence of gametopathies, blastopathies, embryopathies, or fetopathies. Down syndrome refers to genetically determined malformations, which account for about 25–30% of all developmental anomalies. In the general structure of live newborns with malformations, chromosomal diseases make up 10–15%.

Almost all unbalanced chromosomal mutations cause multiple malformations. At the same time, the most severe forms of pathologies (polyploidies and complete trisomies of large autosomes) are lethal—they lead to spontaneous abortion as early as the first trimester. Trisomy 21 is one of the few viable variants of autosomal aneuploidies.

Cytogenetic variants

The disease is based on chromosomal or genomic mutations affecting the 21st chromosome. There are three variants of the anomaly:

• Simple complete trisomy 21. The most frequent variant (94–95% of cases). It occurs due to chromosome nondisjunction in meiosis. This is a complete form—the mutation occurs in the gametes, therefore the abnormal set of chromosomes is present in absolutely all cells of the body.
• Translocation form. Found in 4% of patients.
• Mosaic form (karyotype 47+21/46). Observed in approximately 2% of patients. The mutation affects somatic cells in the early stages of embryogenesis. As a result, the child's body consists of two cell clones: with a normal and with a mutant karyotype.

Specific phenotype

Patients have a readily recognizable appearance due to a characteristic complex of craniofacial dysmorphisms. They typically have a round, flattened face, a flat nasal bridge, and a sloped, low forehead (brachycephaly).

The eyes have an upward slanting palpebral fissure, and a skin fold—epicanthus—is often present at the inner corner. Specific light inclusions—Brushfield spots—are detected on the iris. The auricles are usually small, deformed, and located abnormally low. An excess of skin is noted on the neck, and a large tongue often protrudes from the mouth.

Regarding the musculoskeletal system, muscular hypotonia is prominently expressed. Curvature of the fifth fingers (clinodactyly) and a specific single transverse palmar crease are found on the hands.

Internal organ malformations

In addition to external stigmata, Down syndrome is always accompanied by multiple congenital malformations (MCM), which affect major systems:

1. Cardiovascular system: ventricular septal defects (VSD) and atrial septal defects (ASD) are typical, as well as atrioventricular septal defect (combination of VSD with deformation of the anterior leaflet of the mitral valve).
2. Gastrointestinal tract: atresia or stenosis of the esophagus, duodenum, rectum, and anus are characteristic.
3. Urinary system: renal hypoplasia or dysplasia, dilation of the ureters (hydroureter) and renal pelves (hydronephrosis) are diagnosed.
4. Central nervous system: structural disorganization of the cerebral cortex and cerebellum, hypoplasia of the frontal lobes, temporal gyri, pons, and cerebral peduncles.

Prognosis and complications

A significant portion of patients with Down syndrome die in the first years of life. Early mortality is directly related to the severity of malformations (primarily cardiovascular ones).

In surviving children, physical developmental delay and intellectual disability are observed. The pathology is accompanied by the development of secondary immunodeficiency with a decrease in both cellular and humoral immunity, which makes patients extremely vulnerable to infections. In addition, such patients have a reliably increased frequency of leukemia development.

Class and exam questions

What else to study on this topic

• Ontophylogenetic mechanisms of heart defect formation (heterochrony)
• General classification of congenital malformations (gametopathies, embryopathies, fetopathies)
• Patau syndrome (trisomy 13) and Edwards syndrome (trisomy 18)
• Monogenic syndromes with multiple congenital malformations (Smith-Lemli-Opitz, Lenz syndromes, etc.)
• Viable variants of monosomies (Turner syndrome)

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