Knowledge on rare diseases and orphan drugs

Prevalence at birth of Down syndrome (DS) in a country depends largely on non-medical factors, i.e. public policies regarding prenatal diagnosis and care for disabled people, and view of the population for DS and for abortion. In brief, it varies from 1/400 to 1/3000 live births. The risk of having a baby with Down syndrome (DS) increases with maternal age, identically in every population.

Clinical features include variable (often mild) intellectual disability, almost constant muscular hypotonia and joint laxity, associated with morphological signs, malformations (half of cases) and increased risks of some medical complications all-life-long. Morphological features (upslanting palpebral fissures, epicanthus, flat neck, round face, small nose, bilateral single palmar crease) can be mild and are not pathognomonic of the condition. The main potential malformations and complications include: short stature, congenital cataract, conductive hearing loss, heart defects (atrio-ventricular canal), digestive malformations (duodenal atresia), Hirschsprung disease, seizures, sleep apnea, sensory deficiencies, leukemia, auto-immune and endocrine pathologies (hypothyroidism, celiac disease, diabetes mellitus type 1, alopecia areata, earlier aging and early-onset Alzheimer disease.

In 95% of the cases, trisomy 21 is an additional independent chromosome 21 (47,+21): the extra chromosome is due to an accidental non-disjunction during meiosis. 2-3% of those cases are in a mosaic state. In the remaining 5%, the supernumerary chromosome 21 or portion of chromosome 21 is translocated to another chromosome (Robertsonian translocation in most cases).

The diagnosis is based on karyotyping.

Differential diagnosis includes Zellweger syndrome, 9qter deletion or other chromosomal abnormalities. We can also mention the exceptional Aymé-Gripp syndrome.

In 70-75% of fetuses, increased nuchal translucency can be seen on first-trimester ultrasonography. On the second-trimester, malformations (essentially cardiac and digestive) are present in 60% of the cases, and can be associated with minor morphological signs. Prenatal diagnosis can be confirmed by fetal karyotype on amniocentesis or chorionic villous sampling. Non-invasive prenatal screening on maternal blood is now available in several countries in case of an increased risk of DS on prenatal screening.

For the parents of a child affected by regular trisomy 21, the recurrence risk is only slightly modified (1% until the age of 40 years, linked to maternal age afterwards). In case of DS caused by translocation, the risk is raised only if one of the parents has a balanced rearrangement. For a person with Down syndrome, the risk of transmitting the disease to the descendants is 1/3 (maybe less for males with DS).

Early physiotherapy, psychomotor therapy and speech therapy (including alternative non-verbal communication tools, namely sign language and picture exchange, in order to stimulate early communication and induce oral skills) are essential. A person with DS should be involved as soon as possible in decision-making through self-determination. A well-adapted program, including re-education, schooling and social aspects, should be proposed, aiming at obtaining the best possible integration in society (i.e. more than half of people with DS has capabilities to read and write, even partially). Neuropsychological evaluations are important to recognize the specific difficulties and abilities of each person with DS and thus propose cognitive remediation. An adapted medical follow-up is very important in order to detect and treat as soon as possible medical complications. Guidelines have been published. It can be necessary to maintain some support in the adult age, including re-education. Research in medical treatment to improve cognition in people with Down syndrome is active with ongoing clinical trials.

Median life expectancy is now above the age of 60 years in developed countries.

Last update: September 2019 - Expert reviewer(s): Dr Renaud TOURAINE