The Genetics of Down's Syndrome

1.DOWN SYNDROME 

• Down syndrome is synonymous with trisomy 21 because it is the most common cause of Down syndrome. The person has three copies of chromosome 21 in all cells. Down syndrome is the most common genetic cause of mental retardation /intellectual dysfunction.  It is a fairly common condition seen in every 1 in 733 live births per Nelson's 21st edition. The actual incidence at conception is above twice.

MECHANISM OF DOWN SYNDROME 

• Trisomy due to non-disjunction of chromosome. The most important mechanism of Down syndrome, which is responsible in 95 % of the cases, is Trisomy due to the nondisjunction of chromosomes. It mainly involves maternal chromosomes associated with advanced maternal age. It usually tends to occur during meiosis 1.  Whenever gametogenesis happens initially, there is a germ cell from where the various gametes form.  These germ cells undergo meiosis which will be divided into meiosis 1 & meiosis 2. In meiosis 1, chromosomes are separated, and the total number of chromosomes is 46; there are 23 pairs. Whenever gametes formation happens, both ovum gets one copy of a chromosome. For instance, a female gets pregnant at the age of 45 years; at this age, it is found that chromosome 21 tends to stick together. So, one ovum reaches two chromosomes, and another gets no chromosome. Now the ovum with two copies of the chromosome will combine with the chromosome in the sperm. 

Translocations (4%)

• These translocations involve chromosome 21 with some other chromosomes. Mostly, they are of Robertsonian Translocations Variety. The most common translocation that leads to Down syndrome is translocation t(14;21). There is a genetic exchange happening between chromosomes 14 and 21.  Other translocations include t(15;21) and t(21:21). It should be an unbalanced Robertsonian Translocation. Acrocentric chromosomes are usually chromosomes 13,14,15, and 21. Robertsonian Translocations were also found to involve these chromosomes. 

ROBERTSONIAN TRANSLOCATIONS

• In  Robertsonian translocation,  both the q arms will be joined together, and both the P arms will be joined together. The small chromosome, which has p₁ and p₂ variety, is unstable and tends to disappear. The total number of chromosomes preserved will be less than normal, but functional trisomy will be produced. So, Robertsonian translocation involves acrocentric chromosomes, and the gene present in chromosome 21 produced by the functional exchange of another chromosome is called translocation-producing Down syndrome. So, translocation-producing Down syndrome may or may not have true trisomy when karyotyping is done.

Mosaicism (1%)

• Mosaicism is responsible for causing only one per cent of Down syndrome. There are two distinct cell lines: The first features typical cell lineage. All those tissues or organs which express normal cell lines will not manifest the features of Down syndrome. The second cell line has the feature of trisomy 21. Whereas all those tissues which manifest the features of trisomy 21 will also manifest the features of Down syndrome. For instance, there are two mosaics of Down syndrome patients of those patients expresses head, neck, and face expressing the trisomy 21 cell lines. And the other features are of normal cell lineage, so it is observed that the patient will have face-wise Down syndrome but will not have any cardiac issues related to Down syndrome. There can be another patient with Down syndrome features that are just internal to the body where no physical features of Down syndrome are visible. Mosaicism has the most variable presentation of the cell lines. 

GENES ON CHROMOSOME 21 IMPLICATED IN NEURONAL DYSFUNCTION

CLINICAL FEATURES OF DOWN SYNDROME 

• Children with Down syndrome have a flattened skull called brachycephaly, with a flat occiput. They will have delayed closure of fontanelles. Mongoloid slant of Eyes: It is also called upward slanting of eyes. These children have epicanthal folds. This means the loose skin extends from the upper eyelid, gets attached to the lower eyelid, and covers the medial canthus. Flat nasal bridge is also found in children with Down syndrome. Mid-face hypoplasia is also seen. Open mouth with protruding tongue. Small, dysplastic ears, often lower-set ears. Low-set ears and pinna anomalies relate to a shape or location of the outer ear (pinna or auricle) that is not typical.

2.Neck

• Short, non-webbed neck. Many patients have Atlanto axial instability: According to Nelson, it is found in 10-30%. Many times in children with Down syndrome atlas vertebra is not properly developed and its supporting ligaments are deficient, so there will high chances atlas and axial vertebrae to undergo sublaxation. Atlanto Axial instability will create a problem where there is a higher risk of cervical spine injury. For children with Down syndrome who are involved in active contact Sports or undergo trauma, a lateral view x-ray of the spine is necessary to look for possible potential subluxation or dislocation.

3. Musculoskeletal

• Joint hyper flexibility, short sternum, and pelvic dysplasia, SCFE. There are two ossification centres for the sternal manubrium. Simian crease on single-hand transverse palmar crease. Short metacarpals and clinodactyly, which means the little finger is shorter, and the upper part of the finger is slightly curved inwards. They have a sandal gap in their feet, which means an excess gap between the first and the second toe.

4. GIT

• Most common GIT anomaly in duodenal atresia. 2nd Most Common: is Hirschsprung’s Disease. Annular Pancreas,TEF, Imperforate Anus, Neonatal Cholestasis. Increased risk of Celiac Disease.

5. CVS

• Cardiovascular abnormality risk is significantly elevated. It is found that there is a 45 to 50% chance of having cardiovascular abnormality in Down syndrome.  Congenital heart disease is more common than acquired valvular disease.   Endocardial cushion Defect is the most common congenital heart disease, followed by VSD, then ASD of Ostium Secundum, followed by TOF, pulmonary hypertension, etc.

6. OBESITY, SHORT STATURE, OBSTRUCTIVE SLEEP APNEA

7. ALOPECIA AND PREMATURE AGEING AS AGE ADVANCES

8. ENDOCRINE

• Hypothyroidism: In 13 to 54% of Patients, Diabetes Mellitus, Infertility: Males are mostly sterile. In contrast, females have reduced fertility but are not sterile.

9.EYES

• Brushfield Spots in Iris, Strabismus, Nystagmus, Cataract in 15% of cases and Myopia in 50%.

10. EARS

•  Conductive Hearing Loss: 40 to 60%. Increased risk of serous OM. especially in the 1st year of life. Congenital hearing loss is also common.

11. NEUROPSYCHIATRIC PROBLEMS

• Hypotonia and poor Moro’s Reflex in infancy. Low IQ and development delay. Early-onset Alzheimer’s Disease. Depression and Autistic Spectrum disorders in 5 to 10 % of the cases.

12. CUTANEOUS 

• Cutis Marmorata in early life. Later-Hyperkeratosis, Xerosis, Seborrheic dermatitis, and Peri genital folliculitis.

13. Hematological

• Transient myeloproliferative disorder. It is considered to be a precursor of leukaemia.  Many down syndrome child will have rise in leukocytes and  some blast  cells will be present on PBF , which disappear without any treatment. Increased risk of leukaemia: Most common is acute lymphoblastic leukaemia. Most specific leukaemia of Down syndrome is AML-M7. Neonatal Polycythemia in 18%.

14. INCREASED RISK OF IMMUNE DYSFUNCTION IN LATER LIFE

Also Read : Pigmentary Disorders in Children

LIFE EXPECTANCY IN DOWN SYNDROME

• Life expectancy in Down syndrome is reduced. The current Nelson edition says the life expectancy is around 50 to 55 years.  Cause of death in children with Down syndrome is a recurrent infection, cardiovascular issues, and malignancies.

What are the Hall's criteria for Down syndrome?

• Hall’s 10 cardinal features/ signs for Down syndrome are as follows: - Poor moro reflex, Hypotonia, flat facial profile, upward slanting palpebral fissure, small, dysplastic, rounded ears, redundant skin around a short neck, single transverse palmar crease, large Hyperextensible joints, short 5th digit with clinodactyly, Pelvic dysplasia.

Conditions Less Prevalent in Down Syndrome than General Population 

• Also called negative/protective association. Solid tumours: Neuroblastoma, Wilms tumour in children is less common in Down syndrome than in the general population. In the case of adults, the epithelial tumour is less common in Down syndrome adults than in the general population. Ischemic heart disease: The chances of ischemic heart disease during adolescence are lesser than the general population.

SCREENING IN DOWN SYNDROME

• For congenital heart disease, every Down syndrome child has to be evaluated at birth. Ophthalmic evaluation needed in all Down syndrome children at birth or within 6 months. Then, annual vision assessment.

Screening for hearing loss- At birth or within 3 months by Otoacoustic Emissions test and the Auditory Brainstem Response test. Then every 6 months up to 3 years if TM is not visualised. After 3 years, a life-long annual hearing loss examination will be needed.  Growth assessment-  twice a year, 1st year,  then annually, tell the age of 5.   Screening for hypothyroidism-  First at birth and then at 6 to 12 months, annual screening for hypothyroidism should be done.  Monitor for obstructive sleep Apne at each visit, starting from the first year of age.  Screening for celiac disease:  at 2 years in symptomatic cases, whereas symptoms develop irrespective of age.  Hematological assessment: Screening should be done at birth and then during adolescence. For leukemia:  Two assessments in the first year of age and then on an SOS basis.    Atlantoaxial subluxation or instability: At each visit, a history and physical examination should be made, as radiography is unnecessary for every visit and every patient.  Lateral view x-ray or neck at 3 to 5 years or when planning for a contact Sports. X-ray should be done respective of the age when one neurological symptom is present, even if transient, for example, neck pain, weakness, torticollis, gait disturbances etc. Recurring infections: Check IgG subclass and IgA levels, if present. Gynaecological care includes menstruation care in adolescent girls. Evaluate for psychiatric and behavior disorders at each visit. Check for constipation at birth. Annual Dental examination after tooth eruption.

PRENATAL DIAGNOSIS OF DOWN SYNDROME

• Modalities commonly used: USG ultrasound sonography test: Sonographic Marker. The most important is Nuchal Translucency. Markers: These markers include maternal serum Alpha fetal protein found to be low in patients with Down syndrome. Another marker is unconjugated estriol (UE3) in Down syndrome is low. In contrast, beta HCG, inhibin-A in Down syndrome, is high, and Pregnancy-associated Plasma protein A (PAPP-A) is low in Down syndrome. Karyotyping: It is found to be the gold standard in detecting Down syndrome.