The most frequent viable chromosome disease.
Like other inborn autosomal chromosome diseases, associates dysmorphia + psycho-motor delay, and possible visceral malformations (found in more than 1/3 of cases); a medico-pedagogic care and follow up must be undertaken.

(a question on epidemiology would also include recurrence risks according to the karyotypic findings: see paragraph on the karyotype).

• 1,5 /1 000 births
• Sex ratio: 3 males/2 females
• Increased median maternal age (34 years).
  Maximal trisomy 21 births from mothers aged:
  • 28 yrs (but this is only because the maximal birth rate is for this maternal age).
  • Around 37 yrs.
  • The risk increases with maternal age: <0.1% below 30 yrs; between 0.1% and 1% at ages 30-40 (0.2% at 34 yrs, 0.5% at 38 yrs, 0.7% at 39 yrs);>1% above 40 yrs (5% at 46 yrs, 15% at 50 yrs).

Dysmorphic syndrome associating (to various extend):

• evocative face+++:
  • frequent microcephaly, short neck, flat occiput and brachycephaly
  • moon-shaped face
  
  
  • flat nasal bridge
  • "socket" nostrils
  
  
  • hypertelorism (or pseudo-hypertelorism)
  • epicanthus (regresse with age)
  • upward slanting palpebral fissures
  • Brushfield spots in the iris (pathognomonic, detectable in blue eyes)
  
  
  • macroglossia; glossitis exfoliativa (geographic tongue); scrotal tongue at late childhood and in adulthood
  • mouth frequently open; frequently open mouth
  • narrow/ high arched palate; high arched narrow palate
  • late appearing/malformed teeth (numerical anomalies, agenesis of lateral incisors...)


• hands and feet:
  • short and broad
  • brachymesophalangia of the 2nd and 5th fingers
  • clinodactyly of the 5th finger
  • flat feet
  • first toe set apart from the others by a gap, with a crease.


• dry skin, mottled skin (livedo), with frequent infections around orifices.


• hyperlaxity of ligaments.
• frequent umbilical hernia.

Psycho-motor delay (constant):

• hypotonia +++ at birth (hold his head at 6 mths, sits at age 1 yr, walks at age 2 yrs).
• the mental retardation, not obvious in the infant, will soon become manifest.
• childrens behaviour:
  • affectionate, gentle, cheerful
  • language difficulties
  • like to play, to mime, to tidy up meticulously
  • normal memory
• seizures (in 3% to 9%, as compared to 1% in the general population).

Dermatoglyphics:

• transverse palmar crease in 75% of cases. Beware: it is also present in 1% of the general population; therefore, out of 8 transverse palmar creases at birth, 7 come from the general population and only 1 from a Down syndrome baby (1% risk X 699/700 births versus 75% risk X 1/700 births): one MUST NOT make a diagnosis of trisomy 21 on this isolated sign and throw parents into a panic.
• axial triradius in t" (in 75%)
• transversality index > 30.

This association of signs implicates that visceral malformations have to be searched for, as they can burden the vital prognosis and impose that emergency treatments be started.

Malformations (45% of cases):

• Heart (40%):
  • atrioventricular septal defect (10 %)
  • ventricular septal defect (10 %)
  • patent foramen ovale (5 %)
  • persistence of ductus arteriosus (5 %)...
• Digestive (10 %):
  • duodenal stenosis (1/3 of duodenal stenosis are found in trisomy 21patients)
  • imperforate anus...
• Ocular:
  • cataract (congenital or acquired)
  • astigmatism
  • myopia
  • strabismus
  • congenital glaucoma
  • nystagmus

Other:

• Hematologic:
  • transient leukemoid reaction may occur
  • sometimes with a relapse as acute leukemia (lymphoblastic (ALL) or more frequently non-lymphoblastic (ANLL) leukemias; M7-ANLL (megakaryocytic) is particularly frequent. Watch the hypersensitivity to methotrexate.


• Solid tumors: the risk may be lower (PMID 17009117, 23307327) than in the general population concerning:
  • neuroblastoma
  • medulloblastoma
  • and some digestive tract tumors


• Immunological:
  • tuberculine hyporeactivity
  • immune deficiency


• Metabolic:
  • hyperuricemia
  • abnormal glycemia
  • increased TSH (frequent); hypo or hyper thyroidy

Proves the diagnosis, allows/implicates a genetic counseling:
recurrence risk is about 1 % if the anomaly is de novo, more if one of the parents is a translocation carrier.

• Free and homogeneous trisomy 21 (92,5 % of cases):
  • sporadic (de novo) cases
  • role of maternal age (see above in epidemiology)
  • recurrence risk: 1 to 2 %
  • karyotype: 47,XY,+21 ou 47,XX,+21
  • due to meiotic non-disjunction:
    • of maternal origin:
      • 1st division: 70 %
      • 2nd division: 20 %
    • of paternal origin:
      • 1st division: 5 %
      • 2nd division: 5 %
• Free trisomy 21 in mosaic (2,5 % of cases):
  • sporadic cases
  • karyotype: 46, XY / 47, XY,+21 or 46, XX / 47, XX,+21
  • post zygotic event (mitotic)
  • most often, the phenotype is typical, at times attenuated.
• Trisomy 21 due to translocation:
  • de novo or transmitted from a parental translocation (being a balanced translocation in the parent); genetic coonseling is especially needed in the latter case.
  • karyotype with 46 chromosomes; the extra chromosome 21 is most often translocated with another acrocentric (groupe D: 14, 13 or 15 or groupe G: 21 or 22) chromosome; example: 46, XY, t(14;21).
  • genetic counseling and recurrence risk:
    • t(Dq;21q) et t(21q;22q)
      • of maternal origin: risk = 15 %
      • of paternal origin: risk = 5%
    • t(21q;21q): risk = 100 %:
      • either --> trisomy 21
      • or --> spontaneous miscarriage (monosomy 21).
    • Other:
      • partial trisomy 21 (rare). The segment responsible for most of the syndrome/phenotype is band 21q22.3.
        It was discovered that a microduplication (less than 3 Mb) of DNA on chromosome 21 could be responsible for most of the trisomy 21 phenotype (PMID 2951317), demonstrating that only a very few genes alteration can lead to most of the phenotype in a chromosome aberration syndrome. From this further arose the concept of "critical region" in chromosome syndromes (e.g Down syndrome critical region). As a matter of fact, this concept is close to the concept of "contiguous gene syndrome".
        
      • associated with other chromosome anomalies (rare).

• statural delay (adult = 1,50 m); weight excess (--> diet).
• voice becomes hoarse.
• pelade may appear.
• puberty is delayed but normal; poor libido.
• fecondity in the female ( --> contraception).
• hypothyroidy, Basedow (--> T3, T4, TSH, reverse T3 regular determination).


• mental development:
  • intelligence quotient (IQ) = 50 (mean (and median)); between 30 and 80; Gaussian curve, as in the general population but with a mean shift to 50 instead of 100; vary according to age)
  • social insertion: partly according to the familial environment, the guidance and reassurance that the family receives, and according to the medical, paramedical, and pedagogic cares instaured
  • psychomotor therapy from the age of 6 mths, kinesitherapy, orthophony latter; nursery school, followed if possible by a class of handicapped children within a normal primary school; latter, school and professional school in specialized institutions; apprenticeship, manual professionnal activity; insertion into active life; they must not stay at parents home, where they would remain with a child status, and finally where they would grow old faster as parents get old.
  
  
• early aging:
  • behaviour may suddenly switch from that of a happy and sociable child to a sad, inactive and inexpressive adult
  • risk of senile dementia (Alzheimer disease).

• life expectancy, formerly poor, has greatly increased, due to antibiotherapy and surgery.
• prognosis can be impaired by:
  • the extreme susceptibility to infections
  • malformations, cardiac malformations in particular
  • acute leukemia (in 1 % of trisomy 21 infants/children, i.e. 20 times more frequently than in the general population)
• intellectual prognosis: (see evolution)

• surgery in the case of malformation(s).
• antibiotherapy of infections; antifungal treatment of athletic foot.
• medical-paramedical-pedagogic cares; psychomotor therapy, kinesitherapy, orthophony
• thyroid function repeated examinations (once a year).
• ophtalmologic tests (watch the hypersensitivity to atropine), auditive tests.
• cervical X-rays (cervical instability--> risk of cervical vertebrae dislocation).
• flat foot (special shoes, tricycle are recommended).
• flat dorsum (swimming recommended).
• keloid scars (surgery only when needed, avoid plastic surgery).
• artistic creativity should be developed and supported.see below!