Trisomy 21


Written 2000-08 Jean-Loup Huret, Pierre-Marie Sinet
CNRS UMR 8602, Faculté de Médecine Necker Enfants Malades, Paris, France (PMS)

  1. I. Epidemiology
  2. II. Clinical examination
  3. III. Diagnosis: the karyotype
  4. IV. Evolution
  5. V. Prognosis
  6. VI. Treatments

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.

Figure 1
Figure 1

I. Epidemiology

(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).
Figure 2
Figure 2

II. Clinical examination

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).


  • 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


  • 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

III. Diagnosis: the karyotype

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).

IV. Evolution

  • 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).

V. Prognosis

  • 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)

VI. Treatments

  • 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!
Figure 3
Figure 3


Huret JL, Sinet PM

Atlas of Genetics and Cytogenetics in Oncology and Haematology 2000-08-01

Trisomy 21

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