Down syndrome

2017-07-01   Karen M. Chisholm 

Department of Laboratories, Seattle Childrens Hospital, Seattle, WA, USA;



Down syndrome


Trisomy 21


  • Down syndrome (DS) has an incidence of approximately 1 in 700 live births, and is the most common aneuploidy of the autosomal chromosomes. , 
  • Down syndrome is caused by an extra copy of chromosome 21. Most cases (95%) are the result of nondisjunction, leading to three free copies of the chromosome; this nondisjunction usually occurs in maternal meiosis I, though maternal meiosis II and paternal meiosis II errors also do occur. There is an increased risk of this nondisjunction with increased maternal age. , 
  • Another 4% of cases are the result of an extra copy of chromosome 21 transmitted by translocation with an acrocentric chromosome (usually chromosome 14 or 21). These translocations may be present in the parent who has a balanced translocation such as t(14;21) or t(21;21), and represent a genetic risk of inheritance. However, most of the translocations occur de novo. , 
  • The remaining cases are usually due to mosaicism for trisomy 21 with a normal karyotype. These patients tend to have less severe phenotypes
  • Omim



    Phenotype and clinics

    Many organ system abnormalities are associated with Down syndrome (DS):
  • Craniofacial dysmorphism: Most children are brachycephalic with a relatively flat occiput. They may have microcephaly with upslanting palpebral fissures, small noses, flat nasal bridge, inner epicanthal folds, hypertelorism, and small ears.
  • Central nervous system: Intellectual disabilities are present in most patients. Alzheimer disease develops in more than half of DS patients by the age of 60 years.
  • Cardiovascular: Endocardial cushion defects lead to atrioventricular defects (most common), with less common ventricular septal defects, atrial septal defects, and tetralogy of Fallot.
  • Respiratory: Some respiratory disorders include upper respiratory tract anomalies, obstructive sleep apnea, recurrent aspiration, and recurrent respiratory tract infections.
  • Hematologic: Individuals with DS often have an immunodeficiency, leading to increased risk of infection. Newborns have an increased risk of transient abnormal myelopoiesis, and children and young adults especially those between 1 and 5 years of age have a marked increased risk of leukemia (see below under Neoplastic Risk).
  • Gastrointestinal: Duodenal atresia\/stenosis, Hirschsprung disease, esophageal atresia, pyloric stenosis, and imperforate anus are identified in some DS patients.
  • Endocrine: Hypothyroidism often occurs in neonates. In older patients, hyper- or hypo-thyroidism may be present with or without diabetes mellitus.
  • Musculoskeletal: Hypotonia is present in many. Ligament laxity, including occipitocervical instability and atlantoaxial instability are also common. Joints may be hyperflexible. Hands can be notable for short metacarpals and phalanges and\/or a single palmar transverse (Simian) crease. Fifth finger hypoplasia may also be present. Feet may demonstrate a wide gap between the first and second toes. Talipes equinovarus may also occur.
  • Eye\/vision: Severe refractive errors are present in approximately half of the patients.
  • Hearing: Conductive, mixed, or neurosensory hearing loss is common.
  • Oral: DS patients may have macroglossia, with microdontia
  • Neoplastic risk

  • Those with Down syndrome have a decreased risk of most solid tumors. Exceptions include testicular cancer, including germ cell tumors. The risk of extragonadal and ovarian germ cell tumors is also reportedly increased in DS (Nizetic and Groet, 2012; Englund et al., 2013).
  • Transient abnormal myelopoiesis (TAM) is thought to occur in up to 30% of neonates with Down syndrome. Symptomatic in up to 10%, this disorder is characterized by increased blasts (usually megakaryoblasts) which can lead to hepatomegaly, splenomegaly, and respiratory distress. In these patients, somatic GATA1 gene mutations are present in the clonal population. TAM presents within the first 7 days of life and usually spontaneous resolves within 2-3 months. Some infants who are symptomatic may require chemotherapy.
  • The risk of acute myeloid leukemia in children with DS is 150 times greater than in the general population; the incidence of acute megakaryoblastic leukemia is 500 times more likely in the DS population (Creutzig et al., 1996; Hasle et al., 2000). This myeloid leukemia of Down syndrome (ML-DS) occurs between 1 and 4 years of age, with 16-30% of children also having a history of clinical TAM. Somatic mutations in GATA1 are also identified in ML- DS.
  • The risk of acute lymphoblastic leukemia (ALL) in DS is also elevated, estimated at 40 times greater in children aged 1-5 years with DS compared to those without DS of the same age (Hasle et al., 2000). Unlike those without DS, ALL in DS usually does not have the classic favourable or unfavourable cytogenetic abnormalities. These ALL of DS cases do often have CRFL2 gene rearrangements either with P2RY8, also in the pseudoautosomal region of Xp22.33\/Yp11 ( del(X)(p22.33p22.33) or del(Y)(p11.32p11.32)), or with IGH (immunoglobulin heavy chain locus), on 14q32 ( t(X;14)(p22;q32) or t(Y;14)(p11;q32)) (Mullighan et al., 2009; Hertzberg et al., 2010). JAK2 activating mutations are present in approximately 20% of ALL of DS cases, usually with mutations at R683 in the pseudokinase domain (Bercovich et al., 2008; Kearney et al., 2009; Gaikwad et al., 2009). IKZF1 deletions are also often identified in ALL of DS (Hertzberg et al., 2010; Buitenkamp et al., 2012).
  • Treatment

  • Most cases of TAM (66-84%) will spontaneously resolve without the need for interventions (Klusmann et al., 2008; Gamis et al., 2011). Cytarabine (cytosine arabinose) may be employed in infants with life-threatening symptoms (Massey et al., 2006)
  • ML-DS requires chemotherapy, though at a reduced intensity compared to those without Down syndrome.
  • Those with ALL of DS are treated similarly to those with ALL without DS. These patients have an increased susceptibility and toxicity to methotrexate.
  • Evolution

  • The majority of DS patients with TAM will have spontaneous resolution without treatment within 2-3 months; however, 16-30% of infants may go on to develop ML-DS (Klusmann et al., 2008).
  • For Down syndrome patients in general, Alzheimers disease develops in more than half by 60 years of age.
  • Prognosis

  • The mortality rate for TAM is approximately 15-20%, though approximately half of these deaths are related to other congenital abnormalities of Down syndrome (Klusmann et al., 2008; Gamis et al., 2011).
  • ML-DS has a better prognosis than myeloid leukemia without Down syndrome. However, these individuals are still at a high risk for infection-related deaths. (Lange et al., 1998; Gamis et al., 2003; Rao et al., 2006)
  • Compared to those with ML-DS, ALL of DS has an equivalent to poorer prognosis compared to those with ALL without DS. Some studies have shown increased induction failures, higher relapse rates, and increased therapy-related mortality in those with ALL of DS.
  • For Down syndrome in general, the median age of mortality has increased throughout the years, most recently reported at almost 60 years (Englund et al., 2013). The most common causes of death are infectious diseases (mostly pneumonia), congenital malformations (such as heart defects), circulatory disease, and dementia (Englund et al., 2013).
  • To be noted


    Please also refer to the Myeloid proliferations in Down syndrome and Acute lymphoblastic leukemia in Down syndrome sections under Leukemias.
    See also the chapter on trisomy 21 in the educational files of the Atlas.


    Pubmed IDLast YearTitleAuthors
    164698742006A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481.Massey GV et al
    280291612017Down syndrome and the complexity of genome dosage imbalance.Antonarakis SE et al
    265993192016Down syndrome-A narrative review with a focus on anatomical features.Arumugam A et al
    188055792008Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome.Bercovich D et al
    224412102012Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.Buitenkamp TD et al
    88926661996Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM Study Group.Creutzig U et al
    234364302013Changes in mortality and causes of death in the Swedish Down syndrome population.Englund A et al
    191203502009Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia.Gaikwad A et al
    218494812011Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971.Gamis AS et al
    128858362003Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891.Gamis AS et al
    106751142000Risks of leukaemia and solid tumours in individuals with Down's syndrome.Hasle H et al
    199656412010Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.Hertzberg L et al
    189274382009Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.Kearney L et al
    181825742008Treatment and prognostic impact of transient leukemia in neonates with Down syndrome.Klusmann JH et al
    94277161998Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891.Lange BJ et al
    198381942009Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia.Mullighan CG et al
    229966022012Tumorigenesis in Down's syndrome: big lessons from a small chromosome.Nižetić D et al
    164458302006Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials.Rao A et al