Your activity: 331 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email:

Down syndrome: Clinical features and diagnosis

Down syndrome: Clinical features and diagnosis
Kathryn K Ostermaier, MD, FAAP
Section Editors:
Jan E Drutz, MD
Helen V Firth, DM, FRCP, FMedSci
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Jun 06, 2022.

INTRODUCTION — Down syndrome (DS) is the most common chromosome abnormality among liveborn infants. It is the most frequent form of intellectual disability caused by a microscopically demonstrable chromosomal aberration. DS is characterized by a variety of dysmorphic features, congenital malformations, and other health problems and medical conditions. Not all of them are present in each affected person. The impact of DS for each person is individual, with some persons being profoundly impacted while others are healthy and able to live independently as adults. In general, persons with DS are now reaching fuller potentials secondary to better educational programs, medical advancements, community resources, and the support of family and friends.

The clinical features and diagnosis of DS will be presented here. The epidemiology, genetics, and management are discussed separately. (See "Down syndrome: Overview of prenatal screening" and "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)' and "Down syndrome: Management".)

DYSMORPHIC FEATURES — Upslanting palpebral fissures, epicanthic folds, and brachycephaly are nearly universal features of DS. The other characteristic dysmorphic features of DS are each present in 47 to 82 percent of cases [1,2]. These features predominantly affect the head and neck and the extremities.

Head and neck — Characteristic dysmorphic features of DS affecting the head and neck include:

Upslanting palpebral fissures

Epicanthic folds (picture 1)

Flat facial profile/flat nasal bridge

Folded or dysplastic ears

Low-set small ears


Brushfield spots

Open mouth

Protruding tongue (picture 1)

Furrowed tongue

Short neck

Excessive skin at nape of the neck

Narrow palate

Abnormal teeth

Extremities — Characteristic dysmorphic features of DS affecting the extremities include:

Short broad hands

Incurved fifth finger with hypoplastic middle phalanx

Transverse palmar crease (picture 2)

Space between the first and second toes (sandal gap)

Hyperflexibility of joints

Neonatal features — Ten of the characteristic dysmorphic features are common in newborns with DS and are usually recognized soon after birth. In a series of 48 affected newborns, all had four or more features, and 89 percent had six or more [1,3]:

Flat facial profile

Slanted palpebral fissures

Anomalous ears

Hypotonia (picture 3)

Poor Moro reflex

Dysplasia of middle phalanx of fifth finger

Transverse palmar (Simian) crease (picture 2)

Excessive skin at nape of the neck

Hyperflexibility of joints

Dysplasia of pelvis


Intellectual disability — Almost all individuals with DS have cognitive impairment, although the range is wide. Most are mildly to moderately intellectually disabled, with an intelligence quotient (IQ) in the 50 to 70 or 35 to 50 range, respectively, although some are severely impaired with an IQ of 20 to 35 [4]. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)

Developmental impairment becomes apparent in the first year of life. In general, the average age of sitting (11 months), creeping (17 months), and walking (26 months) is approximately twice the typical age [5]. The sequence of language development is the same, although the rate is slower, with the average age for the first word at 18 months [6]. The child with DS continues to learn new skills. However, IQ declines through the first 10 years of age, reaching a plateau in adolescence that continues into adulthood [2,7,8]. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Approach to surveillance'.)

The profile of cognitive impairment in DS appears to differ from other forms of intellectual disability. The cognitive deficits are primarily in morphosyntax, verbal short-term memory, and explicit long-term memory [9]. The most common profile, in which language comprehension is equal to mental age and language production is more delayed, occurs in two-thirds of affected children [10]. In one-third, language comprehension, mental age, and language production are equal. Impairment in expressive language was noted in another study of children with DS, who had fewer different and total words and decreased mean length of utterance compared with controls matched for nonverbal mental age [11]. Vocabulary skills accelerated more rapidly than syntax (average sentence length and structure) and surpassed mental age in adolescence. Similar findings of increasing differences in comprehension with age were noted in another report, in which children with DS developed relatively stronger skills in vocabulary compared with syntax [12]. Other selective deficits have been described, such as greater difficulty understanding sequences or grammatical rules [2,13].

Behavioral and psychiatric disorders — Behavioral and psychiatric disorders are more common in DS than typical children but less common than in those with other causes of intellectual disability [8]. In one report, psychiatric disorders affected 17.6 percent of individuals with DS less than 20 years of age [14]. Disruptive behavioral disorders, such as attention-deficit hyperactivity disorder, conduct/oppositional disorder, or aggressive behavior, were most common. In the same study, psychiatric disorders, most often consisting of major depressive illness or aggressive behavior, affected 25.6 percent of DS adults. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features' and "Attention deficit hyperactivity disorder in adults: Epidemiology, pathogenesis, clinical features, course, assessment, and diagnosis" and "Unipolar depression in adults: Assessment and diagnosis" and "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)

Autism is a common comorbidity of DS, affecting as many as 7 percent of children with DS [15]. The diagnosis is often delayed compared with children without DS [16]. Some children with DS present in the school-aged years with new-onset or worsening autistic-like features, cognitive decline to the point of dementia, and new-onset insomnia [17]. The term "Down syndrome disintegrative disorder" has been suggested to describe this cluster of clinical findings, although it is not clear if this is one disorder or several different ones with similar presentations. The etiology is not known, but autoimmunity is suspected. There are no established diagnosis or treatment recommendations for this clinical association. Some patients respond to psychiatric care. Further research is needed in this area. (See "Autism spectrum disorder: Clinical features".)

Dementia/Alzheimer disease — Adults with DS usually develop neuropathologic and functional changes typical of Alzheimer disease by the sixth decade of life [8,18,19]. In one report, dementia was present in 49 of 96 (51 percent) DS individuals over the age of 35 years [18]. The average age of onset was 54 years, and seizures developed in 84 percent of patients. In another report, over 75 percent of patients over 65 years of age were affected [9]. (See "Evaluation of cognitive impairment and dementia".)

CARDIOVASCULAR DISEASE — Approximately one-half of individuals with DS have congenital heart disease [20-22]. In the largest population-based study, cardiovascular abnormalities were identified in 342 of 821 (42 percent) infants born with DS from 1985 to 2006 in the northeast region of England [22]. Twenty-three percent had more than one anomaly. The secondary lesion was most commonly an atrial septal defect (ASD) or patent ductus arteriosus (PDA). The following primary lesions were identified:

Complete atrioventricular septal defect (CAVSD) – 37 percent

Ventricular septal defect (VSD) – 31 percent

ASD – 15 percent

Partial atrioventricular septal defect (PAVSD) – 6 percent

Tetralogy of Fallot (TOF) – 5 percent

PDA – 4 percent

Miscellaneous – 2 percent

The clinical features of these defects are discussed separately. (See "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis" and "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults" and "Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot".)

Some asymptomatic adolescents and adults without structural heart disease develop valve abnormalities [23,24]. In a series of 35 patients with DS, mitral valve prolapse occurred in 46 percent and aortic regurgitation in 6 percent at an average age of 20 years [23]. In another report of 30 adults, mitral valve regurgitation occurred in 17 percent [24].

Pulmonary hypertension is also common, occurring in 28 percent of patients with DS in one retrospective review [25]. The median age at diagnosis was five days in this review, with the majority (70 percent) having transient disease that lasted a median of eight months. Recurrent disease occurred in 15 percent and was associated with congenital heart disease, obstructive sleep apnea, recurrent pneumonia, and intermittent hypoxia. The remaining 15 percent had persistent disease. (See 'Pulmonary disorders' below.)

GASTROINTESTINAL ABNORMALITIES — Children with trisomy 21 are at increased risk for gastrointestinal tract anomalies, which occur in approximately 5 percent of cases [26]. Duodenal atresia or stenosis, sometimes associated with annular pancreas, is the most characteristic lesion, occurring in 2.5 percent [2]. Imperforate anus and esophageal atresia with tracheoesophageal fistula are seen less often. Conversely, DS affects 28 percent of patients with duodenal atresia or stenosis and 20 percent with annular pancreas. (See "Intestinal atresia" and "Annular pancreas" and "Prenatal diagnosis of esophageal, gastrointestinal, and anorectal atresia" and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula", section on 'Tracheoesophageal fistula and esophageal atresia'.)

Hirschsprung disease is more common in DS than in the general population, although the risk is less than 1 percent [4]. Among children with Hirschsprung disease, approximately 2 percent have trisomy 21 (with a range of 2 to 15 percent) [27-31]. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

A strong association appears to exist between DS and celiac disease. The prevalence of biopsy-proven celiac disease has been reported to be between 5 and 16 percent, representing a 5- to 16-fold increase compared with the general population [32-36]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'High-risk groups'.)

GROWTH — Birth weight, length, and head circumference are less in DS compared with typical infants. Newborns with DS weigh approximately 0.18 to 0.37 kg less than their siblings [37]. Mean length at birth is approximately 0.5 standard deviations less than control newborns [38]. In a study of 105 children with DS, growth parameters remained lower until puberty, with the growth spurt being earlier (age 11 in males and 9.5 in females), and were blunted compared with controls [39]. Weight gain during the first three years of life has improved since the 1980s, as has stature in males [40-42].

Short stature — Growth rate is reduced in DS compared with typical children, especially in infancy and adolescence. Growth is most reduced in children with severe congenital heart disease [38,40]. In adults with DS, the average height in males and females was 61.7 and 57 inches (157 and 144 cm), respectively, and the average weight was 157 and 140 lb (71 and 64 kg) in males and females in a 1998 study [43]. Measurement of growth in patients with DS is discussed separately. (See "Down syndrome: Management", section on 'Growth'.)

The cause of DS-associated growth retardation remains unknown. Low circulating levels of insulin-like growth factor 1 (IGF-1) and diminished provoked and spontaneous secretion of growth hormone (GH) have been reported in some patients [44,45]. Serum GH levels are not low in children with DS [46,47], but suboptimal endogenous GH production as a result of hypothalamic dysfunction has been demonstrated [48]. Selective deficiency of IGF-1, but not IGF-2, has been seen in DS patients who are older than two years [49,50]. IGF-1 receptors are present in brain cells from fetuses with trisomy 21 [50].

Obesity — The prevalence of obesity (defined as a body mass index [BMI] >27.8 kg/m2 in adult males and >27.3 kg/m2 in adult females) is greater in DS than in the general population (45 versus 33 percent, 56 versus 36 percent, for males and females, respectively) [43]. This is thought to result from the reduced resting metabolic rate in children and adults with DS [51,52]. In general, weight is less than expected for length in infants with DS and then increases disproportionally so that the majority of children are obese by age three to four years [8]. (See "Down syndrome: Management", section on 'Obesity prevention'.)

EYE PROBLEMS — Ophthalmologic disorders that require monitoring and intervention affect the majority of children with DS. Disorders that are the most common include [8,53-57]:

Refractive errors (myopia, hyperopia, astigmatism) – 35 to 76 percent

Strabismus – 25 to 57 percent

Nystagmus – 18 to 22 percent

Cataracts occur in 5 percent of newborns. Starting in the second decade of life, many individuals develop corneal opacities. Children occasionally develop glaucoma. (See "Overview of glaucoma in infants and children" and "Cataract in children", section on 'Clinical features'.)

The frequency of ocular disorders increases with age. In one report, eye abnormalities occurred in 38 percent of infants 2 to 12 months of age and 80 percent of children age 5 to 12 years [53]. These abnormalities may be more prevalent in adults. In one report of 30 institutionalized adults with DS, only one had nearly normal ocular status [58]. Nine had keratoconus, an abnormal shape or thinning of the cornea that impairs visual acuity.

HEARING LOSS — Hearing impairment affects 38 to 78 percent of individuals with DS [8,59,60]. Otitis media is a frequent problem, affecting 50 to 70 percent of DS children, and it is often the cause of hearing loss in this population [4]. Monitoring for this condition is important to preserve hearing. Congenital hearing loss is also more common in DS, identified in 15 percent of newborns with DS compared with 0.25 percent in the total neonate population in one retrospective review [61].

The characteristics of hearing loss were illustrated by a study of 47 children with DS, 2 months to 3.5 years of age, evaluated by auditory brainstem response testing [60]. The following findings were noted:

The loss was unilateral or bilateral in 28 and 38 percent, respectively; 34 percent of patients had normal hearing.

The loss was conductive in 19 ears, sensorineural in 16, and mixed in 14.

The extent of loss was mild, moderate, and severe to profound in 33, 13, and 3 ears, respectively.

Another series of 332 children with DS born in Utah found that [62]:

Forty-six percent had hearing loss, 32 percent of whom were identified on newborn screening and the rest in later infancy.

Most newborns and infants had conductive hearing loss due to serous otitis media and required placement of tympanostomy tubes, although a few children were identified with sensorineural or mixed hearing loss, primarily identified by newborn screening.

ENDOCRINE DISORDERS — Endocrine abnormalities in DS include thyroid dysfunction and diabetes.

Thyroid disease — Thyroid disorders are common in DS. The prevalence varies, depending in part upon the population studied and the age of testing. The prevalence of hypothyroidism ranged from 3 to 54 percent in reports of adults with DS [63]. Hyperthyroidism is also relatively common, occurring in 2.5 percent of institutionalized adults [64].

Thyroid disease is also frequently seen in children with DS, as indicated in the following reports:

In a longitudinal study of 85 DS patients up to 25 years of age, 35 percent had hypothyroidism. One-half developed the disorder before age eight years [63]. Two percent had hyperthyroidism.

In 320 children with DS aged five days to 10 years, 28 percent had abnormal thyroid function tests [65]. Of these, diagnoses included primary congenital hypothyroidism in 6, acquired hypothyroidism in 1, transient hyperthyrotropinemia in 2, compensated hypothyroidism (T4 concentration normal or close to the lower limit of normal and increased thyroid-stimulating hormone [TSH] level) in 16, and mild compensated hypothyroidism (mildly elevated TSH concentration) in 65. None had hyperthyroidism.

In a retrospective cohort study of 122 infants less than four months of age with DS, 17.5 percent had primary hypothyroidism that required therapy, and 15 percent had compensated hypothyroidism [66].

However, there is a shift in thyroid hormone levels in patients with DS who have no overt symptoms of thyroid disease, suggesting that normal values may be different in this group. In a large cohort from a neonatal screening program, T4 concentrations in newborns with DS had a normal distribution but were shifted to lower concentrations than the general population [67]. Mean TSH concentration was significantly increased (9.76 versus 3.96 milli-international units/L), and T4-binding globulin was normal compared with controls. The distribution plots for TSH and free T4 were shifted to higher values in another study of patients with DS (median age 10, range six months to 64 years) [68].

Diabetes — The risk of type 1 diabetes appears to be increased in DS [36,69-71]. Data from a Dutch study in children up to 14 years of age suggest the risk of type 1 diabetes is three times greater in DS than in the general population (50 versus 12.4 per 100,000 per year) [70,71]. In another study, the estimated prevalence of type 1 diabetes in DS children up to nine years of age was eight times greater than the age-matched control population (335 versus 40 per 100,000) [70].

HEMATOLOGIC DISORDERS — Hematologic abnormalities affecting red blood cells, white blood cells, and platelets are common in DS, particularly during childhood. The lifetime risk of leukemia in DS is 1 to 1.5 percent [72,73].

Approximately 65 percent of newborns with trisomy 21 have polycythemia [74]. In one report, plasma erythropoietin concentration measured in umbilical cord blood was higher in infants with DS compared with controls, suggesting that chronic fetal hypoxemia may explain the high incidence of polycythemia [75]. (See "Neonatal polycythemia".)

Children with DS often have macrocytosis [74,76]. In one study, mean corpuscular volume (MCV) was greater in DS children age two to six years compared with controls (86.9 versus 80.6 fL), and MCV >95th percentile for age was more likely to occur (66 versus 11 percent) [76]. Hematocrits were higher in the DS patients (39.1 versus 36.9 percent), although all were normal for age. (See "Macrocytosis/Macrocytic anemia".)

White blood cell counts are decreased in DS [74,76]. In the study cited above, white blood cell counts <5th percentile for age occurred more often in DS than controls (33 versus 6 percent) [76]. The macrocytosis and leukopenia were not explained by folate deficiency, because serum and red blood cell folate concentrations were similar between the patients and controls. Thrombocytosis is common in infancy, and thrombocytopenia is rare [74].

Transient myeloproliferative disorder — Transient myeloproliferative disorder (TMD), also known as transient leukemia or transient abnormal myelopoiesis (TAM), is a form of leukemia that almost exclusively affects newborns with DS. It is typically detected on routine screening with a complete blood count (identification of blasts on the peripheral smear). The majority of newborns are asymptomatic, with spontaneous resolution of the disorder by two to three months (median 54 days), although some develop severe disease including hydrops fetalis, hyperleukocytosis, liver failure, and cardiopulmonary failure. TMD is discussed in greater detail separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

Acute megakaryoblastic leukemia — In prospective and retrospective studies, up to 26 percent of infants with transient leukemia later developed the French-American-British (FAB) classification system M7 subtype of acute myeloid leukemia (AML-M7), also known as acute megakaryoblastic leukemia (AMKL) or myeloid leukemia of DS (ML-DS) [77-79]. AMKL occurs in approximately 1 in 50 to 200 children with DS. The incidence is approximately 500 times greater in children with than without DS. (See "Classification of acute myeloid leukemia (AML)".)

AMKL develops during the first four years of life. It is most commonly seen by two years of age and is invariably associated with variants in guanine-adenine-thymine-adenine (GATA) binding factor 1 gene (GATA1) [73,78,80-85]. In contrast, myeloid leukemias in people with DS aged four years or older are usually negative for GATA1 variants, and their prognosis does not differ from AML in patients without DS. Many affected patients (20 to 69 percent) present with myelodysplastic syndrome, consisting of progressive thrombocytopenia followed by anemia [72]. Some develop hepatomegaly and liver failure due to fibrosis [86]. Neutropenia and infection rarely are seen [86]. Treatment issues are complex as children with DS and either acute lymphoblastic leukemia (ALL) or AMKL are subject to high initial rates of treatment-related mortality [87]. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Down syndrome'.)

There is evidence that these GATA1 variants are acquired in utero and that finding such variants at birth might serve as a biomarker for an increased risk of transient leukemia and subsequent AMKL [88,89]. In one study, three of four children with DS and AMKL had the same GATA1 variant in a neonatal blood spot (Guthrie card) that was found at the time of clinical diagnosis of AMKL 12 to 26 months later [90].

Gene expression profiling may help in distinguishing transient leukemia from AMKL [91] and identifying those at risk of progressing from transient leukemia to AMKL [92], as well as distinguishing the AMKL seen in children with DS from AMKL seen in those without DS [93].

Acute lymphoblastic leukemia — The risk of developing ALL is approximately 10 to 20 times higher in DS compared with children without DS [36,94-96] and accounts for 1 to 3 percent of all patients with ALL. The clinical presentation is similar to that in children without DS. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

In a report comparing ALL in children with and without DS, the following findings were noted at presentation [72,94]:

Leukocyte count and leukemic cell mass were similar.

Age distribution and immunophenotype were similar.

Clinically, they were indistinguishable [73].

Mediastinal mass (1.6 versus 8.9 percent) and central nervous system (CNS) leukemia (0 versus 2.7 percent) were less common in DS, both favorable prognostic signs.

Less T cell leukemia or translocation of (9;22) or t(4;11) were seen in DS, both unfavorable prognostic signs.

Cytogenetic differences occurred, including less hyperdiploidy in DS, an unfavorable prognostic sign.

Children with DS who develop ALL often respond to chemotherapy, similar to children without DS. The treatment and outcome for children with DS and ALL are discussed separately. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Down syndrome'.)

PULMONARY DISORDERS — Sixty percent of 208 children with DS in a 2004 survey were reported by their parents to have respiratory conditions, including sleep apnea and asthma [97], although this may be an underestimate based upon results from other studies [98]. Other pulmonary complications that are more common in children with DS include disorders of the pulmonary vasculature, parenchymal lung disease, upper and lower airway abnormalities, and chronic aspiration [99]. Respiratory tract infections are also more frequent and often more severe than in children without DS.

Sleep apnea — Obstructive sleep apnea (OSA) occurs in at least 30 to 75 percent of children with DS, including those who are not obese [98,100-106]. In a population of 65 unselected 3.5 year olds with DS, polysomnograms were classified as abnormal with evidence of OSA in 57 percent. Among the 45 children whose parents reported no sleep problems, 54 percent had abnormal results [98]. The mechanism includes soft tissue and skeletal alterations that lead to upper airway obstruction. In infants with DS, OSA was associated with dysphagia, gastrointestinal conditions such as gastroesophageal reflux disease, and congenital heart disease [106]. Intermittent hypoxemia may lead to pulmonary hypertension and contribute to mental impairment [107]. (See "Mechanisms and predisposing factors for sleep-related breathing disorders in children".)

SKIN DISORDERS — The majority of DS children have associated skin disorders, which are considered benign [108-110]. In one series, 62 of 71 children (87 percent) had skin abnormalities in the following proportions [111]:

Palmoplantar hyperkeratosis – 41 percent

Seborrheic dermatitis – 31 percent

Fissured tongue – 20 percent

Cutis marmorata – 13 percent

Geographic tongue – 11 percent

Xerosis – 10 percent

Alopecia areata – 8 percent [108,109]

In adolescents, dermatologic problems become particularly bothersome. The most common condition in this age group is folliculitis, which affects 50 to 60 percent of patients [112].

REPRODUCTION — Females with DS are fertile and may become pregnant. In one series, 30 pregnancies in 26 women resulted in 10 offspring with DS, 18 (including one set of twins) without DS, and 3 spontaneous abortions [113]. Appropriate counseling should be provided for management of menstruation and contraception [114].

Nearly all males with DS are infertile. The mechanism is impairment of spermatogenesis [115]. However, cases have been reported of offspring from fathers with DS [116,117].

UROLOGIC ABNORMALITIES — Studies suggest an increased incidence of urologic abnormalities in individuals with DS. These include hypospadias (1 in 250 males), cryptorchidism (14 to 27 percent of males), testicular cancer, and kidney malformations (3.5 percent) [118]. (See "Hypospadias: Pathogenesis, diagnosis, and evaluation" and "Undescended testes (cryptorchidism) in children: Clinical features and evaluation" and "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

ATLANTOAXIAL INSTABILITY — Atlantoaxial instability (AAI), defined as excessive mobility of the articulation of the atlas (C1) and the axis (C2), may lead to subluxation of the cervical spine [119]. Approximately 13 percent of individuals with DS have asymptomatic AAI, while spinal cord compression due to the disorder affects approximately 2 percent [120]. The diagnosis is made by lateral neck radiographs taken in neutral position, flexion, and extension. (See "Down syndrome: Management", section on 'Atlantoaxial instability'.)

Patients with symptomatic spinal cord compression may have neck pain, torticollis, gait abnormalities, loss of bowel or bladder control, or signs of quadriparesis or quadriplegia and require immediate stabilization. Asymptomatic individuals appear to remain asymptomatic whether or not physical activity is restricted [121,122]. In one study, DS children with AAI were randomly assigned to participate or not in athletic activities considered to be risky and evaluated after one year. The groups were similar in motor function, frequency of neurologic signs, and changes in atlantoaxial distance and were also similar to children with DS and without AAI [121].

ARTHROPATHY — DS arthropathy has a prevalence of 8 to 10 per 1000, or approximately six times the prevalence of juvenile idiopathic arthritis in the general population [123]. In a review of 30 cases, 17 had polyarticular disease at symptom onset, and 13 had oligoarticular disease at symptom onset, but 7 of these progressed to polyarticular disease. Average delay from symptom onset to diagnosis was two years.

IMMUNODEFICIENCY — DS is associated with a variety of immunologic impairments that are thought to be related to the increased susceptibility to infection, autoimmune disorders, and malignancies [124-128]. Chemotactic defects [129], decreased immunoglobulin G4 (IgG4) levels [130], and quantitative and qualitative abnormalities of the T cell and B cell systems have been inconsistently demonstrated [124-126,131]. Whether these represent a primary immunodeficiency or early senescence of the immune system is uncertain.

Support for an intrinsic immunodeficiency is provided by a cross-sectional study in which immunophenotyping was used to evaluate lymphocyte subpopulations in 96 children with DS who ranged in age from 1 to 20 years [132]. In another study, children with DS had a diminished expansion of T and B cells in the first years of life compared with previously published data on healthy children without DS [133]. B cells remained diminished (with 88 percent of values below the 10th percentile), although T cells eventually approximated normal levels. Reduced naive mature and memory B cell numbers and evidence of impaired antigen selection for IgM+ and IgA+ memory B cells were seen in one small study [134].

DIAGNOSIS OF DOWN SYNDROME — The diagnosis of DS is often made by prenatal screening. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18" and "Laboratory issues related to maternal serum screening for Down syndrome".)

When no prenatal diagnosis is available, DS is usually recognized from the characteristic phenotypic features present in the newborn (see 'Dysmorphic features' above). Diagnosis should be confirmed with a genetic test (eg, a karyotype performed on a blood sample). Alternative methods (eg, interphase fluorescent in situ hybridization [FISH] for trisomy 21 or quantitative fluorescence-polymerase chain reaction [QF-PCR]) may be used to expedite diagnosis, but these investigations should always be followed by a full karyotype in order to detect DS due to translocations (eg, Robertsonian translocations involving chromosome 21) or mosaic DS.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Down syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Down syndrome (The Basics)")

Beyond the Basics topic (see "Patient education: Down syndrome (Beyond the Basics)")


Diagnosis – The diagnosis of Down syndrome (DS) is often made by prenatal screening. DS is otherwise usually recognized from the characteristic phenotypic features present in the newborn. A clinical diagnosis of DS should be confirmed by genetic testing whenever possible. (See 'Diagnosis of Down syndrome' above and "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18" and "Laboratory issues related to maternal serum screening for Down syndrome" and 'Neonatal features' above.)

Dysmorphic features – The characteristic dysmorphic features of DS predominantly affect the head and neck and the extremities (picture 1 and picture 2). Ten of the characteristic dysmorphic features are common in newborns with DS and are usually recognized soon after birth. (See 'Dysmorphic features' above.)

Neuropsychiatric disorders – Almost all persons with DS have cognitive impairment, although the range is wide. Most are mildly to moderately intellectually disabled, although some are severely impaired. Behavioral and psychiatric disorders are more common in DS than typical children but less common than in those with other causes of intellectual disability. (See 'Neuropsychiatric disorders' above.)

Cardiovascular disease – Approximately one-half of persons with DS have congenital heart disease. Septal defects are the most common. Some asymptomatic adolescents and adults without structural heart disease develop valve abnormalities. (See 'Cardiovascular disease' above.)

Gastrointestinal abnormalities – Children with trisomy 21 are at increased risk for gastrointestinal tract anomalies, including duodenal atresia or stenosis, imperforate anus, and esophageal atresia with tracheoesophageal fistula. They are also at increased risk for celiac disease and Hirschsprung disease. (See 'Gastrointestinal abnormalities' above.)

Growth – Birth weight, length, and head circumference are less in DS compared with typical infants. The growth rate for height is reduced in DS compared with typical children. In general, weight is less than expected for length in infants with DS and then increases disproportionally so that the majority of children are obese by age three to four years. (See 'Growth' above.)

Eye and hearing problems – Ophthalmologic disorders are common in patients with DS and increase in frequency with age. These disorders include refractive errors, strabismus, nystagmus, cataracts, and keratoconus. Hearing loss is also common, and otitis media is a frequent problem. (See 'Eye problems' above and 'Hearing loss' above.)

Endocrine disorders – Endocrine abnormalities in DS include thyroid dysfunction and type 1 diabetes. (See 'Endocrine disorders' above.)

Fertility and reproduction – Females with DS are fertile and may become pregnant. However, nearly all males with DS are infertile. (See 'Reproduction' above.)

Atlantoaxial instability – Persons with DS are at increased risk of atlantoaxial instability (AAI), defined as excessive mobility of the articulation of the atlas (C1) and the axis (C2), although spinal cord compression due to subluxation of the cervical spine is uncommon. (See 'Atlantoaxial instability' above.)

Hematologic abnormalities – Hematologic abnormalities affecting red cells, white cells, and platelets are common in DS and include polycythemia, macrocytosis, leukopenia, thrombocytosis, and leukemia (transient, acute megakaryoblastic, and acute lymphoblastic). (See 'Hematologic disorders' above.)

Immunologic abnormalities – DS is associated with a variety of immunologic impairments that are thought to be related to the increased susceptibility to infection, autoimmune disorders, and malignancies. However, these defects are inconsistently demonstrated. Whether these represent a primary immunodeficiency or early senescence of the immune system is uncertain. (See 'Immunodeficiency' above.)

Other abnormalities – Increased rates of urologic abnormalities, arthropathy, pulmonary disease, and benign skin disorders are also seen in patients with DS. (See 'Urologic abnormalities' above and 'Arthropathy' above and 'Pulmonary disorders' above and 'Skin disorders' above.)

  1. Jones KL. Down syndrome. In: Smith's recognizable patterns of human malformation, 6th ed, Elsevier Saunders, Philadelphia 2006. p.7.
  2. Epstein CJ. Down syndrome (Trisomy 21). In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1223.
  3. Hall B. Mongolism in newborn infants. An examination of the criteria for recognition and some speculations on the pathogenic activity of the chromosomal abnormality. Clin Pediatr (Phila) 1966; 5:4.
  4. Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics 2011; 128:393.
  5. Winders PC. Gross motor milestone statistics. In: Gross motor skills in children with Down syndrome: A guide for parents and professionals, Woodbine House, Baltimore 1997. p.228.
  6. Kumin L. Speech and language skills in children with Down syndrome. MRDD Research Reviews 1996; 2:109.
  7. Brown FR 3rd, Greer MK, Aylward EH, Hunt HH. Intellectual and adaptive functioning in individuals with Down syndrome in relation to age and environmental placement. Pediatrics 1990; 85:450.
  8. Roizen NJ, Patterson D. Down's syndrome. Lancet 2003; 361:1281.
  9. Lott IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down's syndrome. Lancet Neurol 2010; 9:623.
  10. Miller JF. Profiles of language development in children with Down syndrome. In: Improving the communication of people with Down syndrome, Miller JF, Leddy M, Leavitt LA (Eds), Brookes, Baltimore 1999. p.11.
  11. Chapman RS, Seung HK, Schwartz SE, Kay-Raining Bird E. Language skills of children and adolescents with Down syndrome: II. Production deficits. J Speech Lang Hear Res 1998; 41:861.
  12. Chapman RS, Schwartz SE, Bird EK. Language skills of children and adolescents with Down syndrome: I. Comprehension. J Speech Hear Res 1991; 34:1106.
  13. Kernan KT. Comprehension of syntactically indicated sequence by Down's syndrome and other mentally retarded adults. J Ment Defic Res 1990; 34 ( Pt 2):169.
  14. Myers BA, Pueschel SM. Psychiatric disorders in persons with Down syndrome. J Nerv Ment Dis 1991; 179:609.
  15. Kent L, Evans J, Paul M, Sharp M. Comorbidity of autistic spectrum disorders in children with Down syndrome. Dev Med Child Neurol 1999; 41:153.
  16. Rasmussen P, Börjesson O, Wentz E, Gillberg C. Autistic disorders in Down syndrome: background factors and clinical correlates. Dev Med Child Neurol 2001; 43:750.
  17. Worley G, Crissman BG, Cadogan E, et al. Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome. J Child Neurol 2015; 30:1147.
  18. Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 1989; 46:849.
  19. Visser FE, Aldenkamp AP, van Huffelen AC, et al. Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome. Am J Ment Retard 1997; 101:400.
  20. Freeman SB, Taft LF, Dooley KJ, et al. Population-based study of congenital heart defects in Down syndrome. Am J Med Genet 1998; 80:213.
  21. Dennis J, Archer N, Ellis J, Marder L. Recognising heart disease in children with Down syndrome. Arch Dis Child Educ Pract Ed 2010; 95:98.
  22. Irving CA, Chaudhari MP. Cardiovascular abnormalities in Down's syndrome: spectrum, management and survival over 22 years. Arch Dis Child 2012; 97:326.
  23. Geggel RL, O'Brien JE, Feingold M. Development of valve dysfunction in adolescents and young adults with Down syndrome and no known congenital heart disease. J Pediatr 1993; 122:821.
  24. Hamada T, Gejyo F, Koshino Y, et al. Echocardiographic evaluation of cardiac valvular abnormalities in adults with Down's syndrome. Tohoku J Exp Med 1998; 185:31.
  25. Bush D, Galambos C, Ivy DD, et al. Clinical Characteristics and Risk Factors for Developing Pulmonary Hypertension in Children with Down Syndrome. J Pediatr 2018; 202:212.
  26. Fabia J, Drolette M. Malformations and leukemia in children with Down's syndrome. Pediatrics 1970; 45:60.
  27. Moore SW, Johnson AG. Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes. Semin Pediatr Surg 1998; 7:156.
  28. Sarioglu A, Tanyel FC, Büyükpamukçu N, Hiçsönmez A. Hirschsprung-associated congenital anomalies. Eur J Pediatr Surg 1997; 7:331.
  29. Menezes M, Puri P. Long-term clinical outcome in patients with Hirschsprung's disease and associated Down's syndrome. J Pediatr Surg 2005; 40:810.
  30. Garver KL, Law JC, Garver B. Hirschsprung disease: a genetic study. Clin Genet 1985; 28:503.
  31. Ikeda K, Goto S. Additional anomalies in Hirschsprung's disease: an analysis based on the nationwide survey in Japan. Z Kinderchir 1986; 41:279.
  32. Carlsson AK, Axelsson IE, Borulf SK, et al. Serological screening for celiac disease in healthy 2.5-year-old children in Sweden. Pediatrics 2001; 107:42.
  33. Book L, Hart A, Black J, et al. Prevalence and clinical characteristics of celiac disease in Downs syndrome in a US study. Am J Med Genet 2001; 98:70.
  34. Zachor DA, Mroczek-Musulman E, Brown P. Prevalence of celiac disease in Down syndrome in the United States. J Pediatr Gastroenterol Nutr 2000; 31:275.
  35. Mäki M, Mustalahti K, Kokkonen J, et al. Prevalence of Celiac disease among children in Finland. N Engl J Med 2003; 348:2517.
  36. Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D. Cancers and immune related diseases associated with Down's syndrome: a record linkage study. Arch Dis Child 2004; 89:1014.
  37. Pueschel SM, Rothman KJ, Ogilby JD. Birth weight of children with Down's syndrome. Am J Ment Defic 1976; 80:442.
  38. Cronk CE. Growth of children with Down's syndrome: birth to age 3 years. Pediatrics 1978; 61:564.
  39. Toledo C, Alembik Y, Aguirre Jaime A, Stoll C. Growth curves of children with Down syndrome. Ann Genet 1999; 42:81.
  40. Cronk C, Crocker AC, Pueschel SM, et al. Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 1988; 81:102.
  41. Zemel BS, Pipan M, Stallings VA, et al. Growth Charts for Children With Down Syndrome in the United States. Pediatrics 2015; 136:e1204.
  42. Styles ME, Cole TJ, Dennis J, Preece MA. New cross sectional stature, weight, and head circumference references for Down's syndrome in the UK and Republic of Ireland. Arch Dis Child 2002; 87:104.
  43. Rubin SS, Rimmer JH, Chicoine B, et al. Overweight prevalence in persons with Down syndrome. Ment Retard 1998; 36:175.
  44. Annerén G, Gustavson KH, Sara VR, Tuvemo T. Growth retardation in Down syndrome in relation to insulin-like growth factors and growth hormone. Am J Med Genet Suppl 1990; 7:59.
  45. Torrado C, Bastian W, Wisniewski KE, Castells S. Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J Pediatr 1991; 119:478.
  46. Milunsky A, Lowy C, Rubenstein AH, Wright AD. Carbohydrate tolerance, growth hormone and insulin levels in mongolism. Dev Med Child Neurol 1968; 10:25.
  47. Annerén G, Sara VR, Hall K, Tuvemo T. Growth and somatomedin responses to growth hormone in Down's syndrome. Arch Dis Child 1986; 61:48.
  48. Castells S, Beaulieu I, Torrado C, et al. Hypothalamic versus pituitary dysfunction in Down's syndrome as cause of growth retardation. J Intellect Disabil Res 1996; 40 ( Pt 6):509.
  49. Sara VR, Gustavson KH, Annerén G, et al. Somatomedins in Down's syndrome. Biol Psychiatry 1983; 18:803.
  50. Sara VR, Sjögren B, Annerén G, et al. The presence of normal receptors for somatomedin and insulin in fetuses with Down's syndrome. Biol Psychiatry 1984; 19:591.
  51. Allison DB, Gomez JE, Heshka S, et al. Decreased resting metabolic rate among persons with Down Syndrome. Int J Obes Relat Metab Disord 1995; 19:858.
  52. Luke A, Roizen NJ, Sutton M, Schoeller DA. Energy expenditure in children with Down syndrome: correcting metabolic rate for movement. J Pediatr 1994; 125:829.
  53. Roizen NJ, Mets MB, Blondis TA. Ophthalmic disorders in children with Down syndrome. Dev Med Child Neurol 1994; 36:594.
  54. Shapiro MB, France TD. The ocular features of Down's syndrome. Am J Ophthalmol 1985; 99:659.
  55. Caputo AR, Wagner RS, Reynolds DR, et al. Down syndrome. Clinical review of ocular features. Clin Pediatr (Phila) 1989; 28:355.
  56. Kim JH, Hwang JM, Kim HJ, Yu YS. Characteristic ocular findings in Asian children with Down syndrome. Eye (Lond) 2002; 16:710.
  57. Creavin AL, Brown RD. Ophthalmic abnormalities in children with Down syndrome. J Pediatr Ophthalmol Strabismus 2009; 46:76.
  58. Hestnes A, Sand T, Fostad K. Ocular findings in Down's syndrome. J Ment Defic Res 1991; 35 ( Pt 3):194.
  59. Shott SR, Joseph A, Heithaus D. Hearing loss in children with Down syndrome. Int J Pediatr Otorhinolaryngol 2001; 61:199.
  60. Roizen NJ, Wolters C, Nicol T, Blondis TA. Hearing loss in children with Down syndrome. J Pediatr 1993; 123:S9.
  61. Tedeschi AS, Roizen NJ, Taylor HG, et al. The prevalence of congenital hearing loss in neonates with Down syndrome. J Pediatr 2015; 166:168.
  62. Park AH, Wilson MA, Stevens PT, et al. Identification of hearing loss in pediatric patients with Down syndrome. Otolaryngol Head Neck Surg 2012; 146:135.
  63. Karlsson B, Gustafsson J, Hedov G, et al. Thyroid dysfunction in Down's syndrome: relation to age and thyroid autoimmunity. Arch Dis Child 1998; 79:242.
  64. Sare Z, Ruvalcaba RH, Kelley VC. Prevalence of thyroid disorder in Down syndrome. Clin Genet 1978; 14:154.
  65. Tüysüz B, Beker DB. Thyroid dysfunction in children with Down's syndrome. Acta Paediatr 2001; 90:1389.
  66. Purdy IB, Singh N, Brown WL, et al. Revisiting early hypothyroidism screening in infants with Down syndrome. J Perinatol 2014; 34:936.
  67. van Trotsenburg AS, Vulsma T, van Santen HM, et al. Lower neonatal screening thyroxine concentrations in down syndrome newborns. J Clin Endocrinol Metab 2003; 88:1512.
  68. Meyerovitch J, Antebi F, Greenberg-Dotan S, et al. Hyperthyrotropinaemia in untreated subjects with Down's syndrome aged 6 months to 64 years: a comparative analysis. Arch Dis Child 2012; 97:595.
  69. Anwar AJ, Walker JD, Frier BM. Type 1 diabetes mellitus and Down's syndrome: prevalence, management and diabetic complications. Diabet Med 1998; 15:160.
  70. Van Goor JC, Massa GG, Hirasing R. Increased incidence and prevalence of diabetes mellitus in Down's syndrome. Arch Dis Child 1997; 77:186.
  71. Ruwaard D, Hirasing RA, Reeser HM, et al. Increasing incidence of type I diabetes in The Netherlands. The second nationwide study among children under 20 years of age. Diabetes Care 1994; 17:599.
  72. Lange B. The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br J Haematol 2000; 110:512.
  73. Malinge S, Izraeli S, Crispino JD. Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 2009; 113:2619.
  74. Kivivuori SM, Rajantie J, Siimes MA. Peripheral blood cell counts in infants with Down's syndrome. Clin Genet 1996; 49:15.
  75. Widness JA, Pueschel SM, Pezzullo JC, Clemons GK. Elevated erythropoietin levels in cord blood of newborns with Down's syndrome. Biol Neonate 1994; 66:50.
  76. Roizen NJ, Amarose AP. Hematologic abnormalities in children with Down syndrome. Am J Med Genet 1993; 46:510.
  77. Massey GV, Zipursky A, Chang MN, et al. A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 2006; 107:4606.
  78. Zipursky A. Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 2003; 120:930.
  79. Zipursky A, Peeters M, Poon A. Megakaryoblastic leukemia and Down's syndrome: a review. Pediatr Hematol Oncol 1987; 4:211.
  80. Shivdasani RA. Molecular and transcriptional regulation of megakaryocyte differentiation. Stem Cells 2001; 19:397.
  81. Izraeli S. Leukaemia -- a developmental perspective. Br J Haematol 2004; 126:3.
  82. Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer 2005; 5:11.
  83. Mundschau G, Gurbuxani S, Gamis AS, et al. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 2003; 101:4298.
  84. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 2003; 101:4301.
  85. Alford KA, Reinhardt K, Garnett C, et al. Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood 2011; 118:2222.
  86. Zipursky A, Rose T, Skidmore M, et al. Hydrops fetalis and neonatal leukemia in Down syndrome. Pediatr Hematol Oncol 1996; 13:81.
  87. Rao A, Hills RK, Stiller C, et al. Treatment 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. Br J Haematol 2006; 132:576.
  88. Taub JW, Mundschau G, Ge Y, et al. Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. Blood 2004; 104:1588.
  89. Pine SR, Guo Q, Yin C, et al. Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome. Blood 2007; 110:2128.
  90. Ahmed M, Sternberg A, Hall G, et al. Natural history of GATA1 mutations in Down syndrome. Blood 2004; 103:2480.
  91. McElwaine S, Mulligan C, Groet J, et al. Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker. Br J Haematol 2004; 125:729.
  92. Kanezaki R, Toki T, Terui K, et al. Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. Blood 2010; 116:4631.
  93. Bourquin JP, Subramanian A, Langebrake C, et al. Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci U S A 2006; 103:3339.
  94. Dördelmann M, Schrappe M, Reiter A, et al. Down's syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials. Berlin-Frankfurt-Münster Group. Leukemia 1998; 12:645.
  95. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 2000; 355:165.
  96. Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 2006; 135:595.
  97. Thomas K, Bourke J, Girdler S, et al. Variation over time in medical conditions and health service utilization of children with Down syndrome. J Pediatr 2011; 158:194.
  98. Shott SR, Amin R, Chini B, et al. Obstructive sleep apnea: Should all children with Down syndrome be tested? Arch Otolaryngol Head Neck Surg 2006; 132:432.
  99. McDowell KM, Craven DI. Pulmonary complications of Down syndrome during childhood. J Pediatr 2011; 158:319.
  100. Marcus CL, Keens TG, Bautista DB, et al. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991; 88:132.
  101. Stebbens VA, Dennis J, Samuels MP, et al. Sleep related upper airway obstruction in a cohort with Down's syndrome. Arch Dis Child 1991; 66:1333.
  102. Southall DP, Stebbens VA, Mirza R, et al. Upper airway obstruction with hypoxaemia and sleep disruption in Down syndrome. Dev Med Child Neurol 1987; 29:734.
  103. Levanon A, Tarasiuk A, Tal A. Sleep characteristics in children with Down syndrome. J Pediatr 1999; 134:755.
  104. Dyken ME, Lin-Dyken DC, Poulton S, et al. Prospective polysomnographic analysis of obstructive sleep apnea in down syndrome. Arch Pediatr Adolesc Med 2003; 157:655.
  105. Fitzgerald DA, Paul A, Richmond C. Severity of obstructive apnoea in children with Down syndrome who snore. Arch Dis Child 2007; 92:423.
  106. Goffinski A, Stanley MA, Shepherd N, et al. Obstructive sleep apnea in young infants with Down syndrome evaluated in a Down syndrome specialty clinic. Am J Med Genet A 2015; 167A:324.
  107. Breslin J, Spanò G, Bootzin R, et al. Obstructive sleep apnea syndrome and cognition in Down syndrome. Dev Med Child Neurol 2014; 56:657.
  108. Barankin B, Guenther L. Dermatological manifestations of Down's syndrome. J Cutan Med Surg 2001; 5:289.
  109. Madan V, Williams J, Lear JT. Dermatological manifestations of Down's syndrome. Clin Exp Dermatol 2006; 31:623.
  110. Daneshpazhooh M, Nazemi TM, Bigdeloo L, Yoosefi M. Mucocutaneous findings in 100 children with Down syndrome. Pediatr Dermatol 2007; 24:317.
  111. Ercis M, Balci S, Atakan N. Dermatological manifestations of 71 Down syndrome children admitted to a clinical genetics unit. Clin Genet 1996; 50:317.
  112. Pueschel SM. Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet Suppl 1990; 7:52.
  113. Bovicelli L, Orsini LF, Rizzo N, et al. Reproduction in Down syndrome. Obstet Gynecol 1982; 59:13S.
  114. American Academy of Pediatrics. Committee on Genetics. American Academy of Pediatrics: Health supervision for children with Down syndrome. Pediatrics 2001; 107:442.
  115. Johannisson R, Gropp A, Winking H, et al. Down's syndrome in the male. Reproductive pathology and meiotic studies. Hum Genet 1983; 63:132.
  116. Zühlke C, Thies U, Braulke I, et al. Down syndrome and male fertility: PCR-derived fingerprinting, serological and andrological investigations. Clin Genet 1994; 46:324.
  117. Sheridan R, Llerena J Jr, Matkins S, et al. Fertility in a male with trisomy 21. J Med Genet 1989; 26:294.
  118. Mercer ES, Broecker B, Smith EA, et al. Urological manifestations of Down syndrome. J Urol 2004; 171:1250.
  119. Cohen WI. Atlantoaxial instability. What's next? Arch Pediatr Adolesc Med 1998; 152:119.
  120. Pueschel SM, Scola FH. Atlantoaxial instability in individuals with Down syndrome: epidemiologic, radiographic, and clinical studies. Pediatrics 1987; 80:555.
  121. Cremers MJ, Bol E, de Roos F, van Gijn J. Risk of sports activities in children with Down's syndrome and atlantoaxial instability. Lancet 1993; 342:511.
  122. Pueschel SM, Scola FH, Pezzullo JC. A longitudinal study of atlanto-dens relationships in asymptomatic individuals with Down syndrome. Pediatrics 1992; 89:1194.
  123. Juj H, Emery H. The arthropathy of Down syndrome: an underdiagnosed and under-recognized condition. J Pediatr 2009; 154:234.
  124. Ugazio AG, Maccario R, Notarangelo LD, Burgio GR. Immunology of Down syndrome: a review. Am J Med Genet Suppl 1990; 7:204.
  125. Nespoli L, Burgio GR, Ugazio AG, Maccario R. Immunological features of Down's syndrome: a review. J Intellect Disabil Res 1993; 37 ( Pt 6):543.
  126. Cuadrado E, Barrena MJ. Immune dysfunction in Down's syndrome: primary immune deficiency or early senescence of the immune system? Clin Immunol Immunopathol 1996; 78:209.
  127. Bloemers BL, van Bleek GM, Kimpen JL, Bont L. Distinct abnormalities in the innate immune system of children with Down syndrome. J Pediatr 2010; 156:804.
  128. Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol 2011; 164:9.
  129. Novo E, García MI, Lavergne J. Nonspecific immunity in Down syndrome: a study of chemotaxis, phagocytosis, oxidative metabolism, and cell surface marker expression of polymorphonuclear cells. Am J Med Genet 1993; 46:384.
  130. Annerén G, Magnusson CG, Lilja G, Nordvall SL. Abnormal serum IgG subclass pattern in children with Down's syndrome. Arch Dis Child 1992; 67:628.
  131. Berman S, Lee B, Nuss R, et al. Immunoglobulin G, total and subclass, in children with or without recurrent otitis media. J Pediatr 1992; 121:249.
  132. de Hingh YC, van der Vossen PW, Gemen EF, et al. Intrinsic abnormalities of lymphocyte counts in children with down syndrome. J Pediatr 2005; 147:744.
  133. Comans-Bitter WM, de Groot R, van den Beemd R, et al. Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr 1997; 130:388.
  134. Verstegen RH, Driessen GJ, Bartol SJ, et al. Defective B-cell memory in patients with Down syndrome. J Allergy Clin Immunol 2014; 134:1346.
Topic 2917 Version 31.0