Are You Confident of the Diagnosis?

Dr John Langdon Down first described Down syndrome in Britain in 1866. Almost a century later, Jérôme Lejeune in 1959 discovered the role of either a partial or complete third copy of chromosome 21 in this condition. This extra genetic material results from trisomy 21 (most common) chromosomal translocation and mosaicism.

Characteristic findings on physical examination

Persons with Down syndrome have a characteristic facies, physical characteristics and multi-system involvement (eg, congenital heart disease, thyroid disorders, recurrent pulmonary infections, shortened lifespan, etc) and a range of cognitive impairments. Our discussion will mainly focus on the cutaneous manifestations of Down syndrome.


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Down syndrome has a classic clinical phenotype that is easily recognizable.

–Epicanthal folds with upward and outward slanting palpebral fissures

–Hypertelorism (wide set intraocular distance)

–Flattened face and nasal bridge

–Small head (brachycephaly), mouth (micrognathia) and ears with dysplastic earlobes

–Flattened occiput (plagiocephaly), excess nuchal skin, broad neck


Head and Neck

–Premature aging (very common). Look for canities (hair graying), hair loss, wrinkles.

–Alopecia areata (more often in adulthood, 6% to 10%, females>males)

–Oral: macroglossia, fissured tongue (28%, up to 95% by late childhood), geographic tongue (4% to 11.3%), early periodontal disease (common), and angular chelitis (13%)

–Syringoma (approximately 6% to 20%, up to 39%, females:males 2:1)

Trunk and Extremities

–Atopic dermatitis (50%)

–Palmoplantar hyperkeratosis (approximately 40%, up to 75% by age 5)

–Single transverse (simian) palmar crease (approximately 50%)(Figure 1)

–Seborrheic dermatitis (30% to 36%). Look for fine greasy scaling on a background of erythema often affecting the face, scalp and trunk. It may be accompanied by pruritus.

–Xerosis (9.8%, up to 75% above age 5)

–Carotinemia, diffuse alopecia, thin and brittle hair due to hypothyroidism

–Acrocyanosis from congenital heart disease

–Cutis marmarota (8% to 13%, more common in infants) from decreased peripheral circulation

–Elastosis perforans serpiginosa (EPS). EPS, a condition where there is transepidermal elimination of elastic tissue, is associated with Down syndrome although it still remains an uncommon entity. In Down syndrome, it manifests in second decade, in males more than females (4:1) and is often more extensive. It also occurs with Marfan’s and Ehlers Danlos syndrome, pseudoxanthoma elasticum, osteogenesis imperfecta and morphea. Look for coalescent red papules with a central core in an arcuate or serpigionous distribution.

–Higher incidence of cutaneous infections (50% to 60%) due to immunologic dysfunction. Examples include folliculitis, Malassezia folliculitis (10% to 45%), bacterial furunculosis (26%), impetigo, Norwegian scabies, onychomycosis (>50%), tinea pedis (possibly >75%)

Figure 1.

Simian crease in Down syndrome. Photo courtesy of Dr Benjamin Barankin, Dermatology, Toronto, Ontario, Canada.

Miscellaneous Dermatologic Findings

–Anetoderma (localized loss of dermal elastic tissue)

–Leukemia cutis

–Vesiculopustular eruption associated with transient myeloproliferative disease (one case report)

–Milia-like calcinosis cutis

–Pityriasis rubra pilaris

–Psoriasis (1%)

–Vitiligo (2%)


Head & Neck

–Ocular: severe refractive errors (50% to 70%), congenital cataracts (3%), acquired cataracts (30% to 60%), Brushfield spots (approximately 30% to 75% in Down syndrome, less frequent in normal children, small whitish-gray speckles on the periphery of the iris composed of normal connective tissue), strabismus (50%), nystagmus (35%), keratoconus

–Recurrent serous otitis media from defective eustachian tube drainage (50% to 70%)

–Hearing deficits (60% to 80%) due to middle ear dysfunction and recurrent serous otitis media


–Atlantoaxial or atlantooccipital instability (15% to 30%)

–Short stature

–Clindactyly of fifth fingers

–Large space between first and second toes

–Limb shortening


–Polycythemia (newborn)

–Immunodeficiency from T- and B-cell dysfunction resulting in multiple infections (common)

–Recurrent cutaneous and periodontal infections (common)

–Recurrent serous otitis media (common)

–Recurrent pneumonia (common)

–Acute myeloid leukemia (<1%)

–Transient myeloproliferative disorders

Neurologic and Psychiatric

–Alzheimer’s dementia (15% to 25%)

–Hypotonia (infancy)

–Mental retardation (IQ 30-50) with high variability

–Seizure disorders (2.6% to 8.8%)

–Psychiatric: depression, conduct disorder, adjustment disorder

Cardiac and Pulmonary

–Congenital heart disease, particularly endocardial cushion defect (40% to 50%)

–Ventricular and atrial septal defects, tetralogy of Fallot, patent ductus arteriosus

–Pulmonary arterial hypertension from congenital heart disease

–Recurrent pneumonia

–Early death from complications of congenital heart disease and pneumonia


–Hypothyroidism (up to 50%)

–Delayed onset of puberty

Gastrointestinal (12%)

–Duodenal atresias most common (neonatal)

–Tracheoesophageal fistula (neonatal)

–Pyloric stenois (neonatal)

Who is at Risk for Developing this Disease?

The risk of conceiving a child with Down syndrome is estimated at 1 per 700 to 800 live births. There is no gender or race predilection for this condition.

There is a higher risk with advancing parental age, particularly in women above age 35. This is thought to be due to mutagenic effects sustained by reproductive cells over time. Advancing paternal age may also be a contributing factor, but a recent case-controlled analysis was only able to demonstrate a positive association without reaching statistical significance.

Approximately 50% to 80% of children with Down syndrome are born to mothers above age 35. The risk of Down syndrome further increases for mother’s age 40 to 44 years to 1:100 and women older than 45 years to 1:50; 50% of fetuses spontaneously abort.

What is the Cause of the Disease?

Down syndrome has several associated chromosomal aberrations. These include trisomy 21, chromosomal translocation between or within 21 and 22, or mosaicism.

Trisomy 21 is by far the most common genetic anomaly responsible in approximately 95% of cases. Translocation occurs in 4% to 5% (either inherited translocation or de novo). Mosaicism is a post-zygotic event associated with 1% to 2% of patients with Down syndrome and usually more subtle physical and cognitive abnormalities.

Skin conditions associated with Down syndrome are either primary (eg, premature aging) or secondary to an underlying condition (eg, carotinemia and xerosis from hypothyroidism).

Systemic Implications and Complications
  • –Higher mortality rates related to congenital heart disease and recurrent pulmonary infections. Electrocardiograms and radiologic investigations (eg, electrocardiogram, cardiac ultrasound and magnetic resonance imaging, angiogram) are necessary at birth for diagnosis of congenital heart disease followed by surgical repair, if indicated.

  • –Periodic thyroid disease screen. Hypothyroidism and its associated complications are common in Down syndrome.

  • –Overall, reduced life expectancy due to multisystem involvement. Average lifespan is 35 years. With better medical care, patients with Down syndrome have been known to live into their 50s and 60s.

  • –None of the dermatologic conditions are life threatening (except for overwhelming infection) but they may adversely affect quality of life.

Treatment Options

General Measures

–Moisturizers and emollients for xerosis, atopic dermatitis and palmoplantar hyperkeratosis.

Medical Therapy

–Topical corticosteroids (eg, hydrocortisone valerate, mometasone furoate), or calcineurin inhibitor (eg, tacrolimus 0.03% or 0.1%, pimecrolimus 0.1%) for atopic dermatitis

–Appropriate antimicrobial therapy for cutaneous infections

–Thyroid replacement for hypothyroidism

Surgical Therapy: None

Note: Treatment for cutaneous manifestations of Down syndrome is guided by symptomatic relief.

Optimal Therapeutic Approach for this Disease

  • –Regular physical examination and follow-up with primary care physician or pediatrician

  • –Referral to specialists based on symptoms

  • –Ophthalmologic assessment and follow-up due to frequent ocular complications

  • –Dentist for oral hygiene and control of early-onset periodontal disease

  • –Special education programs to aid with psychosocial development and vocational training

Patient Management

A multidisciplinary approach is required for a child with Down syndrome. Prenatal imaging and postnatal imaging and laboratory investigations are required to determine the presence of associated medical conditions (eg, neonatal gastrointestinal abnormalities, congenital heart defects, atlantoaxial instability, hypothyroidism, ocular abnormalities, etc). Involvement of other medical specialties such as neonatology, cardiology, gastroenterology and ophthalmology may be necessary. Genetic counselling with parents to discuss the risk of Down syndrome with future pregnancies should also be performed. Special education and social support will be of benefit for psychosocial development and wellbeing of the child and overall wellbeing of parents.

Unusual Clinical Scenarios to Consider in Patient Management
  • –Atlantoaxial instability. Requires caution with physical activity and sports to avoid permanent neurologic deficits.

  • –Congenital leukemia. This is a rare condition but occurs more frequently in Down syndrome.

  • –Cutaneous carotinemia should raise the suspicion that the patient may have hypothyroidism.

  • –Multiple infections. Requires prompt investigations if patients present with infectious symptomatology. Defects in cell-mediated immunity predispose patients with Down syndrome to serious infections, particularly pneumonia (leading to death) and skin infection.

What is the Evidence?

Barankin, B, Guenther, L. “Dermatological manifestations of Down's syndrome”. J Cutan Med Surg. vol. 5. 2001. pp. 289-93. (A concise review of literature focusing only on the cutaneous aspects of Down syndrome with useful explanations for each skin finding.)

Daneshpazhooh, M, Nazemi, TM, Bigdeloo, L, Yoosefi, M. “Mucocutaneous findings in 100 children with Down syndrome”. Pediatr Dermatol. vol. 24. 2007. pp. 317-20. (A study of 100 children [mean age 11.2 years, age range 3 to 20 years] with Down syndrome in special education centers in Iran. Sixty one percent of these children had mucocutaneous findings including fissured tongue (28%), hypertrophy of tongue papilla (22%), premature graying (14%), cheilitis (13%), xerosis (12%), alopecia areata (11%) and palmoplantar hyperkeratosis (10%).)

De Souza, E, Alberman, E, Morris, JK. “Down syndrome and paternal age, a new analysis of case-control data collected in the 1960s”. Am J Med Genet A. vol. 149A. 2009. pp. 1205-8. (These authors analyzed data from the 1960s originally collected to determine if parental radiation exposure had any correlation with having children with Down syndrome. In their dataset of 471 Down syndrome cases and 456 controls (927 records total) the odds ratio of having a child with Down syndrome for every 10-year increase in paternal age was 1.13, 95%CI (0.85, 1.52). Therefore, while there was a positive association with paternal age and Down syndrome, this did not reach a level of statistical significance.)

Dourmishev, A, Miteva, L, Mitev, V, Pramatarov, K, Schwartz, RA. “Cutaneous aspects of Down syndrome”. Cutis. vol. 66. 2000. pp. 420-4. (A case series of three patients with Down syndrome and a brief review of literature.)

Ercis, M, Balci, S, Atakan, N. “Dermatologic manifestations of 71 Down syndrome children admitted to a clinical genetics unit”. Clin Genet. vol. 50. 1996. pp. 317-20. (One of the few large data sets of patients with Down syndrome ranging from age 2 months to 17 years admitted to Hacettepe University Children’s Hospital Genetics Department where they were examined for skin disorders.)

Hirschhorn, KH, Willner, JW, Spitz, JL. “Disorders with chromosome abnormalities”. Genodermatoses – A clinical guide to genetic skin disorders. 2005. pp. 346-7. (An excellent textbook containing concise text, schematic illustrations and clinical photos for each genodermatosis discussed.)

Piersigilli, F, Diociaiuti, A, Boldrini, R, Auriti, C, Curci, M, El Hachem, M. “Vesiculopustular eruption in a neonate with trisomy 21 syndrome as a clue of transient myeloproliferative disorders”. Cutis. vol. 85. 2010. pp. 286-8. (A case report and review of literature on vesiculopustular eruptions as an indication of transient myeloproliferative disorders (TMD) in Down syndrome. TMD can potentially be a predictor of leukemia in later years.)

Pueschel, SM. “Clinical aspects of Down syndrome from infancy to adulthood”. Am J Med Genet. vol. 7. 1990. pp. 52-6. (A brief, comprehensive overview of medical issues pertinent to Down syndrome.)

Pueschel, SM, Scola, FH. “Atlantoaxial instability in individuals with Down syndrome: epidemiologic, radiographic, and clinical studies”. Pediatrics.. vol. 80. 1987. pp. 555-60. (A prospective study of 404 children with Down’s syndrome identified 14.6% [ie, 59 patients] with atlantoaxial instability. The majority of these patients [53 of 59 patients] were asymptomatic thereby emphasizing the importance of precautions to avoid inadvertent neurologic injury.)

Scherbenske, JM, Benson, PM, Rotchford, JP, James, WD. “Cutaneous and ocular manifestations of Down syndrome”. J Am Acad Dermatol. vol. 22. 1990. pp. 933-8. (A well-written case report and review of literature.)

Schepis, C, Barone, C, Siragusa, M, Pettinato, R, Romano, C.. “An updated survey on skin conditions in Down syndrome”. Dermatology. vol. 205. 2002. pp. 234-8. (A study of 203 patients with Down syndrome ranging from infancy to adulthood. The most consistently reported cutaneous findings were a palmar simian crease and xerosis.)