Diagnosis in Dysmorphology: Clues From the Skin

S.F. Smithson; R.M. Winter


The British Journal of Dermatology. 2004;151(5) 

In This Article

Clues From the Skin

The skin is involved in many different syndromes (at least 1000 of 3500).[1] It is accessible and can provide important diagnostic clues or indicate the presence of other malformations. Very diverse patterns of skin involvement occur and these can be broadly classified into six categories which are highlighted below; some further examples are shown in Table 1 .

Developmental Defects

Numerous genes are involved in the development of normal layers of skin cells, and cutis aplasia occurs in more than 32 distinct syndromes.[1] Adams-Oliver syndrome,[21] often dominantly inherited within families, is the most common of these. The scalp defects are variable in severity from a few small areas to extensive lesions affecting the underlying cranial vault and blood vessels,[22] rarely leading to severe haemorrhage. The limb defects consist of terminal reductions of the fingers and toes similar to those resulting from amniotic bands in utero.[23] Scalp defects can also be a marker for chromosomal abnormalities such as trisomy 13 and Wolf-Hirschhorn (4p-) syndrome.[24]

Changes in Pigment

Pigmentary changes in the skin are very common in syndromes and can be important diagnostic features. LEOPARD syndrome (Fig. 2) is an acronym for lentigines, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth and sensorineural deafness.[25] Some patients with this condition have mutations in PTPN11, the gene that causes Noonan syndrome.[26] Preliminary phenotype-genotype studies suggest that the specific mutations determine the likelihood of cardiac anomalies in these allelic disorders, but the mechanism of the lentigines, not present in Noonan syndrome, is unknown.

In this boy with LEOPARD syndrome the lentigines appeared in infancy (a) but were more obvious at the age of 8 years (b).

Increased or decreased pigmentation following the lines of Blaschko is an important pointer to possible chromosome or single gene mosaicism,[27] and a skin biopsy may be needed to detect this.

Abnormal Hair

Abnormal patterns of hair growth, texture and pigmentation can all provide diagnostic clues to dysmorphic syndromes. Hair colour and texture in Menkes syndrome, which may be normal at birth but becomes thin, brittle and depigmented, is often a key sign in association with lethargy, spasticity, seizures and a characteristic face with pallor, full cheeks, tangled eyebrows and a cupid's bow contour to the upper lip.[28] Light microscopy of the hair shows pili torti and sometimes trichorrhexis nodosa. The diagnosis can be demonstrated by a low serum copper and ceruloplasmin and copper uptake studies in fibroblast cultures, and confirmed by detecting mutations in the gene encoding copper-transporting ATPase[29] on the X chromosome.

Vascular Defects

Vascular anomalies in the skin include localized lesions such as the port-wine stain of Sturge-Weber syndrome[30] in the first two divisions of the distribution of the trigeminal nerve on one side of the face. Vascular defects can also be generalized. In Rothmund-Thomson syndrome diffuse or reticular erythema appears on the face, hands and extensor surfaces of the limbs before 6 months of age.[31] The skin lesions evolve to classical poikiloderma, which may be associated with alopecia, photosensitivity, dystrophic nails, abnormal teeth, cataracts, short stature and hypogonadism. Most cases of this syndrome are caused by mutations in the DNA helicase gene RECQL4.[32]

Altered Texture

Skin texture is affected in many syndromes, reflecting the importance of the integrity of structural proteins. The Ehlers-Danlos syndromes, characterized by hyperelasticity and dystrophic scarring,[33,34] result from mutations in collagen genes[35] and impaired post-transcription modification of collagens.[36] Similarly, the autosomal dominant form of cutis laxa is caused by mutations in elastin.[37] Recessive forms of this condition exist[38] but at present their molecular genetic basis is unknown. The ichthyoses are another genetically heterogeneous group of disorders affecting skin texture. X-linked ichthyosis is caused by mutations in the steroid sulphatase gene,[39] but if part of the X chromosome including this gene is deleted a broader clinical picture results including ichthyosis, chondrodysplasia punctata and mental retardation[40] (an example of a contiguous gene syndrome).


Syndromes with skin neoplasia are numerous and involve many types of tumour. Proteus syndrome (Fig. 3) is characterized by asymmetrical overgrowth, usually of a limb, and the numerous skin lesions include intradermal naevi, linear verrucous epidermal naevi, shagreen patches, haemangiomas, lipomas and varicosities.[41] Classic cases are sporadic and the genetic basis is unknown. The skin findings in this condition overlap with many hamartomatous syndromes (some examples are shown in Table 1 ).

Multiple lipomata on the trunk (a) and asymmetrical overgrowth of digits (b) are characteristic of Proteus syndrome.


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