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Paediatrics: Genetic disorders with dermatological features

Sometimes it is the cutaneous features that are the key to diagnosis of a genetic disorder.

Genetic disorders with dermatological features


Sometimes it is the cutaneous features that are the key to diagnosis of a genetic disorder.


Ehlers–Danlos syndrome (EDS)

   Incidence 71/5000 births.

   There are numerous types of EDS. Classical EDS is autosomal dominant and caused by mutation in the COL5A1 and COL5A2 genes.

   All forms of EDS are characterized by skin fragility, unsightly bruising and scarring, musculoskeletal discomfort, and susceptibility to osteoarthritis. The skin is soft and hyperextensible with easy bruising and thin, atrophic ‘cigarette paper’ scars, joint hypermobility, varicose veins, and a risk of premature delivery in affected fetuses.

   Hypermobile EDS is a common and usually mild autosomal dominant disorder characterized by soft skin with hypermobility of large and small joints.


Neurofibromatosis type 1


   NF1 has a prevalence of 71/4000.

   AD condition caused by mutation in the NF1 gene on 17q11.2.

   For a clinical diagnosis of NF1, the patient should have two or more of the following features:

   6 or more café-au-lait spots (  0.5cm in children);

   2 or more neurofibromata of any type (dermal neurofibromata are small lumps in the skin that appear in adolescence) or 1 or more plexiform neurofibromata;

   freckling in the axilla, neck, or groin;

   optic glioma (tumour in the optic pathway);

   2 or more Lisch nodules (benign iris hamartomas);

   a distinctive bony lesion, e.g. sphenoid wing dysplasia, or dysplasia or thinning of the long bone cortex, e.g. pseudoarthrosis;

   a first-degree relative with NF1.

   NF1 is a highly variable disorder with a small risk of serious complications, e.g. scoliosis, pressure effects of tumours or malignant change, (e.g. neural crest tumours), hypertension. Regular surveillance, e.g. annual review, is recommended to try and detect these early.


X-linked hypohidrotic ectodermal dysplasia


   The condition follows X-linked recessive inheritance and is caused by mutation in the EDA-1 gene.

   Boys have reduced/absent sweating that may cause dangerous hyperpyrexia in infancy.


Carrier females may be mildly affected.


Tuberous sclerosis complex


Affects 71/10 000 individuals.

A highly variable autosomal dominant multisystem disorder caused by mutation in the TSC1 gene on 9q or the TSC2 gene on 16p.

Characterized by hamartomas in the brain, skin, and other organs.

Commonly presents with infantile spasms. Seizures and mental retardation are often associated.

Hypomelanotic macules (‘ash-leaf’ spots) occur in 795% of affected individuals by the age of 5yrs. A Wood’s light (UV) may be needed to visualize these. Angiofibromata occur in later childhood in a butterfly distribution over the nose and cheeks. Other cutaneous features include forehead fibrous plaque, shagreen patches, ungual fibromata, and dental pits.

50% of individuals with TSC have normal intelligence, but children who develop infantile spasms and severe epilepsy in the first year of life often have learning disability.

Thorough clinical evaluation, e.g. cranial MRI, eye exam, renal US, is indicated to make the diagnosis prior to genetic testing.

Expert genetic advice, with careful evaluation of the parents, is important. 760% of cases arise as a result of new mutations.

Genetic testing is possible by mutation analysis of TSC1 and TSC2, but it is helpful to establish a clear clinical diagnosis before embarking on genetic testing.


Incontinentia pigmenti


Rare X-linked dominant disorder caused by mutation in the NEMO gene on Xq28 (780% carry a common deletion).

Affected male pregnancies almost invariably miscarry. Girls present in the neonatal period with blistering lesions, cropping circumferentially on the trunk and in a linear distribution on the limbs. Ultimately, lesions regress by late childhood/adult life to leave atrophic streaky areas of pigmentation or hypopigmentation (often most noticeable on the back of the calves). The child remains well and continues to feed. There is often a marked eosinophilia in the blood.

750% have associated abnormalities of dentition, eye (cataracts), or CNS (seizures, microcephaly).

Genetic testing is possible; 780% of affected individuals carry a large deletion in the NEMO gene.


No specific treatment available.


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