DISEASE CARD

Definition

CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is an X-linked dominant, male lethal, multisystem birth defect characterised by an inflammatory epidermal nevus showing a unique lateralisation pattern and strict midline demarcation. It occurs almost exclusively in females and is related to mutations in the NSDHL gene located at the X chromosome.^1,2

Clinical Description

The most striking manifestation is an inflammatory nevus with unique lateralisation and strict midline demarcation. The nevus may manifest with peculiar inflammatory skin lesions with affinity to body folds (ptychotropism). A bilateral and even symmetrical involvement does not exclude the presence of CHILD syndrome demonstrating the broad range of clinical manifestations. The disorder is either present at birth or develops during the first weeks of life.

Ipsilateral hypoplasia can affect the development of brain, all skeletal structures (frequently causing scoliosis) and viscera such as lungs, heart or kidneys. The limb defect may vary from hypoplasia/shortening of a finger to complete absence of an extremity.^3,4 Internal involvement, especially cardial manifestations, account for a higher degree of premature death.

Like the closely related chondrodysplasia punctata type 2 (CDPX2), the CHILD syndrome is lethal in males and therefore occurs almost exclusively in females. Gene carriers with mild or minimal skin lesions and without any associated extracutaneous defect have been described in families with one severely affected member.¹

Pathogenesis

The syndrome is caused by missense, nonsense or splice site mutations in the NSDHL gene (~ NAD(P)H steroid dehydrogenase-like protein) at Xq28.⁵ Rarely, mutations in EBP (emopamil binding protein) gene are causative.6

Studies carried out on the murine Nsdhl mutants bare patches (Bpa) and striated (Str) have shown that this gene encodes a 3β-hydroxysteroid dehydrogenase (3b-HSD) also known as C3-sterol dehydrogenase.⁷ It is localised within membranes of the endoplasmic reticulum and on the surface of intracellular lipid storage droplets. The enzyme is involved in the removal of C-4 methyl groups in one of the later steps of cholesterol biosynthesis, namely the removal of the two C-4 methyl groups from the sterol backbone of the cholesterol precursor lanosterol. This pathway step is located prior to the 3-b-hydroxysteroid-d8,d7-isomerase gene, the enzyme impaired in Conradi-Hünermann-Happle syndrome (CDPX2). Cholesterol is a key component of cell membranes and the immediate precursor for the synthesis of known steroid hormones and bile acids. Impaired synthesis of cholesterol is involved in the pathology of the CHILD syndrome (non-functional C3 sterol dehydrogenase) as well as other related disorders such as Smith Lemli Opitz syndrome (non-functional 3b-hydoxysteroid-d7-reductase) and Conradi-Hünermann-Happle syndrome (non-functional 3-b-hydroxysteroid-d8,d7-isomerase gene). The respective enzyme blocks may result in the accumulation of toxic intermediates (e. g. interfering with the hedgehog signalling pathway), alternative pathways of cholesterol biosynthesis in different tissues, differential effects on vitamin D metabolism and specific differences in fetal cholesterol transport or metabolism.

Diagnosis

The CHILD nevus constitutes a hallmark of CHILD syndrome and can be distinguished from other epidermal nevi by characteristic features such as ptychotropism, waxy yellowish scaling, the unique lateralisation pattern and characteristic histologic features. The biopsy for histology should be obtained from body folds, where the most characteristic histopathologic feature “verruciform xanthoma” (foamy histiocytes in the papillae, expressing surface markers CD68 and CD163) can be found (however, not in every case). Further histopathological signs include psoriasiform epidermis with hyper- and parakeratosis. Electronmicroscopy might reveal accumulation of lipid droplets or vacuoles in the foam cells within the upper dermis.⁸

X-ray analyses, CT and MRI may be helpful to reveal skeletal dysplasia ranging from minimal extremity shortening to complete absence of bones such as the fibula. However, diagnosis of CHILD syndrome should be confirmed by DNA analysis and by direct sequencing of the NSDHL gene.

Differentialdiagnosis 

Epidermal nevus syndrome, Inflammatory linear verrucous epidermal nevus, Phakomatosis pigmentokeratotixa, Sebaceous nevus syndrome; X-linked dominant chondrodysplasia puncta.⁹

Treatment

Treatment strategy should be adjusted to the severity of the disease.

Complete excision of skin lesions may result in improvement and finally healing, although failures have been reported. Dermabrasio of lesions under general anesthesia leads to recurrence. Some patients suffer from transient exacerbation of inflammatory skin lesions. Bacterial superinfections should be excluded and anti-inflammatory drugs may be useful. Hyperkeratosis and scaling of nevi should be treated with mild keratolytic agents like topical retinoids or urea containing ointments.

Depending on the skeletal involvement orthopaedic surgical corrections may be necessary. Generally, recognition of the CHILD syndrome is important for genetic counselling as women showing an isolated CHILD nevus have an increased risk of giving birth to daughters suffering from a more severe manifestation.

References