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CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects, CS) is an X-linked dominant genodermatosis characterized by unilateral inflammatory and scaling skin lesions with ipsilateral visceral and limb anomalies.
ORPHA:139Classification level: Disorder
Less than 60 cases have been reported to date, mainly in female patients.
CS patients present at birth or shortly thereafter with unilateral yellow ichthyosiform nevi in the form of patches halting abruptly at the midline, with an affinity to skin folds (ptychotropism), generally sparing the face. A claw-like onychodystrophy and periungual hyperkeratosis are common and ipsilateral bald patches may be present. This is accompanied by ipsilateral limb defects, ranging from shortened metacarpals and phalanges to the absence of an entire limb. Additional malformations may include the absence of ribs, vertebrae and long bones, and scoliosis and joint contractures. During the first months of life, punctate calcification of cartilage (stippled epiphyses) may be noted on X-rays. Ipsilateral renal defects have been reported (unilateral hydronephrosis, renal agenesis; see this term). Most patients present with normal intellectual development, although unilateral CNS defects have often been reported including unilateral hypoplasia of cranial nerves and the spinal cord, lissencephaly and cerebellar malformation (see these terms). The involvement may be right or left-sided, but mild contralateral lesions are often noted. Over two-thirds of cases have presented with right-sided involvement, perhaps due to more severe cardiac involvement causing prenatal death in left-sided cases. Lung hypoplasia has also been reported in several cases. Hearing loss, optic atrophy, absence of some facial muscles, thrombocytosis, congenital bilateral hip dislocation, unilateral hypoplasia of the thyroid gland, adrenal glands, ovaries and fallopian tubes have been reported in single cases.
NSDHL (Xq28) encodes a protein responsible for cholesterol biosynthesis, mutations are typically lethal in males. X-inactivation creates a mosaic of cells lacking the enzyme in females, disrupting embryonic development and leading to a highly variable spectrum of anomalies.
In most cases, the striking lateralization of all lesions, also noted on X-rays, is a strong diagnostic clue. Skin lesion histology reminiscent of psoriasis reveals hyperkeratosis and parakeratosis with inflammatory infiltrates. Biopsies from papillomatous lesions involving the body folds, however, show highly characteristic verruciform xanthoma in the form of lipid-laden histiocytes in the papillary dermis. Ultrasound of viscera, echocardiogram and full brain MRI are required to complement X-rays and identify all anomalies. Genetic testing confirms the diagnosis.
Differential diagnoses include X-linked dominant chondrodysplasia punctata, linear nevus sebaceous syndrome and inflammatory linear verrucous epidermal nevus (see these terms).
Genetic testing from chronic villus samples is available; certain anomalies may be identified during routine sonograms.
Transmission is X-linked dominant. Sporadic cases have been reported, but extreme X-inactivation may mask the phenotype. Mothers should be examined for the presence of minimal symptoms and tested for a NSDHL mutation. Carriers have a 50% chance of transmission to daughters, but cannot transmit to live-born sons.
Management and treatment
Lung and heart anomalies are potentially fatal and may require immediate surgical intervention. Renal anomalies may also require draining or removal of the affected kidney. Orthopedic braces or corrective surgery may be necessary. Contralateral autologous skin grafts have been successfully performed. Skin lesions are best treated by topical application of a lotion or ointment containing lovastatin or simvastatin in combination with cholesterol.
Prognosis is highly variable and based upon skeletal or cardiac anomalies. Cases of minimal involvement carry the risk of a severe disease in offspring.