CHILD Syndrome 

Updated: Aug 20, 2019
Author: Amanda T Moon, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome is a rare disorder characterized by birth defects of several organ systems, including the skin, viscera, musculoskeletal system, and central nervous system. The earliest description of the syndrome has been attributed to Otto Sachs in 1903, who comprehensively described the clinical features of CHILD syndrome in an 8-year-old girl.[1] This was followed by a report in 1948 by Zellweger and Uelinger, who reported a patient with a "half-sided osteochondrodermatitis and nevus ichthyosiformis."[2] In 1980, Happle et al reviewed 18 previous cases and introduced two additional cases; they proposed the acronym CHILD syndrome for congenital hemidysplasia, ichthyosiform erythroderma, and limb defects.[3] In 2010, Knape et al reported the first case of CHILD syndrome with ocular manifestations in a patient with progressive bilateral optic nerve atrophy.[4]

Since then, other patients with a similar constellation of defects have been described under a number of designations, including unilateral ichthyosiform erythroderma, unilateral erythrokeratoderma, unilateral epidermal nevus, unilateral ectromelia, inflammatory variable epidermal nevus, and unilateral limb and skin deformities with congenital heart disease.

Pathophysiology

CHILD syndrome is inherited in an X-linked dominant fashion and involves a mutation in the NSDHL (NAD[P]H steroid dehydrogenase–like protein) gene.[5, 6, 7, 8, 9] The gene has been localized to Xq28 and encodes for 3beta-hydroxy sterol dehydrogenase, which is an enzyme that is critical for cholesterol synthesis.[10] Endogenous cholesterol production is essential for human development before and after birth. Cholesterol is necessary for the synthesis of hormones, production of digestive acids, stabilization of cell membranes, and formation of myelin on nerve fibers. The loss-of-function mutation seen in CHILD syndrome prevents the NSDHL enzyme from catalyzing a step in the cholesterol biosynthetic pathway. As a result, cells are unable to produce cholesterol and there is a buildup of toxin byproducts of the cholesterol synthesis pathway.[11] The NSDHL enzyme is located both within the membranes of the endoplasmic reticulum and on the surface of intracellular lipid storage droplets. Several different types of mutations in the gene have been documented, including missense, nonsense, and stop mutations, all resulting in a loss of function of NSDHL.

Clinical variations in the extent of involvement are not thought to be secondary to the specific type of mutation, but rather the differences in the pattern of X inactivation.[12, 13] The striking laterality of the syndrome may arise from this impaired cholesterol processing, causing abnormal sonic hedgehog signaling, which, in embryogenesis, is important in spatial patterning.[14, 15]

Etiology

CHILD syndrome is caused by an X-linked dominant mutation in the NSDHL gene encoding for an enzyme in the cholesterol biosynthetic pathway.[5, 6] Twenty unique mutations along the NSDHL gene have been shown to cause CHILD syndrome.[8] The exact pathogenesis by which this mutation causes the clinical findings in individuals with CHILD syndrome is still under investigation, but contributing factors likely include deficient cholesterol synthesis, buildup of toxic metabolites in the cholesterol biosynthesis pathway, and abnormal sonic hedgehog signaling.[16, 17]

Epidemiology

Frequency

No precise data are available regarding the frequency of the disease; however, around 60 cases have been reported thus far in the literature.

Sex

The vast majority of reported cases occur in females because the disorder is X-linked dominant and lethal in males. However, two known cases have been reported in males, one with a normal 46,XY karyotype, which suggests an early postzygotic somatic mutation.[18]

Age

CHILD syndrome is a congenital disorder. The dermatosis may be present at birth or may develop during the first few weeks of life and persists for the lifetime of the patient.

Prognosis

Patients with left-sided involvement generally have more severe internal abnormalities, especially in regard to cardiac anomalies, and therefore have a worse prognosis. Early death in persons with CHILD syndrome is most commonly due to cardiovascular malformations. However, central nervous system, skeletal, kidney, lung, and other visceral defects can contribute to significant morbidity.

 

Presentation

History

CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome is a congenital disorder, often with a constellation of striking physical anomalies that assist the clinician in making the diagnosis.[19] Nevertheless, taking a careful history and review of systems, in addition to performing a physical examination and further testing, is important in order to determine the extent of involvement in the individual patient. In addition, the family history should also be explored. Although the majority of CHILD syndrome cases are sporadic, there is a known X-linked dominant inheritance pattern. Reports have described families in which there is extreme X-inactivation resulting in milder and limited clinical features of the disease. Therefore, a thorough history may reveal an X-linked dominant pattern.[20]

Physical Examination

CHILD syndrome is a disorder with ipsilateral involvement of the skin, the viscera, and the musculoskeletal and central nervous systems.

Skin and nails

Cutaneous manifestations include unilateral, waxy, scaling, (ichthyosiform) erythematous plaques with a sharp midline demarcation present at birth or shortly thereafter and persistent throughout life. The distinct unilateral pattern may be diffuse and/or linear, with streaks following the lines of Blaschko.[21] The face is usually spared. Right-sided involvement occurs at least twice as often as left-sided involvement. Small patches of involved skin can occur on the contralateral side, and bilateral, symmetric involvement has been described.[6, 22] Skin lesions seen in CHILD syndrome typically involve the neck, body, extremities, and perineum.[8] Unilateral ptychotropism, or affinity for body folds, is common.[23] The most frequently affected skinfolds are the vulva, axillae, and gluteal folds.

Verruciform xanthomas (VXs) have also been associated with CHILD syndrome; VXs are rare benign tumors usually found on the oral mucosa or in the anogenital region, but the VXs found in CHILD syndrome are usually nonoral and nongenital.[24] VXs are also associated with chronic inflammation, graft versus host disease, and lymphedema.[25]

The nails are also commonly affected in CHILD syndrome. According to the Human Phenotype Ontology database, 30-79% of people have nail abnormalities and hyperkeratosis.[11] Additionally, a scarring alopecia can occur, most often on the affected side.[16, 26]

Musculoskeletal

Musculoskeletal abnormalities include ipsilateral limb reduction defects ranging from hypoplasia of the phalanges to agenesis of an extremity. Ipsilateral hypoplasia of the axial skeleton, including the calvaria, mandible, scapula, ribs, and vertebrae, which can lead to scoliosis, can also be present.[27] Unilateral epiphyseal stippling of the pelvis, ribs, vertebrae, and extremities can be noted on radiographs in infants.[3] Of individuals with CHILD syndrome, 80-99% have aplasia/hypoplasia of the extremities and epiphyseal stippling.[11]

Viscera

Multiple ipsilateral anomalies of the viscera and central nervous system are observed in individuals with CHILD syndrome. These anomalies include cardiac malformations and ipsilateral hypoplasia of the brain, lungs, thyroid, and reproductive tract. The ipsilateral kidney also may be involved. Cardiovascular malformations are the most common causes of early death and are encountered most often in left-sided cases.

Complications

Noncutaneous anomalies contribute to the most serious complications. Congenital cardiac defects are the main cause of early death in children. Other significant problems can occur with involvement of the musculoskeletal, renal, pulmonary, or central nervous systems.

 

DDx

Diagnostic Considerations

Also consider the following:

  • X-linked dominant chondrodysplasia puncta [28]
  • Inflammatory linear verrucous epidermal nevus [29, 30, 31]
  • Sebaceous nevus syndrome
  • Phacomatosis pigmentokeratotica [32]
  • Epidermal nevus syndrome [33]
 

Workup

Laboratory Studies

Laboratory testing involves sterol analysis of plasma, tissues, or cultured cells by gas chromatography–mass spectometry, which shows elevated levels of C4-methylated and C4-carboxy sterol intermediates.

Plasma cholesterol is normal in patients with CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome.

Imaging Studies

Radiographic examination of the head, trunk, and extremities is essential for detecting any skeletal abnormalities. Additionally, computed tomography scanning of the head and the trunk may reveal hypoplasia or aplasia of the brain and/or the viscera.

Other Tests

Ultrasonography of the viscera, echocardiography, and full brain magnetic resonance imaging help identify internal anomalies associated with CHILD syndrome.[34] Definitive diagnosis can be made with genetic testing for mutations in the NSDHL gene by DNA sequence analysis.

Procedures

A skin biopsy may be performed. Obtaining samples from both involved skin and uninvolved skin is necessary.

Histologic Findings

The epidermis from involved skin shows marked acanthosis and papillomatosis with alternating orthokeratosis and parakeratosis. Patchy hypergranulosis and a superficial perivascular infiltrate are also observed.[35, 36]

A distinctive phenomenon of verruciform xanthoma, which is characterized by enlarged papillae filled with foamy histiocytes, has been reported when biopsy samples are obtained from body folds.[37, 38] Under electron microscopy, the parakeratotic corneocytes and basal cells contain lipid vacuoles and numerous intercellular vesicular structures.[39] Abnormal cementosomes with electron-dense bodies have also been reported. The papillary dermis is thickened and filled with histiocytes containing large lipid vacuoles. The fibroblasts are similarly filled with lamellated structures.[35, 40, 41]

 

Treatment

Approach Considerations

Skin disease seen in CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome can be treated with topical retinoids, topical emollient ointments, or systemic retinoids.[42, 43] Keratolytics have also been used for symptomatic relief of dry, scaling skin. Lactic acid 12% creams or lotions alleviate itching, while urea creams improve dryness.[34] A cream composed of 2% cholesterol and 2% lovastatin has been shown to be effective in treating ichthyosis through its ability to deliver functional cholesterol while also inhibiting accumulation of toxic metabolites.[9]

Surgical excision of skin lesions is also an option in certain cases. Dermabrasion followed by split-thickness skin grafting from the contralateral, nonaffected side has been successfully performed.[42, 43]

Other medical care is dictated by the organ system(s) involved. Lung, heart, and renal anomalies may be fatal and require immediate surgical intervention.[44] Orthopedic abnormalities can be treated with braces or corrective surgery.

Consultations

Treatment of a patient with CHILD syndrome is multidisciplinary and dictated by the organ(s) involved. Consultations may include the following:

  • A dermatologist for management of the cutaneous findings

  • A pediatric orthopedic surgeon for evaluation and treatment of the musculoskeletal deformities

  • A geneticist for counseling and genetic testing

  • A neurologist, pulmonologist, cardiologist, or nephrologist, depending on the organ system(s) involved

 

Medication

Medication Summary

Cutaneous findings are treated with systemic or topical steroids. Keratolytics have also been advocated.

Keratolytics

Class Summary

These agents are used for symptomatic relief of dry, scaling skin. They also help exfoliate the skin.

Ammonium lactate (Lac-Hydrin, AmLactin)

Ammonium lactate relieves itching and aids healing of skin in persons with mild eczemas and dermatoses, minor wounds, and minor skin irritations. Lactic acid is an alpha-hydroxy acid.

Urea (Ureacin, Ureaphil, Carmol) creams or lotions

Urea is used topically in the treatment of dry skin. It promotes hydration and removal of excess keratin in conditions of hyperkeratosis. At concentrations of 10-40%, it has a keratolytic effect.

Retinoids

Class Summary

Topical and systemic retinoids have been advocated to help normalize the keratinization of the epidermis.

Tretinoin topical (Retin-A, Avita, Renova)

Tretinoin topical normalizes keratinization.