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CHILD Syndrome

Neil Alan Fenske, MD, Chairman, Department of Dermatology and Cutaneous Surgery, Professor, Department of Dermatology and Cutaneous Surgery, Department of Pathology and Cell Biology, Department of Oncologic Sciences, University of South Florida College of Medicine
Elizabeth Arrington, MD, Resident Physician, Department of Dermatology, University of South Florida; Babak Roshdieh, MD, Consulting Staff, Department of Dermatology, Sierra View District Hospital; Richard (Rick) L Moore, MD, Staff Physician, Department of Dermatology and Cutaneous Surgery, University of South Florida

Updated: Mar 10, 2009

Introduction

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

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. In 1980, Happle et al proposed the acronym CHILD for congenital hemidysplasia, ichthyosiform erythroderma, and limb defects.3

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.4,5,6 The gene has been localized to Xq28 and encodes for 3beta-hydroxy sterol dehydrogenase, which catalyzes a step in the cholesterol biosynthetic pathway.7 This 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.8,9 The precise mechanism responsible for the striking laterality typical of the syndrome has yet to be elucidated.

Frequency

United States

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

Mortality/Morbidity

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.

Sex

The vast majority of reported cases occur in females because the disorder is X-linked dominant and male lethal. However, 2 known cases have been reported in males, one with a normal 46,XY karyotype, which suggests an early postzygotic somatic mutation.10

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.

Clinical

History

CHILD syndrome is a congenital disorder, often with a constellation of striking physical anomalies that assist the clinician in making the diagnosis.11 Nevertheless, taking a careful history and performing a 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 inheritance pattern of CHILD syndrome is X-linked dominant, the majority of cases are actually sporadic. However, reports of families in which female relatives exhibit milder and limited clinical features suggest that a thorough history may reveal an X-linked dominant pattern.12

Physical

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.13 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 other side, and bilateral, symmetric involvement has been described.5,14 Ptychotropism, or affinity for body folds, of the dermatosis is common.15 The most frequently affected areas are the vulva, axillae, and gluteal folds.
    • The nails are often affected, and alopecia can occur on the affected side.
  • Musculoskeletal: Musculoskeletal abnormalities include ipsilateral limb reduction defects ranging from hypoplasia of the phalanges to defects of the long bones, including 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. Epiphyseal stippling can be noted on radiographs in infants.
  • 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.

Causes

CHILD syndrome is caused by an X-linked dominant mutation in the NSDHL gene encoding for an enzyme in the cholesterol biosynthetic pathway.4,5 The exact pathogenesis by which this mutation causes the clinical findings in individuals with CHILD syndrome is still under investigation.

Differential Diagnoses

Epidermal Nevus Syndrome

Other Problems to Be Considered

X-linked dominant chondrodysplasia puncta16
Inflammatory linear verrucous epidermal nevus17,18,19
Sebaceous nevus syndrome
Phacomatosis pigmentokeratotica20

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.

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

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 with alternating orthokeratosis and parakeratosis. Patchy hypergranulosis is also observed. 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.21 Under electron microscopy, the parakeratotic corneocytes and basal cells contain lipid vacuoles and numerous intercellular vesicular structures.22 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.23,24,25

Treatment

Medical Care

Skin disease can be treated with topical or systemic retinoids. Surgical excision is also an option in certain cases. Orthopedic abnormalities can be treated with braces or corrective surgery. Other medical care is dictated by the organ system(s) involved.

Consultations

Treatment of a patient with CHILD syndrome is multidisciplinary and dictated by the organ(s) involved. Consultation of the following physicians may be necessary:

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

Medication

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

Keratolytics

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


Lactic acid 12% (Lac-Hydrin, AmLactin) creams or lotions

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.

Dosing

Adult

Apply 1-3 times/d

Pediatric

Apply as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause stinging and burning at the site of application


Urea (Ureacin, Ureaphil, Carmol) creams or lotions

Used topically in the treatment of dry skin. Promotes hydration and removal of excess keratin in conditions of hyperkeratosis. At concentrations of 10-40%, it has a keratolytic effect.

Dosing

Adult

Apply 1-3 times/d

Pediatric

Apply as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; viral skin disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use near eyes; caution if applied to broken or swollen skin; local irritation may occur at site of application; some commercially available preparations contain sulfites, which may cause an anaphylactic response in individuals who are susceptible

Retinoids

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


Tretinoin (Retin-A, Avita, Renova)

Normalizes keratinization.

Dosing

Adult

Apply topically to affected areas qhs

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Other skin irritants (ie, astringents, benzoyl peroxide, salicylic acid, resorcinol, topical sulfur, other keratolytics, abrasives, astringents, spices, lime) may exacerbate irritation; coadministration with other drugs that cause photosensitivity (eg, tetracycline, sulfonamides) may increase risk of sunburn

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with excessive sunlight exposure; burning, stinging, peeling, pruritus, or erythema has been reported at site of application; caution with eczema (may cause severe irritation); avoid contact with mucous membranes, mouth, and angles of nose

Follow-up

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.

Prognosis

Patients with left-sided involvement generally have more severe internal abnormalities, especially in regard to cardiac anomalies, and therefore have a worse prognosis.

References

  1. Bittar M, Happle R. CHILD syndrome avant la lettre. J Am Acad Dermatol. Feb 2004;50(2 Suppl):S34-7. [Medline].

  2. Zellweger H, Uehlinger E. Ein Fall von halbseitiger knochenchondromatose (Ollier) mit naevus ichthyosiformis. Helv Paediatr Acta. May 1948;3(2):153-63. [Medline].

  3. Happle R, Koch H, Lenz W. The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr. Jun 1980;134(1):27-33. [Medline].

  4. Hummel M, Cunningham D, Mullett CJ, Kelley RI, Herman GE. Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. Am J Med Genet A. Oct 15 2003;122A(3):246-51. [Medline].

  5. Konig A, Happle R, Fink-Puches R, Soyer HP, Bornholdt D, Engel H, et al. A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J Am Acad Dermatol. Apr 2002;46(4):594-6. [Medline].

  6. Konig A, Happle R, Bornholdt D, Engel H, Grzeschik KH. Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet. Feb 14 2000;90(4):339-46. [Medline].

  7. Bornholdt D, Konig A, Happle R, et al. Mutational spectrum of NSDHL in CHILD syndrome. J Med Genet. Feb 2005;42(2):e17. [Medline].

  8. Happle R, Konig A, Grzeschik KH. Behold the CHILD, it's only one: CHILD syndrome is not caused by deficiency of 3 beta-hydroxysteroid-Delta 8, Delta 7-isomerase. Am J Med Genet. Oct 2 2000;94(4):341-3. [Medline].

  9. Kim CA, Konig A, Bertola DR, et al. CHILD syndrome caused by a deletion of exons 6-8 of the NSDHL gene. Dermatology. 2005;211(2):155-8. [Medline].

  10. Happle R, Effendy I, Megahed M, Orlow SJ, Küster W. CHILD syndrome in a boy. Am J Med Genet. Mar 15 1996;62(2):192-4. [Medline].

  11. Kaminska-Winciorek G, Brzezinska-Wcislo L, Jezela-Stanek A, Krajewska-Walasek M, Cunningham D, Herman GE. CHILD syndrome: clinical picture and diagnostic procedures. J Eur Acad Dermatol Venereol. May 2007;21(5):715-6. [Medline].

  12. Bittar M, Happle R, Grzeschik KH, et al. CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol. Mar 2006;142(3):348-51. [Medline].

  13. Happle R. The lines of Blaschko: a developmental pattern visualizing functional X-chromosome mosaicism. Curr Probl Dermatol. 1987;17:5-18. [Medline].

  14. Fink-Puches R, Soyer HP, Pierer G, Kerl H, Happle R. Systematized inflammatory epidermal nevus with symmetrical involvement: an unusual case of CHILD syndrome?. J Am Acad Dermatol. May 1997;36(5 Pt 2):823-6. [Medline].

  15. Happle R. Ptychotropism as a cutaneous feature of the CHILD syndrome. J Am Acad Dermatol. Oct 1990;23(4 Pt 1):763-6. [Medline].

  16. Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet. 1979;53(1):65-73. [Medline].

  17. Altman J, Mehregan AH. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. Oct 1971;104(4):385-9. [Medline].

  18. Golitz LE, Weston WL. Inflammatory linear verrucous epidermal nevus. Association with epidermal nevus syndrome. Arch Dermatol. Oct 1979;115(10):1208-9. [Medline].

  19. Happle R. Child naevus is not ILVEN. J Med Genet. Mar 1991;28(3):214. [Medline].

  20. Tadini G, Restano L, Gonzales-Perez R, et al. Phacomatosis pigmentokeratotica: report of new cases and further delineation of the syndrome. Arch Dermatol. Mar 1998;134(3):333-7. [Medline].

  21. Barr RJ, Plank CJ. Verruciform xanthoma of the skin. J Cutan Pathol. Dec 1980;7(6):422-8. [Medline].

  22. Dale BA, Kimball JR, Fleckman P, Herbert AA, Holbrook KA. CHILD syndrome: lack of expression of epidermal differentiation markers in lesional ichthyotic skin. J Invest Dermatol. Apr 1992;98(4):442-9. [Medline].

  23. Emami S, Rizzo WB, Hanley KP, Taylor JM, Goldyne ME, Williams ML. Peroxisomal abnormality in fibroblasts from involved skin of CHILD syndrome. Case study and review of peroxisomal disorders in relation to skin disease. Arch Dermatol. Sep 1992;128(9):1213-22. [Medline].

  24. Goldyne ME, Williams ML. CHILD syndrome. Phenotypic dichotomy in eicosanoid metabolism and proliferative rates among cultured dermal fibroblasts. J Clin Invest. Jul 1989;84(1):357-60. [Medline].

  25. Hebert AA, Esterly NB, Holbrook KA, Hall JC. The CHILD syndrome. Histologic and ultrastructural studies. Arch Dermatol. Apr 1987;123(4):503-9. [Medline].

  26. Cullen SI, Harris DE, Carter CH, Reed WB. Congenital unilateral ichthyosiform erythroderma. Arch Dermatol. Jun 1969;99(6):724-9. [Medline].

  27. Diczfalusy U, Alexson SE. Peroxisomal chain-shortening of prostaglandin F2 alpha. J Lipid Res. Dec 1988;29(12):1629-36. [Medline].

  28. Enjolras O, Guerin D, Hewitt J. [Knowledge of Solomon's epidermal nevus syndrome (author's transl)]. Ann Dermatol Venereol. Sep 1979;106(8-9):673-80. [Medline].

  29. Happle R, Mittag H, Küster W. The CHILD nevus: a distinct skin disorder. Dermatology. 1995;191(3):210-6. [Medline].

  30. Rossman RE, Shapiro EM, Freeman RG. Unilateral ichthyosiform erythroderma. Arch Dermatol. Nov 1963;88:567-71. [Medline].

  31. Solomon LM, Fretzin DF, Dewald RL. The epidermal nevus syndrome. Arch Dermatol. Mar 1968;97(3):273-85. [Medline].

Keywords

CHILD syndrome, congenital hemidysplasia, ichthyosiform nevus, limb defects, unilateral ichthyosiform erythroderma, unilateral erythrokeratoderma, unilateral epidermal nevus, unilateral ectromelia, inflammatory variable epidermal nevus, unilateral limb and skin deformities with congenital heart disease, CHILD nevus, congenital hemidysplasia with ichthyosiform erythroderma and limb defects

Contributor Information and Disclosures

Author

Neil Alan Fenske, MD, Chairman, Department of Dermatology and Cutaneous Surgery, Professor, Department of Dermatology and Cutaneous Surgery, Department of Pathology and Cell Biology, Department of Oncologic Sciences, University of South Florida College of Medicine
Disclosure: Dermik Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching; Graceway Pharmaceuticals Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Warner Chilcott Honoraria Speaking and teaching

Coauthor(s)

Elizabeth Arrington, MD, Resident Physician, Department of Dermatology, University of South Florida
Elizabeth Arrington, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Babak Roshdieh, MD, Consulting Staff, Department of Dermatology, Sierra View District Hospital
Disclosure: Nothing to disclose.

Richard (Rick) L Moore, MD, Staff Physician, Department of Dermatology and Cutaneous Surgery, University of South Florida
Richard (Rick) L Moore, MD is a member of the following medical societies: American Academy of Dermatology and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Abdul-Ghani Kibbi, MD, Chairman and Professor, Department of Dermatology, American University of Beirut Medical Center, Lebanon
Disclosure: none None None

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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