CHILD Syndrome Clinical Presentation
- Author: Neil Alan Fenske, MD; Chief Editor: Dirk M Elston, MD more...
CHILD syndrome is a congenital disorder, often with a constellation of striking physical anomalies that assist the clinician in making the diagnosis. 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 inheritance pattern of CHILD syndrome is X-linked dominant, the majority of cases are 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.
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. 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, 17] Ptychotropism, or affinity for body folds, is common. The most frequently affected areas 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. VXs are also associated with chronic inflammation, graft versus host disease, and lymphedema.
The nails are often affected, and a scarring alopecia can occur, most often on the affected side.[20, 21]
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. Epiphyseal stippling can be noted on radiographs in infants.
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.
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] 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.[21, 23]
Bittar M, Happle R. CHILD syndrome avant la lettre. J Am Acad Dermatol. 2004 Feb. 50(2 Suppl):S34-7. [Medline].
Zellweger H, Uehlinger E. Ein Fall von halbseitiger knochenchondromatose (Ollier) mit naevus ichthyosiformis. Helv Paediatr Acta. 1948 May. 3(2):153-63. [Medline].
Happle R, Koch H, Lenz W. The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr. 1980 Jun. 134(1):27-33. [Medline].
Knape RM, Gandhi KB, Tuli SY, Khuddus N. Optic Nerve Findings in CHILD Syndrome. J Pediatr Ophthalmol Strabismus. 2010 Sep 22. 47 Online:e1-3. [Medline].
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. 2003 Oct 15. 122A(3):246-51. [Medline].
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. 2002 Apr. 46(4):594-6. [Medline].
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. 2000 Feb 14. 90(4):339-46. [Medline].
Bornholdt D, Konig A, Happle R, et al. Mutational spectrum of NSDHL in CHILD syndrome. J Med Genet. 2005 Feb. 42(2):e17. [Medline].
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. 2000 Oct 2. 94(4):341-3. [Medline].
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].
Farese RV Jr, Herz J. Cholesterol metabolism and embryogenesis. Trends Genet. 1998 Mar. 14(3):115-20. [Medline].
Johnson RL, Scott MP. New players and puzzles in the Hedgehog signaling pathway. Curr Opin Genet Dev. 1998 Aug. 8(4):450-6. [Medline].
Happle R, Effendy I, Megahed M, Orlow SJ, Küster W. CHILD syndrome in a boy. Am J Med Genet. 1996 Mar 15. 62(2):192-4. [Medline].
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. 2007 May. 21(5):715-6. [Medline].
Bittar M, Happle R, Grzeschik KH, et al. CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol. 2006 Mar. 142(3):348-51. [Medline].
Happle R. The lines of Blaschko: a developmental pattern visualizing functional X-chromosome mosaicism. Curr Probl Dermatol. 1987. 17:5-18. [Medline].
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. 1997 May. 36(5 Pt 2):823-6. [Medline].
Happle R. Ptychotropism as a cutaneous feature of the CHILD syndrome. J Am Acad Dermatol. 1990 Oct. 23(4 Pt 1):763-6. [Medline].
Blankenship DW, Zech L, Mirzabeigi M, Venna S. Verruciform xanthoma of the upper-extremity in the absence of chronic skin disease or syndrome: a case report and review of the literature. J Cutan Pathol. 2013 Aug. 40(8):745-52. [Medline].
Avgerinou GP, Asvesti AP, Katsambas AD, et al. CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder. J Eur Acad Dermatol Venereol. 2010 Jun. 24(6):733-6. [Medline].
Chander R, Varghese B, Jabeen M, Garg T, Jain M. CHILD syndrome with thrombocytosis and congenital dislocation of hip: A case report from India. Dermatol Online J. 2010 Aug 15. 16(8):6. [Medline].
Seeger MA, Paller AS. The role of abnormalities in the distal pathway of cholesterol synthesis in the Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome. Biochim Biophys Acta. 2014 Mar. 1841(3):345-52. [Medline].
Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet. 1979. 53(1):65-73. [Medline].
Altman J, Mehregan AH. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1971 Oct. 104(4):385-9. [Medline].
Golitz LE, Weston WL. Inflammatory linear verrucous epidermal nevus. Association with epidermal nevus syndrome. Arch Dermatol. 1979 Oct. 115(10):1208-9. [Medline].
Happle R. Child naevus is not ILVEN. J Med Genet. 1991 Mar. 28(3):214. [Medline].
Tadini G, Restano L, Gonzales-Perez R, et al. Phacomatosis pigmentokeratotica: report of new cases and further delineation of the syndrome. Arch Dermatol. 1998 Mar. 134(3):333-7. [Medline].
Hebert AA, Esterly NB, Holbrook KA, Hall JC. The CHILD syndrome. Histologic and ultrastructural studies. Arch Dermatol. 1987 Apr. 123(4):503-9. [Medline].
Barr RJ, Plank CJ. Verruciform xanthoma of the skin. J Cutan Pathol. 1980 Dec. 7(6):422-8. [Medline].
Kurban M, Abbas O, Ghosn S, Kibbi AG. Late evolution of giant verruciform xanthoma in the setting of CHILD syndrome. Pediatr Dermatol. 2010 Sep-Oct. 27(5):551-3. [Medline].
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. 1992 Apr. 98(4):442-9. [Medline].
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. 1992 Sep. 128(9):1213-22. [Medline].
Goldyne ME, Williams ML. CHILD syndrome. Phenotypic dichotomy in eicosanoid metabolism and proliferative rates among cultured dermal fibroblasts. J Clin Invest. 1989 Jul. 84(1):357-60. [Medline].
König A, Skrzypek J, Löffler H, Oeffner F, Grzeschik KH, Happle R. Donor dominance cures CHILD nevus. Dermatology. 2010. 220(4):340-5. [Medline].