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CHILD syndrome


Tuesday 12 December 2006

CHILD syndrome associates congenital hemidysplasia with ichthyosiform nevus and limb defects (MIM.308050). It is an X-linked dominant trait with lethality for male embryos.

A symmetric distribution of this nevus can exceptionally be seen in patients with CHILD syndrome.

The disorder is caused by mutations in NSDHL (MIM.300275), a gene playing an important role in the cholesterol biosynthetic pathway.

CHILD syndrome is due to loss of function of an enzyme involved in cholesterol biosynthesis.

CHILD syndrome overlaps both phenotypically and genetically with CDPX2. This disorder is distinguished by the striking unilateral presentation of ichthyosiform and inflammatory nevus in heterozygous females, although contralateral skin involvement can be present.


- congenital hemidysplasia
- ichthyosiform nevus
- limb defects
- strictly lateralized inflammatory nevus (right side of the body ++)
- Ipsilateral hypoplastic lesions may involve the brain, skeletal structures, lungs, heart or kidneys.
- Absence of metacarpal, metatarsal and phalangeal bones of the left hand and foot resulting in oligodactyly
- ipsilateral inflammatory epidermal nevus with hyperkeratosis, parakeratosis, acanthosis and perivascular lymphohistiocytic infiltrate


In 1980, Happle et al. reviewed the CHILD phenotype in 20 cases and found that ipsilateral limb defects range from phalangeal hypoplasia to limb truncation, and ipsilateral skeletal defects may include hypoplasia of the calvaria, mandible, scapula, vertebrae, or ribs.

Chondrodysplasia punctata was noted in five of these 20 cases. Congenital heart disease has also been described, as well as ipsilateral renal agenesis and lung hypoplasia.

Unlike CDPX2, cataracts are not reported in CHILD syndrome, and the patient’s right side is more often affected than the left.

Defects in cholesterol synthesis in patients with CHILD syndrome were simultaneously reported by two groups in 2000. König et al. reported mutations in the NADPH sterol dehydrogenase–like protein gene (NSDHL) in six patients, and Grange et al. reported mutation of the EBP gene in a single patient.

The NSDHL protein likely functions in concert with a C4-sterol methyloxidase and a 3-ketoreductase to remove the C4 methyl groups of 4,4-dimethylcholesta-8(9)-en-3β-ol or 4,4-dimethylcholesta-8,24-dien-3β-ol to yield cholesta-8(9)-en-3β-ol or zymosterol, respectively. This enzymatic reaction immediately precedes the reaction catalyzed by EBP.

Although the diagnosis of the patient with the EBP mutation has been debated, CHILD syndrome as a clinical diagnosis is distinguished by its predominantly unilateral presentation.

This presentation may reflect a disturbance of laterality determination induced by the presence of abnormal sterol metabolites.

The function of Hedgehog proteins is affected by abnormal sterol metabolites, and both Sonic hedgehog (Shh) and Indian hedgehog (Ihh) are involved in left-right axis determination.

Although an epigenetic effect of random X-inactivation could lead to a unilateral presentation, this mechanism would not explain why all patients with NSDHL mutations appear to present with CHILD syndrome, whereas only some patients with EBP mutations present with a CHILD phenotype.

However, because of the sequential nature of these two inborn errors of cholesterol synthesis, the elevated 4,4-dimethylcholesta-8-en-3β-ol and 4,4-dimethylcholesta-8,24-dien-3β-ol levels that are characteristic of NSDHL mutations could also occur as a result of mutations in EBP.

A sterol-induced effect on left-right axis determination, perhaps specific to one of these metabolites, needs to be considered. Accumulation of different precursor sterols in patients with NSDHL or EBP mutations may explain the differences in the dermatological findings between these two syndromes and the development of cataracts in CDPX2 but not in CHILD syndrome.

Mutations of the Nsdhl are found in the bare patches (Bpa) and striated (Str) mice. Bpa and Str are allelic phenotypes with a hypomorphic presentation in Str. Heterozygous Bpa females demonstrate growth retardation and have patchy hyperkeratotic skin lesions, short limbs, chondrodysplasia punctata, and asymmetrical cataracts.

The Bpa mutation is a preimplantation lethal for hemizygous male embryos. Liu et al. showed that Bpa and Str mice carry mutations of Nsdhl and sterol profiles consistent with impaired Nsdhl function. The striking unilateral presentation of CHILD syndrome is not observed in Bpa, Str, or tattered (Td) mice.


- CHILD syndrome caused by a deletion of exons 6-8 of the NSDHL gene. Kim CA, Konig A, Bertola DR, Albano LM, Gattás GJ, Bornholdt D, Leveleki L, Happle R, Grzeschik KH. Dermatology. 2005;211(2):155-8. PMID: 16088165

- A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. König A, Happle R, Fink-Puches R, Soyer HP, Bornholdt D, Engel H, Grzeschik KH. J Am Acad Dermatol. 2002 Apr;46(4):594-6. PMID: 11907515