NSDHL – CHILD syndrome

NSDHL (HGNC:13398) encodes the 3β-hydroxysteroid dehydrogenase-like enzyme essential for cholesterol biosynthesis and is causative of CHILD syndrome (MONDO:0010621), an X-linked dominant, male-lethal disorder presenting with unilateral ichthyosiform erythroderma, hemidysplasia and ipsilateral limb defects.

The gene–disease relationship was first established by identifying NSDHL mutations in six unrelated CHILD syndrome patients, including loss-of-function and missense alleles (PMID:10710235). To date, at least four truncating variants (c.262C>T (p.Arg88Ter), c.628C>T (p.Gln210Ter) (PMID:10710235); deletion of exons 6–8 (PMID:16088165)) and five missense variants—including the recurrent c.314C>T (p.Ala105Val) (PMID:19906044)—have been reported in diverse cohorts.

Familial segregation of NSDHL variants has been demonstrated in a three-generation kindred with five affected females carrying a c.370G>A (p.Gly124Ser) mutation, confirming X-linked dominant inheritance (PMID:16549711).

Functional studies in murine models and yeast complementation assays show that pathogenic NSDHL missense alleles (e.g., p.Ala94Thr) and truncating mutations fail to rescue sterol dehydrogenase activity, consistent with loss-of-function (PMID:14567972). Furthermore, chemical chaperone studies indicate that select NSDHL mutants can be partially rescued, informing potential therapeutic strategies.

A pathogenesis-based topical therapy combining 2% simvastatin and 2% cholesterol led to marked improvement of verrucous plaques in a CHILD syndrome patient with a large NSDHL deletion, underscoring the role of toxic metabolite accumulation (PMID:29341259).

NSDHL genetic testing provides a definitive diagnosis, informs genetic counseling and enables targeted treatments. Key take-home: Pathogenic NSDHL variants underlie CHILD syndrome and guide both clinical care and research.

References

• American Journal of Medical Genetics • 2000 • Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. PMID:10710235
• Archives of Dermatology • 2006 • CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. PMID:16549711
• Molecular Genetics and Metabolism • 2003 • Identification of two novel mutations in the murine Nsdhl sterol dehydrogenase gene and development of a functional complementation assay in yeast. PMID:14567972
• Dermatology (Basel) • 2005 • CHILD syndrome caused by a deletion of exons 6-8 of the NSDHL gene. PMID:16088165
• Journal of the European Academy of Dermatology and Venereology • 2010 • CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder. PMID:19906044
• JEADV • 2018 • CHILD syndrome mimicking verrucous nevus in a Chinese patient responded well to the topical therapy of compound of simvastatin and cholesterol. PMID:29341259

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