In other species: dog

Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 308050 (trait) , 300275 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: X-linked incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Species-specific name: Many alias names exist for the phenotype. They include congenital cornification disorder; CHILD nevi; CHILD-like nevi; ILVEN. The human phenotype resulting from NSDHL loss-of-function variants is termed congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome). CHILD syndrome is characterized by epidermal nevi and striking unilateral limb defects. Animals (cats, dogs, mice) with NSDHL variants have similar epidermal nevi, but so far were never reported to also have the limb defects seen in human CHILD syndrome.

Species-specific description: De Lucia et al. (2019): "Veterinary clinicians should be aware of cutaneous mosaicism and consider X-linked genodermatoses when seeing female cases with segmental cutaneous diseases like the one following the Blaschko’s lines."

Inheritance: De Lucia et al. (2019): "In heterozygous females, with an X-linked dominant or semidominant genodermatosis, . . . random inactivation of the X chromosome is responsible for the development of normal and abnormal skin segments distributed in a mosaic pattern. In fact, normal skin derives from progenitor cells in which the X-chromosome carrying the pathogenic variant has been inactivated, whereas stripes or patches of abnormal skin result from progenitor cells after the inactivation of the wild-type (normal) X-chromosome. X-linked cutaneous mosaicism can be heritable and is normally observed in heterozygous females." The trait is embryonic lethal in hemizygous mutant males.

Molecular basis: De Lucia et al. (2019): "a heterozygous missense variant in the NSDHL gene: XM_004000985.5:c.397A>G or XP_004001034.1:p.(Ser133Gly). The variant was absent from 93 additional genetically diverse control cats as demonstrated by Sanger sequencing. The variant was predicted to affect the essential serine residue of the catalytic tetrad 109Asn‐133Ser‐160Tyr‐164Lys in the conserved short‐chain dehydrogenase/reductase domain of the feline NSDHL protein and thus most likely leading to a functional inactivation of the protein."

Clinical features: De Lucia et al. (2019): "A 2‐year‐old, female, domestic short hair cat with a history of multiple alopecic, verrucous, hyperpigmented and erythematous skin lesions, following Blaschko's lines on the head, the limbs, the trunk and paw pads." The same authors concluded that the clinical signs of this single cat correspond to the "feline counterpart of human inflammatory linear verrucous epidermal nevus (ILVEN)", which closely resembles a mild form of CHILD syndrome, a disorder caused by mutations in the same gene.

Breed: Domestic Shorthair.
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: