Woolly hair nevus caused by somatic mutation and Costello syndrome caused by germline mutation in HRAS: Consider parental mosaicism in prenatal counseling

Abstract

Germline mutations in HRAS cause Costello syndrome (CS), while mosaic mutations in HRAS show a variability of phenotypes, ranging from mild features such as keratinocytic epidermal nevus (KEN), sebaceous nevus (SN), woolly hair nevus (WHN) with KEN, to severe manifestations of CS with cutis laxa. We report two individuals. The first was a 2‐year‐old boy with woolly hair nevus (WHN) without any other cutaneous involvement, in whom somatic HRAS mutation (c.34G>A; p.Gly12Ser) was identified in his affected scalp and hair follicle specimens. This is the first reported WHN type 1 (no cutaneous involvement) patient caused by somatic HRAS mutation. The other individual was a 12‐year‐old girl with CS caused by germline HRAS mutation (c.34G>A), that manifested with coarse face, palmoplantar keratoderma, deep palmar and plantar creases, hyperpigmented patches, asymmetry and deformity of lower limbs, atopic dermatitis, as well as mental retardation. Of note, a linear hyperpigmented plaque was observed in her father’s lumbosacral region. Although the father refused to provide semen and skin tissue for further examination, this reminds us of possible mosaicism in parents of individuals with germline de novo HRAS mutation and underlines the importance of parental evaluation for prenatal counseling.

Woolly hair nevus type 1 caused by somatic HRAS p.A59T mutation

“…It has been hypothesized that mild activating mutations in HRAS would be associated with a WHN phenotype, while stronger mutations would be associated with nevus sebaceous. 4 p.Ala59Thr mutations does not affect Hras GTPase activity but increases GTP-bound ability. 5 The fact of finding this mild activating mutation in our case of WHN without epidermal nevus seems to support that hypothesis and confirms that HRAS mutations can also be associated with isolated WHN.…”

“…Recently, Liang et al described the first report of WHN without other cutaneous involvement (type 1) related with the same HRAS mutation. 4 In this report, we present a new case of WHN type 1 caused by a distinct mutation in HRAS gene (p.Ala59Thr). Although epidermal keratinocytic nevus may show very subtle features that can occasionally be overlooked, in our case, after a careful and detailed clinicopathological examination, no evidence of underlying epidermal changes was observed.…”