Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia

Abstract

Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low-level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice-site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.

Postzygotic mosaicism in a woman with Goltz syndrome mimics segmental angioma serpiginosum

“…Postzygotic mosaicism has recently been described in two women who both had nonspecific histopathology, but had more pronounced cutaneous disease than our patient. The first patient had syndactyly of the 2nd/3rd and 4th/5th fingers of the left hand along with extensive right‐sided, linear, hyperpigmented and atrophic lesions, and the second patient had left 3rd/4th fingernail involvement and also extensive left‐sided and right flank, hyperpigmented and atrophic cutaneous streaking.…”

“…If she carries this mutation in her germline, this could give rise to FDH in her offspring with loss of affected male pregnancies and a risk of having an affected daughter, who would most probably be more severely affected (functional X‐chromosome mosaicism/germline mutation). The blaschkoid distribution of the lesions in classic, familial FDH and the variable severity is because of random X inactivation . In our case, there are two reasons for the blaschkoid distribution – the postzygotic mosaicism and random X inactivation.…”

“…The first patient had syndactyly of the 2nd/3rd and 4th/5th fingers of the left hand along with extensive right‐sided, linear, hyperpigmented and atrophic lesions, and the second patient had left 3rd/4th fingernail involvement and also extensive left‐sided and right flank, hyperpigmented and atrophic cutaneous streaking. The patients had mutations in the PORCN gene (in either saliva or lesional skin) but not in DNA extracted from peripheral blood lymphocytes …”

Life-long Skin Eruptions along Blaschko’s Lines in a 27-year-old Woman

“…Ninety percent of individuals with FDH are female, as germline PORCN mutations result in embryonic lethality in hemizygous males ( 4 ), and postzygotic mosaic females have been reported occasionally ( 5 , 6 ). Skin lesions along Blaschko’s lines in females with FDH are caused by X-chromosome inactivation or postzygotic mosaicism.…”

A rose is a rose: naevoid manifestations blur the boundary between naevus and classical gene defect in focal dermal hypoplasia

“…In a remarkable case series, Lisa Heinz from Freiburg and her co‐authors from Paris and Dijon report on four cases of women with typical features of the rare skin disease focal dermal hypoplasia (FDH) in whom the underlying PORCN mutation was identified in DNA from affected cutaneous tissue, but not in DNA from peripheral blood . Obviously these women exhibit postzygotic mutations; it is of note that in the same time period, the authors from Germany and France made the diagnosis of classical FDH with a mutation of PORCN in blood DNA in six further cases, implying that mosaicism due to postzygotic mutations is indeed a common finding in this disease.…”