Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia. (30th September 2018)

• Record Type: Journal Article
• Authors: Heinz, L.; Bourrat, E.; Vabres, P.; Thevenon, J.; Hotz, A.; Hörer, S.; Küsel, J.; Zimmer, A.D.; Alter, S.; Happle, R.; Fischer, J.
• Is Part Of: British journal of dermatology. Volume 180:Number 3(2019)
• Page Start: 657
• Page End: 661
• Publication Date: 2018-09-30
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.17024
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: 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. Abstract : What's already known about this topic? Mutations in PORCN cause focal dermal hypoplasia (FDH). In male children, hemizygous PORCN mutations are lethal in utero . To date, only around 300 patients with mutations in PORCN have been reported. What does this study add? In four women affected by FDH, PORCN mutations were found to be present in affected cutaneous tissue but not in peripheral blood. Negative mutation analysis of blood samples does not exclude the diagnosis of FDH, as a mosaic constellation due to postzygotic mutations has been repeatedly observed in female patients with FDH as shown in this study. Linked Comment: Traupe. Br J Dermatol 2019; 180 :461–462. Plain language summary available online