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Goltz Syndrome (Focal Dermal Hypoplasia) 

Goltz Syndrome (Focal Dermal Hypoplasia)
Chapter:
Goltz Syndrome (Focal Dermal Hypoplasia)
Author(s):

Ignatia B. Van Den Veyver

and V. Reid Sutton

DOI:
10.1093/med/9780199934522.003.0041
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date: 28 February 2021

Goltz syndrome (Goltz, 1992), also known as Focal Dermal Hypoplasia (FDH) is a rare, X-linked developmental disorder characterized by variable presentation of multiple abnormalities that result from defects in development of ectodermal and mesodermal structures. These include focal skin manifestations of decreased connective tissue with exposed fat tissue, abnormalities of eyes, hair, nails, teeth and other ectodermal appendages, as well as skeletal defects, comprising absent or deformed digits on hands and feet, and sometimes distal long bone deformities (Goltz, 1992; Sutton and Van den Veyver, 2008). Occasional patients have other rarer phenotypic features that include aplasia cutis and abdominal wall defects, urogenital abnormalities, diaphragmatic hernia and cleft lip and palate. Later in life, FDH patients are prone to developing verrucous papillomas around orifices. FDH is caused by mosaic or heterozygous inactivating mutations or deletions of PORCN, an essential gene on the X chromosome that is subject to X inactivation and encodes the probable Protein-cysteine N-palmitoyltransferase porcupine protein, an important regulator of WNT protein secretion and WNT signaling (Grzeschik et al., 2007; Wang et al., 2007). Consistent with an X-linked mutation in an essential gene, most affected individuals are females, but about 5-10% of patients are males who carry mosaic mutations. These mosaic males can have severely affected daughters. The physical manifestations of FDH are highly variable, ranging from very subtle to very severe and sometimes lethal developmental defects (Grzeschik et al., 2007; Wang et al., 2007). This has been shown to result, in part, from variable X inactivation patterns of PORCN. Mouse models with Porcn inactivation have been generated and the findings in these mice indicate that, as predicted, the phenotypic features of FDH can be explained by disrupted signaling of many WNT proteins in ectodermal and mesodermal-derived tissues (Barrott et al., 2011; Liu et al., 2012). These mouse models confirm that ubiquitous loss of function of Porcn is early prenatally lethal in hemizygous males and in many heterozygous females. These females likely only survive, if there is favorable skewing of X inactivation, as has been found in humans. While present treatment is mostly symptomatic and supportive, in the future therapies that overcome disrupted WNT signaling might provide new options for the phenotypic features that appear or progress after birth (Sutton and Van den Veyver, 2008).

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