Angioma Serpiginosum, X-Linked

Description

Angioma serpiginosum (AS) is a rare benign congenital skin disorder characterized by nonpurpuric red punctate lesions seen histologically as capillary ectasias in the superficial papillary dermis. The lesions often follow Blaschko lines and are most commonly found in females (90%) (Blinkenberg et al., 2007).

See 106050 for additional phenotypic information and possible autosomal dominant inheritance or cutaneous somatic mosaicism (Chen et al., 2006; Blinkenberg et al., 2007).

Clinical Features

Blinkenberg et al. (2007) reported a Norwegian family in which 6 females spanning 4 generations had angioma serpiginosum inherited in an X-linked dominant pattern. Four were alive at the time of the report. The proband was a 46-year-old woman with an asymptomatic punctate and linear erythematous rash that had progressed slowly since birth. The rash followed the lines of Blaschko and was localized on the left shoulder, inside of both arms, the back, and the outside and back of the thighs and calves. Skin biopsy showed nests of slightly dilated and somewhat thick-walled capillaries in the dermal papillae and upper part of the dermis with areas of hyperkeratosis. There was no inflammation. The nails were slightly dysplastic with ridges and incisions, and the hair was thin and straight. Laser treatment improved the rash. Her daughter was similarly affected. The younger sister of the proband was affected but also had small papillomatous tumors in the pharynx and upper part of the esophagus. Histology showed that the tumors were composed of a central core of vascular connective tissue covered by a squamous epithelium with disturbed maturation. The proband was subsequently found to have similar esophageal tumors that were asymptomatic. There was no family history of eye problems, infertility, or spontaneous miscarriage. X-inactivation studies showed 2 patients with 100:0 and 1 patient with 96:4 X-inactivation patterns, consistent with X-linked dominant inheritance and early lethality in males. Blinkenberg et al. (2007) suggested that the disorder may be a mild variant of the Goltz-Gorlin syndrome (focal dermal hypoplasia; FDH; 305600).

Happle (2009) stated that the diagnosis in the 4-generation Norwegian family described by Blinkenberg et al. (2007) should be focal dermal hypoplasia because close inspection of photographs of the erythematous skin lesions revealed small intermingled patches of dermal hypoplasia or atrophy. Happle (2009) further argued that the diagnosis of angioma serpiginosum should have been excluded because some patients had nail dysplasia and bald patches involving the scalp, which are characteristic signs of FDH but unknown in AS, and because esophageal or hypopharyngeal papillomatosis is a typical feature of FDH but absent in AS. In addition, Happle (2009) stated that there was 'not the slightest indication' that AS could be inherited as an X-linked trait. Houge and Hennekam (2009) responded that personal investigation of affected individuals from the Norwegian family, including examination of skin biopsies of affected areas, showed no dermal hypoplasia, and that none of the patients had bald patches; rather, the sparse and thinning hair was so mild that it initially went unnoticed. Houge and Hennekam (2009) also noted that many of the common features of FDH were missing in the Norwegian patients, including ophthalmologic signs and symptoms, papillomas around orifices, clefting, thin and anteverted pinnae, prominent coccyx, and limb anomalies. In support of X-linked inheritance, they pointed out that the vast majority of AS patients are female, that affected skin following Blaschko lines had been described in several cases, and that no male-to-male transmission had been reported.

Mapping

By X-chromosome linkage analysis of a Norwegian family with X-linked dominant angioma serpiginosum, Blinkenberg et al. (2007) identified a candidate region on Xp11.3-q12, flanked by DXS8026 and DXS106 (maximum lod score of 3.31).

Cytogenetics

In all affected females in the Norwegian family with X-linked dominant angioma serpiginosum originally reported by Blinkenberg et al. (2007), Houge et al. (2008) identified a 112-kb deletion on Xp that removed the PORCN gene (300651) and 4 other genes. Houge et al. (2008) noted that this deletion was only 25 kb smaller than a deletion previously found by Grzeschik et al. (2007) in patients with focal dermal hypoplasia, and suggested that modifying genes affecting the timing of X inactivation during embryogenesis may have caused the difference in phenotypic severity.