Vibratory Urticaria

A number sign (#) is used with this entry because of evidence that vibratory urticaria (VBU) is caused by heterozygous mutation in the ADGRE2 gene (606100) on chromosome 19p13.

Description

Autosomal dominant vibratory urticaria is characterized by localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum (Boyden et al., 2016).

Clinical Features

Patterson et al. (1972) described a family of Swedish descent in which members of at least 4 generations showed local erythematous and edematous lesions following local stimulation of a vibratory or frictional nature. Facial or generalized erythema and headache accompanied severe local reactions. Elevated plasma amine levels were found in the venous blood returning from a limb subjected to appropriate stimulation. Goetzl (1978) stated that within a particular family, affected members show sensitivity to the same specific range of frequency of vibrations, which may be different from that in other families.

Epstein and Kidd (1981) described a form of physical urticaria in a Christian Lebanese family and designated it dermodistortive urticaria (DDU). The disorder was characterized by development of pruritic, erythematous, edematous cutaneous swelling confined to areas exposed to repetitive vibratory or stretching stimulation. The lesions developed within several minutes and disappeared within an hour. Extensive stimulation led to systemic responses: faintness, headache, and facial erythema. Histamine was suspected as the mediator of the local and systemic responses. Epstein and Kidd (1981) noted similarities with the phenotype described by Patterson et al. (1972) but questioned whether the disorders were identical.

Boyden et al. (2016) studied a 3-generation Lebanese family segregating autosomal dominant vibratory urticaria. In response to repetitive mechanical stimulation of the skin, such as clothing contact during exercise or towel drying, the 9 affected family members had localized erythematous, edematous, pruritic hives, sometimes accompanied by facial flushing, headache, or the sensation of a metallic taste. Identical symptoms could be provoked by vibration of the forearm on a laboratory vortex, with symptoms appearing within 5 minutes after stimulation and subsiding within 60 minutes. Affected individuals tested negative for dermatographism. Episodes of vibratory urticaria were accompanied by an increase in serum levels of histamine but not of tryptase. Immunohistochemical staining of dermal mast-cell tryptase revealed degranulation resulting from vortex challenge that was more prevalent in patients than controls. Boyden et al. (2016) noted similarities between the presentation in this family and that of a previously described 5-generation Lebanese family with dermodistortive urticaria (Epstein and Kidd, 1981). In addition, Boyden et al. (2016) ascertained the proband from a third Lebanese family segregating dominant vibratory urticaria over 4 generations. None of the families were known to be related to one another, although the similarities in their phenotype and origins strongly suggested a shared ancestor.

Inheritance

The transmission pattern of vibratory angioedema in the family reported by Patterson et al. (1972) was consistent with autosomal dominant inheritance.

Mapping

Boyden et al. (2016) performed linkage scans of DNA from members of 2 Lebanese families with vibratory urticaria, 1 of which was the family originally described by Epstein and Kidd (1981), and identified a 2.2-Mb region on chromosome 19p13 with a combined lod score of 7.224. Boyden et al. (2016) noted that the ADGRE2 gene is located within a 1.7-Mb haplotype shared by affected members of both families.

Molecular Genetics

In a 3-generation Lebanese family with autosomal dominant vibratory urticaria mapping to chromosome 19p13, in which affected members were negative for mutation in the urticaria-associated genes NLRP3 (606416) and PLCG2 (600220), Boyden et al. (2016) performed exome sequencing and identified a heterozygous missense mutation in the ADGRE2 gene (C492Y; 606100.0001) that segregated fully with disease and was not found in 1,105 Lebanese or 100 Israeli controls, or in public variant databases. Heterozygosity for the C492Y variant also segregated perfectly with disease among the 25 available members of the 5-generation Lebanese family with 'dermodistortive urticaria' previously reported by Epstein and Kidd (1981), and was found in the proband of a third Lebanese family with vibratory urticaria. Analysis of the ADGRE2 gene in 60 patients with various sporadic physical urticarias revealed no additional mutations. Functional analysis indicated that the C492Y substitution represents a hypermorphic variant, effecting a gain of function in ADGRE2 by destabilizing the inhibitory interaction between its alpha and beta subunits, thereby sensitizing mast cells to vibration-induced degranulation. Boyden et al. (2016) concluded that the hereditary vibratory urticaria phenotype likely reflects an exaggeration of a normal cellular response to dermal vibration.

History

Epstein et al. (1981) sought linkage of DDU with 18 markers; close linkage with 6 of these was excluded. The most significant positive lod score was for MNSs on chromosome 4, which had a maximum lod score of 1.09 at theta of 0.24.