Capillary Malformations, Congenital

A number sign (#) is used with this entry because of evidence that congenital capillary malformations can be caused by somatic mosaic mutation in the GNAQ gene (600998) on chromosome 9q21.

Sturge-Weber syndrome (185300), which includes port-wine stains, is also caused by somatic mosaic mutation in the GNAQ gene.

Description

Capillary malformations are a form of vascular malformation that are present from birth, tend to grow with the individual, do not regress spontaneously, and show normal rates of endothelial cell turnover. Capillary malformations are distinct from capillary hemangiomas (602089), which are highly proliferative lesions that appear shortly after birth and show rapid growth, slow involution, and endothelial hypercellularity (Spring and Bentz, 2005; Legiehn and Heran, 2006).

Clinical Features

Referred to as birthmarks, nevi flammei consist of dark red, nonelevated, sharply circumscribed patches which blanch on pressure with a glass, leaving a residual brown hyperpigmentation. Nevus flammeus is a frequent birthmark in the newborn infant, especially located in the central forehead; it fades spontaneously over a few months or years, as a rule. Shuper et al. (1984) referred to this lesion in the newborn as salmon patch and stated that it is incorrect to call it nevus flammeus.

The proposita of the family described by Shuper et al. (1984) had 5 nevi flammei, 2 on her neck, 2 on her arms, and a very large purple one on her right groin and upper leg. Selmanowitz (1968) described a family with nevus flammeus of the forehead. Association with Unna nevus (163100) in several members of a family was reported by Merlob and Reisner (1985).

In the family reported by Breugem et al. (2002), 12 members were affected and 11 were examined. The proband was a 6-year-old girl with a capillary malformation on the upper part of the left leg measuring 31 x 27 cm. She had several smaller capillary malformations on both feet and the left arm. The mother had several capillary malformations on her right arm, inside her left lower arm, and on her right lower leg. The sister of the proband had a large capillary malformations (30 x 30 cm) on her right upper leg. Several smaller capillary malformations were seen all over her body. The deceased grandmother was reported to have multiple small capillary malformations on her thorax. An uncle of the proband had a large capillary malformation on the anterolateral side of his left upper leg (30 x 30 cm) and a smaller capillary malformation on the anterior side of his left lower leg (10 x 5 cm). When he was 9 years old, he had an overgrowth of this leg with a 9-cm difference in leg length, which was subsequently treated with an epiphysodesis. As a result, that leg was 0.5 cm shorter when he was an adult, but the difference in leg circumference remained unchanged. He had no symptoms indicative of Klippel-Trenaunay syndrome (149000).

Of 60 subjects with inherited capillary malformation from 13 families studied by Eerola et al. (2002), 19 had a lesion on the face, 15 in the nuchal region, and 26 in other parts of the body.

Lian et al. (2014) studied a man in his seventies who had a predominantly unilateral congenital facial vascular lesion. Examination revealed painless, dark red to violacious macules, patches, coalescent plaques, and nodules on the right side of his face, with marked hypertrophy of the entire lower lip, right cheek and jaw, and right auricle. The lesion extended to the left chin and anterior neck. Sturge-Weber syndrome was ruled out by pertinent studies. The patient underwent staged surgical excision, including biopsy of an untreated auricular nodule. Histopathology showed extensive ectasia and dilatation of papillary dermis capillaries, postcapillary venules, and small veins in the superficial to mid-dermis. The abnormal vascular structures exhibited different sizes and shapes throughout the lesional specimen. The superficial abnormal vessels had very thin walls, in contrast to the thick walls and hyalinized aspect of large vessels. Those larger ectatic structures had thickened walls with multiple duplications of the basement membrane zones and entrapment of pericyte-like cells in the thickened areas. The endothelial cells of some affected vessels were discontinuous along the basement membrane area.

Inheritance

Shelley and Livingood (1949) described 12 patients with multiple nevi flammei in 7 sibships in 4 generations of a family, with 5 instances of male-to-male transmission. Two generations were skipped in one branch of the family.

In a family reported by Shuper et al. (1984), affected persons occurred in 3 generations and by inference someone in a fourth (earliest) generation may have been affected or at least had the gene.

Among 280 consecutive new patients with port-wine stains applying for laser treatment, van der Horst et al. (1999) stated that 55 (19.6%) mentioned relatives with the same anomaly. They constructed pedigrees of 32 families with 2 or more affected members, including probands. They presented 9 representative pedigrees with 3 or more affected members. They concluded that no clear mode of inheritance could be discerned, although the family displayed in their Figure 1 was consistent with autosomal dominant inheritance, including male-to-male transmission.

Mapping

Breugem et al. (2002) described a family with capillary malformations occurring in members of 3 generations. By linkage they mapped the trait to 5q13-q22, in a region spanning 48 cM between markers D5S647 and D5S659. They cited the position of Mulliken and Young (1988), who suggested that vascular tumors (hemangiomas) and vascular malformations represent 2 separate categories. However, the fact that infantile capillary hemangioma also maps to 5q, although in a slightly different area, raises the question of whether they may not be fundamentally the same.

Eerola et al. (2002) studied 13 families with inherited capillary malformation. A genome scan was performed in the 6 most informative families. Capillary malformation segregated as a dominant trait with evidence for incomplete penetrance and phenotypic variation. A non-parametric multipoint linkage analysis gave strong evidence of linkage to chromosome 5q. By adding 7 additional small families, a 69-cM region of linkage was obtained between markers D5S407 and D5S2098 with a maximum Z score of 6.72. Parametric linkage analysis gave a maximum hlod of 4.84 at marker D5S2044 on 5q15. When the 4 unlinked families were excluded from linkage analysis, a maximum multipoint lod score of 7.22 was obtained at D5S2044, and the most likely linked region covered 23 cM between markers D5S1962 and D5S652 corresponding to 5q13-q15. This locus was designated CMC1.

Heterogeneity

Eerola et al. (2003) screened 17 families with cutaneous capillary malformations for mutations in the RASA1 gene (139150). In 6 of these families, manifesting an association of atypical capillary malformations with arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome, they found RASA1 mutations; they named this association CM-AVM for 'capillary malformation-arteriovenous malformation'; see 608354. In 11 of these families no mutation in the RASA1 gene was found, indicating genetic heterogeneity.

Molecular Genetics

In affected skin from 12 (92%) of 13 patients with nonsyndromic port-wine stains, Shirley et al. (2013) detected the presence of a somatic gain-of-function missense mutation in the GNAQ gene (R183Q; 600998.0001). The R183Q mutation was also found in either port-wine-stained skin or brain tissue from 23 (88%) of 26 patients with Sturge-Weber syndrome (185300). Shirley et al. (2013) suggested that nonsyndromic port-wine stains may represent a late origin of the somatic GNAQ mutation in vascular endothelial cells, whereas in Sturge-Weber syndrome, the mutation may occur earlier in development, in progenitor cells that are precursors to a larger variety of cell types and tissues, leading to the syndromic phenotype. Five (0.7%) of 669 samples from the 1000 Genomes database were positive for R183Q; noting that the reported prevalence of port-wine stains is 0.3% to 0.5%, Shirley et al. (2013) hypothesized that the 0.7% prevalence in that database represented the occurrence of port-wine stains in the population.

Using tissue from a patient with a sporadic, long-standing unilateral facial port-wine stain, Lian et al. (2014) screened 275 cancer genes previously implicated in tumorigenesis and detected the GNAQ R183Q mutation at an allelic fraction of 0.05 in port-wine stain tissue; the mutation was not found in paired normal tissue. The percentage of GNAQ mutation was consistent with the percentage of lesional endothelial cells in the specimen. In addition, several novel somatic variants were identified in other genes, including SMARCA4 (603254), EPHA3 (179611), MYB (189990), PDGFRB (173410), and PIK3CA (171834), which were all present at an allelic fraction of less than 0.10.