Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.

Glomuvenous malformations (GVMs) are cutaneous venous lesions characterized by the presence of smooth-muscle--like glomus cells in the media surrounding distended vascular lumens. We have shown that heritable GVMs link to a 4--6-cM region in chromosome 1p21-22. We also identified linkage disequilibrium that allowed a narrowing of this VMGLOM locus to 1.48 Mb. Herein, we report the identification of the mutated gene, glomulin, localized on the basis of the YAC and PAC maps. An incomplete cDNA sequence for glomulin had previously been designated "FAP48," for "FKBP-associated protein of 48 kD." The complete cDNA for glomulin contains an open reading frame of 1,785 nt encoding a predicted protein of 68 kD. The gene consists of 19 exons in which we identified 14 different germline mutations in patients with GVM. In addition, we found a somatic "second hit" mutation in affected tissue of a patient with an inherited genomic deletion. Since all but one of the mutations result in premature stop codons, and since the localized nature of the lesions could be explained by Knudson's two-hit model, GVMs are likely caused by complete loss of function of glomulin. The abnormal phenotype of vascular smooth-muscle cells (VSMCs) in GVMs suggests that glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis--especially in cutaneous veins.

Thirty-five children, three months to 14 years of age, with disfiguring port-wine stains were treated with a flashlamp-pulsed tunable dye laser. All had complete clearing of the stains after an average of 6.5 laser treatments to each lesional area; skin over bony prominences required approximately half as many sessions as skin on the cheek. Children less than seven years old required fewer sessions (mean +/- SD, 5.8 +/- 1.1) than older children (7.1 +/- 1.1; P less than 0.05). Treated skin was identical in texture and color to adjacent normal skin in 33 (94.3 percent) of the children, whereas 2 (5.7 percent) had small, isolated, depressed scars in areas accidentally traumatized soon after laser treatment. The only other side effect was transient hyperpigmentation, which occurred in 20 patients (57 percent). These results can be attributed to two distinguishing characteristics of the flashlamp-pulsed tunable dye laser: an emission wavelength of 577 nm, theoretically ideal for selective absorption by the intravascular target oxyhemoglobin, and a pulse duration of 360 microseconds, which closely matches the thermal relaxation time for dermal blood vessels and hence avoids diffuse nonspecific thermal necrosis with subsequent scarring of the treated skin.