A number sign (#) is used with this entry because of evidence that retinal arterial macroaneurysm associated with supravalvular pulmonic stenosis (RAMSVPS) can be caused by homozygous mutation in the IGFBP7 gene (602867) on chromosome 4q12.

Retinal arterial macroaneurysm is an autosomal recessive condition characterized by the bilateral appearance of 'beading' along the major retinal arterial trunks, with the subsequent formation of macroaneurysms. Affected individuals also have supravalvular pulmonic stenosis, often requiring surgical correction (summary by Abu-Safieh et al., 2011).

Dhindsa and Abboud (2002) reported 3 unrelated Saudi Arabian families in which 2 or more sibs displayed multiple retinal arterial macroaneurysms. Age at onset ranged from 3 months to 19 years; some cases were originally diagnosed as 'atypical bilateral Coats' (see 300216). All 7 patients had beading and macroaneurysms along the major retinal arterial trunks bilaterally. In 5 patients, recurrent bleeding and leakage from the macroaneurysyms occurred, resulting in loss of vision. The clinical course was unpredictable, with leakage developing after periods of seeming stabilization. The blood was mainly located under the internal limiting membrane and resorbed spontaneously with improved visual acuity. Argon laser photocoagulation of leaking macroaneurysms resulted in clinical improvement in 3 patients. Vascular sheathing was seen in some patients, but no signs of active vasculitis appeared, despite many years of follow-up (average, 7.8 years). Thorough examination of all patients, specifically of cardiovascular, neurologic, and musculoskeletal systems, revealed no associated systemic disease. One patient underwent brain MRI with magnetic resonance angiography that showed no vascular anomalies of the central nervous system. Dhindsa and Abboud (2002) stated that the retinal disease in these patients represented a new condition, which they designated 'familial retinal arterial macroaneurysms.'

Abu-Safieh et al. (2011) performed thorough dysmorphologic, ophthalmologic, and cardiologic evaluation in 22 patients with retinal arterial macroaneurysm from 8 consanguineous Saudi Arabian families, including 2 families reported by Dhindsa and Abboud (2002). In addition to typical ophthalmologic findings, the 12 patients who underwent echocardiography were found to have supravalvular pulmonic stenosis, which in some patients required surgical correction. There were no obvious dysmorphic features, and no evidence of other systemic involvement was noted.

In 8 consanguineous Saudi Arabian families segregating autosomal recessive retinal arterial macroaneurysm and supravalvular pulmonic stenosis, including 2 families reported by Dhindsa and Abboud (2002), Abu-Safieh et al. (2011) performed homozygosity and linkage analysis. Each of the 8 families showed a run of homozygosity on chromosome 4, and a collective lod score of 11.4 was obtained for an approximately 5.1-Mb locus delimited by the SNPs rs6833480 and rs10017149. Analysis of microsatellites and additional SNPs refined the region to an approximately 4.7-Mb interval flanked by rs76451666 and D4S398.

In 8 consanguineous Saudi Arabian families with retinal arterial macroaneurysm and supravalvular pulmonic stenosis mapping to chromosome 4q, including 2 families reported by Dhindsa and Abboud (2002), Abu-Safieh et al. (2011) analyzed 6 candidate genes and identified homozygosity for a splice variant in the IGFBP7 gene (602867.0001) that segregated with disease in each family. Although they had different tribal and geographic backgrounds, the 8 families were found to share a common haplotype, and screening of 300 Saudi controls revealed the presence of 1 heterozygous carrier, whose genotypic analysis confirmed carriage of the mutation on the same disease haplotype. Abu-Safieh et al. (2011) concluded that the mutation was of common ancestral origin, and noted that the very small shared haplotype made it likely that it was also ancient in origin.