Hyaline Fibromatosis Syndrome: A Novel Mutation and Recurrent Founder Mutation in the CMG2/ ANTXR2 Gene

Abstract: Hyaline Fibromatosis Syndrome (HFS) is a rare autosomal recessive disorder affecting primarily skin and mucous membranes. Skin appears thickened with subcutaneous nodules, associated with swollen joint contractures, red hyperpigmentation and gingival hyperplasia. Additional findings include osteopenia and osteoporosis, and the affected children are susceptible to infections and protein losing enteropathy (1). Histopathology of skin lesions shows proliferation of spindle-shaped cells, embedded in a homogeneous hyaline-like material, and biochemical alterations in type I and VI collagens as well as in glycosaminoglycans have been reported (2, 3). Initially, infantile systemic hyalinosis and juvenile systemic hyalinosis were considered as two distinct entities on the basis of time of onset. However, subsequent work demonstrated that both forms of hyalinosis were caused by mutations in the CMG2 gene (also known as ANTXR2), indicating that these disorders are allelic and part of the same phenotypic spectrum, now known as HFS (4, 5). The CMG2 gene encodes a 55-kDa type I transmembrane protein known as capillary morphogenesis protein 2. While the precise physiologic function of this protein is currently unknown, its expression is upregulated in endothelial cells during capillary formation. This protein also serves as the main receptor of the anthrax toxin (6). The gene is expressed in all tissues with exception of the brain, a finding consistent with normal cognitive development of the affected individuals (6, 7).mapping, additional primers were designed for typing of 13 informed SNPs within and flanking the CMG2 gene. In Family 1, DNA was not available for mutation analysis from the deceased proband but both parents were heterozygous carriers of a previously unreported splice junction mutation (c.946-2A→G in intron 11) in CMG2, which by Human Splicing Finder program (www.umd.be/HSF/#) is predicted to result in aberrant splicing and a subsequent premature termination codon. Thus, the proband was deduced to be homozygous for this mutation. In Family 2, the proband had an insertion mutation, c.1073_1074insC (p.Pro358ProfsX13), which has been previously reported (8). This mutation in exon 13 causes a frameshift and results in premature termination of translation. In Family 3, a homozygous mutation, c.1074delT (p.Pro358ProfsX50) in exon 13, was detected; this recurrent mutation has been reported in a number of cases. In Family 4, no mutations in the CMG2 gene were noted, and subsequent homozygosity mapping excluded this gene locus at chromosomal region 4q21 (Fig. S11). Since the mutation c.1074delT has been encountered in a number of cases, we examined the possibility that this mutation is either a result of “founder effect” or is a “hotspot” mutation. For this purpose, haplotype analysis with 13 SNPs within and flanking the CMG2 gene was performed with DNA from the proband in Family 2 as well as from another patient with HFS that we have recently described (9). The results revealed a 2 Mb conserved block within a 3 Mb region of the genome which included CMG2 in these probands and suggesting a founder effect in these two Iranian cases of different ethnicity and language group.