Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system

Abstract

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are rare, autosomal recessive disorders of the connective tissue caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2) located on chromosome 4q21. Characteristically, these conditions present with overlapping clinical features, such as nodules and/or pearly papules, gingival hyperplasia, flexion contractures of the joints, and osteolytic bone defects. The present report describes a pair of sibs and three other JHF/ISH patients whose diagnoses were based on typical clinical manifestations and confirmed by histopathologic analyses and/or molecular analysis. A comparison of ISH and JHF, additional thoughts about new terminology (hyaline fibromatosis syndrome) and a modified grading system are also included.

FIG. 1

Clinical photographs of the Patients (A–D) 1, (E–H) 2, (I–M) 3, (N–P) 4, and (Q-T) 5 showing multiple skin nodules distributed on various body regions (mainly, ear and fingers), multiple pearly papules on nose, chin, and cervical regions (mainly, Patients 2, 3, and 5), gingival hyperplasia (Patients 1 and 5), and flexion contractures of the several joints (wrists, knees, ankles, and fingers).

FIG. 2

Patient 1 presenting with nodules on the right ear as a (A) 13- year-old and (B) 7 years later; note the mutilating aspect of the multiple surgeries performed in the right ear due to the recurrent nature of the lesions. Aspect of the pre-and post-surgical resection of the (C–D) nasal (Patient 2) and (E–F) forehead (Patient 3) lesions.

FIG. 3

A: Lesion occupying the papillary and reticular dermis, raising the overlying epidermis (hematoxylin–eosin, original magnification: 50×). B: Dermal lesion showing hyaline material stained by periodic acid-Schiff reagent (original magnification: 100×). C: Hypercellular area displaying multiple strands of spindle cells that sometimes anastomose (hematoxylin–eosin, original magnification: 200×). D: Hypocellular area showing abundant eosinophilic material that is amorphous, homogeneous, and characteristically hyaline (hematoxylin–eosin, original magnification: 200×). E: Clear spaces around the spindle cells, which, combined with the background of hyaline material, confers a chondroid appearance to certain areas of the lesions (hematoxylin–eosin, original magnification: 200×).

FIG. 4

Pedigree and mutation analyses for Families 2–4. Blackened symbols indicate individuals who have the c.1074delT mutation. A: Pedigree for Family 2 showing that the parents are heterozygous for different ANTXR2 mutations. The children are compound heterozygotes. Below the mother is a portion of exon 13 from the mother, demonstrating that she is heterozygous for a known single base deletion (shown by the arrow), c.1074delT. Below the father is a sequence result from cDNA from the father, showing skipping of exons 15 and 16, c.1180_1428del. This is predicted to result in a protein with an in-frame deletion of 83 amino acids, p.Val394_Glu476del. The father and children most likely have a partial gene deletion involving exons 15 and 16. The size (in bp) of the introns is shown below the horizontal lines designating the introns. B: Pedigree for Family 3 showing that the mother is a carrier of the common mutation, c.1074delT. The father is a carrier of another known mutation, c.1073_1074insC (black arrow). The child is a compound heterozygote, with the position of both mutations indicated by a black arrow. In addition the father is heterozygous for a known SNP, rs12647691 (red arrow). C: Pedigree for Family 4 showing that the father is a carrier of the common mutation, c.1074delT. The mother has a novel mutation, c.487-2A>G, that affects the splice acceptor site of intron 5 (shown by black arrow). cDNA analysis demonstrated two transcripts from the mutant allele. Transcript 1 skips exon 6, potentially producing an in frame deletion of 23 amino acids (p.Ala163_Gln185del). A second transcript was produced that only lacked the first 6 nucleotides of exon 6, potentially producing an in frame deletion of 2 amino acids (p.Ala163_Lys164del). As shown on the electropherogram of the mother’s sequence, nucleotides 5 and 6 of exon 6 can function as a splice acceptor site (red underline) when the normal splice acceptor site of intron 5 is mutated. At the bottom is a portion of the ANTXR2 gene showing normal splicing (above the genomic structure) and splicing observed in the presence of the c.487-2A>G splice acceptor mutation (indicated by asterisk).