HYALINE FIBROMATOSIS SYNDROME: MUSCULOSKELETAL MANIFESTATIONS AND BONE HEALTH
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Hyaline Fibromatosis Syndrome (HFS) is caused by biallelic variants in the gene encoding CMG2/anthrax toxin receptor-2 (ANTXR2). The condition is characterized by deposition of hyaline material in the skin, mucous membranes, and gastrointestinal tract. HFS is typically recognized via multiple skin/mucosal nodules, hyperpigmentation over bony prominences and pressure points, or coarse facial features. Protein-losing enteropathy, immunodeficiency, recurrent infections, failure to thrive, and, in severe cases, death is possible; but there are mild cases as well. There is a need to optimize multidisciplinary management for this medical condition, particularly since the brain is spared. Little is known about the etiology of bone involvement. Here, we performed a systematic review of current knowledge on the features of individuals with HFS, focusing particularly on musculoskeletal involvement, given its importance in early management. We report on three new cases of HFS and data on 353 others from literature reports.
Methods:
Genome-based clinical sequence results from individuals and parents were reviewed. Phenotypic data were gathered through the review of medical records. A total of 353 individual cases from the literature with clear clinicopathological and/or genetic diagnoses were reviewed (Shieh et al. GeneReviews). Data on musculoskeletal involvement, radiology findings, and associated laboratory studies were collected.
Results:
Monozygotic twins and a third pediatric case with the clinical findings of HFS were evaluated. A homozygous pathogenic variant (c.1073dup; p.(A359Cfs*13)) in ANTXR2 was found in the former, and the parents were heterozygous. The other patient with clinical findings of HFS was also found to have a homozygous variant (c.652T>C; p.(Cys218Arg)) in ANTXR2. The first variant affects exon 13, which is considered a hotspot, while the second variant affects exon 8 and the vWA domain, which is expected to lead to more severe symptoms. Elevated alpha-1 antitrypsin indicated intestinal involvement, with intestinal lymphangiectasia and colitis on sigmoidoscopy. Interestingly, stool calprotectin was also elevated in these cases, a novel observation.
Osteopenia on X-ray was common. Cases had vitamin D insufficiency but despite the supplementation and normalization of the vitamin D level, one of the twins had progressive bone lesions. The twin had well-circumscribed ovoid and irregular lucencies in the bilateral proximal femurs, faint associated periosteal reaction on one side, and unilateral hip subluxation. The acetabula were shallow. The other twin had humeral head glenoids that were not normally formed. Both had coxa valga. Low lung volumes were present on chest X-ray. The third case had infections, respiratory failure, and immune deficiency requiring IVIG therapy. There was also low vitamin D and persistent diarrhea. Osteopenia was common in the literature cases but there was incomplete information about maintenance of bone health. Notably, there were cases in the literature with osteopenia that did not report gastrointestinal symptoms. It is unclear whether more subtle intestinal involvement could be detected using further laboratory studies. HFS cases of hypercalcemia with osteopenia were found in the literature, however these seem uncommon. The stimulation of osteoclasts by inflammatory factors, as well as immobilization-induced disruption in calcium homeostasis could contribute to pathophysiology. One possibility is that CMG2/ANTXR2 regulates periostin, as well as extracellular collagen VI, which accumulates in hyaline fibromatosis lesions.
Conclusion:
HFS is a multisystemic condition that can include osteopenia. Discrete bone lesions can be seen, and these can predispose to fracture. The appearance of focal lucent lesions discordance in twin pairs suggests additional local factors involved in pathogenesis. Potential contributors to bony involvement include decreased movement due to contractures and vitamin D deficiency, which can be corrected. Gastrointestinal involvement is common which can exacerbate immune problems. Future work should focus on intestinal and skeletal management in tandem and the potential role of inflammation or lesion triggers.
Hyaline Fibromatosis Syndrome (HFS) is caused by biallelic variants in the gene encoding CMG2/anthrax toxin receptor-2 (ANTXR2). The condition is characterized by deposition of hyaline material in the skin, mucous membranes, and gastrointestinal tract. HFS is typically recognized via multiple skin/mucosal nodules, hyperpigmentation over bony prominences and pressure points, or coarse facial features. Protein-losing enteropathy, immunodeficiency, recurrent infections, failure to thrive, and, in severe cases, death is possible; but there are mild cases as well. There is a need to optimize multidisciplinary management for this medical condition, particularly since the brain is spared. Little is known about the etiology of bone involvement. Here, we performed a systematic review of current knowledge on the features of individuals with HFS, focusing particularly on musculoskeletal involvement, given its importance in early management. We report on three new cases of HFS and data on 353 others from literature reports.
Methods:
Genome-based clinical sequence results from individuals and parents were reviewed. Phenotypic data were gathered through the review of medical records. A total of 353 individual cases from the literature with clear clinicopathological and/or genetic diagnoses were reviewed (Shieh et al. GeneReviews). Data on musculoskeletal involvement, radiology findings, and associated laboratory studies were collected.
Results:
Monozygotic twins and a third pediatric case with the clinical findings of HFS were evaluated. A homozygous pathogenic variant (c.1073dup; p.(A359Cfs*13)) in ANTXR2 was found in the former, and the parents were heterozygous. The other patient with clinical findings of HFS was also found to have a homozygous variant (c.652T>C; p.(Cys218Arg)) in ANTXR2. The first variant affects exon 13, which is considered a hotspot, while the second variant affects exon 8 and the vWA domain, which is expected to lead to more severe symptoms. Elevated alpha-1 antitrypsin indicated intestinal involvement, with intestinal lymphangiectasia and colitis on sigmoidoscopy. Interestingly, stool calprotectin was also elevated in these cases, a novel observation.
Osteopenia on X-ray was common. Cases had vitamin D insufficiency but despite the supplementation and normalization of the vitamin D level, one of the twins had progressive bone lesions. The twin had well-circumscribed ovoid and irregular lucencies in the bilateral proximal femurs, faint associated periosteal reaction on one side, and unilateral hip subluxation. The acetabula were shallow. The other twin had humeral head glenoids that were not normally formed. Both had coxa valga. Low lung volumes were present on chest X-ray. The third case had infections, respiratory failure, and immune deficiency requiring IVIG therapy. There was also low vitamin D and persistent diarrhea. Osteopenia was common in the literature cases but there was incomplete information about maintenance of bone health. Notably, there were cases in the literature with osteopenia that did not report gastrointestinal symptoms. It is unclear whether more subtle intestinal involvement could be detected using further laboratory studies. HFS cases of hypercalcemia with osteopenia were found in the literature, however these seem uncommon. The stimulation of osteoclasts by inflammatory factors, as well as immobilization-induced disruption in calcium homeostasis could contribute to pathophysiology. One possibility is that CMG2/ANTXR2 regulates periostin, as well as extracellular collagen VI, which accumulates in hyaline fibromatosis lesions.
Conclusion:
HFS is a multisystemic condition that can include osteopenia. Discrete bone lesions can be seen, and these can predispose to fracture. The appearance of focal lucent lesions discordance in twin pairs suggests additional local factors involved in pathogenesis. Potential contributors to bony involvement include decreased movement due to contractures and vitamin D deficiency, which can be corrected. Gastrointestinal involvement is common which can exacerbate immune problems. Future work should focus on intestinal and skeletal management in tandem and the potential role of inflammation or lesion triggers.