MON-512 A De Novo Frameshift Mutation of FAM111B Gene Resulting in Progressive Osseous Heteroplasia in an African American Boy: First Case Report

Abstract

Introduction: Progressive osseous heteroplasia (POH) is a rare bone disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. Whereas 60-70% of the POH patients have paternally inherited inactivating mutations in GNAS gene, the remaining 30-40% harbor no specific etiologies. FAM111B gene mutations, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poik iloderma with t endon contractures, m yopathy, and p ulmonary fibrosis), a rare autosomal dominant disorder with high frequency of de novo missense mutations, which are believed to cause extensive fibrosis and adiposis of many tissues, though the exact mechanism is unknown. To our knowledge there are no reports of FAM111B associated with POH. Case: We describe a 15-year-old African American boy who presented with generalized calcific nodules, contractures, and muscle weakness leading to immobility, beginning at the age of 6 years. Cutaneous exam showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs showed extensive heterotopic ossification involving soft tissues and muscles surrounding the bilateral humeri, ulnae, femurs, and bilateral tibias/fibulas. Computed tomography of the chest, abdomen, and pelvis showed extensive muscle ossifications involving right latissimus dorsi, left scalene, bilateral pectoralis and external oblique abdominal, right iliacus, bilateral gluteal, left adductor, and left hamstring. There was also an involvement of the subcutaneous tissues of the right upper back and left lower quadrant of the abdomen, left posterior sacral region, bilateral hips, and the fascia superficial to the erector spinae muscles with no abnormal ossifications in the bones. The clinical and radiographic findings were consistent with POH. Whole Exome Sequencing revealed a de novo heterozygous frameshift mutation in FAM111B (OMIM # 615584) of c.1462delT (p.Cys488Valfs*21) variant, causing replacement of C-terminal region with 21 alternative amino acids. Multiple previously reported disease-associated variants appear to localize within the same domain, supporting the functional importance of this region, though none have been previously associated with POH. Thus, we consider this variant to be pathogenic. Conclusion: This is the first case of POH caused by a mutation in FAM111B gene. Whether POH phenotype could be explained by mutations in FAM111B gene traditionally re...

Spontaneous chromosomal instability in peripheral blood lymphocytes from two molecularly confirmed Italian patients with Hereditary Fibrosis Poikiloderma: insights into cancer predisposition

“…Comprehension of the genotype-phenotype relationship is made further trickier by the identification of the first frameshift FAM111B c.1462delT (p.(Cys488Valfs*21)) variant (Figure 2B), subverting the entire cysteine/serine peptidase domain, in a boy with Progressive Osseous Heteroplasia (POH), who also displayed classic POIKTMP signs such as tendon contractures, muscle weakness and ulcerated erupted skin lesions (Panjawatanan et al, 2019).…”

Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases

“…Similarly, a case of progressive osseous heteroplasia (POH), a rare bone disorder characterized by heterotopic ossification of the skin and muscles, was associated with a de novo FAM111B gene frameshift mutation in an American 15‐year‐old male 14 . Although this patient was not diagnosed with POIKTMP, he presented with calcific nodules with a plaque‐like ulcerated skin lesion, contracture and muscle weakness that resulted in patient immobility 14 . Thus, it will be interesting to investigate the molecular mechanism by which the FAM111B gene or mutations contributes to POIKTMP, cancers and POH.…”

“…A recent genomic study on cancer‐predisposing pathogenic germline variants within homologous recombination repair in patients with advanced cancer revealed mutations in the FAM111B gene in two cases of colorectal cancer 8 . Similarly, a case of progressive osseous heteroplasia (POH), a rare bone disorder characterized by heterotopic ossification of the skin and muscles, was associated with a de novo FAM111B gene frameshift mutation in an American 15‐year‐old male 14 . Although this patient was not diagnosed with POIKTMP, he presented with calcific nodules with a plaque‐like ulcerated skin lesion, contracture and muscle weakness that resulted in patient immobility 14 .…”

Proposed Cellular Function of the Human FAM111B Protein and Dysregulation in Fibrosis and Cancer

“…Furthermore, multiple single-nucleotide polymorphisms (SNPs) associated with prostate cancer localize on chromosome 11q12, which houses the FAM111B and FAM111A genes (52). Given the possible involvement of FAM111B in DNA repair (5,10,29), the overexpression of the FAM111B gene can support cancer progression. One possible explanation could be that the overexpression of FAM111B results in the non-specific proteolytic degradation of other DNA-associated proteins such as histones and replication or transcription factors (e.g., RFC1 and RPB1) and cell-cycle-dependent proteins (e.g., p16).…”

“…Mutations of the human FAM111B gene are also associated with a rare multisystemic fibrosing disease-poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP, which is the adopted terminology for this disease) (1)(2)(3)(4). FAM111B gene mutations are also implicated in other clinical manifestations such as progressive osseous heteroplasia (POH) (5), autism spectrum disorders (6), modification of genes associated with cognitive development (7), nevus of Ota with choroidal melanoma (8), and mutations of unknown clinical significance/common genetic polymorphism (9). Furthermore, FAM111B gene mutations correlate positively with increased cancer predisposition (10)(11)(12).…”