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Progressive Osseous Heteroplasia is not an Autosomal Dominant Trait but Reflects Superimposed Mosaicism in Different GNAS Inactivation Disorders.

ABSTRACT: Progressive osseous heteroplasia (POH) is a rarely occurring genetic condition characterized by severe segmental ossification involving the skin and deep connective tissues including the muscles. So far, the disorder is generally described as an autosomal dominant trait. By contrast, the following arguments are in favor of the alternative concept that POH should rather be taken as a non-specific segmental manifestation of different GNAS inactivation disorders such as Albright hereditary osteodystrophy (AHO) with hormone resistance, AHO without hormone resistance, and osteomatosis cutis. Presently, POH has got its own OMIM number 166350 but this is obviously wrong because the disorder does not reflect heterozygosity for a GNAS mutation. Conversely, the disorder is most likely due to an early event of postzygotic loss of heterozygosity with loss of the corresponding wild-type allele. This alternative concept, as proposed in 2016, offers a plausible explanation for the following features of POH. Familial occurrence is usually absent. POH is usually observed in families with one of the three GNAS inactivation disorders as mentioned above. Mosaicism is suggested by the pronounced segmental manifestation of POH and by its lateralization. Some patients have, in addition to POH, bilaterally disseminated features of osteomatosis cutis or AHO, and other patients have family members with one of these nonsegmental disorders. Remarkably, POH tends to appear much earlier than the nonsegmental GNAS inactivation disorders. - Molecular support of the concept was documented in a superficial variant of POH called 'plate-like osteoma cutis'. In several other autosomal dominant skin disorders, molecular corroboration of the theory of superimposed mosaicism has been provided. - For all of these reasons, it is unlikely that POH can further be taken as a distinct autosomal dominant trait. Generation of more molecular data in multiple cases of POH occurring in GNAS inactivation disorders will be crucial to corroborate the proposed concept.

SUBMITTER: Happle R

PROVIDER: S-EPMC8088155 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 poikiloderma with tendon contractures, myopathy, and pulmonary 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 reserved for POIKTMP remains unclear. Further evaluations are necessary to fully elucidate this finding and potential mechanism by which the FAM111B gene mutation contributes to POH.

Project description:Background:Pseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities. Sporadic PHP1B cases, with no known underlying primary genetic lesions, could represent true stochastic errors in early embryonic maintenance of methylation. Previous data confirmed the existence of different degrees of methylation defects associated with PHP1B and suggested the presence of mosaicism, a phenomenon already described in the context of other IDs. Results:With respect to mosaic conditions, the study of multiple tissues is a necessary approach; thus, we investigated somatic cell lines (peripheral blood and buccal epithelium and cells from the urine sediment) descending from different germ layers from 19 PHP patients (11 spor-PHP1B, 4 GNAS mutated PHP1A, and 4 PHP with no GNAS (epi)genetic defects) and 5 healthy controls. We identified 11 patients with epigenetic defects, further subdivided in groups with complete or partial methylation defects. The recurrence of specific patterns of partial methylation defects limited to specific CpGs was confirmed by checking methylation profiles of spor-PHP1B patients diagnosed in our lab (n = 56). Underlying primary genetic defects, such as uniparental disomy or deletion, potentially causative for the detected partial methylation were excluded in all samples. Conclusions:Our data showed no differences of methylation levels between organs and tissues from the same patient, so we concluded that the epimutation occurred in early post-zygotic phases and that the partial defects were mosaics. The number of patients with no detectable (epi)genetic GNAS defects was too small to exclude epimutations occurring in later post-zygotic phases, affecting only selected tissues different from blood, thus leading to underdiagnosis during routine molecular diagnosis. Finally, we found no correlation between methylation ratios, representing the proportion of epimutated cells, and the clinical presentation, further confirming the hypothesis of a threshold effect of the GNAS loss of imprinting leading to an "all-or-none" phenotype.

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Progressive Osseous Heteroplasia is not an Autosomal Dominant Trait but Reflects Superimposed Mosaicism in Different GNAS Inactivation Disorders.

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