Osteoglophonic dysplasia: A ‘common’ mutation in a rare disease

Sow, AJ; Ramli, Roszalina; Latiff, ZA; Ichikawa, Shoji; Gray, AK; Nordin, Rosdiadee; Jabar, MN Abd; Putra, Sha Primuharsa; Siar, Chong Huat; Econs, Michael J.

doi:10.1111/j.1399-0004.2010.01382.x

Cited by 10 publications

(8 citation statements)

References 4 publications

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“…Before being identified in GCLJ, FGFR1 p.N330I and p.C381R mutations had only been reported in osteoglophonic dysplasia (MIM #166250), a rare autosomal dominant disorder characterized by craniosynostosis, rhizomelic dwarfism, and distorted faces with marked depression of the nasal bridge, frontal bossing, and non‐ossifying bone lesions . Interestingly, when reading reports of osteoglophonic dysplasia patients with FGFR1 p.N330I and p.C381R mutations, we observed that the affected patients presented lesions compatible with GCLJ . Since non‐ossifying bone lesions are a feature of osteoglophonic dysplasia, it is not surprising that FGFR1 p.N330I and p.C381R mutations have recently been reported in sporadic cases of non‐ossifying fibromas of bone .…”

Section: Kras Trpv4 and Fgfr1 Mutations Define Giant Cell Lesions Omentioning

confidence: 69%

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

Gomes

Diniz

Bastos

et al. 2019

The Journal of Pathology

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Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information.

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Section: Kras Trpv4 and Fgfr1 Mutations Define Giant Cell Lesions Omentioning

confidence: 69%

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

Gomes

Diniz

Bastos

et al. 2019

The Journal of Pathology

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“…These mutations have previously been reported in osteoglophonic dysplasia 22 , 23 (OGD), a hereditary disease where GCLJ are seemingly absent. However, careful reading of published case reports 24 revealed that OGD patients with p.C381R and p.N330I mutations also presented with GCLJ, an association which had gone unnoticed. Importantly, none of our patients had clinical features suggestive of RASopathies, channelopathies or OGD, further confirming these mutations can be somatic in GCLJ.…”

Section: Resultsmentioning

confidence: 99%

TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw

et al. 2018

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Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies. Here, we analyze 58 sporadic samples using next generation or targeted sequencing and report somatic, heterozygous, gain-of-function mutations in KRAS, FGFR1, and p.M713V/I-TRPV4 in 72% (42/58) of GCLJ. TRPV4 p.M713V/I mutations are exclusive to central GCLJ and occur at a critical position adjacent to the cation permeable pore of the channel. Expression of TRPV4 mutants in HEK293 cells leads to increased cell death, as well as increased constitutive and stimulated channel activity, both of which can be prevented using TRPV4 antagonists. Furthermore, these mutations induce sustained activation of ERK1/2, indicating that their effects converge with that of KRAS and FGFR1 mutations on the activation of the MAPK pathway in GCLJ. Our data extend the spectrum of TRPV4 channelopathies and provide rationale for the use of TRPV4 and RAS/MAPK antagonists at the bedside in GCLJ.

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“…Several groups have reported patients harboring FGFR1 variants linked to non-reproductive signs. Patients with FGFR1 mutations have been reported to suffer from health conditions such as 8p11 myeloproliferative syndrome ( 107 , 108 ), encephalocraniocutaneous lipomatosis ( 109 , 110 ), Hartsfield syndrome, a rare condition characterized by holoprosencephaly, which is an abnormality of brain development ( 111 , 112 ), osteoglophonic dysplasia, a condition characterized by abnormal bone growth that leads to craniofacial abnormalities and dwarfism ( 113 , 114 ) and Pfeiffer syndrome, which is characterized by craniosynostosis ( 115 , 116 ). Somatic pathogenic variants involving the FGFR1 gene have also been reported in several types of cancers, including the lung, breast, esophagous, oral cavity and brain tumors ( 101 , 117 – 119 ).…”

Section: Review Of the Literaturementioning

confidence: 99%

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

et al. 2020

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Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by Gonadotropin-Releasing Hormone (GnRH) deficiency. So far a limited number of variants in several genes have been associated with the pathogenesis of the disease. In this original research and review manuscript the retrospective analysis of known variants in ANOS1 ( KAL1), RNF216, WDR11, FGFR1, CHD7 , and POLR3A genes is described, along with novel variants identified in patients with CHH by the present study. Methods: Seven GnRH deficient unrelated Cypriot patients underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The identified novel variants were initially examined by in silico computational algorithms and structural analysis of their predicted pathogenicity at the protein level was confirmed. Results: In four non-related GnRH males, a novel X-linked pathogenic variant in ANOS1 gene, two novel autosomal dominant (AD) probably pathogenic variants in WDR11 and FGFR1 genes and one rare AD probably pathogenic variant in CHD7 gene were identified. A rare autosomal recessive (AR) variant in the SRA1 gene was identified in homozygosity in a female patient, whilst two other male patients were also, respectively, found to carry novel or previously reported rare pathogenic variants in more than one genes; FGFR1 / POLR3A and SRA1/RNF216 . Conclusion: This report embraces the description of novel and previously reported rare pathogenic variants in a series of genes known to be implicated in the biological development of CHH. Notably, patients with CHH can harbor pathogenic rare variants in more than one gene which raises the hypothesis of locus-locus interactions providing evidence for digenic inheritance. The identification of such aberrations by NGS can be very informative for the management and future planning of these patients.

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Osteoglophonic dysplasia: A ‘common’ mutation in a rare disease

Cited by 10 publications

References 4 publications

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

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