Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly in a Finnish woman: First confirmation of a duplication in RUNX2 as pathogenic variant

Avela, Kristiina; Hirvinen, Heljä; Amor, Mouna Ben; Rauch, Frank

doi:10.1016/j.ejmg.2014.09.010

Cited by 6 publications

(13 citation statements)

References 7 publications

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“…Functional studies showed that this duplication resulted in a gain of function [2]. A similar, though not identical, in-frame duplication of exons 3-5 of RUNX2 was subsequently reported in a 20-year-old Finnish woman with clinical and radiological signs of MDMHB [3].…”

Section: Introductionsupporting

confidence: 54%

“…The clinical findings in our family, together with those in previously reported patients with MDMHB are summarised in (Table 1) [1][2][3]. Dental anomalies are a consistent finding and are usually the presenting feature.…”

Section: Wt Runx2mentioning

confidence: 52%

“…Intragenic duplication encompassing exons 3-5 of the RUNX2 gene was previously reported in a French Canadian family with MDMHB and one other, unrelated case from Finland [2,3]. An intragenic duplication encompassing exons 3-5 of the RUNX2 gene was previously reported in a French Canadian family with MDMHB and one other, unrelated case from Finland [2,3].…”

Section: Wt Runx2mentioning

confidence: 91%

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A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication

et al. 2018

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Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis. To date, only one large French Canadian family and a Finnish woman have been reported with the condition. In both, intragenic duplication encompassing exons 3-5 of the RUNX2 gene was identified. We describe a new, three-generation family with clinical features of MDMHB and an intragenic tandem duplication of RUNX2 exons 3-6. Dental problems were the primary presenting feature in all four affected individuals. We compare the features in our family to those previously reported in MDMHB, review the natural history of this condition and highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies.

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Section: Introductionsupporting

confidence: 54%

Section: Wt Runx2mentioning

confidence: 52%

Section: Wt Runx2mentioning

confidence: 91%

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A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication

et al. 2018

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“…The authors suggested a gain‐of‐function effect and showed in vitro an increased transcriptional activity that strengthened this hypothesis. Recently, a second patient with MDMHB, not of French Canadian origin, has been reported [Avela et al, ]. Molecular characterization showed that exons 3–5 were duplicated, but the exact boundaries of the duplication were different from the first family.…”

Section: Discussionmentioning

confidence: 99%

“…Loss‐of‐function mutations of this gene and deletions including RUNX2 have been identified in patients presenting with cleidocranial dysplasia (CCD, OMIM #119600), an autosomal dominant disorder including delayed closure of cranial sutures, aplastic, or hypoplastic clavicles, moderate short stature and supernumerary teeth [Lee et al, ; Ryoo at al., 2010; Chen et al, ; Lee et al, ]. Conversely, partial intragenic duplications of the gene have been described in patients presenting with metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB; OMIM 156510) [Halal et al, ; Moffatt et al, ; Avela et al, ], whereas complete duplications have been described in patients presenting with craniosynostosis and oligodontia [Mefford et al, ; Greives et al, ]. Both types of duplication are acting as gain‐of‐function mutations.…”

Section: Introductionmentioning

confidence: 99%

Patients with isolated oligo/hypodontia caused by RUNX2 duplication

Molin¹,

Lopez-Cazaux

Pichon

et al. 2015

American J of Med Genetics Pt A

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Loss-of-function mutations of RUNX2 are responsible for cleidocranial dysplasia, an autosomal dominant disorder characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicles, moderate short stature and supernumerary teeth. By contrast, an increased gene dosage is expected for duplication of the entire RUNX2 sequence and thus, a phenotype different from cleidocranial dysplasia. To date, two cousins with a duplication including the entire RUNX2 sequence in addition to MIR586, CLIC5 and the 5' half of SUPT3H have been reported. These patients presented with metopic synostosis and hypodontia. Here, we report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. Interestingly, the mother and one child had isolated hypodontia without craniosynostosis, broadening the phenotype observed in patients with such duplications.

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