ICCBH2015 Poster Presentations (1) (201 abstracts)
Unique occurrence of long bone fragility with cranial hyperostosis: Searching for the genetic culprit
Adalbert Raimann 1 , Uwe Wintergerst 2 , Paul Roschger 4 , Rainer Stelzl 2 , Rainer Biedermann 3 , Michael Rasse 3 , Nadja Fratzl-Zelman 4 , Franco Laccone 1 , Klaus Klaushofer 4 & Gabriele Haeusler 1
1Medical University of Vienna, Vienna, Austria; 2Krankenhaus St. Josef Braunau, Braunau, Austria; 3Medical University of Innsbruck, Innsbruck, Austria; 4Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Vienna, Austria.
Background: Systemic alterations in Runx2 expression have been shown to affect flat and long bone formation differently: Inactivating mutations cause low-turnover bone disease and patent fontanels in cleidocranial dysplasia, while overexpressing mutations cause metaphyseal dysplasia with maxillary hypoplasia and brachydactyly. The two conditions have inverse skeletal phenotypes. We know of no descriptions of these disorders in a patient without duplications or mutations of Runx2.
Presenting problem: The 5-year-old son of non-consanguineous Austrian parents presented with a unique combination of long bone fractures due to bone fragility and severe scoliosis with cranial hyperostosis and craniosynostosis. An iliac crest biopsy showed an extreme decrease in cancellous bone matrix mineralization and an increase in bone turnover, in line with elevated serum ALP and TRAP5b. To date, his linear growth and psychomotoric development are unaffected, but his fracture rate is high (2× right femur, 6× left femur, 5× left tibia, 1× right tibia, 1 sacrum).
Clinical management: Bisphosphonate treatment was withheld until his neuroforaminal width stabilized. Calvarial vault remodeling was necessary due to symptomatic craniosynostosis. Telescopic rods were implanted in both femura because of repeated fractures and bowing.
Genetic analysis: Direct gene sequencing for several possible genetic causes (RUNX2, TNFRSF11B, SOST, LRP5, SERPINF1, FGFR1-3, TWIST1) detected no relevant mutations. SNP microarrays and whole exome sequencing have revealed no underlying alterations so far.
Discussion: We have not been able to identify any underlying genetic cause for our patient’s complex phenotype. Many of his clinical features resemble metaphyseal dysplasia with maxillary hypoplasia and brachydactyly caused by duplications of Runx2 which have been excluded in this patient. We speculate that genetic alterations of a novel key regulator of ossification associated with Runx2 could have caused this uncommon clinical picture.
Disclosure: The authors declared no competing interests.
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