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A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies

D Tatemir

¹ Department of Medical Biology and Genetics, Çukurova University, Adana, Turkey
² Institute for Medical Genetics, Charité, Berlin, Germany
³ Max Planck Institute for Molecular Genetics, Berlin, Germany
⁴ Department of Radiology, Çukurova University, Adana, Turkey

Correspondence to:
Stefan Mundlos
Institut für Medizinische Genetik, Universitätsmedizin Berlin, Charité, Augustenburger Platz 1, 13353 Berlin, Germany; stefan.mundlos{at}charite.de] We present a patient with acromesomelic chondrodysplasia and genital anomalies caused by a novel homozygous mutation in BMPR1B, the gene coding for bone morphogenetic protein receptor 1B. The 16 year old girl, the offspring of a multiconsanguinous family, showed a severe form of limb malformation consisting of aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones. In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism. Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359–366). This mutation is expected to result in a loss of function and is thus different from the heterozygous missense mutations in BMPR1B recently shown to cause brachydactyly type A2 through a dominant negative effect. The patient’s skeletal phenotype shows an overlap with the clinical spectrum of the acromesomelic chondrodysplasias of the Grebe, Hunter-Thompson, and DuPan types caused by homozygous mutations in the gene coding for growth differentiation factor 5 (GDF5) which is a high-affinity ligand to BMPR1B. However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype.

Abbreviations: BDA2, brachydactyly A2; BDC, brachydactyly type C; BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; bp mouse, brachypodism mouse; FSH, follicle stimulating hormone; GDF5, growth differentiation factor 5; LH, luteinising hormone; MCPP, metacarpophalangeal profile; TGF-ß, transforming growth factor-ß

Keywords: acromesomelic chondrodysplasia; bone morphogenetic protein receptor; GDF5; genital malformation; ovarian dysfunction

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