Type I Osteogenesis Imperfecta Caused By a New Mutation

Presentation Number: SAT 321
Date of Presentation: April 1st, 2017

Dorothea Barbara Szczawinska*1, Reinhard Santen1, Martin Engelbach2, H. Skladny3, Peter Herbert Kann4 and Christof Schoefl5
1Endocrine Clinic, Frankfurt am Main, GERMANY, 2Endocrine Clinic, Frankfurt am Main, Germany, 3Synlab Humangenetik Mannheim, 4University Hospital Marburg, Marburg, Germany, 5Endocrine Clinic, Bamberg, Germany



Osteogenesis imperfecta is a clinically and genetically heterogenous connective tissue disorder characterized by bone fragility, deformity and growth deficiency. With its estimated incidence of 1:20000 it’s a differential diagnosis to consider while evaluating for secondary causes of osteoporosis.

Most cases are caused by mutations in the type 1 collagen genes. Elucidating new mutations and correlating them with the clinical phenotype may provide new insights about new possible therapeutic approaches.

Clinical Case

A 36-year old man with a history of multiple (15) non-traumatic fractures during childhood and a recent non-traumatic thoracic spine fracture presented for further evaluation in our endocrine clinic. Physical examination revealed short stature (168cm) and bilateral pendular nystagmus (congenital). There was no evidence of bone deformities or blue sclerae. On further questioning, he was diagnosed with otosclerosis and underwent corrective operations in year 2009 and 2013. There was also a history of primary hyperparathyreoidism with a subsequent parathyroidectomy performed in 1997. Of note, there was no family history of fractures, osteoporosis, bone deformities or primary hyperparathyreoidism. Subsequently performed DXA (04/16) scan confirmed the diagnosis of osteoporosis (Lumbar spine 4 T-score: -4,5 SD, Z-score: -4,5 SD, Hip T- score: -2,4 SD, Z-score: -1.8 SD). Comprehensive biochemical evaluation showed no evidence for possible secondary causes of osteoporosis. Next, genetic testing was done and revealed a new, previously not reported (reference HGMD Professional 2016.1) heterozygous nonsense variant c. 2677G>T in the COL1A1 gene, that most probably arised de novo- This alteration leads to an exchange of a glycin residue for a stopcodon in the protein synthesis, most probably leading to a quantitative defect of type 1 collagen. This may lead to degradation of transcripts from the mutant COL1A1 allele (nonsense-mediated RNA-decay), so that only about half of the amount of the matrix will be deposited. The relatively mild phenotype is most likely due to the presence of almost entirely normal collagen from the normal COL1A1 allele. The bone biopsy showed nonspecific changed and no obvious mineralization defects. Based on clinical findings and the genetic tests the patient was diagnosed with an autosomal dominant classical 'Sillence' type I Osteogenesis imperfecta. On the background of previous diagnosis of primary hyperparathyreoidism additional genetic tests were performed and the presence of RET-oncogene and MEN-1-gene mutation was ruled out.

The patient received genetic counselling and was started on oral bisphosphonates. He has been tolerating the therapy well and has so far not had any further fractures.


This case demonstrates a previously not described mutation in the COL1A1 gene and its phenotypical correlations.


Nothing to Disclose: DBS, RS, ME, HS, PHK, CS