Bone Abstracts

Background: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It is a variable condition with a range of clinical severity. About 90% of patients with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes, which shows an autosomal dominant pattern (AD) of inheritance. Other genes are associated with the autosomal recessive (AR) forms of OI. Mutations in IFITM5 have recently been described in type V OI. Other, rare phenotypes have also been described.

For the purposes of this study, we considered patients with OI who had phenotypic similarities to Russell-Silver syndrome (RSS), OI syndromes (not commonly fitting the Sillence classification) such as Cole-Carpenter and Bruck syndrome and patients with a clinical diagnosis of type V OI. All these conditions were collectively referred to as atypical OI.

Aims: To identify and investigate individuals with atypical forms of OI, with a view to proposing sub-classifications and identify genotype–phenotype correlations.

Methods: Patients who fulfilled the inclusion criteria were recruited from the Sheffield Clinical Genetics and OI Services. One patient was excluded as the family did not consent to participation. Detailed phenotyping, skin biopsy for histology, including electron microscopy (EM) and collagen species analysis (CSA), urine N-terminal telopeptide (Urine NTx), skeletal survey, and sequencing of OI genes and aCGH were performed.

Results: Recruited patients (n=14) were phenotypically divided into three sub-groups: Group 1, predominant features of RSS (n=5); Group 2, OI with additional features (n=6); and Group 3, type V OI (n=3). Common clinical features included poor growth, feeding difficulties, facial dysmorphism±fractures. Pathogenic single gene mutations were identified in seven patients (four in Groups 1 and 2; three in Group 3); chromosomal imbalances were identified in three patients. Skeletal surveys and skin biopsies (histology and EM) have revealed some common findings. CSA has shown good correlation with molecular findings.

Conclusions: This study has enabled us to start to sub-classify patients with atypical OI. It has also established the need to consider aCGH, skin histology, EM and CSA, routinely in the investigation of such patients.

Reference: Parker MJ, Balasubramanian M, et al. Type 1 collagenopathy presenting with a Russell-Silver phenotype. Am J Med Genet A 2011 155 (6) 1414–1418.