Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by increased bone fragility and deformities. Although most patients with OI have heterozygous mutations in COL1A1 or COL1A2, 17 genes have been reported to cause OI, most of which are autosomal recessive (AR) inherited, during the last years. The aim of this study is to determine the mutation spectrum in Turkish OI cohort and to investigate the genotype-phenotype correlation. METHODS: 150 patients from 140 Turkish families with OI phenotype were included in this study. Mutations in OI-related genes were identified using targeted gene panel, MLPA analysis for COL1A1 and whole exome sequencing. 113 patients who had OI disease-causing variants were followed for 1-20 years. RESULTS: OI disease-causing variants were detected in 117 families, of which 62.4% in COL1A1/A2, 35.9% in AR-related genes. A heterozygous variant in IFITM5 and a hemizygous in MBTPS2 were also described, one in each patient. Eighteen biallelic variants (13 novel) were identified in nine genes (FKBP10, P3H1, SERPINF1, TMEM38B, WNT1, BMP1, CRTAP, FAM46A, MESD) among which FKBP10, P3H1 and SERPINF1 were most common. The most severe phenotypes were in patients with FKBP10, SERPINF1, CRTAP, FAM46A and MESD variants. P3H1 patients had moderate, while BMP1 had the mild phenotype. Clinical phenotypes were variable in patients with WNT1 and TMEM38B mutations. We also found mutations in ten genes (PLS3, LRP5, ANO5, SLC34A1, EFEMP2, PRDM5, GORAB, OCRL1, TNFRSF11B, DPH1) associated with diseases presenting clinical features which overlap OI, in eleven families. CONCLUSION: We identified disease-causing mutations in 83.6% in a large Turkish pediatric OI cohort. 40 novel variants were described. Clinical features and long-term follow-up findings of AR inherited OI types and especially very rare biallelic variants were presented for the first time. Unlike previously reported studies, the mutations that we found in P3H1 were all missense, causing a moderate phenotype.

Low back complaints worse, but not more frequent in subjects with congenital lumbosacral malformations: a study on 5000 recruits.

The authors studied the plain radiographs and medical records of 5000 military recruits, mean age 19.1 years (range: 18 to 22), screened in a Turkish Military Hospital in the period November 2008-October 2009. They focused on the incidence of congenital lumbosacral malformations, such as spina bifida occulta and transitional vertebra, trying to find a correlation with subsequent low back complaints. Only 80 out of 748 subjects (10.7%) with low back complaints had one or more malformations, versus 744 out of 4252 subjects (17.5%) without low back complaints. This pleaded against a correlation between malformations and low back disorders. Also the literature is completely divided as to this problem, which means that there is probably no correlation at all. Interestingly, the 80 subjects with low back complaints and malformation estimated their pain level at +/- 4.6 on a Visual Analog Scale for pain, while the 668 with low back complaints but without malformation estimated their pain level at only +/- 2.2 (p = 0.007). At least two other studies led to the same conclusion. This paradox might be due to the fact that congenital malformations concentrate all external stress on the adjacent levels.