Cranial base abnormalities in osteogenesis imperfecta: Phenotypic and genotypic determinants

Abstract

Cranial base abnormalities are an important complication of osteogenesis imperfecta (OI), a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. To elucidate which clinical characteristics are associated with the occurrence of cranial base abnormalities in OI, we compared cephalometric results of 187 OI patients (median age 12.0 years, range 3.4 to 47 years; 96 female) with those of 191 healthy subjects and related findings to clinical descriptors of the disease. Overall, 41 patients (22%) had at least one unambiguously abnormal skull base measure. Multivariate logistic regression analysis in patients with OI types I, III, and IV (n ¼ 169) revealed that height Z-score [odds ratio (OR) ¼ 0.53, 95% confidence interval (CI) 0.43-0.66, p < .001]-but not age, gender, scleral hue, lumbar spine areal bone mineral density, or a history of bisphosphonate treatment-was a significant independent determinant of skull base abnormalities. Among patients with a height Z-score below -3, 48% had a skull base abnormality regardless of whether they had received bisphosphonate treatment in the first year of life or not. Genotype-phenotype correlations were evaluated in patients with detectable mutations in COL1A1 or COL1A2, the genes coding for collagen type I (n ¼ 140). Skull base abnormalities were present in 6% of patients with haploinsufficiency (frameshift or nonsense) mutations, in 43% of patients with helical glycine substitutions caused by COL1A1 mutations, in 32% of patients with helical glycine substitutions owing to COL1A2 mutations, and in 17% of patients with splice-site mutations affecting either COL1A1 or COL1A2. However, multivariate logistic regression analysis showed that height Z-score but not the type of collagen type I mutation was independently associated with the prevalence of skull base abnormalities. In conclusion, this study shows that clinical severity of OI, as expressed by the height Z-score, was the strongest predictor of skull base abnormalities. We did not find evidence for the hypothesis that bisphosphonate treatment protects against skull base abnormalities. ß

Cranial base pathology in pediatric osteogenesis imperfecta patients treated with bisphosphonates

“…Our finding that cranial base anomalies may develop despite bisphosphonate treatment is consistent with previous studies. 4,11 Further studies in larger patient cohorts with extended follow-up are needed to confirm our findings; the use of MRI in longitudinal follow-up would give more detailed data on the progression of cranial base pathology. The overall effects of bisphosphonates on the skeleton are growth dependent, and thus early treatment initiation is recommended.…”

Osteogenesis Imperfecta and Other Defects of Bone Development as Occasional Causes of Adult Osteoporosis

“…An analysis of cephalometric abnormalities in OI types I, III, and IV (n = 169) by Cheung et al showed that height z-score, but not the type of collagen type I mutation, was independently associated with the prevalence of skull base abnormalities [196]. About 48% of patients with a height z-score below -3 had a skull base abnormality regardless of whether or not they had received bisphosphonate treatment as infants.…”

Recent Advances in Osteogenesis Imperfecta

“…A number of recent publications have addressed this topic, and the data are summarized in Table 1 [1,[7][8][9][10]. In brief, in patients with haploinsufficiency the phenotype is milder in almost all respects than those producing an abnormal collagen (the exception is the high prevalence of hearing impairment in the former, but this may in part reflect the longer life expectancy of these patients).…”