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Objectives In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI. Methods A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor’s technique) and basilar invagination (McRae’s technique)), and clinical features at the time of imaging. Results Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients. Conclusion The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI.

Background\ud \ud Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit.\ud \ud Report\ud \ud Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G > A p.(Arg1914His); c.3010C > T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G > A p.(Arg1914His); c.2032C > T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency.\ud \ud Discussion\ud \ud Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from ‘Classical’ OI.\ud \ud Conclusions\ud \ud Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

Fractures are common in childhood with incidence maximal during puberty, around the time of peak height velocity. The relationships between single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2 , bone mass acquisition, and childhood fractures are unclear. We recruited 394 children and adolescents aged 4 to 16 years into a noninterventional case control study. All had suffered an episode of trauma leading to hospital presentation; 205 had sustained a fracture. We determined the frequency of COL1A1 Sp1 and COL1A2 PvuII SNPs. Lumbar spine dual-energy X-ray absorptiometry (DXA) measurements were compared between fracture and control groups according to genotype. Subgroup analyses were performed according to sex, pubertal status, and site of injury. We found that the COL1A2 ‘PP’ genotype approximately halved the odds of fracture in the study group as a whole (OR = 0.45 [95% CI = 0.24–0.82], p = 0.01). In particular, possession of the same genotype by subjects who had not yet progressed beyond midpuberty was associated with reduced odds of fracture (OR = 0.38 [95% CI = 0.19–0.79], p = 0.01) and significantly increased lumbar spine bone mineral content ( p = 0.03) and areal bone mineral density ( p = 0.007). The COL1A1 Sp1 binding site ‘s’ allele was associated with a trebling of the odds of fracture in prepubertal children (OR = 3.1 [95% CI = 1.43–6.61], p = 0.004), but there was no association with any DXA measures. This is the first paediatric study to our knowledge that shows an association of the COL1A2 PvuII restriction site ‘PP’ genotype with a reduced risk of fracture and of the COL1A1 Sp1 binding site ‘s’ allele with an increased risk. The association of these variants with fracture risk is greatest during periods of predominantly appendicular bone growth.

Background: COL1A1 and COL1A2 mutations can result in increased bone fragility but the effect of SNPs on fracture risk in childhood is poorly understood. Functional data relate the COL1A1 Sp1 T allele to reduced bone strength but its relationship with bone size and mineral content in paediatric populations is inconsistent. The conservative COL1A2 PvuII SNP was over-represented in a small prepubertal Finnish population with fractures. Aim: Our study aimed to determine whether COL1A1 Sp1 and COL1A2 PvuII SNP alleles are over-represented in a population of children in the north of England who have sustained fractures. Methods: Over 400 children aged 4–16 years presenting to hospital following trauma were divided into two approximately equal groups according to whether or not this had resulted in fracture. Each child had total body and lumbar spine DEXA scans. DNA extracted from buccal brushings was analysed for the SNPs with pyrosequencing technology. Results: There was no significant difference in frequency of the COL1A1 Sp1 TT genotype between the two groups (p=0.51; % difference 1.5% (−1.4% to 4.4%)). However the COL1A2 PvuII GG genotype was significantly lower in the fracture group compared to controls (p=0.016; % difference 8.9% (2.1% to 15.6%)). No relationship was found between genotype and bone size or mass at any site. Discussion: The COL1A2 PvuII GG genotype is less frequent in children who sustain fractures, in contrast to the Finnish data. The lack of a relationship of genotype with bone size or mass implies an effect of genotype either on bone quality or an aspect of bone architecture not captured by DEXA.