Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.

BACKGROUND: 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. REPORT: 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. DISCUSSION: 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. CONCLUSIONS: 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.

Femoral artery dissection in vascular type Ehlers-Danlos syndrome; leave well alone?

Vascular Ehlers-Danlos Syndrome (EDS) is a rare autosomal dominant condition resulting from a defect in type III procollagen synthesis. This causes the development of severe vascular pathologies, including arterial rupture and pseudoaneurysm formation. We present a case of a young boy previously diagnosed with vascular EDS due to a Gly975Val substitution in the collagen α1(III) chain presenting with a common femoral artery dissection secondary to minimal trauma. This was managed conservatively with serial duplex scans and gentle mobilization. At follow up the patient had returned to normal activities, with MRA and duplex scans showing complete resolution of the dissection.

Are aberrant BCR--ABL transcripts more common than previously thought?

We report the use of multiplex polymerase chain reaction (PCR), using 4% polyacrylamide gel electrophoresis (PAGE) for the detection of BCR-ABL transcripts in Philadelphia-positive disease. Three out of 50 cases [two out of 37 chronic myeloid leukaemia (CML), one out of 13 acute lymphoblastic leukaemia (ALL)] possessed rare breakpoints; an e19a2 and e13a3 in CML and an e1a3 in the ALL. We suggest that multiplex PCR using 4% PAGE and optimized for smaller transcript detection may lead to a higher detection rate of rare BCR-ABL breakpoints. Multiplex PCR, however, failed to distinguish e13a2 from e1a3 transcripts. Finally, the presence of e13a3 in CML supports the view that abl exon 2 sequences are unnecessary for the pathogenesis of 'classic' CML.