http://www.biosciproceedingsandabstracts.com/

ISSN 2052-1219 (online)

Bone Abstracts (2015) 4 P179 | DOI: 10.1530/boneabs.4.P179

An atypical case of bone fragility and dysmorphism with an unusual and novel de novo COL1A1 mutation

Mars Skae1, Frank Rauch2, Zulf Mughal1, Jo Sims3, Naomi Davis4, B Scott5, Paul Arundel6 & Emma Hobson7


1Department of Paediatric Endocrinology, Royal Manchester Childrens Hospital, Manchester, UK; 2Department of Paediatrics, McGill University, Shriners Hospital for Children, Montreal, Canada; 3Department of Paediatrics, Calderdale Royal Hospital, Halifax, UK; 4Department of Paediatric Orthopaedics, Royal Manchester Children’s Hospital, Manchester, UK; 5Department of Paediatric Orthopaedics, Leeds General Infirmary, Leeds, UK; 6Department of Metabolic Bone Disease, Sheffield Children’s NHS Foundation Trust, Sheffield, UK; 7Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.


We report a male child presenting with antenatally diagnosed bilateral talipes equinovarus, short stature, bilateral cryptorchidism and poor weight gain; born at 39 weeks gestation (birth weight 2.56 kg) to non-consanguineous Caucasian parents. Facial dysmorphism included a prominent forehead, brachycephaly, shallow orbits, a high anterior hairline, a narrow nasal bridge and small mouth with a thin upper lip. He had white sclera and was short for height (−4.4 SDS) with a relatively large head circumference (−2.2 SDS). His dentition evolved with dental enamel hypoplasia.

Presentation

At 6 weeks of age, he had a right transverse femoral fracture, followed by two right tibial fractures after Ponseti casting for correction of talipes. Delayed gross motor development due to prolonged periods of casting and mild speech delay were noted at the time. His bones were presumed osteopenic due to limb disuse.

Treatment: Pamidronate therapy was commenced at age 14 months before further casting and tenotomies. However, a non-union of the tibial fracture (pseudoarthrosis) was noted after an initial cycle of bisphosphonates. Further splinting after further bisphosphonate therapy resolved talipes and motor development normalised.

Investigations: A skeletal survey confirmed generalised osteopenia, with lambdoid Wormian bones and normal vertebrae. Lumbar spine DXA scanning reported low bone mineral density. Bone biochemistry was normal including vitamin D and PTH. A transiliac bone biopsy demonstrated severe trabecular and moderate cortical osteopenia.

Array CGH found a small duplication variant of uncertain significance at Xp, with no obvious association to the child’s phenotype. Sequence analysis found a novel de novo in-frame deletion of COL1A1 in exon 2, causing deletion of one amino acid residue in the N-propeptide of the α-1 chain of collagen type I. No N-propeptide in-frame mutations are reported in the OI mutation database (https://oi.gene.le.ac.uk). However, triple helix domain in-frame deletions of COL1A1, although uncommon, have been reported in cases usually with a severe OI phenotype. Abnormalities in N-propeptide processing have been reported to cause an Ehlers-Danlos (EDS) type VII (exon 6 mutations) or an EDS/OI overlap syndrome (triple helical mutations in exon 6 or higher). Functional work looking at COL1A1 expression in fibroblasts is currently being undertaken.

Disclosure: The authors declared no competing interests.

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