[source]
pmid = PMID:29382611
title = Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment
[diagnosis]
disease_id = OMIM:613849
disease_label = Osteogenesis imperfecta, type XII
[text]
The proband (II.5) was the 4th of eight children born from an uncomplicated pregnancy to healthy
consanguineous parents of Iraqi descent (Fig. 1, Fig. 2). There were no perinatal issues and psychomotor
development progressed normally. Between 5 and 10 years of age, his family noticed he had insidious
and progressive hearing difficulties. He was later diagnosed with hearing impairment and required hearing aids. The individual immigrated to Australia with his family at the age of 12 years and serial hearing assessments revealed profound sensorineural hearing loss with normal middle ear function. By the time he was referred to our service he was 14 years of age and his hearing had further deteriorated requiring maximal amplification and he was awaiting cochlear implants. Risk factors for hearing loss, such as prolonged hyperbilirubinemia, ototoxic medications, recurrent acute otitis media, skull fracture or noise exposure, were excluded.
From a bone health perspective, he had a significant history of low trauma fractures starting at 13 years of
age. These included 2 separate forearm fractures from being hit by a soccer ball, a distal radial metaphyseal
fracture, and 2 separate femur fractures requiring surgical correction, the last of which was further
complicated by a transverse fracture at the level of the orthopaedic hardware. Furthermore, while recovering
from his lower limb fractures, he sustained an olecranon stress fracture after using crutches as a mobility
aid and a pelvic avulsion fracture with unknown mechanism of injury.

Physical examination revealed short stature (142.6 cm; 0.1th percentile, SDS-3.01) for his
midparental height on the 28th centile. Weight (43.2 kg; 7th percentile, SDS -1.41),
head circumference (54.5 cm; 49th percentile, SDS 0.0) and body mass index (BMI) were
normal (21.3 kg/m2; 70th percentile, SDS 0.53).
Facial features included white sclerae, mild facial asymmetry, high prominent forehead,
prominent supraorbital ridges, midface hypoplasia, prominent ears, depressed nasal bridge,
microstomia and high-arched palate (Fig. 2). There was a history of delayed tooth eruption,
but no evidence of dentinogenesis imperfecta. Whilst limbs were symmetrical and proportional,
knee joint hyperlaxity and valgus deformities were noted bilaterally. Spinal exam revealed a mild scoliosis
with thoracic spinal tenderness.
At 14 years and 8 months, he had Tanner stage 2–3 pubic hair with testes measuring 12–15 mL bilaterally.
CT scan images revealed significant bilateral otospongiosis (osteosclerosis) and poor mineralization of
the ossicles and petrous temporal bone (Fig. 3). Magnetic resonance imaging of the brain and internal
auditory meatus were normal without evidence of auditory nerve or inner ear anomalies.
Spinal radiography revealed thoracic platyspondyly and reduced vertebral body height at all
levels with pronounced vertebral crush fractures (VFs) at the thoraco-lumbar junction (Fig. 4).
A skeletal survey showed generalized osteopenia and a striking under-tubulation of long bones,
metatarsals and metacarpals with associated thickening of cortices (Fig. 5).
No bowing deformities were noted. Non-traumatic anterior subluxation at the C2–C3 cervical spine
was also noted on imaging.
Bone densitometry indicated diffuse low bone mineral density (Table 1). pQCT showed strikingly reduced cortical volumetric
bone mineral density (vBMD) and elevated cortical cross-sectional area.
A transiliac bone biopsy (Fig. 6) revealed very high cortical porosity, with long canals that traversed the cortex parallel to the periosteal surface. Cortical width was 60% of the mean for age. Cancellous bone volume was in the lower part of the reference range and hyperosteocytosis was also noted. Surface based parameters of bone formation and bone resorption were very high. Inferred bone formation rate was +9 standard deviations (SD) above the normal mean for age. Osteoclast parameters were similarly elevated.
There was no mineralization defect (Table 2). Overall, the qualitatively elevated cortical porosity
and very high trabecular bone turnover (Table 1) was reminiscent of hyperphosphatasia;
this was not in keeping with his preliminary blood results. Vitamin D insufficiency
(37 nmol/L; range 50–200 nmol/L) was corrected with supplementation and treatment with intravenous
Zoledronate (0.025 mg/kg 3 monthly) was initiated.
