PMC6067660_01
a-e: 1a-c: Facial features as an infant and aged >1, 2 and 9 years showing grey sclerae, broad forehead, bilateral low-set ears, proptosis and progeric appearance; 1d-e: Hands and feet at 2-years of age.
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F1
On examination at 9-years of age, he was dysmorphic, with proptosis, progeric appearance to his skin, bilateral low-set ears, dentinogenesis imperfecta, and bilateral 5th finger clinodactyly with bulbous tips to his fingers and toes (Figure 1a-e).
a-d: Radiographs demonstrating slender ribs, tubular long bones with thin cortices and osteopenia consistent with a diagnosis of OI. 2a: AP skull radiograph (aged 6 years) There are multiple Wormian bones; the clavicles are slender and the erupted teeth are relatively dense. The anterior fontanelle remains open.. 2b-d: Selected images from a full dysplasia skeletal survey (aged 9 years 8 months). 2b: Left hand. There is significant periarticular osteopenia (see Fig 2c). The metacarpals (and less marked) the proximal phalanges are overmodelled and there is an ivory epiphysis of the terminal phalanx of the fifth finger. The terminal tufts are prominent.. 2c: AP Chest. The ribs and clavicles are slender; however, there are no fractures and vertebral body height is preserved. Note the presence of a gastrostomy.. 2d. AP Right Femur: Overmodelled with slender diaphysis and relatively flared distal metaphysis. Periarticular osteopenia is again noted (see Fig 2a). 2e: Peripheral blood film in Patient 1 demonstrating a hypolobulated neutrophil (left) and a Pelger-Huet cell (right).
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F2
A dysplasia skeletal survey showed multiple Wormian bones, slender tubular bones and osteopenia (Figure 2a-d).
a-b: 3a: Toluidine blue-stained section of an undecalcified trans-iliac bone biopsy, original magnification x400 demonstrating cortex, with periosteum on the right showing high turnover osteopenia with marked sub-periosteal bone resorption (arrow) and normal lamellar bone matrix structure in Patient-1, aged 9 years; 3b: appearance in 'Classical OI' with abnormal matrix pattern and increased periosteal bone formation surface (arrow). Toluidine blue; Original magnification of 400x.. c-d: 3c: Electron Microscopy of skin biopsy from Patient 1(left image) compared to normal control (middle image) showing normal collagen in mid-reticular dermis with mildly reduced mean collagen fibril diameter (CFD); Original magnification of 20,000x; Lower magnification (right image) with arrows indicating deep reticular dermal fibroblast with expanded protein filled rough endoplasmic reticulum; Original magnification x2,600.. 3d: normal collagen species analysis with no deviation from control (1 and 3) in comparison to patient with a COL1A1 variant (2).
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F3
A transiliac bone biopsy at 7-years of age, following recurrent low-trauma fractures, demonstrated osteoporosis with high bone turnover with marked periosteal bone resorption, which was different to appearances in classical OI (Figure 3a-b). Collagen species analysis on SDS-Page gel was normal with no obvious shift, but electron microscopy showed multiple small collagen flowers, variable shaped collagen fibrils with a mean collagen fibril diameter (CFD) of 75nm (Figure 3c-d).
PMC6067660_02
a-e: 4a-c: Facial appearance of Patient 2 aged <2, 3 and 5 years demonstrating similar facial dysmorphism to Patient 1 with progeric appearance, grey sclerae, broad forehead, bilateral low-set ears, proptosis; 4d-e: Skull and right lower limb X-rays demonstrating thin skull vault, slender bones and osteopenia.
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F4
On examination at 5-years of age, he was dysmorphic, with brachycephaly, proptosis, progeric appearance to his skin, bilateral low-set ears, greyish sclerae, and bilateral 5th finger clinodactyly with bulbous tips to his fingers and toes (Figure 4a-c). A dysplasia skeletal survey subsequently confirmed similar features as reported previously (Figure 4d-e).