Osteogenesis Imperfecta — Sillence Types

Osteogenesis imperfecta (OI) is a heterogeneous group of heritable connective tissue disorders characterised by bone fragility, multiple fractures, and skeletal deformity due to abnormalities of type I collagen — the principal structural protein of bone. It is the most common genetic cause of increased fracture risk in children. The clinical spectrum is extremely wide, ranging from mild forms with slightly increased fracture tendency and normal life expectancy to lethal perinatal forms incompatible with survival. Management requires a multidisciplinary team including orthopaedic surgery, endocrinology, physiotherapy, and genetics.

• Molecular pathology: approximately 85–90% of OI cases are caused by mutations in COL1A1 or COL1A2 genes (autosomal dominant) encoding the pro-α1 and pro-α2 chains of type I procollagen; mutations cause either quantitative deficiency (reduced amount of structurally normal collagen — typically milder phenotypes) or qualitative defects (structurally abnormal collagen chains that disrupt the triple helix — typically more severe phenotypes); the remaining 10–15% are caused by mutations in genes encoding proteins involved in collagen post-translational modification, folding, or secretion (autosomal recessive forms — CRTAP, LEPRE1/P3H1, PPIB, SERPINH1, FKBP10, SP7 — associated with Sillence Types VII–XII and beyond)
• Bone biology: defective type I collagen leads to impaired bone matrix mineralisation and reduced bone mass (osteoporosis); the bone is brittle and fails under minimal trauma; bones heal (callus forms) but remain abnormally fragile; woven bone predominates over lamellar bone; osteoporosis in OI is now treated with bisphosphonates (the major pharmacological advance of the last 30 years)

The Sillence classification (1979), revised and expanded, classifies OI into clinical types based on severity, inheritance pattern, and associated features. Types I–IV are the original Sillence types; Types V–XII (and beyond) represent subsequently identified biochemically and genetically distinct subtypes, mostly autosomal recessive.

• Types VI–XII and beyond (autosomal recessive): these are rarer forms caused by mutations in genes for collagen modification enzymes and chaperone proteins; examples — Type VI (SERPINF1 mutation — hypermineralisation abnormality; `fish scale` lamellar bone pattern on histology); Type VII (CRTAP mutation — similar to Type III severity); Type VIII (LEPRE1/P3H1 — severe-lethal phenotype similar to Type II); important for genetics counselling in families with consanguinity or negative COL1A1/COL1A2 sequencing

• Intravenous pamidronate (Glorieux protocol): the landmark advance in OI management; introduced by Glorieux et al. (1998); cyclical IV pamidronate (1 mg/kg/day × 3 days, every 4 months); reduces osteoclast activity → increases bone mineral density (BMD) by 30–50% → reduces fracture frequency by ~40–50%; improves bone cortical thickness and trabecular density on X-ray (dense horizontal growth arrest lines — `zebra lines` or `rugger jersey` bands — are the radiological hallmark of bisphosphonate therapy in growing children); also reduces vertebral collapse, improves bone pain, and facilitates ambulation; started from infancy in severe (Types II–III) and early in Types I and IV
• Zoledronic acid (IV): now widely used as an alternative to pamidronate (once or twice yearly administration vs quarterly pamidronate); equivalent or superior efficacy to pamidronate in published trials; greater convenience; BRNO (Bone-related outcomes in Neonates and Osteogenesis imperfecta) trial data supports use from infancy
• Bisphosphonate-associated complications in OI: `zebra lines` (growth arrest lines — hallmark of bisphosphonate therapy; not pathological); fractures through the `hard` bisphosphonate bone — bisphosphonate-induced oversuppression of bone remodelling can theoretically make bone more brittle at high doses; atypical femoral fractures (rare in children compared to adults); impaired healing of osteotomy sites (bisphosphonate-related suppression of remodelling; drug holidays before elective osteotomy); osteonecrosis of the jaw (extremely rare in paediatric patients; more relevant in adults)
• Emerging biological therapies: denosumab (anti-RANKL monoclonal antibody) — inhibits osteoclast activity more specifically than bisphosphonates; being investigated in OI; fresolimumab (anti-TGF-β) — experimental; anti-sclerostin antibody (romosozumab) — activates osteoblasts; anti-Wnt inhibitor approaches being investigated to stimulate bone formation

• Intramedullary rodding (Bailey-Dubow / Fassier-Duval rods): the cornerstone of orthopaedic surgical management in moderate-to-severe OI; intramedullary telescoping rods are inserted into the long bones (femur, tibia, humerus) to prevent fractures and correct deformity; Bailey-Dubow (BD) rod: the original telescoping rod — consists of two components (inner T-rod and outer rod) that telescope as the bone grows; provides longitudinal support along the bone; Fassier-Duval (FD) threaded rod: the modern standard — a threaded design that allows the rod to telescope more reliably through the growth plates and reduces the risk of rod migration or rod `backing out` that was a problem with BD rods; indication — three or more fractures in the same bone per year in a walking child; progressive deformity; before each fracture episode (prophylactic); the decision to rod must balance surgical risks (anaesthetic in OI — jaw fixity, airway, temperature instability; intraoperative fracture) against fracture prevention benefit
• Scoliosis in OI: occurs in up to 80% of patients with severe OI (Types III, IV); progressive and may be severe; managed initially with bracing (limited effectiveness); surgical correction (posterior spinal fusion with instrumentation) when Cobb angle progresses despite bracing or reaches approximately 40–50°; high complication rates — blood loss (defective collagen in vessel walls), rod pullout (poor bone quality), pseudarthrosis; vertebral augmentation (vertebroplasty) may be needed for collapsed vertebrae
• Basilar invagination: the most dangerous neurological complication of OI — upward migration of the odontoid into the foramen magnum; caused by abnormally soft (brittle) occipital bone and skull base that gradually deform under the weight of the head and the forces of the neck muscles; presents with cervical myelopathy, syringomyelia, hydrocephalus, lower cranial nerve palsies, or sudden unexpected death; MRI of the craniovertebral junction is essential surveillance in Types III and IV OI; management — stabilisation (posterior cervical fusion) with or without decompression if neurological compromise

• Sillence classification: Type I (mild, blue sclerae, hearing loss, DI in IB, dominant, quantitative collagen defect); Type II (lethal, dark blue sclerae, crumpled bones, beaded ribs); Type III (severe-progressive, blue→white sclerae, popcorn metaphyses, basilar invagination, DI, scoliosis); Type IV (moderate, WHITE sclerae — key differentiator, DI in IVB); Type V (moderate, white sclerae, hypertrophic callus, interosseous calcification, IFITM5)
• Blue sclerae: Types I, II, III (blue); Type IV = WHITE sclerae (no blue); Type V = white; blue sclerae = thin sclerae + visible choroid; also seen in iron deficiency, Ehlers-Danlos, Marfan syndrome
• Dentinogenesis imperfecta (DI): opalescent/amber teeth; Types IB, IVB, III; involves dentine abnormality; teeth chip and wear excessively; early dental referral; DI absent in Types IA, IIA (no subgroup), VA
• Genetics: Types I–IV = COL1A1/COL1A2 mutations (autosomal dominant); Type V = IFITM5 (AD); Types VI–XII = autosomal recessive (SERPINF1, CRTAP, P3H1, etc.)
• Bisphosphonates (pamidronate/zoledronic acid): reduce osteoclast activity; increase BMD ~30–50%; reduce fracture rate ~40–50%; `zebra lines` = growth arrest lines on X-ray = NORMAL hallmark of bisphosphonate therapy; NOT a sign of pathology
• Intramedullary rodding: Bailey-Dubow (telescoping T-rod) — original; Fassier-Duval (threaded telescoping) — modern standard, better anti-migration; indication = 3+ fractures per year same bone, progressive deformity, prophylactic before fracture; anaesthetic risk in OI (airway, temperature control)
• Popcorn metaphyses: cystic calcific areas in metaphyses/epiphyses; pathognomonic of severe OI (Type III); seen on plain X-ray; indicates severe physeal disruption
• Basilar invagination: Type III and severe OI; odontoid migrates upward into foramen magnum; myelopathy, syringomyelia, sudden death; MRI surveillance mandatory; posterior cervical fusion if symptomatic — the most dangerous complication
• Hypertrophic callus (Type V): exuberant large callus at fracture sites; may mimic sarcoma on imaging — important differential; combined with interosseous membrane calcification and no DI = Type V
• Child abuse vs OI: OI can mimic non-accidental injury (NAI) — multiple fractures at different stages of healing; blue sclerae, family history, skin laxity, DI, and genetic testing distinguish OI; metabolic bone disease screen essential; OI does NOT cause bruising or retinal haemorrhages (these favour NAI); when in doubt, multidisciplinary safeguarding review