What are the clinical features, classification, diagnostic criteria, and management options for osteogenesis imperfecta (OI) relevant to NEET‑PG preparation?

Osteogenesis Imperfecta (OI) for NEET PG

Osteogenesis imperfecta is a genetic disorder of type I collagen characterized by bone fragility, with 85-90% of cases caused by autosomal dominant mutations in COL1A1 and COL1A2 genes, presenting across a clinical spectrum from mild fractures with blue sclerae to lethal perinatal forms. 1, 2

Genetic Basis and Pathophysiology

• Most common cause: Mutations in COL1A1 and COL1A2 genes encoding type I collagen chains account for 85-90% of cases, inherited in autosomal dominant pattern 1, 2
• De novo mutations: Many children have new mutations without family history, making negative family history unreliable for exclusion 3
• Autosomal recessive forms: OI type VII and other rare forms exist, caused by mutations in genes regulating collagen post-translational modification, secretion, and processing 3, 2
• Phenotypic variability: Expression varies even within families due to mutation type, mosaicism, and tissue-specific expression 3

Classification (Sillence Classification)

Type I (Mild/Classic Non-Deforming)

• Blue sclerae (present in all patients, often dramatic) 4, 5
• Fractures with minimal or no limb deformity 3
• Normal or near-normal stature (in approximately two-thirds of patients) 4
• Hearing loss (develops later in life) 3
• Dentinogenesis imperfecta (variable) 3
• Autosomal dominant inheritance 3

Type II (Lethal Perinatal)

• Lethal in perinatal period 3
• Undermineralized skull, micromelic bones 3
• "Beaded" ribs on radiography (pathognomonic finding) 3
• Severe bone deformity, platyspondyly 3
• Detectable by ultrasound at 14-16 weeks gestation 3, 6
• Autosomal dominant (usually de novo) 3

Type III (Progressively Deforming/Severe)

• Moderate to severe limb deformity at birth 3
• Very short stature (most severe growth impairment) 3
• Scleral hue varies (may be blue, gray, or normal) 3
• Progressive skeletal deformities 3
• Dentinogenesis imperfecta common 3
• Detectable by ultrasound at 18 weeks when long bone length falls away from normal 3, 6
• Autosomal dominant 3

Type IV (Moderately Severe)

• Normal sclerae (key distinguishing feature) 3, 4
• Mild to moderate limb deformity with fractures 3
• Variable short stature 3
• Dentinogenesis imperfecta present 3
• Some hearing loss 3
• Autosomal dominant 3

Type V

• Similar to Type IV clinically 3
• Calcification of interosseous membrane of forearm (unique feature) 3
• Radial head dislocation 3
• Hyperplastic callus formation (distinguishing feature) 3
• Autosomal dominant 3

Type VI

• More fractures than Type IV 3
• Vertebral compression fractures prominent 3
• No dentinogenesis imperfecta (distinguishing from Type IV) 3
• Inheritance pattern unknown 3

Type VII

• Autosomal recessive (important for genetic counseling) 3
• Congenital fractures 3
• Blue sclerae 3, 4
• Early deformity of legs 3
• Coxa vara 3
• Osteopenia 3

Clinical Features (High-Yield for NEET PG)

Skeletal Manifestations

• Recurrent fractures (most common site: femur, followed by other long bones) 5
• Transverse fractures in long bone shafts (typical pattern) 3
• Multiple long bone or rib fractures unusual except in severe types 3
• Limb deformities, bowing 3
• Scoliosis and/or kyphosis 3
• Short stature (variable by type) 3

Craniofacial Features

• Blue sclerae (80.3% of patients, pathognomonic when present beyond infancy) 4, 5
• Macrocephaly 3
• Triangular-shaped face 3
• Wormian bones of skull (radiographic finding) 3

Dental Abnormalities

• Dentinogenesis imperfecta (32.8% of patients) 5
• Hypoplastic, translucent, carious teeth 3
• Late-erupting or discolored teeth 3

Other Features

• Hearing impairment from otosclerosis (1.6-10% depending on age) 3, 5
• Easy bruisability 3
• Inguinal and/or umbilical hernias 3
• Hyperextensible joints 3
• Demineralized bones on radiography 3

Diagnostic Approach

Clinical Diagnosis

• Family history of fractures, short stature, blue sclera, poor dentition 3
• Physical examination for characteristic features listed above 3, 4
• Radiographic evidence of low bone density/osteopenia 3
• Referral to medical geneticist when clinical findings equivocal 3

Laboratory Testing

First-line genetic testing:

• COL1A1/COL1A2 mutation analysis (DNA-based testing from blood sample) 7, 1
• High sensitivity for Types I-IV 7
• Turnaround time: 7-14 days when familial mutation known 3

Biochemical testing (when genetic testing inconclusive):

• Collagen screening from cultured skin fibroblasts 4, 7
• Evaluates type I procollagen production and structure 7
• Requires skin biopsy and cell culture (3-4 weeks) 3, 7

Supportive laboratory studies:

• Serum calcium, phosphorus, alkaline phosphatase 4
• Urinary calcium excretion 4
• These help exclude metabolic bone disorders in differential 4

Radiographic Studies

• Skeletal survey for fractures and bone abnormalities 4
• Dual-energy X-ray absorptiometry (DEXA) for bone mineral density 5
• Look for demineralization, Wormian bones, fractures 3

Prenatal Diagnosis

• Ultrasound at 13-14 weeks for Type II (severe/lethal) 3, 6
• Ultrasound at 16-20 weeks for Type III 3
• Types I and IV rarely detected prenatally (after 20 weeks if at all) 3
• Biochemical collagen analysis on CVS cells when parent affected 3
• DNA mutation analysis on CVS/amniocytes when familial mutation known 3

Differential Diagnosis (Critical for NEET PG)

Must Exclude:

• Non-accidental injury (child abuse) - more common than OI; if fractures continue in protective environment, pursue OI workup 3
• Hypophosphatasia - blue sclera, low alkaline phosphatase, elevated urinary phosphoethanolamine 4, 7
• Osteopenia of prematurity - infants <28 weeks or <1500g, fractures in first year of life 3
• Rickets/hypophosphatemic osteomalacia - metaphyseal irregularities, biochemical abnormalities 4, 7

Prenatal Differential (14-16 weeks ultrasound):

• Achondrogenesis types IA, IB, II 3
• Severe infantile hypophosphatasia 3
• Thanatophoric dysplasia 3

Management

Pharmacological Treatment

• Intravenous bisphosphonates (most widely used intervention) 1
  • Significant favorable effects on areal BMD 1
  • Vertebral reshaping following fractures in growing children 1
  • Modest effect on long bone fracture incidence 1
  • Effects in adults limited to BMD only 1
  • Caution: Reports of atypical subtrochanteric fractures 1

Emerging Therapies

• Denosumab, teriparatide, sclerostin inhibition showing promise 1, 8
• TGF-β inhibition under investigation 1
• Gene therapy and stem cell approaches in development 8

Multidisciplinary Approach

• Physiotherapy and occupational therapy 8
• Orthopedic surgery for fracture management and deformity correction 8
• Hearing assessment and management 3
• Dental care for dentinogenesis imperfecta 3

Key Clinical Pitfalls

• Do not exclude OI based on negative family history - many cases are de novo mutations 3
• Do not exclude OI based on normal BMD - rare high BMD variants exist 9
• Blue sclerae in infants <12 months can be normal - pathologic if persists beyond infancy 4
• Children with OI can also be abused - OI diagnosis does not exclude non-accidental injury 3
• Not all OI types have blue sclerae - Types IV, V, VI typically have normal sclerae 3, 4
• Rib fractures in infancy without other OI features are unusual - consider abuse 3