A child with fractures out of proportion to the reported mechanism. A toddler who rolls off the couch and breaks a femur. A neonate with rib fractures on chest film. An older child with multiple healed fractures of different ages. The clinical question is: is the bone itself fragile (genetic), is there a metabolic reason it cannot mineralize (also treatable), or is the history not what it seems? The genetics workup runs in parallel with the safety assessment; the two are not in competition.
Osteogenesis imperfecta is the dominant differential and dictates the structure of the workup. The Sillence classification organizes the type I collagen phenotypes; the recessive forms and the OI mimics fill in the rest. Three orthogonal questions:
- How severe? Lethal perinatal (Sillence II) vs progressively deforming (III) vs moderate (IV) vs mild blue-sclerae form (I).
- What is the biochemistry? Quantitative haploinsufficiency of type I collagen (mild) vs qualitative glycine substitution (severe). The biochemistry tracks with phenotype.
- Is this OI at all? Hypophosphatasia is the most important mimic because it is treatable and the alkaline phosphatase is the giveaway.
The OI spectrum (collagen I, AD, by far the most common)
| Sillence type | Severity | Sclerae | Inheritance | Genetics | Key features |
|---|---|---|---|---|---|
| I | Mild | Blue | AD | COL1A1 haploinsufficiency | Adult-onset hearing loss, normal stature |
| II | Lethal perinatal | Blue/grey | AD (de novo) | COL1A1/COL1A2 glycine subs | Crumpled long bones at birth, beaded ribs |
| III | Progressive deforming | Blue at birth, lightening | AD | COL1A1/COL1A2 glycine subs | Very short stature, severe bowing |
| IV | Moderate | Normal/white | AD | COL1A1/COL1A2 | Variable severity, often dentinogenesis imperfecta |
Recessive and non-collagen OI (rare, often severe)
- CRTAP, P3H1/LEPRE1, PPIB: prolyl-3-hydroxylation complex; recessive, severe phenotype overlapping Sillence II/III.
- SERPINH1, FKBP10: chaperone defects.
- SP7, WNT1, CREB3L1, SPARC: other osteoblast pathway genes.
- Bruck syndrome (PLOD2, FKBP10): OI plus congenital contractures.
- Osteoporosis-pseudoglioma syndrome (LRP5): bone fragility plus congenital blindness from persistent fetal vasculature.
The treatable mimic
- Hypophosphatasia (ALPL): defective bone mineralization. Alkaline phosphatase is LOW (the opposite of what you might expect with fractures), urine phosphoethanolamine is elevated. Asfotase alfa enzyme replacement therapy is approved and changes the natural history. This is the diagnosis to chase first because missing it is the only error in this differential that has a treatment cost.
Other heritable bone fragility
- Cole-Carpenter syndrome: OI features plus craniosynostosis and proptosis.
- Idiopathic juvenile osteoporosis: diagnosis of exclusion in older children with sudden fragility around puberty.
- Gnathodiaphyseal dysplasia, IFITM5-related OI (type V): distinguished by hyperplastic callus formation and ossification of the interosseous membrane of the forearm; recognized by a recurrent variant in the 5' UTR of IFITM5.
- Fractures + blue sclerae + family history of "weak bones or hearing loss in adulthood" → OI type I. Sclerae lighten with age, so check the family.
- Fractures + dentinogenesis imperfecta (gray-blue translucent teeth, rapid wear) → OI types III, IV (and some I). The dental phenotype runs with the skeletal one.
- Fractures + wormian bones (>10) on skull film → highly suggestive of OI; not specific to a Sillence type.
- Fractures + LOW alkaline phosphatase → hypophosphatasia. This is the one biochemical test that changes the differential in a single step.
- Fractures + congenital contractures → Bruck syndrome (PLOD2, FKBP10).
- Fractures + congenital blindness → osteoporosis-pseudoglioma syndrome (LRP5).
- Beaded ribs and crumpled long bones in a stillborn or neonate → Sillence II.
Genetic bone fragility and inflicted injury are not mutually exclusive, and the workup has to address both. A complete evaluation includes a skeletal survey with radiographic age-dating of fractures, a careful family history (consanguinity, parental fragility, hearing loss), examination of the sclerae and teeth, biochemistry (alkaline phosphatase, calcium, phosphate, vitamin D, PTH), and OI / fragility panel testing where the radiographic or clinical picture warrants. The geneticist's job is to give a clean answer about what the bones are doing biologically; the safety team handles the rest.
- Skeletal survey with radiographic age-dating of fractures. Look for wormian bones, gracile long bones, beaded ribs, vertebral compression.
- Sclera and dental exam. Photograph if uncertain.
- Hearing screen. OI type I hearing loss begins in adulthood but documenting baseline matters.
- Alkaline phosphatase, calcium, phosphate, vitamin D, PTH. Low ALP is the hypophosphatasia red flag; the others screen for nutritional/metabolic rickets.
- Family history: parental fragility, hearing loss, dental anomalies, blue sclerae, prior unexplained infant deaths.
- OI / bone fragility gene panel if any of the above are positive or if the pattern is suggestive even with negative biochemistry. Panels typically cover COL1A1, COL1A2, the recessive collagen modifiers, ALPL, and LRP5 in a single send-out.
- Always send alkaline phosphatase. Hypophosphatasia is treatable, and the lab value is the diagnostic pivot.
- Blue sclerae lighten with age. Examine the parents and grandparents if the proband's sclerae look only marginally blue.
- Dentinogenesis imperfecta is the most reliable bedside marker of moderate-to-severe OI in an older child. The teeth declare the diagnosis even when the fracture history is ambiguous.
- The recessive forms (CRTAP, P3H1, etc.) often look as severe as Sillence III but with negative collagen biochemistry on initial workup. A panel that covers the full pathway prevents the false-reassurance pitfall.
- The biochemistry-phenotype relationship matters for counseling: a haploinsufficient COL1A1 variant tends to give mild OI (type I), while a glycine substitution in either COL1A1 or COL1A2 tends to give the moderate-to-severe phenotypes (II, III, IV). The variant report can change the predicted course before any follow-up imaging.
- A neonate with rib fractures of varying ages, beaded ribs, and bell-shaped chest on the routine chest film is Sillence II until proven otherwise; the radiograph is often the first diagnostic test, not the genetic panel.