OPBSPathologyMusculoskeletal
Must Know
- A rare disease affects fewer than 200,000 people in the United States (Orphan Drug Act 1983).
- The 2015 nosology sorts genetic skeletal disorders into 42 groups.
- An IOF working group sorts them by mechanism. Bone cells, matrix proteins, microenvironment or calciotropic hormones.
- Careful clinical phenotyping must come before molecular testing, given variable expression and incomplete penetrance.
More on diagnosis and classification
- Next-generation sequencing (whole genome, whole exome, RNAseq) has characterised many previously undiagnosed diseases.
- The Undiagnosed Disease Network phase 1 diagnosed 35 percent of referred cases, 10 percent with a musculoskeletal phenotype.
- Of those diagnoses, 74 percent came from new genetic information. Management changed in 21 percent and 31 new syndromes were found.
- Metabolomics may add information on metabolic phenotype.
Disorders at a Glance
| Disorder | Gene or defect | Inheritance | Hallmark |
|---|---|---|---|
| Osteopetrosis | TCIRG1, CLCN7 (acidification) | AD benign, AR malignant | Failed osteoclast resorption |
| Fibrous dysplasia | GNAS activating (Gsα) | Postzygotic mosaic | Fibro-osseous lesions, Chinese writing |
| Osteogenesis imperfecta | COL1A1, COL1A2 | Varies | Fragility fractures, blue sclera |
| Paget disease | SQSTM1 (p62) | Familial in some | Osteoclast-driven mosaic bone |
| Marfan syndrome | FBN1 (fibrillin microfibrils) | Heritable | Tall, lax, aortic root dilatation |
| Ehlers-Danlos syndrome | Collagen I, III, V genes | Varies by subtype | Hypermobility, fragile skin |
| Hypophosphatasia | Tissue-nonspecific ALP | AR most severe | Rickets, early tooth loss |
| Gaucher disease | GBA1 (glucocerebrosidase) | AR | Lysosomal storage in macrophages |
| FOP | ACVR1/ALK2 activating | Not stated | Great toe malformation, heterotopic bone |
| Achondroplasia | FGFR3 activating, G380R | AD, over 80 percent de novo | Disproportionate dwarfism |
| XLH | PHEX loss of function | X-linked | FGF23 phosphate wasting |
High Bone Mass and Remodelling Disorders
- Osteopetrosis. Defects in differentiation, ruffled border or acidification. Acidification defects are commonest.
- TCIRG1 and CLCN7 explain about 70 percent of the autosomal recessive form.
- Infantile form is lethal with fractures, marrow failure, pancytopenia and infection.
- Carbonic anhydrase II mutation adds renal tubular acidosis, cerebral calcification and cognitive impairment.
- Radiographs show rugger jersey spine and bone within bone.
- Cartilage bars or islands of calcified primary spongiosa are pathognomonic on histology.
- Stem cell transplant suits only osteoclast-poor recessive forms with intrinsic osteoclast defects.
- Paget disease. Abnormal osteoclasts drive excessive, uncoordinated remodelling with a mosaic cement line pattern.
- Commonest in Anglo-Saxon descent, rare in Asian or Scandinavian people and rare under 50.
- Paramyxovirus link proposed from osteoclast inclusions and falling incidence with vaccination.
- Commonest sites are pelvis, lumbar and thoracic spine, femur, skull and tibia.
- Cotton wool skull and fissure fractures on the convex side of bowed bones.
- Zoledronic acid is first-line. Bisphosphonate or calcitonin before hip replacement reduces bleeding.
More on osteopetrosis and Paget treatment
- Adult-onset osteopetrosis may be silent or cause pain, fractures, nerve compression and carpal tunnel syndrome.
- Calcitriol and PTH analogue have been used in milder osteopetrosis. Interferon gamma can restore haematopoiesis.
- SQSTM1/p62 regulates RANK-mediated NFκB signalling. Carriers have severe, highly penetrant disease.
- After remission, check ALP every 1 to 2 years since relapse can occur anytime.
Matrix and Connective Tissue Disorders
- Fibrous dysplasia. Mutant stromal cells form skeletal progenitors at the expense of fat and marrow.
- Commonest sites are proximal femoral metaphysis and skull base.
- Abnormal Sharpey fibre collagen and retracted stellate osteoblasts are diagnostic hallmarks.
- Excess FGF23 can cause osteomalacic change.
- McCune-Albright adds café-au-lait macules and endocrinopathy such as precocious puberty.
- Lesions become sclerotic and stable with age.
- Osteogenesis imperfecta. Type I collagen abnormal in 85 to 90 percent of clinical cases.
- Marfan syndrome. Arachnodactyly, scoliosis, protrusio acetabuli, pectus excavatum, ectopia lentis, dural ectasia.
- Aortic root dilatation and mitral valve prolapse raise mortality. Pregnant women and athletes need close monitoring.
- FBN2 mutation causes congenital contractural arachnodactyly without aortic or eye disease.
- Ehlers-Danlos syndrome. 13 subtypes. Hypermobile type (type III) is commonest.
| Sillence type | Severity | Features |
|---|---|---|
| I | Mildest | Blue sclera, hearing loss, normal height, few deformities |
| II | Lethal perinatal | Multiple fractures, pulmonary hypoplasia |
| III | Most severe survivable | Progressive deformity, short stature, kyphoscoliosis |
| IV | Moderate | Between I and III |
| V (added 2015) | Not graded | Interosseous membrane calcification, hypertrophic callus |
More on fibrous dysplasia and connective tissue care
- GNAS missense mutations reported are R201H, R201C and R201G.
- One series found 28 sarcomas in 1,122 cases of fibrous dysplasia.
- Bisphosphonates reduced pain in a phase III study. IL-6 receptor and RANKL antagonists are options.
- Proximal femoral fracture in fibrous dysplasia can be stabilised with an intramedullary nail.
- Marfan scoliosis over 45 degrees may need surgery.
- Ehlers-Danlos instability of shoulder and patella may need arthroscopic reconstruction.
Metabolic, Storage and Growth Disorders
- Hypophosphatasia. Low ALP gives rickets or osteomalacia, premature tooth loss, chondrocalcinosis.
- Perinatal form is fatal. Infantile form (under 6 months) adds craniosynostosis and respiratory compromise.
- Asfotase alfa is recombinant ALP enzyme replacement.
- Gaucher disease. Common in Ashkenazi Jews. Skeletal disease mainly in type 1.
- Bone features are osteopenia, pain, osteonecrosis and lytic lesions.
- Treatment is enzyme replacement (imiglucerase, velaglucerase, taliglucerase) or substrate reduction with eliglustat.
- FOP. Ossification spreads dorsal, axial, cranial and proximal first, then ventral, appendicular and distal.
- Heart, smooth muscle, diaphragm, tongue and extraocular muscles are spared.
- Minor trauma triggers flares. Steroids and NSAIDs aim to prevent them.
- Achondroplasia. Commonest skeletal dysplasia. Linked to raised paternal age.
- FGFR3 gain of function slows growth plate cartilage, giving short limbs, normal trunk, frontal bossing, spinal stenosis.
- CNP agonist and meclizine block FGFR3 signalling via MAP kinase. They prevent but do not correct deformity.
- XLH. Commonest heritable phosphate wasting disorder, a form of vitamin D-resistant rickets.
- FGF23 lowers renal sodium phosphate cotransporter and inhibits 1-alpha hydroxylase.
- Low phosphate with low-normal 1,25 dihydroxyvitamin D. Fasting tubular phosphate reabsorption aids diagnosis.
- Treated with calcitriol and phosphate. Overtreatment risks secondary hyperparathyroidism and nephrocalcinosis.
More on storage and growth disorders
- Gaucher glucocerebrosides accumulate in macrophage lysosomes, causing organomegaly and cytopenias.
- Gba-deleted mice show reduced osteoblast viability from toxic sphingosine.
- Activin A antibody and the retinoid agonist palovarotene are in FOP trials.
- Growth hormone gives a variable response in achondroplasia.
- An anti-FGF23 antibody is approved for XLH.
- Other hypophosphataemic rickets include autosomal dominant, autosomal recessive and tumour-induced osteomalacia.
Osteochondrodysplasia Classification
- Skeletal dysplasias occur in about 1 in 3,000 to 5,000 births. Most are inherited.
- The International Working Group on Constitutional Diseases of Bone groups them by clinical, radiographic and molecular features.
- Unger approach to disproportionate short stature starts with history, including prenatal history, birth length, age at growth failure and family history.
- Examination records height, weight, head circumference and arm span to height ratio.
- Arm span to height ratio separates short spine from short limb patterns.
- A skeletal survey comes next, then targeted molecular testing.
| Group | Example | Gene |
|---|---|---|
| Achondroplasia group (AD) | Thanatophoric dysplasia, achondroplasia, hypochondroplasia | FGFR3 (4p16.3) |
| Diastrophic group (AR) | Diastrophic dysplasia, achondrogenesis IB | SLC26A2 sulphate transporter |
| Type II collagen group | SED congenita, Kniest, achondrogenesis II, hypochondrogenesis | COL2A1 |
| Pseudoachondroplasia and MED (AD) | Pseudoachondroplasia, multiple epiphyseal dysplasia | COMP. MED also COL9A1 to 3, MATN3 |
| Membranous bone dysplasia (AD) | Cleidocranial dysplasia | RUNX2 (6p21) |
| Bent bone dysplasia | Campomelic dysplasia | SOX9 |
| Multiple dislocations (AD) | Larsen syndrome | FLNB |
| Mesomelic dysplasia | Dyschondrosteosis | SHOX, pseudoautosomal |
| Metaphyseal dysplasia (AR) | McKusick cartilage hair hypoplasia | RMRP |
| Decreased density (AR) | Osteoporosis pseudoglioma syndrome | LRP5 |
| Increased density (AR) | Pyknodysostosis | CTSK (cathepsin K) |
| Increased density (AD) | Camurati-Engelmann disease | TGFB1 |
| Increased density (AD) | Osteopoikilosis, some melorheostosis | LEMD3 |
| Endosteal hyperostosis | van Buchem disease and sclerosteosis (AR), Worth disease (AD) | SOST, SOST, LRP5 |
| Increased density (AR) | Osteoectasia with hyperphosphatasia | TNFRSF11B (osteoprotegerin) |
| Disorganised cartilage (AD) | Multiple cartilaginous exostoses | EXT1, EXT2 |
| Disorganised cartilage (AD) | Metachondromatosis | PTPN11 |
| Disorganised fibrous tissue | McCune-Albright syndrome | GNAS |
| Disorganised fibrous tissue (AD) | Cherubism | SH3BP2 |
| Idiopathic osteolysis (AD) | Hajdu-Cheney syndrome | NOTCH2 |
| Idiopathic osteolysis (AD) | Familial expansile osteolysis | TNFRSF11A (RANK) |
| Idiopathic osteolysis (AR) | Multicentric osteolysis | MMP2 |
More on dysplasia features
- Ollier enchondromatosis and Maffucci syndrome are sporadic.
- Thanatophoric dysplasia shows short ribs with cupped costochondral junctions and flat vertebrae.
- Diastrophic dysplasia shows hitchhiker thumb, severe foot deformity and progressive scoliosis.
- Rhizomelic chondrodysplasia punctata (PEX7, AR) gives stippled epiphyses. Warfarin embryopathy can mimic it.
- Cleidocranial dysplasia shows absent clavicles, wide sutures, Wormian bones and pubic hypoplasia.
- Pyle disease gives Erlenmeyer flask femora.
- Craniodiaphyseal dysplasia is also linked to SOST.
- Hunter syndrome (IDS) is X-linked recessive. Other mucopolysaccharidoses are autosomal recessive, Morquio A from GALNS.
- Homocystinuria (CBS) and Menkes syndrome (ATP7A) fall in the decreased density group.
Source
Schwartz AC. Appendix V, Classification of Osteochondrodysplasia. In. Vigorita VJ, Ghelman B, Mintz D. Orthopaedic Pathology. 3rd ed. Philadelphia, Wolters Kluwer, 2016.
Numbers to Remember
- Osteopetrosis. AD 1 in 20,000. AR 1 in 200,000 to 250,000.
- OI. About 1 in 20,000 births.
- Marfan. 1 in 5,000. Ectopia lentis in 80 percent.
- FOP. 1 in 2 million.
- Paget. Family history in 10 to 40 percent. SQSTM1 in up to 50 percent of familial cases. Sarcoma under 1 percent.
- Zoledronic acid. Single 5 mg infusion gives biochemical remission in 87 percent.
- Achondroplasia CNP agonist. Growth rate up about 50 percent.
Memory Aids
- Gain makes trouble. GNAS, ACVR1 and FGFR3 are activating mutations. PHEX and ALP are losses.
Exam Traps
- The autosomal recessive osteopetrosis is the malignant form. The dominant form is benign.
- Fibrous dysplasia is postzygotic and mosaic, never inherited through the germline.
- OI type III is the most severe survivable type. Type II is lethal.
- ALP is high in Paget disease and low in hypophosphatasia.
- Achondroplasia drugs do not reverse established deformity.
Related pages. Osteogenesis Imperfecta, Osteopetrosis, Hypophosphatasia, Paget's Disease, Marfan's Syndrome, Ehlers-Danlos Syndrome, Gaucher's Disease, Homocystinuria, Achondroplasia, Neurofibromatosis, Multiple Epiphyseal Dysplasia (MED), Ochronosis
Source
Taneja C, Yuen T, Iqbal J, New M, Aaron RK, Zaidi M, Kim SM. Rare Genetic Bone Diseases of Orthopaedic Significance. In. Aaron RK, editor. Orthopaedic Basic Science. Foundations of Clinical Practice. 5th ed. Philadelphia, Wolters Kluwer, 2021.
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Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 17 October 2026.