Hereditary Bone and Cartilage Disorders: OI, Osteopetrosis, Achondroplasia, MPS, Rickets

The Falling Child: Osteogenesis Imperfecta and the Abuse Trap

One gene pair makes the scaffold of bone, and when it fails the child fractures from a couch roll. Learn the stigmata abuse cannot fake, then the Sillence ladder that grades the severity.

Osteogenesis imperfecta is a type I collagen defect from COL1A1 and COL1A2 mutations, autosomal dominant in the classic forms with autosomal recessive forms in the severe types. Collagen is the bone scaffold, so the child fractures from minor trauma, the sclera thins and shows the blue choroid through it (blue-gray sclera), the teeth develop dentinogenesis imperfecta (gray-brown, translucent, easily worn), and the skull shows wormian bones on the film. Hearing loss from otosclerosis joins the picture in adolescence or young adulthood, which is why the family history question asks about early hearing aids.

The board pairs OI with abuse on purpose, and the discriminator is a checklist. Blue sclera, wormian bones, dentinogenesis imperfecta, and a positive family history belong to OI, and abuse cannot fake any of them. Retinal hemorrhages, fractures at different healing stages, posterior rib fractures, and a history that changes between tellings belong to abuse. Fractures at different healing stages occur in both, which is why the stem hands you the eyes and the family history. The OI fracture mechanism is out of proportion to the injury with a normal retinal examination, and that package routes the workup to the collagen, not to child protective services.

Flip between the two fracture children.

Marble Bone: Osteopetrosis and the Osteoclast That Cannot Resorb

Dense bone is a resorption failure: the osteoclast cannot pump acid into the pit, so the skeleton keeps building and never remodels. The bone gets denser, the nerves and marrow get squeezed, and the film shows marble.

Osteopetrosis is a failure of bone resorption. The osteoclast attaches to bone but cannot acidify the resorption lacuna, so mineralized bone is deposited and never removed. The two defects the boards name are CLCN7, the chloride channel that keeps the acid compartment working, and carbonic anhydrase II, the enzyme that makes the hydrogen ion. The result is dense, brittle marble bone with the bone-within-bone appearance and the Erlenmeyer flask deformity of the metaphyses, where remodeling failure widens the bone ends.

The complications are a checklist that follows the crowding. Dense bone compresses the cranial nerves: blindness, facial palsy, and deafness. Dense bone crowds the marrow: anemia, thrombocytopenia, and leukopenia. And marrow failure drives hepatosplenomegaly from extramedullary hematopoiesis. The malignant infantile form is autosomal recessive and lethal without treatment; the adult form is autosomal dominant and mild, often an incidental finding on a film. The carbonic anhydrase II deficiency variant pairs marble bone with renal tubular acidosis, because the same enzyme makes hydrogen ions for the osteoclast pit and the renal tubule.

Name the form behind the infant with marble bone.

Short Limbs: Achondroplasia and the Growth Receptor Stuck On

FGFR3 is a brake on growth, and achondroplasia jams the brake on. The proximal segments suffer most, and the first screen is the foramen magnum, not the limb length.

Achondroplasia is a gain-of-function FGFR3 mutation, autosomal dominant, and the most common form of short-limbed dwarfism. The constitutively active receptor inhibits chondrocyte proliferation, so endochondral ossification fails at the growth plates and the limbs shorten with rhizomelic predominance: the proximal segments, humerus and femur, suffer most because they depend on the growth plates that drive most of the bone length. The signature is macrocephaly with frontal bossing, a trident hand (the fingers spread with a gap between the third and fourth digits), lumbar lordosis, and normal intelligence.

The genetics are the board trap. More than 85 percent of cases are new mutations with a paternal age effect, so two average-statured parents commonly have an affected child, and germline mosaicism explains the rare family with more than one affected child. The complications to screen are the two narrowings: foramen magnum stenosis in infancy, with sleep apnea, hypotonia, and arching with stiffening from cord compression, and spinal stenosis in adulthood. Snoring plus arching plus long tract signs is the foramen magnum until imaging says otherwise.

Tap the segment that rhizomelia shortens, then the screen.

The Sillence Ladder and the Osteopetrosis Complications

Severity in this family is a ladder and a checklist. The Sillence types grade OI; the crowded-structure checklist grades osteopetrosis. Hold both orders and the two treatment conversations.

The Sillence types grade OI severity, and the boards ask the type number with the phenotype. Type I is mild: blue sclera, normal or near-normal stature, fractures from minor trauma. Type II is lethal perinatal: multiple in-utero fractures, severe limb deformities, and respiratory failure in the first days of life. Type III is progressively deforming, with fractures at birth and worsening deformity through childhood. Type IV is moderate, with white or light sclera and variable fracture burden. Across the types, bisphosphonate therapy reduces the fracture burden; vitamin D alone cannot fix the collagen scaffold, and teriparatide is not the pediatric first-line.

The osteopetrosis complications run a fixed order. Marble bone crowds the skull base first, compressing cranial nerves (blindness, facial palsy, deafness); then the marrow fails (anemia, thrombocytopenia, leukopenia); then hepatosplenomegaly appears from extramedullary hematopoiesis. The infantile form is autosomal recessive and lethal, the adult form autosomal dominant and mild, and the carbonic anhydrase II variant pairs marble bone with renal tubular acidosis.

Put the crowded-structure checklist in order.

Grade the newborn with fractures at birth.

Lysosomes and Phosphate: Mucopolysaccharidoses and the Rickets Variants

Two metabolic families, two questions: does the cornea cloud, and what does the phosphate do? The enzyme names the MPS; the lab pattern names the rickets.

The mucopolysaccharidoses are lysosomal enzyme defects that pile up glycosaminoglycans, producing coarse facies, hepatosplenomegaly, skeletal dysplasia, and developmental regression. The corneal clouding question splits the pair the boards use. Hurler (MPS I) is alpha-L-iduronidase deficiency, autosomal recessive, with corneal clouding. Hunter (MPS II) is iduronate sulfatase deficiency, X-linked, with clear corneas and the maternal-uncle family pattern. Treatment is enzyme replacement therapy plus, for eligible patients, hematopoietic stem cell transplantation, with the best results when started early.

The rickets variants are mineralization failures, and the lab pattern names each one. Vitamin D dependent type I is 1-alpha-hydroxylase deficiency, autosomal recessive, with low calcium, low phosphate, and low calcitriol. Vitamin D dependent type II is a vitamin D receptor mutation with alopecia and a high calcitriol level: the receptor cannot respond, so the hormone accumulates. The board favorite is X-linked dominant hypophosphatemic rickets: a PHEX mutation raises FGF23, the kidney wastes phosphate, and the triad reads low phosphate, normal calcium, high alkaline phosphatase. Plain vitamin D cannot overcome the renal leak; the treatment is phosphate plus calcitriol.

Tick the labs you see, and read the diagnosis off the pattern.

The Broken or Short Child Router

The hereditary bone family announces itself with one of five headlines. The headline picks the gene family; the findings pick the diagnosis; the diagnosis picks the screen.

Run the headlines in order. Recurrent fractures from minor trauma is OI until the stigmata checklist is empty; blue sclera, wormian bones, dentinogenesis, and family history route it to the collagen, while retinal hemorrhages and a changing story route it to abuse, with a skeletal survey and a retinal exam either way. Diffusely dense bones is osteopetrosis: the infant with marrow failure gets the HSCT evaluation, the adult with incidental marble bone gets reassurance and monitoring, and marble bone plus a urine that will not acidify is carbonic anhydrase II deficiency. Short stature with rhizomelic limbs is achondroplasia until proven otherwise, and the screen is the foramen magnum in infancy and the spinal canal later. Coarse facies with hepatosplenomegaly is a mucopolysaccharidosis: clouded cornea is Hurler, clear cornea in a boy with maternal uncles affected is Hunter, and the enzyme assay names the subtype. Bowed legs with a low serum phosphate is the renal phosphate leak, and the therapy is phosphate plus calcitriol; add low calcium and low calcitriol for the 1-alpha-hydroxylase defect, and alopecia with a high calcitriol level for the receptor defect.

Route the child by headline, then commit to the screen.

The Mutation Map: Genes, Signatures, and the Tumor Syndromes

The family closes with cartilage and fibrous tissue run loose. Every gene pairs with a signature and a screen, and the tumor syndromes add the one risk to name: malignant transformation.

Hereditary multiple exostoses is an autosomal dominant EXT1 or EXT2 defect with sessile and pedunculated osteochondromas, and about 1 percent undergo malignant transformation to chondrosarcoma: an exostosis that grows or hurts after skeletal maturity is reimaged. Enchondromatosis (Ollier disease) is multiple enchondromas; Maffucci syndrome adds soft tissue hemangiomas, and the hemangioma is the entire split. McCune-Albright syndrome is an activating GNAS mutation present as somatic mosaicism: polyostotic fibrous dysplasia with the shepherd crook femoral deformity, coast of Maine cafe-au-lait spots (jagged borders), and precocious puberty. The board asks one question across the whole family: which gene, which inheritance, which signature, and what do you screen for?

Tap each letter of the cornea and coast mnemonics.

Open each gene and hold the signature and the screen.

Walkthrough: seven hereditary bone decisions

Original practice scenarios, one at a time. Choose an answer, then open any option to work its reasoning.