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Bone and Soft-Tissue Disorders

= rare hereditary disorder

Path: normal / increased number of osteoclasts → defective acidification function of osteoclast required to dissolve bone matrix → failure of proper reabsorption and remodeling of primary spongiosa → bone sclerotic + thick but structurally weak + brittle

Cx:

  1. Usually transverse fractures (common because of brittle bones) with abundant callus + normal healing
  2. Crowding of marrow (myelophthisic anemia + extramedullary hematopoiesis)
  3. Frequently terminates in acute leukemia

Rx: bone marrow transplant

DDx:

  1. Heavy metal poisoning
  2. Melorheostosis (limited to one extremity)
  3. Hypervitaminosis D
  4. Pyknodysostosis
  5. Fibrous dysplasia of skull / face

Infantile Autosomal Recessive Osteopetrosis!!navigator!!

= congenital more severe form / malignant subtype

Cause: defect on chromosome 11q13

Genetics:

  1. inactivation mutation of T-cell immune regulator 1 encoding α3 subunit of vacuolar proton pump ATP6i, responsible for proton transport in resorption lacunae
  2. homozygous mutations in chloride 7 channel
  3. defect in gray-lethal / osteopetrosis-associated transmembrane protein gene
  • failure to thrive; lymphadenopathy
  • premature senile appearance of facies; severe dental caries
  • pancytopenia (= anemia, leukocytopenia, thrombocytopenia) ← severe marrow depression
  • cranial nerve compression → optic atrophy, deafness
  • hepatosplenomegaly ← extramedullary hematopoiesis
  • subarachnoid hemorrhage ← thrombocytopenia

May be associated with: renal tubular acidosis + cerebral calcification

  • dense skeleton
  • splayed metaphyses + costochondral junctions
  • fractures from minor trauma ← brittle bones

Prognosis: stillbirth / early demise, survival beyond middle life uncommon (death due to recurrent infection, massive hemorrhage, terminal leukemia)

DDx: chronic renal failure, oxalosis, pyknodysostosis, physiologic sclerosis

Benign Adult Autosomal Dominant Osteopetrosis!!navigator!!

= Osteopetrosis type 2 = = ALBERS-SCHÖNBERG DISEASE = MARBLE BONE DISEASE

[Heinrich Ernst Albers-Schönberg (1865–1921), radiologist, founder of the journal Fortschritte auf dem Gebiete der Röntgenstrahlen]

Cause: defect on chromosome 1p21

Genetics:

  1. deactivation of one allele of chloride 7 channel gene → some loss of function of the chloride 7 channel
  2. mutations in carbonic anhydrase II, T-cell immune regulator 1, osteopetrosis-associated transmembrane, and pleckstrin homology domain–containing family M member 1 (PLEKHM1)

Onset: in adolescence / adulthood with variable penetrance

  • 50% asymptomatic; recurrent fractures
  • mild anemia ← narrowed medullary canals
  • occasionally cranial nerve palsy
  • increased density of medullary portion of bone with relative sparing of cortices (HALLMARK)

Phenotype I:

Distribution: long bones, skull, spine

  • diffuse osteosclerosis = generalized dense amorphous structureless bones with obliteration of normal trabecular pattern; mandible least commonly involved
  • Erlenmeyer flask deformity = clublike long bones with cortical thickening and medullary encroachment ← lack of tubulization + flaring of ends

Phenotype II:

Distribution: pelvis, spine

  • bone-within-bone appearance (= endobones)
  • “sandwich” vertebrae / rugger-jersey spine = dense endplate sclerosis with sharp margins
  • longitudinal metaphyseal striations:
    • alternating sclerotic + radiolucent transverse metaphyseal lines (phalanges, ilium) = indicators of fluctuating course of disease
  • sclerosis predominantly involving base of skull; calvaria often spared:
    • obliteration of mastoid cells, paranasal sinuses, basal foramina by osteosclerosis

Prognosis: normal life expectancy

Outline