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A. Achondroplasia [1]navigator

  1. Most common form of short limb dwarfism in humans
  2. ~250,000 patients worldwide
  3. Genetics
    1. Autosomal dominant linked to chromosome 4p16.3
    2. >95% have same pint mutation in gene for fibroblast growth factor receptor 3 (FGF-R3)
    3. Mutation Gly380Arg causes gain of FGF-R3 function
    4. ~80% of cases are "new" mutations, correlating with increased maternal age
  4. Pathophysiology
    1. Normal function of FGF-R3 is thought to be negative regulator of chondrocytes
    2. FGFs 2, 4, 9, 18 likely major ligands for FGF-R3
    3. Signaling through STAT1 and MAPK (PLCgamma and PI3K-AKT also)
    4. Signaling inhibits chondrocyte proliferation, differentiation and matrix formation
    5. Achondroplasia mutations in FGF-R3 enhance its negative signaling
    6. Disordered growth at growth plate occurs
  5. Irregular calcium at plate, zone of provisional calcification
  6. Symptoms
    1. ~80% of cases recognized at birth
    2. Long, narrow trunk and short limbs
    3. Head is large with frontal bossing
    4. Hyperextensibility of joints
    5. Full extension and rotation of elbow usually restricted
    6. MIld to moderate hypotonia at infancy is common
  7. Characteristic radiographic changes correspond to symptoms
  8. DNA testing usually not required for diagnosis, but readily available commercially
  9. Complications
    1. Head often large, cranial-cervical junction small
    2. This can lead to internal hydrocephalus
    3. Head growth should be monitored in first few years (associated with hydrocephalus)
    4. Cervical cord compression at cervical medullary junction common, may require surgery
    5. Otitis media common in infants, ~25% chronic recurrent disease
    6. Cardiorespiratory and sleep dysfunction: spinal cord changes, narrow breathing passages
    7. Sleep apnea in ~10-16% of patients
    8. Spinal stenosis and neurogenic claudication common older children, adults
    9. Obesity common
  10. Treatment
    1. Minimal benefits of growth hormone on stature
    2. Surgical limb lengthening: multiple surgeries, long recovery, 15-30cm has been added

B. Osteogenesis Imperfecta [2]navigator

  1. Autosomal dominant disease with variable penetrance
    1. Most cases due to mutation in one of two genes that encode collagen type 1 alpha chains
    2. These genes are COL1A1 and COL1A2
    3. Type I due to mutations only in COL1A1
    4. Types II-IV due to mutations in either gene
    5. Types V-VII due to unknown mutations
    6. Recently described novel autosomal recessive lethal form due to mutations in cartilage associated protein (CRTAP), which is required for prolyl 3-hydroxylation of cartialge [3]
  2. Classification
    1. Type I: mild, blue sclerae, hearing loss, easy bruising, mild short stature (COL1A1 only)
    2. Type II: perinatal lethal, stillborn to one year
    3. Type III: severely deforming, severe bone fragility, in utero fractures, osteoporosis
    4. Type IV: moderately deforming, usually preambulatory fractures, long bone bowing
    5. Type V: moderately deforming, short sature, disolcated radial head, white sclera
    6. Type VI: moderately to severely deforming moderate short, scoliosis, osteioid in bone tissue
    7. Type VII: moderately deforming, short humeri and fermora, white sclera
  3. Brittle bone disease
    1. Abnormal collagen production with poor crosslinking
    2. Specific gene mutations correlate with each type of disease
    3. Disordered bone remodelling and architecture
    4. Bones thin and wispy
  4. Multiple fractures in utero (often fatal)
  5. Hundreds of fractures resulting in marked deformities
  6. Treatment
    1. Physiotherapy
    2. Rehabilitation
    3. Orthopedic surgery
    4. Intravenous bisphosphonate therapy with calcium and vitamin D
  7. Cyclic Pamidronate Therapy [4]
    1. Administration of 5-7mg/kg IV every 4-6 weeks
    2. Treatment for 1.3 to 5 years
    3. Reduced all bone markers
    4. Increased bone mineral density by ~40%
    5. Incidence of radiographically confirmed fractures dropped from 2.3 to 0.6 per year
    6. No effects on rate of fracture healing
    7. Mobility and ambulation improved in 16 of 30 children
    8. Chronic pain and fatigue were reduced in all children
  8. Alternative Pamidronate Schedule [2]
    1. Age <2 years: 0.5mg/kg/day x 3 days q 2 months
    2. Age 2-3 years: 0.75mg/kg/d x 3 days q 3 months
    3. Age >3 years: 1.0mg/kg/d x 3 days q 4 months to maximum dose 60mg/d
  9. Olpadronate [5]
    1. 10mg dose equivalent to 150-300mg pamidronate
    2. Oral dose 10mg/m2 given to children with osteogenesis imperfecta for 2 years
    3. Calcium and vitamin D supplements to all children
    4. Olpadronate increased BMD and 31% reduction in fracture risk versus placebo
    5. Well tolerated

C. Hereditary Forms of Rickets navigator

  1. Definition of Rickets
    1. Vitamin D (Vit D) deficiency of any etiology prior to closure of epiphysial plate
    2. Failed signalling and/or conversion is cause of hereditary forms of Rickets
    3. Short stature and weak, deformable bones are main symptoms
  2. Role of Vitamin D
    1. Vit D decrease leads to reduction in utilizable Calcium
    2. Low Calcium at growth plate causes cartilage hyperplasia with wide epiphyseal plate
  3. There are three hereditary forms of Rickets
    1. Pseudovitamin D-deficiency (Type 1) - mutations in 25-OH-D3 hydroxylase gene [6]
    2. Hypocalcemic vitamin D dependent Rickets (Type II) - mutant Vit D receptor
    3. X-linked hypophosphatemic vitamin D dependent Rickets (Type III) - PEX gene (X chr)
  4. X-linked hypophosphatemic rickets [7]
    1. Serum fibroblast growth factor 23 (FGF-23) mutations lead to renal phosphorus wasting
    2. FGF-23 levels very high in X-linked in this disease

D. Fibrous Dysplasia [8] navigator

  1. Developmental bone disorder involving bone mesenchyme
    1. Replacement of bone by large masses of cellular fibrous tissue
    2. Consists of bone spicules and islands of cartilage
  2. Slow progression of disease resulting in fracture and/or deformity
  3. Affects either sex equally
  4. May occur in one (mono-ostotic, more common) or many (polyostotic) bones
    1. Mono-ostotic usually develops during 2nd or 3rd decade of life
    2. Polyostotic usually manifests before 10 years of age
    3. Fibrous dysplasia is responsible for ~5% of bone disease in children
  5. Femur, tibia, rib, facial bones involved most frequently
  6. Radiographic appearance includes thin cortices and ground-glass appearance
  7. Alkaline phosphatase activity elevated; normal calcium and phosphate
  8. Increased risk of osteosarcoma
  9. Encasement leading to narrowing of optic canal, with no or minimal visual loss [9]
  10. Surgical resection for mono-ostotic disease

E. McCune-Albright Syndrome [10] navigator

  1. Definition of Syndrome
    1. Polyostotic Fibrous Dysplasia is a prominant feature
    2. Precocious puberty - usually females (may have anovulation also)
    3. Skin pigmentation and true cafe-au-lait spots (hyperpigmented macules, rough border)
  2. Autosomal Dominant [11]
    1. Due to activating mutations of the alpha subunit of stimulatory G-protein, Gs(alpha)
    2. Mutations (Arg201His or Arg201Cys) within exon 8 of Gs(alpha) gene
    3. Mutations result in constitutive activation of Gs(alpha) protein
    4. Result is nonpulsatile constant signalling through affected G-protein coupled receptors
    5. Constitutive signalling through FSH-R and LH-R is most likely
    6. Etiology of bone disease is not clear
  3. Girls more commonly affected, usually with pseudoprecocious puberty
  4. Other endocrinopathies may be found
    1. Multinodular goiter (may be toxic)
    2. Pituitary gigantism (elevated growth hormone)
    3. Galactorrhea / Amenorrhea (hyperprolactinemia)
    4. Cushing's Syndrome
  5. No specific treatment for bone disease
  6. Testolactone (aromatase inhibitor) may improve precocious puberty in females

F. Osteopetrosis [12]navigator

  1. Family of congenital bone disease with "marble" bones due to impaired remodelling
    1. Infantile malignant form (Albers-Shoenberg Disease): autosomal recessive
    2. "Benign" autosomal dominant form (usually normal life)
    3. Possibly other varieties poorly characterized
  2. Persistence of cartilaginous bars within metaphyseal and diaphyseal bone
  3. Pathogenesis
    1. Defects in osteoclastic activity either intrinsically or due to microenvironment
    2. Defects in acidification, chloride channels, or carbonic anhydrase most common
    3. Often with increased infections due to impaired superoxide generation by neutrophils
  4. Genetics of Human Osteopetrosis [12]
    1. TCIRG1: defects in alpha3 subunit of osteoclast vacuolar proton pump found in ~60% of severe auotomsal recessive form
    2. CLCN7: defects in chloride channel found in ~15% of severe autosomal recessive form and in cases of autosomal dominant form
    3. CAII: abnormal carbonic anhydrase II activity; renal tubular acidosis; <5% of severe autosomal recessive form
    4. gl/gl mutants - single case of severe form described; fatal as infant
  5. Symptoms
    1. Blindness due to optic atrophy (from narrowed optic nerve foramen)
    2. Deafness - narrowed auditory canal
    3. Splenomegaly and recurrent infections (often sepsis, chronic osteomyelitis)
    4. Anemia and thrombocytopenia - bone marrow is shrunken due to inability to resorb bone
    5. Death usually within first decade
  6. Treatment
    1. Calcitriol, prednisone, low calcium diet generally ineffective
    2. Bone marrow transplantation often corrective but high morbidity and mortality
    3. Interferon gamma (1.5µg/kg sc 3X per week) very effective in improving many aspects
    4. IFNg also reduces infections, transfusion requirements, markers of bone turnover

G. Legg-Calve-Perthe Disease navigator

  1. Disorder of the hip causing limp
  2. Idiopathic ischemic necrosis of capital femoral epiphysis
  3. Boys > Girls ~5:1, mean age 7 years
  4. Probably due to increased intracapsular pressure due to developmental anomalies
  5. Associated with limp and bilateral hip osteonecrosis

H. Fibrodysplasia Ossificans Progressiva (FOP)navigator

  1. Autosomal dominant disorder of connective tissue
    1. Congential malformation of great toes
    2. Postnatal formation of heterotopic bone
    3. Severe scoliosis
    4. Diffuse ankylosis present in young adults, wheelchair bound
  2. Trauma induces increased formation of heterotopic bone in these patients
  3. Bone morphogenic protein 4 (BMP-4) is overexpressed in patients with FOP [13]
  4. No current therapy but BMP-4 overexpression may provide clues

I. Disappearing Bone (Gorham-Stout) Disease [14]navigator

  1. Also called phantom bone disease or vanishing bone disease
  2. Very rare disease, primary osteolyses class
  3. Bones lose structure, mainly in long bones, shoulder and pelvis
  4. Progressive osteolysis of 1 or more bones in children and young adults
  5. Minor trauma often leads to pathologic fracture
  6. Vascular malformations in affected bone and surrounding soft tissues
  7. Capillary, venous or lymphatic malformative processes
  8. Pathophysiology not understood
  9. Cutaneous vascular malformations may also occur

J. Genetic Predisposition to Osteoporosis [15] navigator

  1. Strong genetic component
  2. Vitamin D receptor polymorphisms
  3. Estrogen Receptors
  4. Collagen Ialpha1
  5. Apolipoprotein E
  6. Transforming growth factor ß-1 (TGF-ß1) gene polymphorphisms

References navigator

  1. Horton WA, Hall JG, Hecht JT. 2007. Lancet. 370(9582):162 abstract
  2. Rauch F and Glorieux FH. 2004. Lancet. 363(9418):1377 abstract
  3. Barnes AM, Chang W, Morello R, et al. 2006. NEJM. 355(26):2757 abstract
  4. Glorieux FH, Bishop JN, Plotkin H, et al. 1998. NEJM. 339(14):947 abstract
  5. Sakkers R, Kok D, Engelbert R, et al. 2004. Lancet. 363(9419):1427 abstract
  6. Kitanaka S, Takeyama KI, Murayama A, et al. 1998. NEJM. 338(10):653 abstract
  7. Jonsson KB, Zahradnik R, Larsson T, et al. 2003. NEJM. 348(17):1656 abstract
  8. Ready JE and Keel SB. 2000. NEJM. 343(22):1634 (Case Record)
  9. Lee JS, FitzGibbon E, Butman JA, 2002. NEJM. 347(21):1670 abstract
  10. Adashi EY and Hennebold JD. 1999. NEJM. 340(9):709 abstract
  11. Farfel Z, Bourne HR, Iiri T. 1999. NEJM. 340(13):1012 abstract
  12. Tolar J, Teitelbaum SL, Orchard PJ. 2004. NEJM. 351(27):2839 abstract
  13. Shafritz AB, Shore EM, Gannon FH, et al. 1996. NEJM. 335(8):555 abstract
  14. Bruch-Gerharz D, Gerharz CD, Stege H, et al. 2003. JAMA. 289(12);1479 abstract
  15. Yamada Y, Hosoi T, Makimoto F, et al. 1999. Am J Med. 106(4):477 abstract