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Skeletal Dysplasias (eg, Achondroplasia)
Achondroplasia Marfan syndrome Hereditary multiple osteochondromas (aka hereditary multiple exostoses) Enchondromatosis (aka Ollier's Syndrome) Polyostotic fibrous dysplasia Fibrous dysplasia ossificans (aka progressive myositis ossificans) Hereditary hypophosphatemic rickets

Skeletal Dysplasias (eg, Achondroplasia)

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the skeletal dysplasias
Achondroplasia
  • This is an ossification anomaly that manifests with short limbs.
  • Patients have short stature, pronounced lordosis, and bowed legs.
  • This is a more severe form of hypochondroplasia.
Systemic complications
  • Obstructive sleep apnea (OSA)
  • Recurrent otitis media
Neurologic manifestations
  • Macrocephaly
  • Spinal stenosis
  • Hydrocephalus
Genetics
  • Autosomal Dominant (80%) of patients have denovo mutations
  • FGRFR3 gene Mutation
Achondrogenesis
  • Think Achondroplasia but as a Lethal Skeletal Dysplasia -- prenatally morbid or stillbirth.
Marfan syndrome
  • Patients have abnormally long bones.
Systemic complications
  • Dislocated lens (ectopia lentis)
  • Aortic aneurysm and dissection
  • Mitral valve prolapse
  • Long, narrow face, with crowded teeth
  • Scoliosis or kyphosis
Neurologic manifestations
  • Dural ectasia
  • Spinal stenosis
  • Hydrocephalus
Genetics
  • Autosomal Dominant
  • FBN1 gene
  • Fibrillin-1 protein with mycrofibril abnormalities with decreased elasticity
hereditary multiple osteochondromas (aka hereditary multiple exostoses)
  • Bone tumors (osteochondromas) form at the end of long bones and cause shortening of growth.
Systemic complications
  • Transformation from benign tumor to malignancy (sarcoma)
Neurologic manifestations
  • Direct nerve pressure
Genetics
  • EXT1 and EXT2 gene
  • Heparan sulfate is nonfunctional
  • Autosomal Dominant
enchondromatosis (aka Ollier's Syndrome)
  • Bone tumors form at the ends of long bones, near the growth plates, thus these patients generally have short stature.
Systemic complications
  • Transformation from benign tumor to malignancy (chondrosarcoma)
Genetics
  • Somatic (non-heritable)
  • IDH1 & IDH2 genes for isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2
polyostotic fibrous dysplasia
  • Fibrous scar tissue develops in bones.
Mccune-Albright Syndrome
A genetic disorder that occurs in females, involves of polyostotic fibrous dysplasia and also multiple endocrinopathies that notably manifest with precocious puberty and café-au-lait spots.
Endocrinopathies in Mccune-Albright Syndrome
  • Precocious Puberty
  • Hyperthyroidism
  • Goiter
  • Acromegaly
  • Cushing's syndrome (rare)
Dermatologic Manifestations
  • Café-au-lait spots
Genetics
  • GNAS gene for guanine nucleotide-binding protein (G-protein)
fibrous dysplasia ossificans (aka progressive myositis ossificans)
Musculoskeletal structures (muscles, tendons, ligaments) are replaced with bone (ossified). This extra-skeletal ossification causes immobility, manifesting with difficulty even opening one's mouth to eat or ability to breath.
Genetics
  • AVCR1 gene for BMP type 1 receptor
  • Autosomal Dominant
hereditary hypophosphatemic rickets
  • Patients suffer from a bowing of bones due to chronic hypophosphatemia (in adults, this causes osteomalacia – bone softening).
Pathophysiology
  • Hypophosphatemia
Genetics
  • PHEX gene
  • Most common: X-linked dominant
osteopetrosis
  • Bones are abnormally dense (thick).
Systemic complications
  • Anemia
  • Hepatosplenomegaly
  • Immunodeficiency
Neurologic manifestations
  • Cranial neuropathies
osteopoikilosis
  • Bones are spotted with round areas of increased bone density.
osteogenesis imperfecta
  • Bones are abnormally fragile: fractures occur commonly.
  • Mild forms of the disease are associated with blue-appearing sclera.
  • Severe forms are lethal just after birth due to inability to adequately breathe.
Genetics
  • COL1A1 and COL1A2 genes (mostly)
  • Autosomal Dominant (mostly)
Ehlers-Danlos
  • Causes hypermobile joints.
Systemic complications
  • Hypermobile joints
  • Elastic skin
  • Kyphoscoliosis
  • Respiratory changes from severe scoliotic abnormalities
Genetics
  • Autosomal recessive
cleidocranial dysplasia
  • Manifests with abnormalities in the clavicles and skull [delayed closure of the fontanelles], most notably (hence its name).
  • These bones develop from intramembranous ossification, thus we can remember the disorder as one of pathologic intramembranous ossification.
Bony abnormalities
  • Clavicles
  • Skull
  • Teeth
Genetics
  • RUNX2 gene
  • Autosomal Dominant
Additional notable causes of skeletal dysplasia include:
Neurofibromatosis
Storage Disorders: Gaucher Disease and the Mucopolysaccharidoses.
limb and digit development
  • The upper limb bud forms at ~ day 24, followed shortly thereafter by the lower limb bud (at ~ day 28).
  • The limb bud comprises a core of mesenchyme, surrounded by ectoderm.
  • The AER (apical ectodermal ridge) forms a thickening at the distal end of the limb bud.
  • The distal upper limb bud forms a digital plate, distally (for the fingers) and a carpal plate (for the hand). Then, via programmed cell death, digital rays form.

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