WEISMANN-NETTER-STUHL SYNDROME
SKELATAL SYNDROMES
- WEISMANN-NETTER-STUHL
- OSTEOGENESIS IMPERFECTA
  SYNDROME
- MARFAN SYNDROME
- ACHONDROPLASIA
- FAMILALIAL HYPOPHOSPHATEMIC
  RICKETS



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Osteogenesis Imperfecta (Types I–IV)
Chromosome and Gene Location:
- COL1A1 gene (Chromosome 17)
- COL1A2 gene (Chromosome 7)
Inheritance:
-  Autosomal dominant, often due to new mutation
Clinical:
Type I : Autosomal Dominant. Bone fragility, blue sclera, hearing loss.
Type II: Autosomal dominant, but usually new. Perinatal lethal, calvarial under-mineralization germline mutation, beaded ribs, compressed femurs.
Type III: Autosomal Dominant/Recessive. Multiple prenatal bone fractures, limb shortening, limb deformities, deafness, blue sclera
Type IV Autosomal Dominant Mild, short stature, mild deformity, dentinogenesis imperfecta, white sclera.
Incidence:
!-1/5000–1/10,000
Molecular Genetics:
- Collagen is the major protein of the white fibers of
  connective tissue, cartilage, and bone.
- There have been numerous types of collagens identified
- Mutations in the procollagen genes, whose products make
  up the triple helix of type 1 collagen, lead to the various
  types of Osteogenesis Imperfecta
- Clinical presentation is dependent on the extent to which
  the mutation alters the protein product
Laboratory:
- X-ray implicates skeletal involvement
- Direct molecular analysis of procollagen genes available
Treatment:
- Not curable, supportive/symptomatic
- Surgical intervention when indicated

Marfan Syndrome
Chromosome and Gene Location:
- 15q
Inheritance:
- Autosomal dominant
-15–30% result from a new mutation
Incidence:
- 1/10,000
Clinical:
- Diagnosis based on clinical criteria
- Tall, thin habitus
- Long extremities
- Arachnodactyly
- Pectus deformity
- Scoliosis
- Ectopia lentis
- Retinal detachment
- Mitral valve prolapse
- Aortic dilation
- Aortic aneurysm
- Life expectancy is reduced to about 2/3 of normal life
  span
Molecular Genetics:
- Mutations in gene for fibrillin, a structural protein which
  is the major constituent of microfibrils
Laboratory:
- Mutation analysis and molecular linkage analysis to 15q
  for familial cases is available
Treatment:
- Surgical intervention when indicated
- Close monitoring of heart defects as they can lead to
sudden death
- Use of " adrenergic blockade
Achondroplasia
Chromosome and Gene Location:
- 4p16.3
Inheritance:
- Autosomal dominant; 80% result from a new mutation
Incidence:
- 1/25,000
Clinical:
- Short stature, due to shortened limbs
- Genu varum
- Large head
- Frontal bossing
- Hypoplasia of midface
- Infantile hypotonia
- Gross motor developmental delay
- Normal intelligence
- Normal life expectancy
- Also at risk for cord compression due to odontoid hypoplasia
Molecular Genetics:
- Mutation in transmembrane domain of fibroblast growth
  factor transmembrane receptor (FGFR-3)
Laboratory:
- X-ray implicates skeletal involvement
- Molecular testing for FGFR-3 mutation is available
Treatment:
- Not curable, supportive/symptomatic
Familial Hypophosphatemic Rickets
Chromosome and Gene Location:
- Xp22.2-p22.1
Inheritance:
- X-linked dominant (also autosomal recessive and
  sporadic forms)
Incidence:
- 1/1,000,000
Clinical:
- Bowing of lower extremities
- Waddling gait
- Short stature
- Decreased femur/shaft angle
- Dolichocephaly
- Tooth deformities
Molecular Genetics:
- Deficiency interferes with phosphate reabsorption in kidney
  and conversion of 25-hydroxy-d to 1,25-hydroxy-2d
Laboratory:
- Hyperphosphaturia
- Normal amino acids
- X-rays show metaphyseal widening and fraying, cupping
  of metaphyses at tibia, femur, radius, and ulna
- Molecular mutation analysis available
Treatment:
- Phosphate supplements, surgery for limb deformities