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thanatophoric dysplasia

MIM.187600

Tuesday 5 July 2005

Definition: Autosomal dominant osteochondrodysplasia associating short limbs, narrow thorax and normal trunk length.

Thanatophoric dysplasia type 1 (TD1) and SADDAN dysplasia are caused by mutation in the gene encoding the fibroblast growth factor receptor-3 (FGFR3; MIM.134934). Thanatophoric dysplasia type 2 (TD2; MIM.187601) and achondroplasia (ACH; MIM.100800) are allelic disorders.

Types

- thanatophoric dysplasia type 1
- thanatophoric dysplasia type 2

Synopsis

- systemic anomalies

- craniofacial anomalies

  • macrocephaly (large head)
  • prominent forehead (frontal bossing)
  • secondary skull deformity due to premature closure of cranial sutures (craniostenosis and craniosynostosis)
  • relatively large calvaria
  • protruding eyes
  • small facies (small facial bones)
  • depressed nasal bridge
  • cloverleaf skull deformity (more frequent in type 2 TD than type 1 TD)

- skeletal anomalies

  • relatively normal trunk length
  • narrow thorax due to short ribs (respiratory insufficiency) with protuberant abdomen
  • wide-cupped costochondral junctions
  • small abnormally formed scapulae
  • short ribs
  • small foramen magnum
  • cloverleaf skull rarely
  • severe platyspondyly
  • distinct flattening of the ossification centers of the vertebral bodies (lee severe in type 2 TD than type 1 TD)
  • H-shaped appearance of vertebrae
  • notch-like ossification defects of the central portion of the upper and lower plates
  • short iliac bones
  • small iliac bones
  • small sacroiliac notches
  • short and broad iliac bones
  • short and broad ischial bones
  • very short limbs (micromelia)
  • short and broad long tubular bones
    • bowed in type 1 TD (long bone bowing with femorla bowing)
    • straigth in type 2 TD
  • marked shortness and bowing of long bones
  • ’french telephone receiver femurs’
  • flared and irregular metaphyses
  • short metacarpal bones
  • short metatarsal bones
  • short phalanges
  • bullet-shaped phalanges

- cerebral anomalies

  • temporal lobe heterotopia
  • neuronal heterotopia
  • megalencephaly
  • cerebral gyral disorganization
  • hippocampal malformation
  • nuclear dysplasia
  • abnormal axonal bundles
  • cerebellar hypoplasia
  • hydrocephalus
  • profound mental retardation and hypotonia in survivors
  • polymicrogyria

Variants

- thanatophoric dysplasia type 1 (TD1) (MIM.187600)
- thanatophoric dysplasia type 2 (TD2) (thanatophoric dysplasia with cloverleaf skull) (MIM.187601)

Associations

- bilateral non-obstructive renal dysplasia (BNORD) (17375526)

Differential diagnosis

- achondroplasia
- PLSDs (platyspondylic lethal short-limbed dysplasias)

  • Torrance type PLSD (MIM.151210) (no FGFR3 mutations described)
  • San Diego type PLSD (MIM.270230) (FGFR3 mutations)
  • Glasgow type PLSD (MIM.273680)

- SADDAN syndrome (severe achondroplasia with developmental delay and acanthosis nigricans) (FGFR3 mutations)

Etiology

- Locus 4p16.3: germline mutations in the FGFR3 gene

  • new cystein in extramembranous segment of the FGFR3
  • Lys650GLu in type 2 TD

Case records

- Case 10552
- Case 10555
- Case 10556
- Case 13202

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