104 Thanatophoric Dysplasia
Thanatophoric Dysplasia 907
Thanatophoric dwarfism, TD, thanatophoric dysplasia type 1 and 2 included
Lethal short-limb dwarfism, relatively normal trunk length, narrow chest, large head, frontal bossing, de- pressed nasal bridge, redundant skin folds on arms/
legs
Frequency: 1 in 40,000 births.
Genetics
Autosomal dominant, due to mutations of fibroblast growth factor receptor-3 (FGFR3) gene at 4p16.3;
allelic to achondroplasia, hypochondroplasia, Crouzon syndrome with achantosis nigricans, and Muenke syndrome. Two thanatophoric dysplasia variants are recognized, caused by mutations at different sites in FGFR3: TD, type 1 (OMIM 187600) has Arg248Cys substitution, and is characterized by curved femurs, very flat vertebrae and, occasionally, cloverleaf skull;
and TD, type 2 (thanatophoric dysplasia with Klee- blattschaedel, OMIM 187601) has Lys650Glu substi- tution in the tyrosine kinase domain of the receptor, and is characterized by straight femurs, less promi- nent vertebral involvement, and severe cloverleaf skull.
Clinical Features
• Usually perinatally lethal
• Severe growth deficiency (36–46 cm at birth)
• Large head, frontal bossing, cloverleaf skull (un- common)
• Small facies, hypertelorism, proptosis, flat nasal bridge
• Narrow thorax, respiratory distress
• Protruding abdomen
• Very short limbs, extended away from trunk, thighs adducted and externally rotated, brachy- dactyly with conical fingers
• Increased skin folds on extremities
• Hypotonia
Differential Diagnosis
• Achondroplasia (heterozygous and homozygous)
• Achondrogenesis (different types)
• Severe hypophosphatasia
Radiographic Features Chest
• Long narrow thorax with very short ribs
• Wide-cupped costochondral junctions
• Posterior rib scalloping
• Small abnormally formed scapulae Spine
• Severe platyspondyly (less severe in TD type 2)
• Anteriorly rounded vertebral bodies
• U- (upper) or H-shaped (lower) vertebral bodies (AP projection), owing to better ossification of posterior elements
• Apparent wide disc spaces
• Craniocaudal interpediculate narrowing Pelvis
• Short and small iliac bones
• Horizontal acetabular roofs, with medial and lat- eral spikes
• Small sacroiliac notches
• Accessory ossification centers in ischia and ilia at gestational age less than 24 weeks, with fusion to main bone after 24 weeks of gestation
Limbs
• Marked shortness of long bones
• Bowed,‘telephone receiver-like’ femurs, with prox- imal oval translucencies and flared distal ends (TD type 1); straight or only slightly bowed long bones (TD type 2)
• Irregularity and flaring of metaphyses
• Severe shortness, broadness and deformity of tu- bular bones of hands and feet
Skull
• Relatively large calvarium with frontal bossing, small face
• Short and narrow skull base
• Small foramen magnum
• Cloverleaf skull (uncommon in TD type 1, con- stant in TD type 2)
T
Bibliography
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9: 53–61
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Kitoh H, Lachman RS, Brodie SG, Mekikian PB, Rimoin DL, Wilcox WR. Extra pelvic ossification centers in than- atophoric dysplasia and platyspondylic lethal skeletal dys- plasia-San Diego type. Pediatr Radiol 1998; 28: 759–63 Kozlowski K, Prokop E, Zybaczynski J. Thanatophoric
dwarfism. Br J Radiol 1970; 43: 565–8
Martinez-Frias ML, Ramos-Arroyo MA, Salvador J. Than- atophoric dysplasia: an autosomal dominant condition.Am J Med Genet 1988; 31: 815–20
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Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ. Thanatophoric dysplasia (types I and II) caused by dis- tinct mutations in fibroblast growth factor receptor 3.
Nature Genet 1995; 9: 321–8
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Thanatophoric dysplasia type I: new radiologic, morpho- logic, and histologic aspects toward the exact definition of the disorder. J Pediatr Orthop B 1998; 7: 1–9
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Thanatophoric Dysplasia 908
Fig. 104.1. Patient 1, following death after 2 hours of life.
Severe growth deficiency, large head, frontal bossing, small facies, hypertelorism, flat nasal bridge, narrow thorax, pro- truding abdomen, and short limbs. (Reprinted, with permis- sion, from Mastroiacovo et al. 1990)
Thanatophoric Dysplasia 909
T
Fig. 104.2. a Patient 2, following death after 30 hours of life. (Cour- tesy of Dr. S. Fasanelli, Ospedale Bambino Gesù, Rome, Italy). b Pa- tient 3, stillborn. (Reprinted, with permission, from Canepa et al.
1996). Note very short ribs with cupped ends, and narrow thorax.
Scapulae are small and deformed.
Vertebrae are flat, U-shaped (up- per thoracic) or H-shaped (lower thoracic and lumbar) in AP pro- jection, owing to better ossifica- tion of posterior elements. Inter- pediculate distance is narrowest at L3–4. Iliac bones are short, squared off, with narrow sciatic notches and horizontal acetabula with medial and lateral spikes. Is- chial and pubic bones are short and broad. Tubular bones are markedly shortened, bowed, with irregular, flared, and cupped meta- physes. Femurs look like ‘French telephone receivers’ and have ovoid lucent proximal ends. Tubu- lar bones in hands and feet are short and stubby. This phenotype corresponds to TD type 1. c Pa- tient 4, stillborn. (Reprinted, with permission, from Canepa et al.
1996). Findings are similar to those described in (a and b), ex- cept that there is cloverleaf defor- mity of the skull, the thorax is not as narrow and the long bones are straight or only slightly bowed. In addition, the spine is less severely affected. This phenotype corre- sponds to TD type 2
a
c b
