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Thanatophoric Dysplasia.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2004 May 21 [updated 2013 Sep 12].

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1
DNA Diagnostic Laboratory, Johns Hopkins University, Baltimore, Maryland

Excerpt

CLINICAL CHARACTERISTICS:

Thanatophoric dysplasia (TD) is a short-limb dwarfism syndrome that is usually lethal in the perinatal period. TD is divided into type I, characterized by micromelia with bowed femurs and, uncommonly, the presence of cloverleaf skull deformity (Kleeblattschädel) of varying severity; and type II, characterized by micromelia with straight femurs and uniform presence of moderate-to-severe cloverleaf skull deformity. Other features common to type I and type II include: short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported.

DIAGNOSIS/TESTING:

Diagnosis of TD is based on clinical examination and/or prenatal ultrasound examination and radiologic studies. Characteristic histopathology is also present. FGFR3 is the only gene in which mutation is known to cause TD. Up to 99% of pathogenic variants causing TD type I and more than 99% of pathogenic variants causing TD type II can be identified through molecular genetic testing of FGFR3.

MANAGEMENT:

Treatment of manifestations: Management focuses on the parents' wishes for provision of comfort-care for the newborn. Newborns require respiratory support (with tracheostomy and ventilation) to survive. Anesthetic management may include: intubation with a flexible fiberoptic scope with the cervical spine in a neutral position; use of evoked potential monitoring during the procedure; and avoidance of volatile anesthetic agents and muscle relaxants that may interfere with evoked potential recordings. Other treatment measures may include: antiepileptic drugs to control seizures, shunt placement for hydrocephaly, suboccipital decompression for relief of craniocervical junction constriction, and hearing aids. Surveillance: Long-term survivors need neurologic, orthopedic, and audiologic evaluations, CT to monitor for craniocervical constriction, and EEG to monitor for seizure activity. Pregnancy management: When TD is diagnosed prenatally, treatment goals are to avoid potential pregnancy complications including prematurity, polyhydramnios, malpresentation, and delivery complications from macrocephaly and/or a flexed and rigid neck; cephalocentesis and cesarean section may be considered to avoid maternal complications.

GENETIC COUNSELING:

TD is inherited in an autosomal dominant manner; the majority of probands have de novo pathogenic variant of FGFR3. Risk of recurrence for parents who have had one affected child is not significantly increased over that of the general population. Germline mosaicism in healthy parents, although not previously reported, remains a theoretic possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.

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