Thanatophoric Dysplasia

Excerpt

Clinical characteristics: Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in the perinatal period. TD is divided into subtypes: TD type 1 is characterized by micromelia with bowed femurs and, uncommonly, the presence of craniosynostosis of varying severity. TD type 2 is characterized by micromelia with straight femurs and uniform presence of moderate-to-severe craniosynostosis with cloverleaf skull deformity. Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative 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: The diagnosis of TD is established in a proband with characteristic clinical and/or radiologic features and/or a heterozygous pathogenic variant in FGFR3 identified on molecular genetic testing.

Management: Treatment of manifestations: Most individuals with TD die in the perinatal period because of the multisystem complications of the disorder. Management goals should be established with the family and may focus on provision of comfort care. Newborns require long-term respiratory support (typically with tracheostomy and ventilation) to survive. Anesthetic management guidelines for skeletal dysplasias are applicable to individuals with TD. Other treatment measures may include shunt placement for hydrocephalus, suboccipital decompression for relief of craniocervical junction constriction, anti-seizure medication to control seizures, and hearing aids.

Surveillance: Long-term survivors need neuroimaging to monitor for craniocervical constriction, assessment of neurologic status, and EEG to monitor for seizure activity, as well as developmental, orthopedic, and audiology evaluations.

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 a de novo FGFR3 pathogenic variant. Risk of sib 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 reported to date, remains a theoretic possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.