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Thanatophoric dysplasia (TD) is a severe and generally lethal skeletal dysplasia presenting in the prenatal period and characterized by micromelia, macrocephaly, narrow thorax, and distinctive facial features. It includes TD, type 1 (TD1) and TD, type 2 (TD2) (see these terms), that can be differentiated from each other by femur and skull shape.
The estimated incidence is about 1/20,000 to 1/50,000 births.
Characteristic morphological features are seen prenatally. Late in the 1st trimester, shortening of the long bones is apparent on ultrasound. In the 2nd trimester a marked growth deficiency (limb length below 5th percentile) is noted along with macrocephaly, ventriculomegaly, and a well mineralized skull. Thorax is narrow with normally mineralized, but flattened vertebral bodies. Bowed ''telephone receiver'' femurs (in TD1), cloverleaf skull (in TD2 and a few cases of TD1) and polyhydramnios can also be seen. Neonates are macrocephalic with a large anterior fontanelle, frontal bossing, severe midface hypoplasia and proptosis. Limbs are micromelic with redundant skin folds and hands show brachydactyly with a trident configuration. Thorax is narrow and bell shaped. Generalized hypotonia is present. CNS abnormalities can include temporal lobe dysplasia, hydrocephalus, and injury from critical foramen magnum stenosis. Rarely, cardiac and renal abnormalities have been reported as well as seizures.
TD is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene (4p16.3) which cause overactivity of the FGFR3 protein, resulting in the disturbances in bone growth and other tissues that are characteristic of TD.
Diagnosis is usually made in the 2nd to 3rd trimester but is possible earlier with short limbs identified during standard 1st trimester dimensional ultrasound. Other imaging findings include platyspondyly, irregular metaphyses and rhizomelic shortening of the long bones, as well as bowed femurs in type 1 TD and cloverleaf skull (kleeblattschaedel) in type 2 TD. Molecular genetic testing can be used to screen for FGFR3 mutations and definitely diagnose TD.
Differential diagnoses include homozygous achondroplasia, achondrogenesis (types 1A, 1B, and 2), SADDAN, short rib-polydactyly syndromes, osteogenesis imperfecta type 2, platyspondylic lethal skeletal dysplasias, dyssegmental dysplasia Silverman-Handmaker type, and campomelic dysplasia (see these terms).
Antenatal diagnosis is usually suspected by prenatal ultrasound and can be confirmed by molecular analysis of amniocytes, or by chorionic villus sampling (CVS), or recently by cell free fetal DNA.
TD is inherited autosomal dominantly but the majority of cases are due to a de novo mutation in the proband. Genetic counseling allows families who have already had one child with TD to know that recurrence rate is about 2%, so their chance of having a healthy child is high. Advanced paternal age effect for TD has been reported.
Management and treatment
There is no cure for TD. In a prenatal setting, treatment aims to avoid potential pregnancy and delivery complications. In the newborn period, management should focus on the parents' wishes for provision of comfort-care for the newborn versus aggressive management. Respiratory support with a tracheostomy and ventilation is essential for survival in all infants. Hydrocephaly can be treated with the placement of a shunt. Suboccipital decompression can be done when needed to relieve craniocervical junction constriction. Antiepileptic drugs can be given to those with seizures. Hearing aids can be provided to those with hearing loss.
Prognosis is poor with death occurring in utero or shortly after birth in almost all cases. A few rare cases have been reported where patients survived into childhood with significant medical intervention. Death is likely due to respiratory insufficiency and/or spinal cord/brain stem compression.