Thanatophoric dysplasia (ORPHA:2655)
A primary bone dysplasia with micromelia characterized by micromelia, macrocephaly, narrow thorax, and distinctive facial features. It includes TD, type 1 (TD1) and TD, type 2 (TD2), that can be differentiated from each other by femur and skull shape.
Epidemiology
Thanatophoric dysplasia (TD) estimated incidence is about 1/20,000 to 1/50,000 births.
Clinical description
Characteristic morphological features are seen on prenatal ultrasounds. Late in the 1st trimester, shortening of the long bones is apparent on ultrasound along with increased nuchal translucency. In the 2nd trimester a marked growth deficiency (limb length below 5th percentile) is noted along with relative macrocephaly, a well mineralized skull, and narrow thorax with 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. The thorax is narrow and bell-shaped. There is significant micromelia with redundant skin folds and brachydactyly with a trident hand configuration is common. 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.
Etiology
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.
Diagnostic methods
Diagnosis is usually made in the 2nd to 3rd trimester but is possible earlier with short limbs identified during standard 1st trimester dimensional ultrasound. Molecular genetic testing can be used to screen for FGFR3 mutations and definitely diagnose TD.
Differential diagnosis
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.
Antenatal diagnosis
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.
Genetic counseling
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 the likelihood of having a healthy child is high.
Management and treatment
Prenatally, treatment aims to avoid potential pregnancy and delivery complications. Postnatally, 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
Prognosis is poor with death occurring in utero or shortly after birth in almost all cases. Death is likely due to respiratory insufficiency and/or spinal cord/brain stem compression. A few rare cases have been reported where patients survived into childhood with significant medical intervention.

                            Last update: 
                            September 2019


                            - Expert reviewer(s): 
                            Dr Elaine PEREIRA