Abnormal posterior brain and molar tooth sign in a fetus with Joubert syndrome at 11 – 13 weeks – new gene mutation discovered: Case report

Purpose: Joubert syndrome (JS), a rare autosomal recessive disorder, is characterized by the molar tooth sign on an axial magnetic-resonance-imaging (MRI). This abnormality results from a complex brainstem malformation and co-occurs with agenesis/hypoplasia of the cerebellar vermis, that leads to an abnormal enlargement of the fourth ventricle (4V). The adverse outcome of JS is characterized by episodes of hyperpnea, abnormal ocular movement, hypotonia, ataxia and developmental delay. Variable features, including cystic kidneys have led to a broader classification, such as JS and related disorders.

Results: We describe abnormal sonographic findings of 4V, brainstem and kidneys in one fetus with JS. A 26-year-old nulliparous woman was referred for evaluation after a nuchal translucency of 3.5 mm had been measured (11+4wks). The midsagittal view displayed: enlarged 4V/cisterna magna, increased BSOB, decreased BS/BSOB-ratio and horizontalization of the brainstem. A high risk for cystic posterior fossa malformations, particularly Dandy-Walker continuum, was suspected. The molar tooth shaped cerebellar peduncles on an axial view in the first trimester were noted in the sonographic imaging review. The kidneys appeared normal at this stage. Chorionic villus sampling was performed and revealed a normal male karyotype. Sonographic evaluation (15+4wks) showed marked vermian hypoplasia, deep interpeduncular fossa, brainstem dysplasia, echogenic kidneys. Confirmed by fetal-MRI (16+4wks). After termination of pregnancy (17+6wks), further fetal-DNA analysis revealed two mutations in the INPP5E-gene, which carry a high probability in causing JS in this family and of which one mutation has not been previously described. This allows early prenatal genetic diagnosis in their future pregnancies.

Conclusion: As exact prenatal genetic testing may not always be compelling in Joubert syndrome, the ability to identify the molar tooth sign in prenatal ultrasound before 17 weeks provides a valuable adjunct to differentiate between posterior fossa abnormalities, particularly Dandy-Walker malformation, Blake's pouch cyst, isolated vermin hypoplasia, encephalocele and to select appropriate genetic analysis.