A 26-year-old G1P0 woman presented for initial prenatal care around 25 weeks' gestation after pregnancy conception in Mexico. Detailed ultrasound at 33 weeks' gestation showed severe microcephaly with head circumference measuring 7 weeks behind estimated gestation (<1%ile, Z −7.8).[1]

Fetal magnetic resonance imaging showed markedly diminished volume of cerebral hemispheres with absence of expected gyration pattern, particularly affecting frontal lobes ([Fig. 1]). Brainstem and cerebellum were small for gestation with normal morphology. Findings were reminiscent of congenital Zika infection.[2] Given the poor prognosis, pregnancy was terminated. Maternal Zika serologies were negative. Duo exome sequencing identified the fetus was compound heterozygous for variants of uncertain significance (VUS) in ANKLE2 NM_015114.2:c.1606C > T p.(Arg536Cys) (de novo origin cannot be excluded); c.1696G > A p.(Gly566Arg) (maternally inherited). Although the variants here were classified as VUS, one was previously reported in affected patients.[3]

Pathogenic variants in ANKLE2 are associated with primary autosomal recessive microcephaly-16 [OMIM 616681].[3] ANKLE2 is a membrane-bound protein in the nuclear envelope that regulates cell division and is a target of the Zika virus. Accordingly, variants in ANKLE2 cause a phenotype similar to congenital Zika infection.[4]

Therefore, we are suspicious that the fetus was affected with ANKLE2-related microcephaly, and, to our knowledge, this is the first prenatally diagnosed case.