Prenatal Diagnosis of ANKLE2-Related Microcephaly Mimicking Zika Infection

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]

Fig. 1 Axial, coronal, and sagittal T2-weighted magnetic resonance images of the fetal brain show markedly diminished volume of the cerebral hemispheres with absence of the expected gyration pattern. There is no significant asymmetry between the cerebral hemispheres. The frontal lobes are underdeveloped and smoother than the posterior cerebral hemispheres. The brainstem shows normal morphology but appears slightly small for gestational age. The cerebellum and vermis are small for gestational age.

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.

Location where work was performed

Lucile Packard Children's Hospital, Palo Alto, California, United States.

Publication History

Received: 30 April 2025

Accepted: 01 September 2025

Article published online:
12 September 2025

• References

• 1 Hadlock FP, Deter RL, Harrist RB, Park SK. Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters. Radiology 1984; 152 (02) 497-501
• 2 Araujo Júnior E, Carvalho FHC, Tonni G, Werner H. Prenatal imaging findings in fetal Zika virus infection. Curr Opin Obstet Gynecol 2017; 29 (02) 95-105
• 3 Thomas AX, Link N, Robak LA. et al. ANKLE2-related microcephaly: a variable microcephaly syndrome resembling Zika infection. Ann Clin Transl Neurol 2022; 9 (08) 1276-1288
• 4 Link N, Chung H, Jolly A. et al. Mutations in ANKLE2, a ZIKA virus target, disrupt an asymmetric cell division pathway in Drosophila neuroblasts to cause microcephaly. Dev Cell 2019; 51 (06) 713-729.e6