Expanding the natural history of CASK-related disorders to the prenatal period

Aim: To assess whether microcephaly with pontine and cerebellar hypoplasia (MICPCH) could manifest in the prenatal period in patients with calcium/calmodulin-dependent serine protein kinase (CASK) gene disorders. Method: In this international multicentre retrospective study, we contacted a CASK parents' social media group and colleagues with expertise in cerebellar malformations and asked them to supply clinical and imaging information. Centiles and standard deviations (SD) were calculated according to age by nomograms. Results: The study consisted of 49 patients (44 females and 5 males). Information regarding prenatal head circumference was available in 19 patients; 11 out of 19 had a fetal head circumference below –2SD (range −4.1SD to −2.02SD, mean gestational age at diagnosis 20 weeks). Progressive prenatal deceleration of head circumference growth rate was observed in 15 out of 19. At birth, 20 out of 42 had a head circumference below –2SD. A total of 6 out of 15 fetuses had a TCD z-score below –2 (range −5.88 to −2.02). Interpretation: This study expands the natural history of CASK-related disorders to the prenatal period, showing evidence of progressive deceleration of head circumference growth rate, head circumference below –2SD, or small TCD. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements and genetic studies are advised in the presence of progressive deceleration of head circumference growth rates or small TCD. What this paper adds: Progressive deceleration of fetal head circumference growth rate can be observed. A small transcerebellar diameter is an additional important manifestation. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements are advised when measurements are within the low range of norm.