Parietal foramina 2 in a 5-year-old girl with persistent open fontanels and dysmorphic features

We present the case of a 5-year-old girl with persistent open fontanelles and craniofacial dysmorphism. She was born at 39 weeks after induction for maternal hypertension, with a birth weight of 2920 g, length 50 cm, head circumference 34.5 cm, and Apgar score of 9/9. A cephalhematoma was noted at birth. Abnormal cranial shape was detected at 3 months of age. Neurological evaluation at 10 months of age showed mild axial hypotonia and facial dysmorphic features. Cranial ultrasound performed at the same time showed persistent open sutures and excluded craniosynostosis. Motoric developmental milestones were achieved at a normal age, with independent sitting achieved at 8 months and walking at 12 months. She was referred to our institution for genetic diagnostics at 14 months of age, where we observed dyscrania, prominent ears with poorly formed helices, deep-set eyes, ptosis, and pectus excavatum. Family history revealed delayed closure of anterior fontanelle in the mother and maternal grandmother, while the patient’s older sister is healthy and developed normally. Exome sequencing in the patient identified a heterozygous pathogenic nonsense variant in ALX4 (NM_001168.3:c.793C>T; p.Arg265Ter), previously associated with Parietal foramina 2 (OMIM:609597) in the heterozygous state, and with Frontonasal dysplasia type 2 (OMIM 613451) in the homozygous state. ACMG criteria employed fort he classification of the variant and its association with Parietal foramina 2 were PVS1, PS3, PM2, PM3. An additional heterozygous variant of uncertain significance in ALX4 (c.624G>C; p.Glu208Asp) was also detected (ACMG criteria PM2). The clinical and molecular findings are consistent with the diagnosis of Parietal foramina 2.