Introduction: Campomelic dysplasia is a rare skeletal dysplasia characterized by Pierre-Robin sequence, craniofacial dysmorphism, shortening and angulation of long bones, tracheobronchomalacia, and occasionally sex reversal. The disease is due to mutations in SOX9 or chromosomal rearrangements involving the long arm of chromosome 17. Intracranial abnormalities, including ventriculomegaly, which has only been reported once before, are poorly understood and management is unclear.

Methods: The clinical chart was reviewed for the index patient. Comparative genomic hybridization (CGH) and whole exome sequencing (WES) were performed in blood-derived DNA.

Results: The patient was diagnosed with campomelic dysplasia at birth, demonstrating angulation and shortening of long bones and external female genitalia on prenatal ultrasound and found to have 46, XY, t(6;17) (p21.1;q24.3) on prenatal genetic testing. At birth, no intracranial abnormalities were noted on surveillance imaging. At two-months, she presented with lethargy and acute respiratory distress requiring intubation. Head ultrasound and subsequent brain MRI demonstrated new ventriculomegaly with globally dilated ventricles but patent flow around the foramen magnum. Clinically, she showed no signs of increased ICP over the following two months and was managed expectantly with serial examination and imaging. Further testing via CGH revealed deletions at 6p21.1 and 17q24.3, the latter being 2.3Mb upstream of SOX9. WES did not identify pathogenic variants in SOX9, suggesting that the 17q24.3 deletion may affect expressivity of SOX9 and may represent a cluster of translocation breakpoints farther upstream of SOX9 than previously described.

Conclusions: The case demonstrates acquired ventriculomegaly as a novel presentation of campomelic dysplasia that may be secondary to an ex vacuo phenomenon related to neural migration defects from SOX9 dysfunction and thus not neurosurgical intervention. It also demonstrates a novel chromosomal breakpoint and suggests a new cluster of noncoding loci that control expression of SOX9, which may preferentially affect neuronal development.

Patient Care: Ventriculomegaly is a rare but potential manifestation of campomelic dysplasia which warrants neurosurgical evaluation. Our case, like the sole prior report in the current literature, suggests the observed ventriculomegaly may be secondary to an ex-vacuo phenomenon and such may be managed conservatively without neurosurgical intervention. Further reports like ours are needed to define the role of the neurosurgeon in ventriculomegaly in campomelic dysplasia. In addition, we describe a novel chromosomal breakpoint further upstream of SOX9 than previously described, which may preferentially affect neuronal development and warrants further laboratory study.

Learning Objectives: 1. Recognize ventriculomegaly is a rare but potential neurological manifestation of campomelic dysplasia. 2. Understand that the ventriculomegaly in campomelic dysplasia may be secondary to an ex vacuo phenomenon with normal ICPs and thus not require neurosurgical intervention. 3. Recognize chromosomal deletions at 17q24.3 as novel pathogenic translocation breakpoints far upstream of SOX9 in campomelic dysplasia, which may preferentially affect neuronal development.

References: Matsumoto A, Imagawa E, Miyake N, et al. The presence of diminished white matter and corpus callosal thinning in a case with a SOX9 mutation. Brain Dev. Apr 2018;40(4):325-329.