Early Diagnostic Signs and the Natural History of Typical Findings in Cohen Syndrome

Abstract

To describe the clinical presentation and long-term clinical features of a molecularly confirmed cohort with Cohen syndrome. Twelve patients with Cohen syndrome aged 0.2-13.9years from 8 families with a median follow-up of 7years were enrolled to the study. Genetic analyses were made by VPS13B and whole-exome sequencing analyses. Biallelic VPS13B variants, including 3 nonsense, 1 frameshift, and 1 splice-site variant, and a multiexon deletion were detected. Prader-Willi syndrome-like features such as hypotonia, small hands, round face with full cheeks, almond-shaped eyes, and micrognathia were observed in all infantile patients. Beginning from age 4years, it was noticed that the face gradually elongated and became oval. The typical facial features of Cohen syndrome such as a long face, beak-shaped nose, and open-mouth appearance with prominent upper central incisors became evident at age 9. Other Cohen syndrome features including retinopathy (11/11), neutropenia (11/12), truncal obesity (5/12), and myopia (5/11) were detected at the median ages of 7.8, 7, 7.5, and 5years, respectively. Eleven patients aged older than 5years at their last examination had severe speech delay. A differential diagnosis of Cohen syndrome in the infancy should be made with Prader-Willi syndrome, and that the typical facial features for Cohen syndrome is prominent at age 9years, when retinopathy, neutropenia, and truncal obesity become evident. Moreover, adding the severe speech delay to the diagnostic criteria should be considered.