[CNKSR2 gene variants causing Houge type of X-linked syndromic intellectual developmental disorder: Seven cases and literature review].

OBJECTIVES

Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) caused by CNKSR2 gene variants is a rare neurodevelopmental disorder. Patients commonly present with refractory epilepsy and are prone to developing electrical status epilepticus during sleep (ESES), which may further aggravate cognitive impairment. This study analyzes 7 patients with CNKSR2 gene variants causing MRXSHG, combined with a literature review, aiming to provide a reference for the clinical diagnosis of similar patients.

METHODS

A retrospective analysis was conducted on the clinical data of 7 children diagnosed with CNKSR2 gene mutations by whole‑exome sequencing at the Children's Medical Center, Xiangya Hospital, Central South University, from June 2020 to November 2025. Combined with a literature review (15 publications involving 42 patients), a total of 49 patients were summarized and analyzed.

RESULTS

The reported age ranged from 4 months to 62 years, with a male-to-female ratio of 11.2꞉1. Major clinical manifestations included global developmental delay/intellectual disability (100%, 49/49), epilepsy (91.8%, 45/49), attention deficit hyperactivity disorder (77.6%, 38/49), absence of speech (75.5%, 37/49), and sleep disturbances (28.6%, 14/49). Among 36 patients with available sleep electroencephalogram data, 16 (44.4%) exhibited ESES. A minority of patients also presented with feeding difficulties (12.2%, 6/49), autism spectrum disorder (10.2%, 5/49), abnormal muscle tone (6.1%, 3/49), microcephaly (6.1%, 3/49), and facial dysmorphism (4.1%, 2/49). Four patients from our center exhibited short stature and/or malnutrition, which have not been previously reported. Among 34 patients with known epilepsy outcomes, 14 (41.2%) achieved seizure control with valproate, carbamazepine, or lamotrigine; 16 (47.1%) had refractory epilepsy; and 4 (11.8%) were untreated, had unclear seizure status, or were still undergoing treatment adjustment.

CONCLUSIONS

For male patients presenting with intellectual disability and prominent language delay, particularly those with refractory epilepsy and ESES, MRXSHG caused by CNKSR2 variants should be considered. Genetic testing is essential for definitive diagnosis and for providing genetic counseling.