Abstract
BACKGROUND: Kleefstra syndrome is a rare genetic disorder attributed to loss of function of EHMT1, either due to a point mutation or a microdeletion in the chromosome region 9q34.3. This gene encodes an enzyme that modifies histone function and is essential for normal development. Individuals with Kleefstra syndrome typically present intellectual disability (from moderate to severe), language delay, autism spectrum disorders, generalized hypotonia, and distinctive facial dysmorphic features. Additional manifestations in children may include cardiac defects, renal and urological malformations, genital anomalies, respiratory infections, epilepsy (including febrile seizures), and psychiatric disorders. Panayiotopoulos syndrome is a specific type of epilepsy, usually presenting in early to mid-childhood with benign focal seizures. These seizures are characterized by primarily autonomic symptoms, abnormal EEG findings showing shifts or multiple seizure foci (often located in occipital lobe), and other autonomic manifestations such as pallor, redness or cyanosis, mydriasis or miosis, heart and breathing problems, thermoregulatory changes, urinary and/or fecal incontinence, hypersalivation, and altered gut motility. CASE PRESENTATION: We present the case of a child with Kleefstra syndrome and Panayiotopoulos epilepsy. The patient is a 12-year-old male born from a full-term pregnancy to non-consanguineous healthy parents with a family history of neurodevelopmental disorders. At birth, he presented dysmorphic facial features including receding forehead, low-set ears and lingual protrusion. From 6 months of age, he manifested predominantly axial and lower limb hypotonia, associated with a delay in acquiring psychomotor developmental milestones. Genetic counseling was requested, and array-CGH was then performed. Molecular analysis detected a 9q34.3 microdeletion which included the EHMT1 gene, leading to Kleefstra syndrome diagnosis. From the age of 6 years, he began experiencing seizures with features typical of Panayiotopoulos epilepsy and started treatment with valproic acid. CONCLUSIONS: We highlight the association between Panayiotopoulos epilepsy and Kleefstra syndrome, which has not been previously reported in the literature. Although this kind of epilepsy is quite frequent in pediatric age and the possibility of a casual co-occurrence should be considered, however in Kleefstra syndrome patients carrying 9q34.3 microdeletion a potential additional role of genetic (besides EHMT1) and epigenetic factors in developing seizures cannot be excluded. The present data expand the genomic and phenotypical features of the syndrome, providing new insights about research, which are useful to achieve genotype/phenotype correlations and better management of affected subjects.