Difficult-to-treat Epilepsies in Children with SMC1A Mutations without Facial Abnormalities: An “Atypical Cornelia-de-Lange Syndrome“? – Five More Cases

Background: Cornelia-de-Lange Syndrome (CdLS) features a large clinical and phenotypical variability. The spectrum of clinical characteristics ranges from typical facial dysmorphism, skeletal anomalies (in particular ulnae stream), macrosomia, microcephaly, hirsutism, developmental problems, cognitive deficits, and cardiac defect to therapy-refractory epilepsies. Besides the most frequently found mutation in the NIPBL gene, mutations in the SMC1A gene have been described as the (second most common) cause of CdLS. On the basis of whole exome sequencing of severe infantile epilepsies, children were found with SMC1A mutations without the CdLS-typical facial dysmorphism (Huisman et al, 2017). Here, we describe five more cases of this constellation.

Material and Methods: Analysis of clinical and paraclinical data from patients with SMC1A mutations and difficult-to-treat epilepsies.

Results: All five patients are girls, ranging in age from 1 to 9 years. First seizures occurred between 5 months and 2.5 years. Despite anti-convulsive medication (3 to 12 prescribed drugs), no child has become permanently seizure-free. The seizure semiologies range from unclassified seizures, absences, and tonic seizures to clonic seizures with status epilepticus. EEGs mostly show slowing, often multiregional epilepsy-typical potentials, and even electro-encephalographic status epilepticus. Magnetic resonance tomography was normal for three children, while two patients have an unspecific enlargement of lateral ventricles. All patients suffer from a combined developmental delay. None of the children has CdLS-typical facial or skeletal anomalies (one child of Spanish origin has questionable mild facial features, though). Two children have heart defects (coarctation of the aorta, persistent foramen ovale).

Conclusion: Our case series further corroborates that SMC1A-mutations can cause difficult-to-treat epilepsies without CdLS-typical facial dysmorphism. For this constellation, we propose the term “SMC1A epileptic encephalopathy” in the context of an “atypical Cornelia-de-Lange syndrome”. Huisman et al (2017). Phenotypes and genotypes in individuals with SMC1A variants. In: American Journal of medical genetics, Vol. 173, Issue 8, Pages 2108–2125.