Acute lymphoblastic leukemia in a child with Weiss-Kruszka syndrome: Casual or causal association?

Weiss-Kruszka syndrome is a recently described genetic disorder characterized by craniofacial features, ptosis, dysgenesis of the corpus callosum, and neurodevelopmental impairment. It is caused by heterozygous loss-of-function variantsin ZNF462 gene. During the time, the original phenotype was expanded, including several complications, sensorineural hearing loss, congenital hypogonadotropic hypogonadism with anosmia and complete growth hormone deficiency associated with empty sella syndrome. Here we report the first case of Weiss-Kruszka syndrome, associated to a de novo 9q31.1q31.3 microdeletion showing an acute lymphoblastic leukemia. A speculation on the contribution of our case to the phenotypic expansion of WSKA is here discussed. More clinical and functional studies are needed to elucidate this association. A possible expansion of the WSKA phenotype is discussed.

Genetic paroxysmal neurological disorders featuring episodic ataxia and epilepsy.

OBJECTIVE: This review article focuses on clinical and genetic features of paroxysmal neurological disorders featuring episodic ataxia (EA) and epilepsy and help clinicians recognize, diagnose, and treat patients with co-existing EA and epilepsy. It also provides an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders. METHODS: Based on a literature review on Pubmed database, a list of genes linked to paroxysmal neurological disorders featuring EA and epilepsy were compiled. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Among the various forms of EAs, only EA1 (KCNA1), EA2 (CACNA1A), EA5 (CACNB4), EA6 (SLC1A3), and EA9 (SCN2A) phenotypes with associated epilepsy have been described. Next-generation sequencing (NGS) has helped in the identification of other genes (e.g.: KCNA2, ATP1A3, SLC2A1, PRRT2) which have shown an overlapping phenotype with EA and epilepsy. CONCLUSION: Overlapping clinical features between EA and epilepsy may hinder an accurate classification, and complex genotype-phenotype correlation may often lead to misdiagnosis. NGS has increased the awareness of common genetic etiologies for these conditions. In the future, extensive genetic and phenotypic characterizations can help us to elucidate the boundaries of a wide phenotypic spectrum. These insights may help develop new precision therapies in paroxysmal neurological disorders featuring EA and epilepsy.

Epilepsy in isolated parenchymal neurocutaneous melanosis: A systematic review.

PURPOSE: Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by giant melanocytic cutaneous nevi and melanosis within the central nervous system (CNS), often sparing leptomeninges and concentrated in the brain parenchyma. Epilepsy and neurodevelopmental abnormalities are the only complications reported in children with isolated parenchymal melanosis. A minority of patients experience drug-resistant epilepsy, and up to now, no predictors of epilepsy prognosis have been identified. METHODS: In this systematic review, according to preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, we aggregated clinical cases of patients with isolated parenchymal melanosis affected by epilepsy, in order to recognize predictors of clinical outcome and to clarify indications of available therapeutic approaches. RESULTS: Sixteen articles (19 patients) were included in the final analysis from initial database research; 4 articles (4 patients) were selected from reference lists and 1 from conference abstracts (1 patient). In our series, distribution of parenchymal melanosis was the best predictor of epilepsy outcome: frequencies of seizure-free patients were different between cases of isolated/bilateral amygdale melanosis and those of multiple localizations (p = 0.037). Failure of antiepileptic drugs (AEDs) and/or surgical epilepsy therapy were associated with poor cognitive outcome (p = 0.03). CONCLUSION: Antiepileptic drugs were effective in the majority of patients with epilepsy with parenchymal melanosis. In case of multifocal distribution, more than one-third of patients presented a drug-resistant epilepsy. Epilepsy surgery is the best choice in patients with isolated amygdala localization. We propose the recognition of a multifactorial nature of cognitive impairment in neuromelanosis, emphasizing the role of drug-resistant epilepsy.