Admixed phenotype of NEDD4L associated periventricular nodular heterotopia

Abstract

Rationale: Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene. Patient concerns: We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband's older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus . In addition, the patient suffered from many other symptoms. Diagnoses: The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband's genome that absented in any other analyzed family member, suggesting its de novo origin. Interventions and outcomes: The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus . Lessons: We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.

Genetic analysis of periventricular nodular heterotopia 7 caused by a novel NEDD4L missense mutation: Case and literature summary

“…After reviewing data from previously reported cases (Broix et al, 2016 ; Elbracht et al, 2018 ; Kato et al, 2017 ; Pecimonova et al, 2021 ; Stouffs et al, 2020 ), we observed that nearly all 15 patients (seven male, eight female) in the 11 reported families presented with psychomotor retardation, hypotonia, and variable degrees of syndactyly (usually second/third toe). Among them, 53% also exhibited cleft palate, while 46% experienced seizures.…”

“…After reviewing data from previously reported cases (Broix et al, 2016;Elbracht et al, 2018;Kato et al, 2017;Pecimonova et al, 2021;Stouffs et al, 2020), we observed that nearly all 15 patients (seven male, eight female) in the…”

“…Of the eight reported NEDD4L pathogenic variants, seven occur in the HECT domain, while only one occurs in the WW structure (Broix et al, 2016 ; Elbracht et al, 2018 ; Kato et al, 2017 ; Pecimonova et al, 2021 ; Stouffs et al, 2020 ). HECT is a bi‐lobed domain.…”

“…At present, only eight NEDD4L pathogenic variants have been identified across 15 cases of PVNH7 worldwide. Common manifestations in these patients have included psychomotor retardation, intellectual disability, and hypotonia, although some patients also exhibit cleft palate and seizures (Broix et al, 2016 ; Elbracht et al, 2018 ; Kato et al, 2017 ; Pecimonova et al, 2021 ; Stouffs et al, 2020 ).…”