Pseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant electrolyte disorder characterized by hypertension, hyperkalemia, metabolic acidosis, and suppressed renin activity, usually with preserved renal function. Pathogenic variants in WNK1, WNK4, KLHL3, and CUL3 have been identified, with CUL3 mutations particularly associated with early-onset and severe phenotypes. Thiazide diuretics are effective in correcting both electrolyte imbalance and hypertension. We report a pediatric patient with early-onset PHA2 caused by a de novo splice-site variant (c.1207-2A>C) in the CUL3 gene. The patient, first evaluated at 2 years and 7 months of age for recurrent vomiting, was found to have hyponatremia, hyperkalemia, and metabolic acidosis, initially treated with fludrocortisone. On referral, significant hypertension, hyperkalemia, and suppressed renin and aldosterone were observed. Initiation of low-dose thiazide therapy led to normalization of blood pressure and electrolytes. Long-term follow-up confirmed clinical stability, normal growth, and appropriate developmental milestones. Aldosterone pathway defects may be misdiagnosed during the initial clinical assessment. This underscores the importance of a comprehensive diagnostic approach incorporating biochemical profiling and genetic testing to ensure accurate identification. Next-generation sequencing has emerged as a valuable tool for establishing a definitive diagnosis, particularly in cases with aldosterone defects. Timely and accurate diagnosis of PHA2 is critical, as persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments in pediatric patients. Despite the potential severity of clinical manifestations associated with CUL3-related PHA2, it is noteworthy that treatment with thiazide diuretics alone can effectively restore electrolyte balance and support normal growth and development.

Lenticulostriate vasculopathy (LSV) refers to hyperechogenic vessels detected in thalami and basal ganglia, using cranial ultrasound. Awareness of LSV has revealed its links to various neonatal diseases that can affect brain development ante- or postnatally. Congenital infections and hypoxic- ischemic conditions are the main risk factors of LSV. However, precise etiology of LSV remains unknown. The aim of this study was to analyze the whole genome sequencing (WGS) data of newborns diagnosed with LSV to evaluate genetic linkages with LSV manifestation. We analyzed whole genome sequencing variation data of newborns with LSV (n = 6) and control group newborns (n = 19). WGS variation data was annotated using ANNOVAR in GRCh37 (hg19), RefSeqGene, gnomAD, SIFT, dbSNP151, CADD and gerp++gt2. Bash language was used to develop a program that counts variant frequency and compares them between groups. We identified one exonic nonsynonymous variant putatively associated with LSV, located in WNK1 gene [NM_213655.5: c.2219T > C p.(Leu740Pro)]. This variant is associated with pseudohypoaldosteronism type 2C and hereditary sensory and autonomic neuropathy type 2A. Pseudohypoaldosteronism can increase blood pressure, resulting in damaged or stiff blood vessels, similar to LSV. The variant is currently classified as a variant of uncertain significance due to insufficient evidence to determine its definitive role in these conditions. The identification of this unique variant in WNK1 provides a potential genetic link to the etiopathogenesis of LSV, offering new insights into this condition. However, further functional studies and more comprehensive genetic research are required to establish definitive associations.

CUL3-related neurodevelopmental disorder is a recently described rare genetic condition characterized by global developmental delay and intellectual disability. Five affected individuals have been reported worldwide. The molecular and phenotypic spectrum of the disorder has yet to be fully elucidated. Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder. We report the first individual with a neurodevelopmental disorder attributed to a CUL3 splice site variant. The patient presented with congenital developmental dysplasia of the hip and global developmental delay. A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site. This is the first report of an individual with a splice site variant causing CUL3-related neurodevelopmental disorder and expands our understanding of this rare condition.

The with no lysine (WNK) protein kinase family is conserved among many species. Some mutations in human WNK gene are associated with pseudohypoaldosteronism type II, a form of hypertension, and hereditary sensory and autonomic neuropathy type 2A. In kidney, WNK regulates the activity of STE20/SPS1-related, proline alanine-rich kinase and/or oxidative-stress responsive 1, which in turn regulate ion co-transporters. The misregulation of this pathway is involved in the pathogenesis of pseudohypoaldosteronism type II. In the neural system, WNK is involved in the specification of the cholinergic neuron, but the pathogenesis of hereditary sensory and autonomic neuropathy type 2A is still unknown. To better understand the WNK pathway, we isolated WNK-associated genes using Drosophila. We identified Glycogen synthase kinase 3ß (GSK3ß)/Shaggy (Sgg) as a candidate gene that was shown to interact with the WNK signaling pathway in both Drosophila and mammalian cells. Furthermore, GSK3ß was involved in neural specification downstream of WNK. These results suggest that GSK3ß/Sgg functions as a positive effector in the WNK signaling pathway.