Unveiling the pathogenic mechanisms of NPR2 missense variants: insights into the genotype-associated severity in acromesomelic dysplasia and short stature.

Introduction: Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established. Methods: In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity. Results and Discussion: Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.

Isolated tectal cavernomas: A comprehensive literature review with a case presentation.

Intracranial cavernous angiomas or cavernomas (ICCs) are abnormal blood-filled vasculatures made of mono-endothelial layer and characterized by their bubble-like caverns. Brainstem cavernomas (BSCs) is a critical form of ICCs since slight changes in the lesion can result in devastating or life-threatening outcomes. We hereby present a rare case of BSC developed in the mesencephalic tectum with intraventricular bleeding and Parinaud's Syndrome. Our patient was managed by complete surgical resection of the lesion through an infra-tentorial supracerebellar approach. Additionally, we reviewed and analyzed the hitherto reported cases of isolated tectal cavernomas (TCs) in the literature, including our case, to elucidate the main factors associated with the management outcomes of TCs. There have been 25 cases of isolated TC reported until now. Most of the patients were adults between 18-77 y of age, except for two children (7 and 13 y). There was no sex predominance. Symptomatic patients presented with headache 56%, altered level of consciousness 24%, and/or double vision 20%. Most cases (64%) had hemorrhagic lesions at presentation, and 60% of all cases experienced recurrent hemorrhages. Parinaud's Syndrome was recorded in five cases, including the current one. All cases affected with Parinaud's were males. Lesion size was a determinant of the outcome as larger lesions were more likely to result in persistent deficits. Surgical resection of the lesion was an effective management modality with ∼79% (15/19) of patients who underwent surgery ended up with complete recovery.