Severe Congenital Neutropenia Due To G6PC3 Deficiency Case Series of Five Patients and Literature Review

Abstract

Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern, and cardiovascular and urogenital malformations, caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. We describe five new cases from Mexico, and review 89 more patients reported in the past decade, to delineate the most frequent laboratory and genetic features, their treatment, and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in these patients.

Severe congenital neutropenia type 4: a rare disease harboring a <i>G6pc3</i> gene pathogenic variant particular to the mexican population

“…In our group of patients, IVSV was a relatively common finding. Although patient four did not show this anomaly, veins may probably become more prominent with age 5 , being this finding present in two-thirds of patients 16 .…”

“…Furthermore, our patients (Table 1) fulfilled the criteria for SCN and cyclic neutropenia, as all showed variable degrees of severe neutropenia associated with periods of remission and affected platelet and lymphocytes cell lines. Regarding non-hematological abnormalities, congenital heart defects were the most frequent, as others have noticed 16,19 . We found that in all positive cases presented with ASD, these defects usually occurred as soft murmurs or were asymptomatic for a long time, making them a common undiagnosed abnormality 20 .…”

“…Although our patients denied inter-family relationships, the family residences of patients 1, 2, and 3 are within a 35 km distance, which makes it possible that these families share a common ancestor, also supported by the fact that two of the families share an uncommon surname. In another study of Mexican patients, Velez-Tirado et al reported 5 patients carrying this variant; 3 of them were homozygotes, and although they denied consanguinity, the authors mentioned that they might come from geographically close communities 16 . Our findings and the above reports strongly support that the c.210delC variant is particular to the Mexican population and sheds light on a possible founder effect 5,[16][17][18] .…”

“…In another study of Mexican patients, Velez-Tirado et al reported 5 patients carrying this variant; 3 of them were homozygotes, and although they denied consanguinity, the authors mentioned that they might come from geographically close communities 16 . Our findings and the above reports strongly support that the c.210delC variant is particular to the Mexican population and sheds light on a possible founder effect 5,[16][17][18] .…”

“…Patient 1 had a rare splice donor site variant (c.199_218+1del), which has only once been submitted to the ClinVar database (ID: 691994), in a patient with pulmonary arterial hypertension, leukopenia, and an ASD, probably having SCN4, although not specified in the report 15 . The c.210delC variant has been well characterized as pathogenic and has only been described in patients of Hispanic descent 5,16 . Interestingly, 31 heterozygous carriers for the c.210delC variant are reported in the gnomeAD database, all in Latino/Admixed Americans 17 ; in addition, 395 alleles were identified in 92,041 individuals (184,082 alleles) of Native Mexican ancestry, with a prevalence of 0.00215 in the Mexico City Prospective Study (MCPS) database 18 .…”