Extended Spectrum of Human Glucose-6-Phosphatase Catalytic Subunit 3 Deficiency: Novel Genotypes and Phenotypic Variability in Severe Congenital Neutropenia

• Published in: The Journal of pediatrics Vol. 160; no. 4; pp. 679 - 683.e2
• Main Authors: Boztug, Kaan, Rosenberg, Philip S., Dorda, Marie, Banka, Siddharth, Moulton, Thomas, Curtin, Julie, Rezaei, Nima, Corns, John, Innis, Jeffrey W., Avci, Zekai, Tran, Hung Chi, Pellier, Isabelle, Pierani, Paolo, Fruge, Rachel, Parvaneh, Nima, Mamishi, Setareh, Mody, Rajen, Darbyshire, Phil, Motwani, Jayashree, Murray, Jennie, Buchanan, George R., Newman, William G., Alter, Blanche P., Boxer, Laurence A., Donadieu, Jean, Welte, Karl, Klein, Christoph
• Format: Journal Article
• Language: English
• Published: Maryland Heights, MO Mosby, Inc 01.04.2012; Elsevier
• Subjects: abnormal development; Adolescent; Biological and medical sciences; Child; congenital; Female; General aspects; genes; genetic variation; genetics; Genotype; glucose-6-phosphatase; Glucose-6-Phosphatase - genetics; Glycogen Storage Disease Type I; Glycogen Storage Disease Type I - genetics; Humans; Infant; integument; Male; Medical sciences; mutation; myeloid leukemia; neutropenia; Neutropenia - congenital; Neutropenia - genetics; patients; Pediatrics; Phenotype; phenotypic variation; protein subunits; risk; somatotropin; AML; G6PC3; HAX1; CN; HSCT; MDS; ELANE; SCN; Glucose-6-phosphatase catalytic subunit 3; HS1-associated protein X1; Myelodysplastic syndrome; Congenital neutropenia; Severe congenital neutropenia; Neutrophil elastase; Acute myeloid leukemia; Hematopoietic stem cell transplantation; Human; Catalytic subunit; Pediatrics; Typing; Enzyme; Deficiency; Phosphoric monoester hydrolases; Genotype; Esterases; Kostmann syndrome; Phenotype variation; Hydrolases; Activity spectrum; Glucose-6-phosphatase
• ISSN: 0022-3476; 1097-6833; 1097-6833
• DOI: 10.1016/j.jpeds.2011.09.019

To delineate the phenotypic and molecular spectrum of patients with a syndromic variant of severe congenital neutropenia (SCN) due to mutations in the gene encoding glucose-6-phosphatase catalytic subunit 3 (G6PC3). Patients with syndromic SCN were characterized for associated malformations and referred to us for G6PC3 mutational analysis. In a cohort of 31 patients with syndromic SCN, we identified 16 patients with G6PC3 deficiency including 11 patients with novel biallelic mutations. We show that nonhematologic features of G6PC3 deficiency are good predictive indicators for mutations in G6PC3. Additionally, we demonstrate genetic variability in this disease and define novel features such as growth hormone deficiency, genital malformations, disrupted bone remodeling, and abnormalities of the integument. G6PC3 mutations may be associated with hydronephrosis or facial dysmorphism. The risk of transition to myelodysplastic syndrome/acute myeloid leukemia may be lower than in other genetically defined SCN subgroups. The phenotypic and molecular spectrum in G6PC3 deficiency is wider than previously appreciated. The risk of transition to myelodysplastic syndrome or acute myeloid leukemia may be lower in G6PC3 deficiency compared with other subgroups of SCN.