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

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• 作者：Kaan Boztug ; MD¹ ; ² ; ³ ; ^{kboztug@cemm.oeaw.ac.at} ; Philip S. Rosenberg ; PhD⁵ ; Marie Dorda³ ; Siddharth Banka ; MD⁷ ; Thomas Moulton⁸ ; Julie Curtin ; PhD⁹ ; Nima Rezaei ; MD¹⁰ ; ¹¹ ; John Corns ; DO¹³ ; Jeffrey W. Innis ; MD ; PhD¹⁴ ; Zekai Avci ; MD¹⁶ ; Hung Chi Tran ; MD¹⁷ ; Isabelle Pellier ; MD¹⁸ ; Paolo Pierani ; MD¹⁹ ; Rachel Fruge²⁰ ; Nima Parvaneh ; MD¹¹ ; Setareh Mamishi ; MD¹² ; Rajen Mody ; MD¹⁵ ; Phil Darbyshire ; MD²² ; Jayashree Motwani ; MD²² ; Jennie Murray²³ ; George R. Buchanan ; MD²¹ ; William G. Newman ; MD ; PhD⁷ ; Blanche P. Alter ; MD ; MPH⁶ ; Laurence A. Boxer ; MD¹⁵ ; Jean Donadieu ; MD ; PhD²⁴ ; Karl Welte ; MD⁴ ; Christoph Klein ; MD ; PhD³ ; ²⁵
• 关键词：AML ; Acute myeloid leukemia ; CN ; Congenital neutropenia ; ELANE ; Neutrophil elastase ; G6PC3 ; Glucose-6-phosphatase catalytic subunit 3 ; HAX1 ; HS1-associated protein X1 ; HSCT ; Hematopoietic stem cell transplantation ; MDS ; Myelodysplastic syndrome ; SCN ; Seve
• 刊名：The Journal of Pediatrics
• 出版年：2012
• 出版时间：April, 2012
• 年：2012
• 卷：160
• 期：4
• 页码：679-683.e2
• 全文大小：318 K

文摘

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Objective

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).

Study design

Patients with syndromic SCN were characterized for associated malformations and referred to us for G6PC3 mutational analysis.

Results

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.

Conclusions

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.