Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry

Abstract

BackgroundThe purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry.MethodsAmong 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations.ResultsMedian age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn’s disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate. The bone marrow smears exhibited mild late-stage granulopoeitic defects. One patient developed myelodysplasia followed by acute myelogenous leukemia with translocation (18, 21) at age 14 years, cured by chemotherapy and hematopoietic stem cell transplantation. Four deaths occurred, including one from sepsis at age 5, one from pulmonary late-stage insufficiency at age 19, and two from sudden death, both at age 30 years. A new homozygous mutation (c.249G > A /p.Trp83*) was detected in one pedigree.ConclusionsSevere congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia.

A Severe Congenital Neutropenia Type 4 Case (G6PC3 Mutation) Presented With Large Platelets in the Peripheral Smear

“…20 In patients with G6PC3 mutation myelokatexis, dysplasia of granulocytes and megakaryocytes is also reported. 15,16,18 Our patient had no maturation arrest of myeloid lineage in the bone marrow. However, we found that he had single nucleated megakaryocytes, hypolobulation, and hypogranulation at mature neutrophils.…”

“…Intermittent thrombocytopenia is the another feature of G6PC3 mutation. 2,4,15,16 Our patient had mild thrombocytopenia at admission, and the thrombocytopenia improved within 24 hours. Although counts of thrombocytes were normal in range, his peripheral blood smear revealed giant platelets and his MPV was high, in accordance with large platelets on the peripheral smear of the patient's mother, and this finding continued for repeated examinations of blood smears.…”

“…It may be accompanied by maturation arrest of granulocytes at the promyelocyte/myelocyte stage. 2,4,15 In SCNs, dysplastic features of granulocytes can be seen. 20 In patients with G6PC3 mutation myelokatexis, dysplasia of granulocytes and megakaryocytes is also reported.…”

“…2,14 The bone marrow morphology of SCN4 may show myeloid hypoplasia/hyperplasia, granulocyte maturation arrest at the myelocyte/ promyelocyte stage, or no maturation arrest at granulocytes, myelokatexis, and dysplasia of granulocytes and megakaryocytes. 2,15,16 A definitive genotype-phenotype association of G6PC3 mutations has not been established yet.…”

New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

“…27 In 2010, McDermont et al 28 found that G6PC3 defects result in a neutrophil release defect rather than differentiation arrest; 4 years later, Desplantes et al proposed that defects in neutrophil release from the bone marrow might be due to ER stress and protein glycosylation. 29 …”