322 - A Novel Pathogenic Variant of G6PC3 Gene Presenting as Cyclic Neutropenia in a Pediatric Patient

Poster Number: 322
Publication Number: 322.113

Christian M. Bruni, The Children's Regional Hospital at Cooper, Camden, NJ, United States; WENDY DE LA RUA, The Children's Regional Hospital at Cooper, CHERRY HILL, NJ, United States; Sara Sadre, Cooper Medical School of Rowan University, Philadelphia, PA, United States; Jennifer Nestor, The Children's Regional Hospital at Cooper, Philadelphia, PA, United States; Maria Irene Scarano, Cooper Medical School of Rowan University, Camden, NJ, United States; Julie D. Kaplan, Cleveland Clinic, Cleveland, OH, United States; Rafat Ahmed, Cooper Medical School of Rowan University, Camden, NJ, United States

Background: Cyclic neutropenia is a rare hematologic disorder affecting neutrophils.  It is classified by recurrent neutropenia with associated symptoms including fever and malaise, as well as recurrent mucosal infections and skin infections. Pathogenic variants of ELANE- gene that encodes neutrophil elastase, are thought to cause these findings, however, other pathogenic variants of different genes have also been reported.  The estimated frequency of cyclic neutropenia is 1:106 in the general population. It is most commonly diagnosed in children and there is no known increased prevalence in women as compared to men. Whole Exome Sequencing can be used for diagnosis when genetic concerns are present.

Objective: This case report aims to describe a novel pathogenic variant in a pediatric patient with cyclic neutropenia. 

Design/Methods: Single subject case report 

Results: This is a single case report of a 7-year-old female with past medical history of cyclic neutropenia, anemia, recurrent infections, and learning difficulty. The patient initially presented at age 1 with high fevers and skin infections and was found to have decreased neutrophil counts. Bone marrow aspirate and biopsy performed at 1 and 7 years of age showed decreased neutrophil count with normal maturation and normal cytogenetics. Her peripheral blood for bone marrow failure evaluation was non-contributory.  With her severe persistent neutropenia, normal bone marrow findings, and need for weekly chronic G-CSF administration; whole exome sequencing was evaluated.  Results of which showed a novel compound heterozygous pattern for two variant copies of the G6PC3 gene, with our patient inheriting a copy from each parent.Conclusion(s): The G6PC3 gene encodes the expressed glucose-6-phosphate enzyme which catalyzes the final step in glycogenolysis. It is hypothesized that this deficiency causes unregulated levels of glucose, resulting in increased stress of the endoplasmic reticulum leading to apoptosis of neutrophils. Pathogenic variants of G6PC3 cause autosomal recessive G6PC3 deficiency and this can be clinically characterized as severe congenital neutropenia. Classic G6PC3 deficiency includes severe congenital neutropenia as well as cardiovascular, urogenital abnormalities, and pulmonary hypertension. This novel pathogenic variant is likely responsible for the cyclic neutropenia observed in our patient. Of note, our patient has learning difficulties, which have been noted in other etiologies of neutropenia. Whole Exome Sequencing is a cost-effective method for diagnosis and a valuable tool in evaluation and management of complex hematological disorders.