autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency is a disorder primarily affecting blood cell production and multiple organ systems. The condition is caused by pathogenic variants in the G6PC3 gene, which compromise the normal development and function of neutrophils. It is characterized by an abnormally low neutrophil count and a range of additional clinical findings, with manifestations appearing in early childhood. Given its very rare occurrence, affecting fewer than 1 in 1,000,000 people, outcomes and presentations can vary considerably among affected individuals.

The clinical presentation of this condition is heterogeneous. A hallmark finding is a persistently decreased total neutrophil count, which is always present and forms the basis for the diagnosis. Many affected individuals may also experience intermittent thrombocytopenia, features of cardiac involvement such as secundum atrial septal defect, and an increased predisposition to neonatal sepsis as well as recurrent infections including urinary tract and respiratory tract infections. Additional findings, reported in a subset of patients, include prominent superficial veins, global developmental delay, microcephaly, sensorineural hearing impairment, and other structural abnormalities such as mitral regurgitation and patent ductus arteriosus. Not all individuals experience all features, and severity varies considerably.

This condition is caused by pathogenic variants in the G6PC3 gene, which plays a crucial role in neutrophil development and function. It follows an autosomal recessive inheritance pattern, meaning that an affected individual inherits two altered copies of the gene, one from each parent. The condition is more common when parents share a common ancestor, a situation that increases the likelihood that both parents carry the same rare variant. Due to variable expressivity, even among individuals with the same genetic changes, the severity and range of symptoms can differ significantly. Genetic counseling is recommended for families to understand the implications for family planning.

Currently, management focuses on supportive care and symptom management, with treatment tailored to the individual’s specific clinical presentation. As no foundational or FDA-approved treatments are linked to this condition, care typically involves a multidisciplinary team to address chronic infection prevention and the management of complications such as cardiac or developmental concerns. Regular surveillance is an essential part of long-term care, helping to identify potential complications early. Genetic counseling is recommended, and patients should discuss treatment options with their healthcare team to determine which therapies and supportive interventions may be most appropriate.

The course of autosomal recessive severe congenital neutropenia due to G6PC3 deficiency is variable, with outcomes depending on the severity of infections, cardiac involvement, and other associated features. With current standards of supportive care and ongoing monitoring, many individuals can manage their symptoms effectively, and quality of life has improved over the past two decades. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with this condition and benefit from genetic counseling to discuss future family planning options.

Clinical trials are underway exploring new treatment approaches for this condition. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team regarding eligibility.