G6PC3 Deficiency

CLINICAL CHARACTERISTICS

G6PC3 deficiency is characterized by severe congenital neutropenia which occurs in a phenotypic continuum that includes the following: Isolated severe congenital neutropenia (nonsyndromic). Classic G6PC3 deficiency (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities). Severe G6PC3 deficiency (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines, additional extra-hematologic features, and pulmonary hypertension; known as Dursun syndrome). Neutropenia usually presents with recurrent bacterial infections in the first few months of life. Intrauterine growth restriction (IUGR), failure to thrive (FTT), and poor postnatal growth are common. Other findings in classic and severe G6PC3 deficiency can include inflammatory bowel disease (IBD) resembling Crohn disease, and endocrine disorders (growth hormone deficiency, hypogonadotropic hypogonadism, and delayed puberty).

DIAGNOSIS/TESTING: The diagnosis of G6PC3 deficiency is established in a proband with severe congenital neutropenia and biallelic (homozygous or compound heterozygous) pathogenic variants on molecular genetic testing.

MANAGEMENT

Treatment with granulocyte colony stimulating factor (G-CSF) that maintains absolute neutrophil counts above 0.5x10/L reduces the number of infections and improves the quality of life. A few mildly affected individuals have been reported to be adequately managed with prophylactic antibiotics alone. Fevers and infections require prompt treatment with antibiotics. Routine management of congenital heart disease, renal and urinary tract malformations, and hormone deficiencies as needed. Good dental hygiene, including careful brushing and flossing and regular visits to the dentist, helps decrease the potential for infection. Prophylactic antibiotics should be considered in those with uncorrected neutropenia undergoing dental procedures, especially in those with heart defects at increased risk for subacute bacterial endocarditis. Frequent follow up by a hematologist or immunologist to monitor infection frequency and neutrophil counts to ensure an adequate response to G-CSF. Monitor growth in children, pubertal development in adolescents, and development of varicose veins, especially in adults. Monitoring for osteopenia/osteoporosis. It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early diagnosis and management of the hematologic, cardiac, renal, and endocrine abnormalities of G6PC3 deficiency. The genetic status of at-risk sibs can be clarified by molecular genetic testing (if the pathogenic variants in the family are known) or by clinical findings.

GENETIC COUNSELING

G6PC3 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants have been identified in the family.