Clinical Guidance

No obvious genotype-phenotype correlations explain the difference between the marked cellularity of myeloid cells in the bone marrow of individuals with G6PC3 deficiency . Based on limited data, certain pathogenic variants (e.g., p.Phe44Ser) appear to be more often (or only) associated with nonsyndromic neutropenia .

Source: GeneReviews — "G6PC3 Deficiency"

Diagnostic Criteria

Consensus diagnostic criteria for G6PC3 deficiency have not been established.

Suggestive Findings

G6PC3 deficiency should be suspected in individuals with the following:

• Severe congenital neutropenia defined as an absolute neutrophil count 0.5 x 109/L which usually results in early-onset, frequent, severe bacterial infections

Note: Although maturation arrest of myeloid cells was initially thought to be the typical finding on bone marrow examination , subsequent reports identified bone marrows that were hypercellular and normocellular . More recently, sequential bone marrow examinations have typically revealed normal maturation and only rarely arrested maturation .

• A family history consistent with autosomal recessive inheritance

Source: GeneReviews — "G6PC3 Deficiency"

Differential Diagnosis

Severe congenital neutropenia is genetically heterogeneous . The differential diagnosis of G6PC3 deficiency can be divided into inherited conditions in which neutropenia predominates and those in which neutropenia may be a part of a multisystem disorder.

Inherited Conditions in which Neutropenia Predominates

Severe congenital neutropenia type 1 (SCN1), an autosomal dominant disorder caused by mutation of ELANE, is the most common genetic cause of congenital neutropenia. ELANE-related congenital neutropenia is characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy . Mutation of ELANE also causes cyclic neutropenia, a less severe disorder.

Source: GeneReviews — "G6PC3 Deficiency"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with G6PC3 deficiency, the following evaluations are recommended:

• Full blood count to look for evidence of other hematologic involvement (i.e., intermittent thrombocytopenia and/or lymphopenia)

• Immunologic evaluation for T-cell subsets in individuals with a more severe presentation and unusual non-bacterial infections

• Consultation with a cardiologist to evaluate for congenital heart disease

• Renal and pelvic ultrasound examination to look for urogenital malformations

• Growth parameters in children and pubertal development in adolescents

• Age appropriate endocrine assessment for evidence of the hormone deficiencies reported (i.e., growth hormone, gonadotropins, thyroid hormone)

• Biochemical investigations to look for abnormalities in the lipid profile

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Neutropenia. Treatment with granulocyte colony stimulating factor (G-CSF) improves neutrophil numbers, reduces the number of infections, and improves the quality of life . Of note, the dose required to keep absolute neutrophil counts above 0.5x109/L can vary greatly among affected individuals. In some individuals G-CSF – even in large doses – may fail to control infections . A few mildly affected individuals have been reported to be adequately managed with prophylactic antibiotics alone .

Source: GeneReviews — "G6PC3 Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "G6PC3 Deficiency"

Surveillance Guidelines

The following are appropriate:

• Frequent follow up by a hematologist or immunologist to monitor infection frequency and neutrophil counts to ensure an adequate response to G-CSF (i.e., absolute neutrophil counts above 0.5x109/L)

• Monitoring of growth in children and pubertal development in adolescents

• Biochemical profile including lipid profile

• Monitoring for development of varicose veins, especially in adults

• Monitoring for osteopenia/osteoporosis

Source: GeneReviews — "G6PC3 Deficiency"