G6pc3 Deficiency

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2021-01-18
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Summary

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's 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) G6PC3 pathogenic variants on molecular genetic testing.

Management.

Treatment of manifestations: Treatment with granulocyte colony stimulating factor (G-CSF) that maintains absolute neutrophil counts above 0.5x109/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.

Prevention of secondary complications: 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.

Surveillance: 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.

Evaluation of relatives at risk: 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 G6PC3 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 pregnancies at increased risk are possible if the G6PC3 pathogenic variants have been identified in the family.

Diagnosis

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 [Boztug et al 2009], subsequent reports identified bone marrows that were hypercellular [McDermott et al 2010] and normocellular [Banka et al 2011b]. More recently, sequential bone marrow examinations have typically revealed normal maturation and only rarely arrested maturation [Desplantes et al 2014].
  • A family history consistent with autosomal recessive inheritance [Banka & Newman 2013]

To date all individuals with G6PC3 deficiency have had severe congenital neutropenia; the phenotypic spectrum is a continuum that ranges from nonsyndromic (isolated severe congenital neutropenia) to classic (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities) to severe (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines and additional extra-hematologic features).

Nonsyndromic G6PC3 deficiency includes only hematologic findings –predominantly severe congenital neutropenia [Smith et al 2012, Banka et al 2013].

Classic G6PC3 deficiency (known as severe congenital neutropenia type 4) includes severe congenital neutropenia as well as additional features [Boztug et al 2009, Banka et al 2011a, Boztug et al 2012]:

  • Other hematologic abnormalities: intermittent thrombocytopenia (66%)
  • Cardiovascular defects
    • Congenital heart defects (~77%) (see Clinical Description)
    • Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
  • Urogenital defects (44%), especially in males in whom cryptorchidism is the most common anomaly

Severe G6PC3 deficiency (Dursun syndrome) comprises the findings of classic G6PC3 deficiency as well as additional features:

  • Primary pulmonary hypertension (PPH) developing in the newborn period
  • Non-myeloid cell involvement: severe lymphopenia
  • Thymic hypoplasia

Establishing the Diagnosis

The diagnosis of G6PC3 deficiency is established in a proband with severe congenital neutropenia and identification of biallelic (homozygous or compound heterozygous) G6PC3 pathogenic variants on molecular genetic testing (see Table 1). Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of G6PC3 followed by consideration of deletion/duplication analysis if only one or no pathogenic variant is found. It should be noted that to date no exon or whole-gene deletions/duplications have been reported.
  • A multigene panel that includes G6PC3 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multigene panels vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of G6PC3 deficiency. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in G6PC3 Deficiency

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
G6PC3Sequence analysis 316/31 (43%) 4, 5
Gene-targeted deletion/duplication analysis 6None reported
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

An estimate based on a single nonsystematic study in which Boztug et al [2012] sequenced G6PC3 in individuals with syndromic forms of congenital neutropenia.

5.

To date more than 91 individuals with molecularly confirmed G6PC3 deficiency have been reported [Alangari et al 2013, Banka & Newman 2013, Estévez et al 2013, Racek et al 2013, Desplantes et al 2014, Kaya et al 2014, Notarangelo et al 2014, Ozgül et al 2014, Tavil et al 2014, Yeshayahu et al 2014, Arikoglu et al 2015, Lebel et al 2015].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

G6PC3 deficiency is highly variable in its severity and associated clinical features. Individuals with "nonsyndromic" disease have only severe congenital neutropenia. The majority of persons with G6PC3 deficiency have cardiovascular and/or urogenital features (so-called classic G6PC3 deficiency). Of those with classic disease, a subset is more severely affected (so-called Dursun syndrome), because of the additional involvement of myeloid cells, primary pulmonary hypertension developing in the newborn period, and minor dysmorphic features.

While it is estimated that nearly 10% of G6CP3 deficiency is the nonsyndromic form, this could be an underestimate due to ascertainment bias (i.e., selection of more severe phenotypes for testing of G6PC3 in previous studies) [Banka & Newman 2013]. It is also possible that some patients who initially present with the nonsyndromic form may develop features of the classic form in later life [Notarangelo et al 2014].

G6PC3 deficiency usually presents in the first few months of life with recurrent bacterial infections. A range of bacterial infections have been reported [Desplantes et al 2014]; respiratory tract infections, otitis media, stomatitis, urinary tract infections, pyelonephritis, skin abscesses, cellulitis, and sepsis are particularly common. The first serious infection can occur at any age, ranging from immediately after birth to adulthood.

Hematologic. Persistent severe neutropenia is present in all affected individuals and is the core phenotype of the condition.

Intermittent thrombocytopenia is seen frequently but usually does not cause symptoms.

Lymphopenia associated with hypoplasia of the thymus can be seen in more severely affected individuals [Dursun et al 2009, Banka et al 2010, Ozgül et al 2014].

Cardiovascular. Congenital heart defects are common. In their recent review, Banka & Newman [2013] found that 44 (77%) of 57 of individuals with G6PC3 deficiency described in the literature had congenital cardiac defects. By far the most common anomaly was atrial septal defect. Other rare heart anomalies include patent foramen ovale; cor triatriatum; patent ductus arteriosus; critical pulmonary stenosis and hypoplastic left ventricle; mitral valve prolapse, insufficiency, and/ or regurgitation; tricuspid insufficiency; and bicuspid aortic and pulmonary valves.

A prominent superficial venous pattern begins to emerge between late infancy and early childhood in most affected children [Banka et al 2011a]. This pattern can be seen on the trunk, extremities, and sometimes on the head. Experience with adults is limited but older patients have a tendency to develop varicose veins and venous ulcers.

In Dursun syndrome early-onset primary pulmonary hypertension can be difficult to control [Dursun et al 2009]. In a few individuals primary pulmonary hypertension may be detected later in life [McDermott et al 2010, Fernandez et al 2012].

Urogenital anomalies are more common in males than females [Banka & Newman 2013]. In males the most common feature is cryptorchidism.

Hydronephrosis, poor renal cortico-medullary differentiation, small kidneys, and vesico-uretric reflux are observed in some patients. Other features include inguinal hernia, ambiguous genitalia in undervirilized males, and urachal fistula.

Inflammatory bowel disease (IBD) resembling Crohn's disease has been described in a few individuals [Cullinane et al 2011, Fernandez et al 2012, Smith et al 2012, Bégin et al 2013, Desplantes et al 2014, Kaya et al 2014]. Treatment that improves neutrophil counts can also help resolve the bowel disease [Kaya et al 2014].

Endocrine. Growth hormone deficiency has been described in two affected individuals [Boztug et al 2012].

Hypogonadotropic hypogonadism and delayed puberty have been reported in both males and females [Germeshausen et al 2010, Banka et al 2011a, Boztug et al 2012, Aytekin et al 2013]. One male, who had no detectable gonadal structures in the scrotum, inguinal canals, or abdomen, had a low testosterone level (unresponsive to HCG stimulation) and extremely high LH and FSH levels [Yeshayahu et al 2014].

Hypothyroidism has been reported in three individuals [Banka et al 2011a, Desplantes et al 2014].

Growth. Intrauterine growth restriction (IUGR), failure to thrive (FTT), and poor postnatal growth are common. The basis of growth problems is not known. It could be secondary to repeated infections or part of the primary phenotype of G6PC3 deficiency.

Other findings

  • Minor dysmorphic features in some young children, such as a triangular face, depressed nasal bridge, thick lips, and prognathism [Dursun et al 2009, Banka et al 2011a, Boztug et al 2012, Desplantes et al 2014]
  • Neurodevelopmental involvement:
    • Mild learning difficulties were initially described in four affected individuals from a single family [Banka et al 2011a], although it was not clear whether the findings were attributable to G6PC3 deficiency.
    • Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in G6CP3. Notably, one was said to have major developmental problems with bilateral atrophy on MRI [Desplantes et al 2014].
  • Skeletal involvement, such as scoliosis and pectus carinatum [Dursun et al 2009, Boztug et al 2012]
  • Cutis laxa, described in at least seven patients [Boztug et al 2012, Desplantes et al 2014]
  • Microcephaly [Boztug et al 2009, Germeshausen et al 2010, McDermott et al 2010], which could be an effect of overall poor growth
  • Myopathy:
    • One patient with a single episode of myositis [Smith et al 2012]
    • One sib pair with proximal muscle weakness [McDermott et al 2010], one of whom developed at age 2.5 years recurrent episodes of proximal muscle pain and cramps; muscle histology suggested glycogen accumulation.
    • Two individuals reported with nonspecific myopathy but no clinical details [Boztug et al 2009, Desplantes et al 2014]

Rarer features (some of which could be coincidental associations)

  • Myelodysplasia followed by acute myelogeneous leukemia with translocation (18, 21) (with no exposure to G-CSF) reported in one affected individual age 14 years [Desplantes et al 2014]
  • Mild to moderate bilateral sensorineural hearing loss which may be asymptomatic and is sometimes only detected on audiometry [McDermott et al 2010, Gatti et al 2011, Boztug et al 2012, Desplantes et al 2014]. The age of onset is not clear from the published reports.
  • Congenital ptosis [Boztug et al 2012]
  • Cleft palate [Boztug et al 2009] and Pierre Robin sequence [Desplantes et al 2014].
  • Low HDL serum levels and persistently increased amylase activity described in one individual [Banka et al 2011a]

Disease course. When neutropenia is treated (see Management), most patients have a good prognosis with reduced rate and severity of infections.

If neutropenia is untreated, G6PC3 deficiency can lead to death in early childhood from infections [Alizadeh et al 2011] or severe respiratory distress [Dursun et al 2009]. One adult who was noncompliant with treatment died at age 37 years of bacterial endocarditis [Fernandez et al 2012].

Four deaths in the 14 individuals in the French Severe Congenital Neutropenia Registry were reported: one at age five years with sepsis, one at age 19 years from pulmonary insufficiency, and two from sudden death of unknown cause during sleep at age 30 years.

Genotype-Phenotype Correlations

No obvious genotype-phenotype correlations explain the difference between the marked cellularity of myeloid cells in the bone marrow of patients with G6PC3 deficiency [Banka et al 2011b].

Based on limited data certain pathogenic variants (e.g., p.Phe44Ser) appear to be more often (or only) associated with nonsyndromic neutropenia [Banka et al 2013].

Prevalence

To date more than 91 individuals with the molecularly proven diagnosis of G6PC3 deficiency have been reported [Alangari et al 2013, Banka & Newman 2013, Estévez et al 2013, Racek et al 2013, Desplantes et al 2014, Kaya et al 2014, Notarangelo et al 2014, Ozgül et al 2014, Tavil et al 2014, Yeshayahu et al 2014, Arikoglu et al 2015, Lebel et al 2015].

The prevalence is likely to vary significantly from population to population based on the presence of founder variants in certain populations [Smith et al 2012, Banka & Newman 2013] and cultural practices such as consanguinity. For example, G6PC3 deficiency was found to be the most common cause of severe congenital neutropenia in Israel, accounting for the diagnosis in 25% of patients [Lebel et al 2015].

The French Neutropenia Registry has estimated incidence at birth at 0.4:1,000,000 [Desplantes et al 2014].

Differential Diagnosis

Severe congenital neutropenia is genetically heterogeneous [Klein 2009, Donadieu et al 2011, Klein 2011]. 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 [Dale et al 2000]. Mutation of ELANE also causes cyclic neutropenia, a less severe disorder.

Severe congenital neutropenia type 2 (SCN2) (OMIM 613107), an autosomal dominant disorder caused by mutation of GFI1, is characterized by an increased susceptibility to bacterial infections [Person et al 2003]. Mutation of GFI1 also causes chronic non-autoimmune neutropenia which manifests as monocytosis in adults.

Kostmann disease (severe congenital neutropenia type 3) (OMIM 610738), an autosomal recessive disorder caused by mutation of HAX1, is characterized by neutropenia, maturation arrest of the promyelocyte or myelocyte stage with or without seizures, and developmental delay [Klein et al 2007].

Severe congenital neutropenia type 5 (SCN5) (OMIM 615285), an autosomal recessive disorder caused by mutation of VPS45, is characterized by neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly resulting from renal extramedullary hematopoiesis [Vilboux et al 2013].

Severe congenital neutropenia, X-linked (XLN), caused by mutation of WAS, is characterized in males by recurrent bacterial infections, persistent neutropenia, and arrested development of the bone marrow at the promyelocyte/myelocyte stage in the absence of other clinical findings of Wiskott-Aldrich syndrome.

JAGN1-related severe congenital neutropenia (severe congenital neutropenia type 6) (OMIM 616022), an autosomal recessive disorder, is characterized by severe congenital neutropenia, increased susceptibility to bacterial infections, maturation arrest at the promyelocyte/myelocyte stage in the bone marrow, and poor response to treatment with human granulocyte colony-stimulating factor (rhG-CSF) [Boztug et al 2014]. Occasionally abnormalities are observed in bone, pancreas, and/or teeth.

Inherited conditions in which neutropenia may be part of a multisystem disorder

  • Barth syndrome
  • Cartilage-hair hypoplasia
  • Charcot-Marie-Tooth disease caused by mutation of DNM2 (OMIM 606482)
  • Chediak-Higashi syndrome
  • Clericuzio poikiloderma with neutropenia
  • Cohen syndrome
  • Glycogen storage disease type 1b
  • Griscelli syndrome type 2 (OMIM 607624)
  • Hermansky-Pudlak syndrome type 2
  • Immunodeficiency due to defect in MAPBP-interacting protein (P14 deficiency) (OMIM 610798)
  • Pearson syndrome
  • Shwachman-Diamond syndrome
  • WHIM syndrome (OMIM 193670)
  • Wiskott-Aldrich syndrome

Management

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 [Boztug et al 2009, McDermott et al 2010, Boztug et al 2012]. Of note, the dose required to keep absolute neutrophil counts above 0.5x109/L can vary greatly among patients. In some patients G-CSF -- even in large doses -- may fail to control infections [Smith et al 2012].

A few mildly affected individuals have been reported to be adequately managed with prophylactic antibiotics alone [Banka et al 2013]. However, prophylactic antibiotics have a limited use for preventing severe infections or bronchiectasis and inflammatory bowel disease.

Fevers and infections require prompt treatment with antibiotics.

Other

Prevention of Secondary Complications

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 with dental procedures, including routine dental repair and cleaning, especially in individuals with heart defects.

Surveillance

The following are appropriate:

  • Routine management of congenital heart disease, renal and urinary tract malformations
  • Routine management of hormone deficiencies
  • Consideration of oral steroids for inflammatory bowel disease [Desplantes et al 2014] or anti-TNF treatment [Bégin et al 2013]. Some complications of IBD such as bowel stenosis may require appropriate surgical intervention.
  • Consideration of pancreatic enzyme supplementation if steatorrhea is present [Desplantes et al 2014]
  • Chemotherapy and hematopoietic stem cell transplantation for acute myelogeneous leukemia
  • 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
  • If the G6PC3 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the G6PC3 pathogenic variants in the family are not known, the following evaluations can be used to help clarify the disease status of at-risk sibs: full blood count, bone marrow examination (if persistent severe neutropenia is detected on full blood count), directed general examination for prominence of superficial veins, echocardiogram, and a renal and pelvic ultrasound examination.

Evaluation of Relatives at Risk

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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.