Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.2
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: G6PD
• Condition: Glucose-6-phosphate dehydrogenase deficiency
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• G6PD ⇔ 0005775 (g6pd deficiency): Moderate Actionability

Actionability Rationale

All experts agreed with upgrading the assertion from the generated assertion, due to long-standing management practices for those identified with G6PD deficiency and that follow-up studies after genotyping can assess severity. There is lack of evidence on the likelihood of severe complications. G6PD deficiency has the highest prevalence in populations traditionally underrepresented in research. Additional research into penetrance could be helpful to the field.

Final Consensus Scores

Gene Condition Pairs: G6PD ⇔ 0005775 (OMIM:305900)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality associated with hemolysis / Avoidance of substances that can induce hemolysis	1	0D	3D	3	7DD
Morbidity and mortality from perioperative complications related to hemolysis / Preoperative assessment of G6PD class to guide perioperative management	2	0D	2C	3	7DC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency, estimated to affect 400 million people worldwide. Estimated global prevalence of G6PD deficiency is 4.9%. G6PD deficiency most commonly affects individuals of African, Asian, Mediterranean, or Middle Eastern descent. In the United States, Black males are most commonly affected, with a prevalence of approximately 10%. In tropical areas, the prevalence of G6PD deficiency is typically 3-35%. Prevalence of G6PD deficiency is correlated with the geographic distribution of malaria which has led to the theory that carriers of G6PD may have protection against malarial infection. The prevalence of severe hemolytic anemia associated with G6PD deficiency is reported to be less than 1/1,000,000. Cases of sporadic (de novo) variants occur in all populations. [1, 2, 3, 4, 5, 6, 7]

Clinical Features

G6PD deficiency is an enzyme deficiency that results in damage to blood cells by oxidative stressors which causes a spectrum of disease including neonatal hyperbilirubinemia, acute hemolysis, and chronic hemolysis. Oxidative stressors include infection, oxidative drugs, metabolic conditions (diabetic ketoacidosis, metabolic acidosis), fava beans, lawsone (Henna), or stress related to surgical interventions. The most common clinical manifestations are neonatal jaundice and signs and symptoms of acute hemolysis (such as fatigue, back pain, anemia, and jaundice). Chronic hemolysis can be further exacerbated by oxidative stress and may lead to chronic non-spherocytic hemolytic anemia. Individuals may also be asymptomatic. [1, 2, 4, 5, 6, 7]

Natural History

Variation in G6PD levels account for differences in sensitivity to oxidants, with chronic hemolysis occurring in association with very low enzyme levels, while the majority of affected individuals remain asymptomatic. Variants in G6PD are grouped corresponding to disease severity:
• Class I variants have severe enzyme deficiency with chronic non-spherocytic hemolytic anemia (<10% residual enzyme activity)
• Class II variants also have severe enzyme deficiency (<10% residual enzyme activity) but with intermittent acute hemolysis
• Class III variants have moderate enzyme deficiency (10-60% residual enzyme activity) with intermittent acute hemolysis
• Class IV and V variants are of no clinical significance. Class IV has no enzyme deficiency and Class V has increased enzyme activity.
Severity of hemolysis is also impacted by other genetic factors, age of erythrocytes, type and dose of drug, and presence of other risk factors (e.g., infections). Sex can also impact severity given the X-linked nature of the condition; enzyme activity in females will vary based on X chromosome inactivation. Though it is typically more severe in individuals who are homozygous, individuals who are heterozygous can also be symptomatic. Chronic hemolysis is uncommon because it is related to sporadic variants rather than the more common inherited variants.
G6PD deficiency can be life threatening, though it is rarely fatal. Acute hemolysis typically occurs 24 to 72 hours after ingestion of oxidative compound, with resolution within four to seven days. In rare instances it can be severe enough to warrant a blood transfusion. In chronic non-spherocytic hemolytic anemia, hemolysis occurs during normal erythrocyte metabolism. In these cases, the severity of the hemolysis varies, causing mild hemolysis to transfusion-dependent anemia, and exposure to oxidative stress can cause acute hemolysis. Oxidative drugs ingested by an individual who is breastfeeding may be transmitted in breast milk and can cause acute hemolysis in a
child with G6PD deficiency. In certain populations, likely based on genetic variants common to certain ethnic groups, neonatal hyperbilirubinemia secondary to G6PD deficiency results in an increased rate of kernicterus and death. Individuals with G6PD deficiency due to certain variants (A-) are predisposed to the development of sepsis and complications related to sepsis after a severe injury. [1, 2, 4, 5, 6, 7]

2. How effective are interventions for preventing harm?

Patient Management

Patients should be informed about the signs and symptoms of hemolysis, which usually arises within 24 to 72 hours after exposure to the triggering agent. (Tier 3) [2]

Prior to surgery, it is recommended to check the class of G6PD deficiency by verification of enzyme defect to know degree of deficiency and disease manifestation. It is also recommended to assure the availability of cross matched blood products in the event of significant hemolysis, especially in patients with severe enzyme deficiency (class I and class II variants). (Tier 3) [2]

For surgery, patients should have priority on the surgical schedule to reduce preoperative stress response. Perioperative hyperglycemia should be treated aggressively. (Tier 4) [2]

For surgery, temperature should be monitored closely to avoid hypothermia and blood gases should be checked to detect acidosis and hyperglycemia, potential precipitating factors for hemolysis. Excreted urine should be monitored to detect hemoglobinuria as a sign of active hemolysis. (Tier 3) [2]

Surveillance

No surveillance recommendations have been provided for the Pediatric context.

Circumstances to Avoid

The main treatment for G6PD deficiency is avoidance of oxidative stressors which can induce hemolysis. Thus, patients with G6PD deficiency should avoid exposure to oxidative drugs (which includes certain anesthetics and antimalarials) and ingestion of fava beans. (Tier 3) [2, 6]

The standardized review process did not identify evidence to inform the impact of avoiding oxidative stressors, however, one study looked at lethality. A review article of clinical complications of G6PD deficiency in Latin America and Caribbean countries identified studies reporting acute hemolytic anemia. In 47 cases of primaquine-induced hemolysis (all male, median age 17 years, age range 8-57 years), there was a lethality rate of 4.3%. However, the lethality rate was 0% in 18 cases of hemolysis due to other substances (88.9% male, median age 16 years, age range 2-41 years), 9 cases of favism (all male, median age 11 years, age range 2-67 years), and 3 cases of infection-induced hemolysis (all male, median age 8 years, age range 2-50 years). (Tier 5) [8]

Patients with G6PD deficiency should also avoid exposure to drugs that induce methemoglobinemia. Methylene blue treatment for methemoglobinemia is ineffective in G6PD deficient patients and it may also lead to severe hemolysis due to its weak oxidizing ability. Therapy of methemoglobinemia in G6PD deficient patients consists of blood transfusions, hyperbaric oxygen therapy and urine alkalinization. (Tier 3) [2]

Primaquine, an antiparasitic mainly administered for prophylaxis and treatment of malaria, is contraindicated in pregnancy and lactation, unless the breastfed infant has been tested and is known not to be G6PD deficient. (Tier 2) [7]

Ambulatory anesthesia is not recommended for individuals with G6PD deficiency given the signs and symptoms of hemolysis usually arise within 24 to 72 hours after exposure to the triggering agent. (Tier 4) [2]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked [1, 2, 3, 4, 6, 7]

Prevalence of Genetic Variants

More than 400 variants have been identified, with most occurring sporadically. The G6PD Mediterranean and the G6PD A- variants occur with increased frequency in certain populations: G6PD Mediterranean variant in individuals of Italian, Grecian, Spanish, Arabic, Jewish (Kurdish) descent and the G6PD A- variant in individuals of African descent. (Tier 3) [6]

Class II variants are estimated to be present in 10% of Black males in the US. (Tier 3) [6]

A systematic review identified 20 studies that assessed G6PD status and performed meta-analyses using different approaches to estimate the global prevalence of G6PD deficiency. The total random effects estimate for the total global prevalence was 7.1% (95% CI: 6.7-7.4%). Limiting to only those studies that used DNA analysis, the prevalence estimate was 6% (95% CI: 5.4-6.6%). Lastly, summing all region-specific summary prevalence estimates provided a global estimate of 5%. The highest estimates were in sub-Saharan Africa and the Middle East. Importantly, analyses were not stratified by variant class which is associated with severity of the phenotype. (Tier 1) [5]

Penetrance

Even for individuals with G6PD deficiency and enzyme activity that is substantially reduced, there may be few or no clinical symptoms. (Tier 4) [6]

Although persons who experience hemolysis after the ingestion of fava beans can be presumed to have G6PD deficiency, not all of them will exhibit hemolysis. (Tier 3) [6]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Information on variable expressivity was not available for the Pediatric context.

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified for G6PD deficiency include avoiding exposure to oxidative drugs, drugs that can include methemoglobinemia, and ingestion of fava beans.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

In the absence of exposure to an oxidant agent, G6PD deficiency rarely causes clinical manifestations, so many individuals are unaware of their G6PD status. In patients with acute hemolysis, testing for G6PD deficiency may be falsely negative because older erythrocytes with a higher enzyme deficiency have been hemolyzed. Female heterozygotes may be hard to diagnose because of X-chromosome mosaicism leading to a partial deficiency that will not be detected reliably with screening tests. (Tier 4) [6, 7]

Date of Search: 08.18.2021

Reference List

1. Class I glucose-6-phosphate dehydrogenase deficiency. (2021) Accessed: 2021-12-07. Website: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=24102&Disease_Disease_Search_diseaseGroup=g6pd&Disease_Disease_Search_diseaseType=Gen&Disease(s)/group%20of%20diseases=Class-I-glucose-6-phosphate-dehydrogenase-deficiency&title=Class%20I%20glucose-6-phosphate%20dehydrogenase%20deficiency&search=Disease_Search_Simple

2. Anaesthesia recommendations for patients suffering from Glucose-6-phosphate dehydrogenase deficiency. Orphananesthesia. (2015) Website: https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/glucose-6-phosphate-dehydrogenase-deficiency/193-glucose-6-phosphate-dehydrogenase-deficiency/file.html

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. GLUCOSE-6-PHOSPHATE DEHYDROGENASE; G6PD. MIM: 305900: 2019 Aug 05. World Wide Web URL: http://omim.org.

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ANEMIA, NONSPHEROCYTIC HEMOLYTIC, DUE TO G6PD DEFICIENCY. MIM: 300908: 2018 Feb 14. World Wide Web URL: http://omim.org.

5. Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood cells, molecules & diseases. (Blood) 42(1096-0961):267-78.

6. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. (2005) 72(0002-838X):1277-82.

7. WHO Guidelines for Malaria. (2021) Website: https://www.who.int/publications/i/item/guidelines-for-malaria

8. Monteiro WM, Franca GP, Melo GC, Queiroz AL, Brito M, Peixoto HM, Oliveira MR, Romero GA, Bassat Q, Lacerda MV. Clinical complications of G6PD deficiency in Latin American and Caribbean populations: systematic review and implications for malaria elimination programmes. Malar J. (2014) 13(1475-2875):70.