We treated a Japanese male with severe and refractory jaundice and progressive, early onset normocytic anemia born to non-consanguineous parents. The signs of hemolysis were obscure at the onset of jaundice. Rh, ABO compatibilities and spherocytosis were not observed. Because the erythrocyte enzyme test is not easily accessible in Japan, the infant was referred to a specific institute, and was eventually diagnosed as having a G6PD deficiency on day 75. The instructive aspects of the present report are as follows. First, although G6PD deficiency is uncommon in Japan, the patient was born to Japanese parents. Second, the case presented as severe jaundice and hemolytic anemia, although most cases are asymptomatic, particularly in the neonatal period. Third, he apparently did not have any triggers for an acute episode of hemolysis.
The prevalence of G6PD deficiency is estimated at approximately 0.1% in Japan (Nakashima et al. 1977). In most hemolytic cases, it was inferred that the mothers were of non-Japanese ethnicity because gene variants found in Japan were not associated with severe hemolytic anemia (Nakashima et al. 1977). This also might be attributed to the fact that the incidence of gene mutation was quite different from southern Chinese in the Taiwan-Hakka population and Philippines (5.5% and 6.0% each) (Nakashima et al. 1977). In fact, case reports of G6PD deficiency with severe hemolytic anemia published in Japan often describe the family history of foreign mothers (Shimomura et al. 2002; Akazawa et al. 2011). Therefore this case was also characteristic in the point that both the father and mother are Japanese.
Most G6PD-deficient individuals are entirely asymptomatic (Mehta 1994). The most common clinical manifestation in the neonatal period is neonatal jaundice, and acute hemolytic anemia is usually rare; this is because neonatal jaundice due to G6PD deficiency is not due to hemolysis, and hyperbilirubinemia is thought to be secondary to reduced hepatic conjugation and bilirubin excretion (Cappellini & Fiorelli 2008; Beutler 1994; Kaplan & Hammerman 2002). Our case presented neonatal jaundice in advance of the hemolytic anemia; however, the increased reticulocyte count on day 2 suggests that both hyperbilirubinemia and hemolysis may occur simultaneously. Kawaguchi et al. also reported a suspected antenatal hemolysis case in Japan (Kawaguchi et al. 1997). In this case, an extremely high reticulocyte level (344‰) was presented, and intrauterine hemorrhage was strongly suspected. They attributed the early onset hemolysis to oxidative stress as a result of maternal history of the common cold or drug use.
This illness generally manifests as acute hemolysis in childhood, which usually arises when red blood cells undergo oxidative stress triggered by infection or the ingestion of fava beans. Despite conducting a thorough and precise interview, we could not identify any history of drug or food intake during the pregnancy. There have been a few G6PD deficiency cases presenting acute hemolysis in the absence of any trigger that have also been reported in the literature (Dhillon et al. 2003; Shah & Yeo 2007). Our case supports the theory that massive hemolysis may occur in neonates with G6PD deficiency even in the absence of obvious triggering factors.
The abnormal genetic mutations of this disease are classified into 3 categories. Class V/IV is clinically asymptomatic, and class III/II (the border between III and II is not obvious) is basically asymptomatic; both are without the risk of hemolytic anemia and neonatal jaundice. Class I presents (severe) neonatal jaundice and acute exacerbation of hemolytic anemia (WHO Working Group 1989). The limitation of our report is that this case should be classified as class I because the patient showed both acute and chronic hemolytic episodes. However, no genetic testing has been performed. Differences in the clinical course due to genetic transmutation may be present in this disorder. Therefore, genetic testing is one of important part of the management of G6PD patients.
The Japanese male neonate with G6PD deficiency in this report simultaneously presented with severe jaundice and acute hemolysis. Given the lack of family history, triggers, definite laboratory data, and rare disease status among patients with Japanese ethnicity, we recommend further investigation for G6PD deficiency in cases of neonatal hemolytic anemia complicated with jaundice.