Hemoglobin H-constant spring in North America: an alpha thalassemia with frequent complications.

Hemoglobin H-constant spring (Hb H-CS), the most common nondeletional alpha thalassemia in Asia is increasingly recognized in North America due to shifts in immigration patterns. In California, alpha (a)thalassemia syndromes are the second most frequent finding among newborns screened for hemoglobinopathies with a two-fold increase compared to a decade earlier [1,2]. Though known to have a more severe anemia than Hb H disease, the other clinical findings of Hb HCS are not well described. Moreover, beneficial therapies that have become available in the last decade are often not applied to their care. This analysis of 46 patients enrolled in the Thalassemia Clinical Research Network (TCRN) age 13+/10 years old, with Hb H-CS revealed moderate anemia (mean 8.7 ± 1.5 g/dl), regular transfusion therapy in 24% of patients, and splenomegaly or prior splenectomy in one-third of them. Serum transferin receptor (sTfr), was elevated; (44.4 ± 18 mcg/ml normal range 2.9–8.3 mcg/ml), reflecting ineffective erythropoiesis, which in turn leads to high iron absorption and increased ferritin levels in younger (median 1⁄4 187 ng/ml) and older (median 1⁄4 465 ng/ml) nontransfused patients. These findings along with moderate growth delay and low bone mass were more prevalent in Hb H-CS patients compared to deletional Hb H disease. Our results highlight the required monitoring of the extent of anemia, growth, splenomegaly, iron overload, gallstones, bone density and assessment of need for transfusions and specific treatments for disease complications. The constant spring (CS) termination codon mutation (a ; TAA? CAA), is the most prevalent nondeletional a globin mutation in Southeast Asia (SEA) and southern China. DNA diagnosis of Hb H-CS, a combination of two cis a-gene deletions and one CS mutation is often required because the Constant Spring, a slow moving band produced in small quantities, can be missed by electrophoresis. It is inadvertently mistaken for the more common, three agene deletion—Hb H disease—typically a milder type of a thalassemia. In North America, clinical data on a thalassemia, in particular concerning Hb HCS, is lacking. Moreover, recent advances in technology for diagnosis and treatment of thalassemia-induced complications are therefore rarely considered for this patient population. We sought to characterize the clinical and hematological findings in patients with Hb H-CS in North America, addressing findings that can impact on their clinical care. Genotyping of 836 thalassemia patients identified 106/836 (12.7%) with Hb H (three gene deletion) and 46/836 (5.5%) with a nondeletional mutation; 44 with Hb H-CS, and two (twin sibling) patients with Hb Dartmouth [3]. Among the patients with Hb H-CS–/aa was the most common genotype, detected in 86% of genotyped patients. (Table I). Mean Hb, available in a subset of patients, was lower in the nontransfused Hb H-CS patients; 8.7 g/dl ± 1.5, compared to patients with Hb H; 9.4 g/dl ± 0.8. Mean Hb in 2/5 patients with Hb H-CS who also carry an E beta globin mutation was lower 7.6 g/dl ± 0.9. All patients were prescribed folic acid supplementation (1 mg daily) and compliance was similar among Hb H and Hb H-CS individuals, at 80%. Splenomegaly or a prior splenectomy was common among the Hb H-CS patients, but rare in those with Hb H disease; 26% vs 3%, p1⁄4 0.0001. In the nontransfused patients with Hb H-CS, splenectomy lead to a higher mean Hb level: 9.62 ± 2.44 g/dl vs. 8.40 ± 1.00 g/dl. Postsplenectomy portal vein thrombosis was reported in one subject with Hb H-CS. Cholelithiasis was common, detected in eight patients (18%), 4 symptomatic cases underwent cholecystectomy. Patients with Hb H-CS had significantly higher levels of sTfr in comparison to the Hb H patient group; 44.4 ± 18 mcg/ml vs. 19.0 ± 9.6 mcg/ml (P < 0.0001, normal 2.9–8.3 mcg/ml). sTfr levels were lower in transfused Hb H-CS patients; 37.6 ± 33.7 mcg/ml. Eleven of the 46 (24%) with Hb H-CS and 2 (1.8%) of the Hb H patients were placed on regular transfusions and chelation therapy. Mean age of initiation of transfusions was 3.5 ± 1.3 years (range 2–5 years). Among nontransfused patients, mean ferritin level was higher in Hb H-CS than in the Hb H (375.2 ± 406.1 ng/ml vs. 175.9 ± 304.2 ng/ml, P < 0.0001). Ferritin levels were higher in those 18 years or older (n 1⁄4 9, mean age 1⁄4 26.7 years) compared to the younger cohort (n 1⁄4 22, mean age 1⁄4 10.4 years): 490 ± 285 (median 1⁄4 465 ng/ml, range:137–1153 ng/ml) vs. 328 ± 443 (median 1⁄4 187 ng/ml, range: 37–1835 ng/ml). Among transfused Hb H-CS patients mean ferritin concentration was 2511 ± 2262 (median 1⁄4 1833 ng/ml, range: 329–6852 ng/ml) and liver iron concentration obtained in five of them showed significantly elevated levels (27 ± 14 mg/gm dry wt). None of the patients were reported to have clinically evident iron-induced heart disease. Growth delay was more apparent in the Hb H-CS patients (n 1⁄4 19) in compared to 20 Hb H patients; Mean height Z score was "1.34 ± 0.98 for Hb H-CS vs. "0.82 ± 1.15 for Hb H (P 1⁄4 0.16) (Fig. 1). Mean weight Z score was "1.15 ± 0.88 for Hb H-CS vs. "0.83 ± 1.61 for Hb H (P 1⁄4 0.47). On average, patients with Hb H-CS had lower spine bone mineral density (BMD) Z-scores compared to those in Hb H patients: mean L1-L4 spine Z/Tscore of "1.60 ± 0.86 vs. "0.93 ± 0.80 (P 1⁄4 0.02). None of the Hb H-CS patients had evidence of growth hormone deficiency, diabetes mellitus, hypothyroidism or hypoparathyroidism. Four out of ten (40%) adult females had one or more successful pregnancies, most of whom required transfusion support during pregnancy. The compound heterozygocity for a deletional mutation in combination with the CS mutation results in less a-globin mRNA production by the remaining functional a-gene in comparison to a three a-gene deletion. Therefore more a/b imbalance occurs and more Hb H (b4 tetramers) preTABLE I. Patients Main Clinical and Hematological Characteristics