Case Presentation:

Unstable hemoglobins occasionally occur as de novo mutations, often causing diagnostic dilemmas[1-3]. We herein present the 18th case and only the second recorded male case of Hemoglobin Hammersmith (HbHS)[4].

A 14-year-old Caucasian male with HbHS diagnosed at six months post-partum was conservatively managed with periodic blood transfusions and desafirox. Physical examination revealed growth failure (10th percentile height and weight) and splenomegaly of 12cm below costal margin. Laboratory parameters revealed Hb 11.2 mg/dL, absolute reticulocyte count 255.7k/mcL, total bilirubin 6.1mg/dL, aspartate transaminase 78 U/L and ferritin 875 ng/mL. Evaluation for iatrogenic hemosiderosis with chemistry and magnetic resonance imaging (MRI) confirmed normal pituitary, pancreatic, adrenal and cardiac function. However, severe renal siderosis consistent with intravascular hemolysis, mild hepatic siderosis and splenomegaly with mild siderosis were noted.

High metabolic burden secondary to massive splenomegaly and non-suppressed bone marrow was hypothesized to be contributing to the growth failure. Patient was planned for higher frequency of blood transfusion with concurrent workup for palliative splenectomy and stem-cell transplant. 

Discussion:

HbHS is an electro-phonetically silent mutation of the β-globin gene, the DNA basis of which was described in 1991[1-5]. Presently, 16 of the 17 cases being female frequently associated with other congenital anomalies[3-5].

Most patients are asymptomatic or vaguely symptomatic with anemia, developmental delay and jaundice, with appropriate compensatory mechanisms[1-5]. Arterial hypoxemia is often present without concomitant cyanosis, hypothesized to be due to a difference in the absorption spectra[2]. Hemoglobin electrophoresis fails to detect HbHS often revealing low HbA2 and moderately elevated HbF[2]. Treatment includes frequent blood transfusions and folic acid supplementation with an unclear role for hydroxyurea. Palliative splenectomy maybe indicated for therapy failure[5]. Our case furthers the argument against the negative, fatal intra-uterine selection against males as previously speculated[3,4]. Oxidative stress on the male embryo at the blastocyst level has been postulated, but the extent of beta-chains expression and use of in-vitro fertilization are potential confounders[4].

Conclusions:

Reporting the second male case of HbHS, we question the postulated etiopathogenic mechanisms necessitating further insight into diagnosis, therapy and counselling.

References:

1. Dianzani I et al. A spontaneous mutation causing unstable Hb Hammersmith: detection of the beta 42 TTTàTCT change by CCM and direct sequencing. Br J Hematol. 1991 Sep;79(1):127-9

2. Mariette S et al. Pulse oximetry and genetic hemoglobinopathies. Intensive Care Med. 2005 Nov;31(11):1597

3. Akiyama M et al. Hemoglobin Hammersmith [β 42(CD1)PheàSer] causing severe hemolytic anemia in a Japanese girl. Pediatr Blood Cancer. 2006 Nov;47(6):839-41.

4. Park S et al. A case report of a male patient with Hb Hammersmith [β42(CD1)PheàSer,TTT>TCT]. Hemoglobin. 2012;36920:161-5

5. Tuohy AM et al. Hb Hammersmith [beta 42(CD1) Phe–>Ser]: occurrence as a de novo mutation in black monozygotic twins with multiple congenital anomalies. J Pediatr Hematol Oncol. 1998 Nov-Dec;20(6):563-6.