Fatal bone marrow embolism in a child with hemoglobin SE disease

Abstract

A 7-year-old girl with HbSE experienced fever and pain in her legs and back while on a car trip with her family, but did not seek medical attention. She complained of sudden respiratory distress and then collapsed. An emergency squad responded within minutes, and the child was evacuated by helicopter to a local tertiary care pediatric emergency room, where she was admitted in full cardiopulmonary arrest. After prolonged attempts at resuscitation, she was pronounced dead. An autopsy was performed. Hemoglobin E (HbE) is a beta chain variant characterized by lysine substitution for glutamic acid at amino acid 26 [b] [1]. The GAG to AAG mutation in the b-globin exon 1 also results in abnormal RNA splicing that produces an unstable mRNA [2], resulting in a mild thalassemic phenotype in individuals with homozygous HbE and a more severe phenotype when combined with beta thalassemia (HbE/beta thal) [3–7]. Due to a weakened interface between the a-globin and b-globin chains, HbE is also unstable [8], causing hemolysis that may be exacerbated by fever or oxidant stress [9]. HbE is common in Southeast Asia, where the gene frequency may be as high as 60% in some localities [8]. HbS is widely distributed in Africa and to a lesser degree in the eastern Mediterranean and India [10]. Compound heterozygosity for HbE and HbS (HbSE) is relatively rare, but there are a significant number of individuals with HbSE in India [11] and in Arab countries such as Oman [12]. With population admixture and racial intermarriages, the incidence of HbSE is increasing in the West [3,7,13]. The current literature generally associates HbSE with a benign clinical course, although vaso-occlusive complications have been reported [3–7]. The child in this case was born to an African-American father and a mother of mixed Cambodian and European descent, with no family history of sickle cell anemia, bleeding or clotting disorders, or pulmonary embolism. A newborn screen performed showed HbSE. Records of counseling the family received at the time of diagnosis are not available; however, they believed that the condition was benign and did not require follow-up care. The patient was not seen by a hematologist and was not placed on penicillin prophylaxis in infancy. At the age of five the child was referred to a pediatric orthopedic surgery clinic for complaints of intermittent leg pain that had begun six months earlier. A bone scan showed mildly increased uptake in the physis of the left tibia and femur (not shown). MRI evaluation revealed two areas of abnormal signal within the mid and distal left femoral diaphysis (see Fig 1), interpreted as most consistent with bone infarction. Review of her medical records at that time revealed the diagnosis of HbSE, and she was referred to a comprehensive sickle cell center. When first seen in the hematology clinic at age 5 [1/2], she appeared well, with growth parameters in the 50th percentile. Physical examination was normal, except for a palpable spleen tip. There was no jaundice and no cardiac murmur. Over the next 2 years, the patient’s hemoglobin averaged 11.4 gm/dl (114 gm/L) ranging from 10.5 to 11.5 gm/dl. Reticulocyte count was slightly elevated, typically 1.5–1.7% (ranging from 1.1 to 3.0%). Bilirubin was 0.9 to 1.4 mg/dL (normal: 0.0–1.1) and urine urobilinogen typically was 1.0 to 2.0 mg/dL (normal: 0.2–1.0). These findings suggested slight, but variable hemolysis; LDH was not measured. The red blood cells were microcytic, with a mean cell volume ranging from 68.8 to 74.2 fL (nl 77.0– 95.0 fL) and with mean cell hemoglobin averaging 26.4 pg. (nl 25.0–33.0 pg) Blood smear showed microcytosis, occasional target cells, rare sickle cells, mild hypochromia, and mild polychromasia, no Howell–Jolly bodies. Platelet counts ranged from 180,000 to 220,000 per lL. Electrolytes and urinalysis were normal. Quantification of hemoglobin by high performance liquid chromatography showed 55% HbS, 31% HbE, and 1.3% HbF, with normal amounts of hemoglobin A2 and minor hemoglobins. Between the ages of 5 [1/2] and 7 [1/2] years, the child was hospitalized twice for pain management of vaso-occlusive events. On one of these occasions, a repeat bone scan revealed decreased uptake in the proximal and distal left femur and distal right femur consistent with a new bone infarction (not shown). Cerebral MRI/MRA was normal (not shown). She was treated with narcotics and nonsteroidal anti-inflammatory agents for pain relief. During several comprehensive care visits over this time, she exhibited no jaundice or splenomegaly on physical exam. In the days before her death the patient complained intermittently of pain in her back and legs. By parental report, the patient was febrile the day she died, but it is not clear when the fever began. The onset of respiratory distress was acute and severe, and loss of consciousness occurred very shortly thereafter. On arrival