Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

Alice S. Chau,Deborah A. Nickerson,Jason S. Debley,Eric J. Allenspach,Michael J. Bamshad,Aaron B. I. Rosen,Bonnie L. Cole,Troy R. Torgerson,Kabita Nanda

doi:10.1186/s12969-020-00474-1

Abstract

BackgroundHeme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited.Case presentationWe present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1(NM_002133.3):c.262_268delGCCCTGGinsCC (p.Ala88Profs*51) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells.ConclusionsHere, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

Highlights

Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin
Here, we describe a phenotype expansion for HMOX1-deficiency to include asplenia and hepatomegaly, and interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow
Heme oxygenases are rate-limiting enzymes that catalyze the degradation of heme to carbon monoxide (CO), ferrous iron, and biliverdin, which becomes bilirubin via the action of biliverdin reductase

Summary

Introduction

Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Heme oxygenases are rate-limiting enzymes that catalyze the degradation of heme to carbon monoxide (CO), ferrous iron, and biliverdin, which becomes bilirubin via the action of biliverdin reductase. HMOX1 deficiency is an extremely rare autosomal recessive disorder with a small number of cases reported to date [2,3,4,5,6,7,8] (Supplemental Table 1). Clinical presentation is complex and diverse, including direct antibody negative hemolytic anemia, low bilirubin, and hyperinflammation [3]. Diagnosis of HMOX1 deficiency lies within clinical findings and laboratory studies with genetic testing of HMOX1 required for confirmation

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