HMOX1 – heme oxygenase 1 deficiency

HMOX1 deficiency is an autosomal recessive disorder characterized by severe growth failure and hemolytic anemia due to loss of heme oxygenase-1 (HO-1) activity. The original report describes a six-year-old boy with pronounced growth retardation, persistent intravascular hemolysis with erythrocyte fragmentation, paradoxically elevated haptoglobin, low bilirubin, and endothelial injury evidenced by elevated thrombomodulin and von Willebrand factor levels, together with subendothelial deposits on renal electron microscopy. Immunoblotting and immunohistochemistry of patient-derived lymphoblastoid cells confirmed complete absence of HO-1 protein production, and these cells displayed marked sensitivity to hemin-induced cytotoxicity (PMID:9884342). A subsequent autopsy revealed mesangioproliferative glomerular changes, amyloid deposits in liver and adrenal glands, and widespread iron deposition, recapitulating key features of HO-1–deficient mice (PMID:11823983). Genetic analysis identified compound heterozygous truncating mutations, including c.287G>A (p.Trp96Ter) and a two-nucleotide deletion in exon 3, confirming loss-of-function alleles.

Functional studies in patient cells and HO-1–targeted mice demonstrate that absence of HO-1 underlies the clinical phenotype. The patient’s lymphoblastoid cells lack HO-1 induction upon cadmium stimulation and show heightened vulnerability to oxidative stress. HO-1–knockout mice display growth retardation, anemia, iron overload, and endothelial damage analogous to the human presentation, establishing mechanistic concordance between human and animal models. Collectively, these observations support a Limited level of clinical validity for the association of HMOX1 with heme oxygenase 1 deficiency. Genetic evidence includes a single proband with biallelic truncating variants and no segregation data; experimental evidence is Strong, with complete absence of HO-1 in patient cells and faithful recapitulation in mouse models. Key Take-home: HMOX1 testing should be considered in unexplained pediatric hemolytic anemia with growth delay to enable timely diagnosis and management.

References

• The Journal of clinical investigation • 1999 • Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. PMID:9884342
• Human pathology • 2002 • Heme oxygenase-1 deficiency: the first autopsy case. PMID:11823983

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