DISCUSSION
HMOX1, an inducible enzyme, plays a crucial role in defense against oxidative stress by degrading heme, a strong pro-oxidant causing high oxidative stress in the body, to biliverdin, iron, and CO. These products help in further reducing oxidative stress, endothelial functioning, and iron recycling. The HMOX1 genes are located on chromosome 22q12. A rare autosomal recessive condition called heme oxygenase-1 deficiency occurs due to a missense or nonsense mutation in these genes. Nine cases of heme oxygenase deficiency have been reported so far (Table 3).
Table 3
In HMOX1 deficiency, the response to oxidative stressors is impaired and is characterized by high heme and low bilirubin, ferritin, and CO (13). This causes uncontrollable cell injury, particularly in the liver, kidneys, monocytes, and endothelium. HMOX1 deficiency causes the continuous death of splenic macrophages due to the inability to detoxify heme. This causes splenic fibrosis and asplenia. In some cases, the spleen initially enlarges postnatally and later atrophies (3, 14). Asplenia was detected in 3 out of 9 case reports, apart from ours (5,6,11). Macrophage dysfunction also impedes iron trafficking from peripheral tissues, causing iron deposition in the liver and kidneys, as reported by Tahghighi et al (12). Severe hemolytic anemia with elevated heme, Hp-Hb complexes, and low bilirubin ensues (3). HMOX1 deficiency causes severe systemic inflammation from monocyte dysfunction; abnormal fibrinolysis, coagulation, and DIC due to systemic vascular endothelial injury; renal tubulointerstitial damage; and increased heme-catalyzed LDL oxidation, promoting atherosclerosis (13). It primarily results in recurrent miscarriages or intrauterine deaths, but due to various genetic and environmental factors, disease presentation can be delayed until a later age (14).
Heme oxygenase (HO) deficiency exhibits diverse clinical manifestations contingent upon the specific enzyme subtype affected. The onset of clinical features demonstrates significant variability, ranging from the neonatal period to fifteen years of age. The most commonly seen characteristic facial features are a depressed nasal bridge, a prominent forehead, and significant eyelid edema, as seen in the current case. Other common clinical presentations include hepatomegaly, asplenia, hemolytic anemia, hyperbilirubinemia, iron overload, and chronic systemic inflammation. These pathological processes may culminate in pain, fatigue, and recurrent pyrexia. Two studies reported renal impairments such as hematuria and proteinuria as recognized complications associated with HO deficiency (10,12). However, urine abnormalities were not found in the current case. Rarely, neurological manifestations such as intellectual disability, developmental delays, and seizures may present. Patients with HO deficiency frequently exhibit immunological dysfunction and increased susceptibility to infections. Notably, hypertension, cerebral hemorrhage, and fungal sepsis have been implicated in contributing to mortality (3). A partial deficiency in HO-1 increases the progression and mortality of sepsis (15). A familial history of intrauterine fetal demise and consanguineous marriages is observed in a subset of patients with HO-1 deficiency (3).
The absence of HMOX-1 can lead to significant sequelae in organ systems across the body. The cases of HMOX-1 deficiency reported so far demonstrated signs of asplenia with signs of leucocytosis and thrombocytosis. In a case reported by Gupta et al, asplenia or hyposplenism along with leucocytosis with thrombocytosis serves as an important clue to diagnosing HMOX-1 deficiency (9).
Examination of the first autopsy case by Yachie et al revealed a characteristic tissue injury predominantly in the liver, kidney, vascular endothelial cells, and monocytes in the blood. The kidney showed injuries to the glomerulus along with tubulointerstitial injury with tubular atrophy. Glomerulus under electron microscopy showed mild mesangial proliferation along with capillary loop thickening. The liver demonstrated a massive increase in size due to amyloid accumulation, resulting in hepatocyte atrophy. Iron deposits were present across the liver and kidney. The monocytes showed a central vacuolation and decreased expression of surface antigens (3). In a case reported by Chau et al, a lung biopsy showed signs of interstitial pneumonia, patchy pleural fibrosis as well as scattered cholesterol granulomas due to repeated flares of hyperinflammation triggered by an infection (7). Tahghighi et al, reported massive pericardial effusion in a 17-month-old patient diagnosed with HMOX-1 deficiency (12).
The laboratory data from various cases surprisingly demonstrate uniformity. In each instance, the CBC shows an elevation in leukocyte and platelet count. Urine analysis consistently reveals hematuria and proteinuria in Japanese and Indian cases, indicating potential kidney injury. Interestingly, LFTs demonstrate elevated AST and ALT levels in all cases, yet bilirubin levels persistently remain low or within normal ranges despite the presence of active hemolytic anemia, establishing this as the primary hallmark feature. Additionally, markedly elevated serum ferritin and LDH values serve as a second hallmark. Furthermore, there is inconsistency in the levels of CRP and ESR, some cases exhibit elevated levels, while others display normal levels. A bone marrow biopsy in one of the cases revealed slight hemophagocytosis. Lastly, on ultrasound abdomen or CT abdomen, the absence or hypoplasia of the spleen is a frequent occurrence, although even a normal-sized or enlarged spleen does not rule out HO-1 deficiency.
Heme oxygenase deficiency is diagnosed primarily through a genetic study using techniques such as whole exome, whole genome, and targeted sequencing. Sequence analysis showed that the paternal allele had a 2-nucleotide deletion inside exon 3 and the maternal allele had a full deletion of exon 2 (3). Because consanguinity increases the likelihood of heterozygosity and genetic drift, it also increases the prevalence of heme oxygenase deficiency. Several cases of heme oxygenase deficiency have been linked to consanguinity similar to the current case. Among these, a notable case was reported by Tahghighi et al. (2019), involving an Iranian boy with heme oxygenase deficiency, who was born to consanguineous parents (12). Thus, genetic counseling and screening are crucial for its prevention.
The patient’s clinical presentation suggests a potential diagnosis of Ivermark syndrome, a unique variant of heterotaxy characterized by congenital heart defects and abnormal arrangements of internal organs, particularly with right-sided involvement, (16) leading to absent spleen development (17). Another differential diagnosis to consider is autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome (APECED), a rare autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene (18). APECED typically presents with hypoparathyroidism, primary adrenal insufficiency (Addison’s disease), and chronic mucocutaneous candidiasis (CMC) (18). Additionally, Stormorken syndrome, a rare genetic condition associated with mutations in the stromal interaction molecule 1 (STIM1) gene, may be considered (19). This syndrome is characterized by thrombocytopenia, asplenia, muscle weakness (myopathy with tubular aggregation), and miosis (19).
Based on an extensive review of the literature, it is evident that a universally accepted therapeutic protocol for Heme Oxygenase deficiency is currently deficient. Clinical management mainly involves administering treatment modified to meet the specific needs of the affected individuals. Particularly, corticosteroids, hydroxyurea, and immunosuppressants such as mycophenolate mofetil, tacrolimus, and blood transfusions have been vital to disease management. In addition, various antibiotics, including azithromycin, vancomycin, ceftriaxone, cotrimoxazole, and monoclonal antibodies, such as rituximab and anakinra, were used to modulate the immune response. Other interventions included recombinant factor VIIa, peritoneal dialysis, and packed cell transfusions. There is only one piece of literature supportive of the effectiveness of HLA-matched stem cell transplantation. As such non-myeloablative allogeneic matched sibling donor (MSD) stem cell transplantation emerges as a viable therapeutic avenue for individuals afflicted with autoinflammatory disorder resulting from Heme Oxygenase (HO) deficiency. Despite its promise, mixed chimerism raises apprehensions about this treatment modality (11). 
The prognosis of the Heme Oxygenase (HO) deficiency may vary among people. Several factors like the severity of the disease, time of intervention, and effectiveness of the treatment play vital roles in determining the same. The rarity of Heme Oxygenase (HO) deficiency leads to the availability of limited data, underscoring the need for additional research and larger case studies to understand better the prognosis and ideal management approach for this condition.