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.