To the Editor:
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare group
of genetic disorders characterized by infections with weakly virulent
environmental mycobacteria (EM) or Mycobacterium bovis bacillus
Calmette-Guérin (BCG). Various EM can infect patients with MSMD, such asM. abscessus, M. asiaticum, M. avium , M. bohemicum,M. chelonae, M. elephantis , M. fortuitum, M.
genevense , M. gordonae, M. kansasii, M. mageritense, M.
peregrinum, M. porcium, M. scrofulaceum, M. smegmatis , M.
simiae , M. szulgai, M. triplex, and M. tilburgii.The more virulent M. tuberculosis has also been implicated in
some patients. Genetic etiologies of MSMD affect the pathways involved
in the production of and/or response to the interferon-gamma (IFN-γ)
(1). Herein, we report a 4.5-year-old Iranian patient with disseminatedMycobacterium simiae and a homozygous frameshift mutation in theIL12B gene, c.527_528delCT (p. S176Cfs*12).
The patient was an Iranian male born to consanguineous parents. The
family history was unremarkable for unusual infections or early death.
Patient received BCG vaccine at birth without any complication. At the
age of 2 years, he presented with abdominal distension. Further
evaluation showed hepatosplenomegaly and abnormal liver function tests.
He underwent diagnostic laparotomy which revealed gallbladder hydrops, a
retroperitoneal tumor-like lesion near the pancreas head, as well as
celiac and para-aortic lymphadenopathies. The pathologic findings were
consistent with the non-necrotizing granulomatous inflammation in lymph
nodes and focal centers of narrow septate mycelia within the gallbladder
wall and pancreatic stroma without any microorganism found in special
staining. He had been empirically treated with a combination of
antibiotics and antifungal agents with partial improvement.
One year later, he presented with fever and abdominal pain. He was also
suffering from recurrent episodes of oral thrush. He received packed
cells and albumin infusion due to the evidence of anemia and
malabsorption. The purified protein derivative (PPD) skin test was
negative but gastric washing culture was positive for acid-fast bacilli
(AFB), of which the subspecies were not identified. The colonoscopy at
the time revealed severe nodularity, fragile mucosa, and multiple
pseudo-polyps in all parts of the colon. The colon biopsy was negative
for different bacterial and fungal microorganisms by PCR method but
reported to be positive for mycobacteria species (unknown species). With
suspicion of EM infection, the patient had been treated with isoniazid,
rifampin, ethambutol, and clarithromycin.
At the age of 4.5 years, he was referred to our center as he had not
responded to anti-mycobacterial treatment. He suffered from protracted
diarrhea, fever, growth failure, and recurrent oral herpetic lesions.
In the physical examination, oral candidiasis, abdominal distension,
hydrocele, and cervical lymphadenopathy were found. The complete
laboratory survey including immunologic workup was in normal range
except for elevated erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP) (Table 1 ). The gastric lavage PCR was positive
for M. simiae , later confirmed by culture. He received
fluconazole for oral candidiasis and was placed on amikacin,
levofloxacin, clarithromycin, and cotrimoxazole, which offered moderate
improvement.
We enrolled his genomic DNA to whole exome-sequencing (WES) program and
identified a frameshift homozygous mutation in exon 5 of theIL12B gene, c.527_528delCT (p. S176Cfs*12), verified by sanger
sequencing method. This mutation has been already reported in other MSMD
patients and the diagnosis of complete autosomal recessive (AR) IL-12p40
deficiency was established (2). Both parents were heterozygous with
respect to the mutation. The exogenous recombinant human IFN-ɣ treatment
was added to the regimen of antibiotics. At the age of 6, while
receiving the above-mentioned medications, he was hospitalized again due
to refractory diarrhea, abdominal distension, and malabsorption. In the
ultrasound examination, he was found to have abdominal wall thickening
and ascites. The colonoscopy was repeated with almost the same results
mentioned before and in the histopathologic examination, histiocytic
infiltration and focal granuloma in rectosigmoid and villous blunting by
an infiltrate of foamy macrophages with numerous AFB were observed. His
clinical condition gradually deteriorated and he developed
protein-losing enteropathy. His condition was complicated by
hyponatremia, acid-base disturbance, and hypoxia. He was admitted to the
intensive care unit (ICU) and eventually died.
To our knowledge, this is the first AR complete IL-12p40 deficiency case
with disseminated M. simiaeinfection.
M. simiae is a slowly-growing EM that usually affects
immunocompromised individuals (3). The most common symptoms include
productive cough, dyspnea, fever, weight loss, and hemoptysis, mostly
associated with micronodular or cavitary lesions and bronchiectasis in
radiological studies (4). Furthermore, rare involvements of
extra-pulmonary organs such as the parotid gland, skin, genitourinary
tract, lymph nodes, and vertebral column are reported in the literature
(5, 6).
M. simiae infection seems to be restricted to certain ethnic
groups, particularly those from the Middle East countries (7). Among
patients with MSMD, four patients have been reported to be complicated
with M. simiae infection. De Beaucoudrey et al. in a cohort of
141 MSMD patients with AR IL-12Rβ1 deficiency, reported a 5-year-old
male from Saudi Arabia with disseminated BCG disease and mutation in theIL12RB1 gene (Y88*), who was found to have M. simiaeinfection (8). In 2014, M. simiae infection was reported in two
patients with AR IFN-γ receptor 2 (IFN-γR2) deficiency (9). One of them
initially presented with pneumonia and pleural effusion and later
complicated with abdominal lymphadenopathy and hepatosplenomegaly.M. simiae was found in the lymph node culture. The other patient
suffered from severe diarrhea, anemia, and peripheral lymphadenopathy.M. simiae was cultured from liver tissue and brain abscess. Both
patients died despite early anti-mycobacterial treatments. Later, Braueet al . described another Caucasian patient with granulomatous
skin lesions, lymphadenopathy, persistent fever, and disseminatedMycobacterium avium-intracellulare infection. The M.
simiae was also cultured from his skin biopsy and he was finally found
to have a mutation in the NEMO gene (c.1-16G>C)
(10).
The treatment of M. simiae infection is challenging and no
therapeutic protocol has been defined yet. However, the most frequent
drug regimens applied included clarithromycin in different combinations
with trimethoprim/sulfamethoxazole, moxifloxacin (or ofloxacin), and
amikacin (5). Our case exemplifies the importance of consideringM. simiae infections in patients with genetic defects in the
IFN-γ mediated immunity, due to its difficult to treat nature.