When she was 3 years old, she presented with a cough and fever for 3 weeks. Upon physical examination, she had generalized lymphadenopathy and left posterior lung field crepitation. Laboratory investigation showed leukocytosis with left shift and raised ESR. Her chest X-ray revealed left paratracheal and basal ill-defined opacity. Tests for malaria, hepatitis B, and hepatitis C were all negative. Gene expert MTB/RIF test and acid-fast staining from gastric aspirate did not show Mycobacterium Tuberculosis, FNA from lymph nodes showed caseous necrosis, and she was treated with first-line anti-TB (2RHZE/4RH) for the second time.
At the age of 4 years and 3 months, she presented with right lower extremity pain, limping, and swelling over her head. On physical examination, she had boggy swelling over her scalp, multiple enlarged cervical lymph nodes, and anterior chest wall swelling at two sites. Her ESR was 124 mm/hr. Her abdominal ultrasound showed hepato-splenomegaly and multiple enlarged iliac groups of lymph nodes bilaterally. Fine needle aspiration from the chest wall abscess and lymph nodes suggested features of tuberculosis. Multi-drug-resistant TB (MDR TB) was considered clinically, but it was not possible to confirm with TB culture and drug sensitivity tests. She was treated with second-line anti-TB drugs for 2 years. This was the time that her mom claimed, she had marked improvement.
At the age of 7 years and 9 months, she presented with right-side limping, loss of appetite, weight loss, fever, and occasional cough. On physical examination, she had boggy swellings over her scalp in three different areas; acne-like rashes on the back, trunks, and arms; and shortening of the right lower limb with limited range of movement. Her MRI showed lumbosacral multifocal osteomyelitis; unilateral sacroiliac arthritis with adjacent epidural abscess; and lytic lesions over the left femoral head and neck. The skull X-ray was normal. Her C-reactive protein (CRP) and parathyroid hormone were within normal limits. Rheumatoid factor (RF) and antinuclear antibody (ANA) were both negative. The FNAC from the scalp lesion showed caseous granulomatous inflammation and the biopsy from the skin lesion was suggestive of lupus vulgaris. (Figures 1(a)-1(d)). The disseminated mycobacterial disease was considered, and she was treated with anti-TB for the 4th time (2RHZE/10RH).
Despite the treatment with the anti-TB, the indurated plaque skin lesions (Figures 2(a) and 2(b)) became cauliform-like (Figures 3(a)-3(c)) and the boggy scalp lesion became crusted (Figure 4(a)); another skin biopsy was suggestive of juvenile xanthogranuloma. Other blood tests and ophthalmologic evaluation were normal, and she completed her anti-TB course.
At the age of 11 yr and 3 months, she developed right flank pain with swelling, associated with low-grade fever, in addition to the existing scalp and skin lesions. Her vital signs were stable, she had abdominal tenderness and a limited range of movement of the right hip joint. She had a yellowish-crusted plaque with an indurated erythematous background on the right side of the anterior scalp and forehead (Figures 5(a)-5(c)), and a well-demarcated skin-colored indurated plaque with a fine scale on the right side of the cheek, chin, chest, and abdomen. Her abdominal ultrasound and MRI were suggestive of right-side unilateral sacroiliac arthritis with adjacent paraspinal abscess; her ESR was raised with leukocytosis and anemia. FNAC from lymph nodes showed a granulomatous lesion with caseous necrosis; blood PCR showed the Mycobacterium Tuberculosis complex (species identification was not possible). Anti-TB (2RHZE/10RH) was started for the 5th time.
At the age of 12 years and 10 months, she came back with a complaint of cough, high-grade fever, and chest pain of 3 weeks' duration. She was chronically sick-looking, tachypneic with an oxygen saturation of 56% (corrected with 3 liters of oxygen). She was severely underweight and stunted, and her body mass index (BMI) was <5th percentile (CDC BMI chart for her age).
She had frontal bossing, multiple deep punched-out ulcers over the scalp covering an approximate area of 15 by 12 centimeters on the frontal, temporal, and parietal parts of the head (Figure 6).
She had proptosis of eyes, multiple nontender enlarged lymph nodes (2-4 cms) at the axillary and inguinal regions, coarse crepitation over the left upper third of lung field, hepatomegaly of 16.5 cms, and spleen size of 2 cms. She had a nodular ulcer 1 cm by 1 cm over the two shoulders. She had multiple hyper and hypopigmented circular scars. She had a deep scar over her left buttock. She was extremely irritable; slight deviation of the left eye to the left side; other neurologic examinations were normal.
Her investigations had a WBC of 23800/mm3, with a neutrophil count of 83%; her ESR was 140 mm/hr; hemoglobin was 9.2 gm/dl; Gene-Xpert from sputum showed no mycobacteria tuberculosis. Thyroid, liver, and renal function tests were within normal limits. Her Skull X-ray showed multiple punched-out lytic lesions without sclerotic border involving frontal, parietal, and occipital bones bilaterally (Figures 7(a) and 7(b)).
Ultrasound of the abdomen showed a liver size of 15.8 cm, and a spleen size of 12 cm. Both had smooth contours and uniform echo textures.
Multiple lytic bone lesions involving the bilateral humeral head, both right and left acromion processes of scapula and body of scapula, right 2nd to 6th rib, left 3rd to 5th rib with a narrow zone of transition and no associated periosteal reaction or sclerosis except for mild physical sclerosis at the left humeral head, with C6 vertebral compression fracture, heterogeneously enhancing anterior mediastinal mass with punctate calcification likely to be an enlarged thymus with calcification, bilateral nonsegmental multifocal consolidative airspace opacities, bilateral pleural effusion (right side-scant, left side-moderate), bilateral axillary and cervical lymphadenopathy.
Multiple trans-diploic lesions with inner and outer calvarial bone destruction involving frontal-parietal and occipital regions with subtle parenchymal edema from the mass effect from frontal lesion suggestive findings of delayed/arrested sphenoid sinus pneumatization.
Genetics test: Sequencing analysis and deletion/duplication testing of the 407 genes showed a pathogenic variant in IFNGR1, (Med Gen UID: 863300) c.819_822del (p.Asn274Hisfs*2) suggestive of IFN-gamma-R1 defect and this result is consistent with a predisposition to autosomal dominant mendelian susceptibility to mycobacterial disease (MSMD) one increased risk allele, NOD2 (MedGen UID: 348835) c.2722 G > C (p.Gly908Arg) was identified, which could be associated with an increased risk of Crohn's disease.
She was managed with intravenous ceftazidime and vancomycin, followed by Meropenem for 2 weeks. Rifampicin, INH, ethambutol, azithromycin, and Cotrimoxazole were given to cover for possible nontuberculous mycobacteria and superinfection with staphylococcus aureus, Salmonella, and Listeria. Surgical debridement was done and pathology from the necrotic scalp and lytic skull bone fragments was suggestive of only chronic inflammation (not LCH).
Thereafter, she went to the National Institute of Allergy and Infectious Disease (NIAID) in Maryland where she received a PCR test from sputum and scalp wound which showed Mycobacterium avium complex (MAC) and culture grew Mycobacterium Intracellulare; and a PET scan to see the extent of disease showed spots of osteomyelitis on arms, shoulders, legs, ribs, the skull, and sacral area. She was started on Azithromycin, Linezolid, Moxifloxacin, and Bedaquiline. The ophthalmologist's evaluation revealed uveitis; she was started on steroid eye drops and her vision has improved.
After three months of the above therapy, she developed prolonged QT syndrome as a side effect of bedaquiline, and it was discontinued. The sensitivity pattern of the identified MAC from the sputum and mediastinal mass was resistant to azithromycin, however the MAC from the scalp was sensitive to azithromycin, hence azithromycin was continued and clofazimine was added. Surgery to excise the mediastinal mass differed. interferon gamma was started. Now she is not requiring oxygen, she has gained weight and the scalp wound is healing (Figure 8), even though her progress is not satisfactory Hence, bone marrow (BM) transplant is planned and her donors are being investigated for matching.