Obstructive uropathy in STAT 3 hyper immunoglobulin E syndrome

STAT 3 hyper immunoglobulin E syndrome (STAT3-HIES) is a rare primary immune deficiency, accounting for approximately 1/1000000 patients worldwide.¹ It was first described as Job’s syndrome in 1966, which later came to be known as STAT3-HIES, based on its characteristic clinical features and genetic mutations. The defect in STAT 3 is inherited as an autosomal dominant-negative mutation resulting from in-frame deletion or missense mutations. However, most cases have been identified as a de novo mutation.^2,3

STAT 3 hyper immunoglobulin E (IgE) syndrome is a complex disease that affects the immune system, bone, connective tissue, and teeth. Patients present with various symptoms, including eczematous dermatitis, recurrent skin abscesses, pneumonia, bronchiectasis, pneumatocele, characteristic facial findings (broad nasal bridge, deep-set eyes, and prominent forehead), retained primary teeth, joint hyperextensibility, increased susceptibility to fracture, elevated serum IgE >2000 IU/ml, and an increased risk of aneurysm.^4,5

The most common infections in these patients are those of skin (73%) and lung (90%).⁵ Liver and other deep infections (pancreas, prostate, and breast) are rare but have been previously reported.⁶ Staphylococcus aureus and Candida are the most common organisms that contribute to recurrent infections in patients with STAT 3-HIES. Our patient presented with obstructive uropathy, acute kidney injury and hyperkalemia secondary to huge pelviabdominal collections.

Presently, management of STAT3-HIES primarily involves intensive care for dermatitis, prompt administration of broad-spectrum antibiotics or antifungal medications to treat infections, surgical drainage of abscesses, prevention of infection by antibiotic prophylaxis +/- antifungal prophylaxis, immunoglobulin replacement, and long-term follow-up. Recent data on hematopoietic stem cell transplantation (HSCT) have shown promising outcomes compared with previous studies.^7-9 However, the effects of HSCT on non-immunological aspects of the disease remain uncertain.¹⁰

Case Report

A 5-year-old Middle Eastern boy from non-consanguineous parents presented to the emergency room (ER) with 2 months of progressive abdominal distention, abdominal pain, decreased appetite, scrotal swelling with urinary frequency, and enuresis. Two months before the current admission to our hospital, the patient was admitted to another hospital with progressive abdominal distention for one month. Abdomen computed tomography (CT) revealed multiple large intraabdominal abscesses. The patient was discharged against medical advice (due to financial reasons) after receiving ceftriaxone, clindamycin, and ciprofloxacin. Due to limited access to the healthcare system, the patient stayed at home from discharge with progressive abdominal distention until presentation to the ER, when he developed more severe symptoms that necessitated ER visits.

The patient was born at full term and his mother had an uncomplicated pregnancy. Since infancy, the patient experienced severe uncontrolled eczema with recurrent otitis media.

At the age of 1.5 years, the patient was admitted to the pediatric intensive care unit (PICU) in another hospital for 40 days with complicated pneumonia and left-sided empyema with febrile seizures. The patient received mechanical ventilation and required high-frequency ventilation and chest tube insertion. The pleural fluid was positive for Staphylococcus aureus and Streptococcus pneumoniae. A few months later, the patient developed an inguinal abscess that required aggressive debridement at a polyclinic site. At the age of 2 years and 3 months the patient developed another complicated pneumonia that required admission for a month with chest tube insertion and no intubation. Between the age of 2.5 years to date the patient has had >10 incisions and drainages (I&D) for recurrent skin abscesses, and the last 2 were in the axilla region.

The patient exhibited no previous mucocutaneous infection, viral skin infection, or fracture and his weight was appropriate for age. The patient was vaccinated until 2 years of age, without any complications. The patient had 2 younger healthy siblings (aged 1 and 2 years). No family history of atopy, autoimmune disease, or recurrent infections was noted.

Diagnostic assessment

Chest and abdominal CT revealed multiple thick-walled collections compressing the ureters, nondisplaced rib fractures, and pneumatoceles (Figures 1&2).

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Figure 1

- Enhanced CT of the chest. a) Sagittal reformats in bone window showing a rib fracture (arrow). b) Coronal reformats showing right upper lobe pneumatocele (asterisk).

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Figure 2

- Coronal enhanced CT abdomen and pelvis showing multiple walled-off collections (asterisks) displacing the thickened urinary bladder (circle) and compressing the right iliac vein (small arrows). Multiple bilateral inguinal enlarged lymph nodes (bold arrows), one showing central necrosis (arrowheads). These collections were compressing the ureters causing bilateral upstream pelvicalyceal dilatation (not shown).

The patient was required to be admitted to PICU due to hyperkalemia (potassium of 6.4 mmol/L) that was found on initial labs. The patient was referred to the immunology department to investigate the possibility of an underlying inborn error of immunity based on the significant past medical history. Laboratory results are presented in Table 1.

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Table 1

- Laboratory results.

Follow-up and outcomes

As the patient exhibited a high HIES score (score of ≥60) based on the scoring system (Appendix 1), whole exome sequencing (WES) was directly carried out, which identified a heterozygous missense pathogenic variant of the STAT3 gene. STAT3 (NM_139276.3): c.1145G>A (p. Arg382Gln), Chr17(GRCh37): g.40481660C>T. This mutation was previously reported in several reports. Th17 response and STAT3 phosphorylation were not measured in this patient due to the unavailability of the tests in our institute.

Once the patient improved with no more fever, abdominal pain, and repeated abdominal ultrasound showed decreasing abscess size. After completing the antibiotics course, the patient was provided prophylactic trimethoprim (TMP)-sulfamethoxazole (2.5 mg/kg of TMP component twice daily). Since discharge with prophylactic antibiotics, the patient did not require another admission for the last 2 years with regular phone follow-up.

The timeline from the initial patient presentation until the discharge is summarized in Figure 3.

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Figure 3

- The timeline from the initial patient presentation until the discharge.

Discussion

Hyper IgE syndrome results from different mutations, among which autosomal dominant STAT3-HIES and autosomal recessive DOCK8 mutations are the most common. Our patient exhibited a high HIES score (score of 60) based on the scoring system; therefore, we directly carried out WES, confirming the diagnosis.³

Given the disease’s rarity and the general pediatricians and family physicians’ unfamiliarity with the characteristic clinical features, a considerable delay is usually observed in the diagnosis from the onset of the symptoms with a mean delay of 13.7 years.⁶ Our patient was diagnosed 4 years after the initial presentation as he had a significant past infectious history that required PICU admission and clinical characteristic features of HIES.

Hyper IgE syndrome affects the immune system as well as other systems and connective tissues. This disorder is known to cause staphylococcal skin and lung infections but rarely affects deep organs such as the liver and kidney.⁷ However, our patient presented with huge thick-walled abscesses and low inflammatory markers (highest C-reactive protein was 22.7) with secondary uropathy. This substantial infection could be attributed to a delay in presentation to the healthcare system. Although the patient exhibited signs and symptoms suggestive of STAT3-HIES, such as uncontrolled eczema, 2 previous severe complicated pneumonia, recurrent skin abscesses, and facial features, the patient was not diagnosed earlier because they were seeking medical care at different centers without proper follow-up. Once the patient was diagnosed and treated with trimethoprim/sulfamethoxazole prophylaxis, the patient experienced less frequent and less severe infections, with no admissions in the last 2 years.

Managing HIES continues to present challenges owing to the aforementioned rarity of HIES. Complications in HIES are not limited to infections and can be life threatening. In our patient, hyperkalemia developed secondary to obstructive uropathy which could lead to cardiac arrythmias if left untreated. Fortunately, our patient completely recovered with normalization of renal function once the obstructive abscesses were drained.

In conclusion, trainees and physicians are encouraged to take a detailed past medical history, especially in children with a significant past infectious history that includes unusual pathogens or required PICU admissions. Furthermore, we recommend an early referral to a clinical immunologist, especially with inborn errors of immunity are suspected, this leads to the early diagnosis of this syndrome, and early intervention like starting prophylactic antibiotics in our patient was life-changing with no recurrence of the symptoms.