A rare convergence: Pleural amyloidosis in H syndrome – A diagnostic surprise in a young Indian male

Dear Editor, H syndrome is a rare autosomal recessive auto-inflammatory disease caused by mutations in the SLC29A3 gene, with only approximately 130 cases reported worldwide, and fewer than ten identified in India to date.[1-3] The syndrome features multi-system manifestations—most notably, hyperpigmentation, hypertrichosis, hypogonadism, hyperglycaemia, hypothyroidism, hepatosplenomegaly, heart anomalies, and hearing impairment.[1,2] This letter presents a case of secondary amyloidosis with pleural effusion in a young Indian male with genetically confirmed H syndrome, a phenomenon not previously documented in the literature to our knowledge. A 21-year-old man with a known history of H syndrome presented with a 2-week course of pleuritic chest pain, chest tightness, dry cough, and progressive breathlessness. His history included typical features [Figure 1a, 1b] and confirmed SLC29A3 mutation. Imaging revealed a massive left-sided pleural effusion [Figure 1c]. Fluid aspirated via intercostal drainage was exudative, lymphocytic, and low in ADA, becoming jelly-like on stagnation in ICD bag. Despite drainage, lung re-expansion was incomplete. CECT chest demonstrated persistent pleural thickening [Figure 1d] and moderate effusion prompting diagnostic thoracoscopy. Thick, translucent, jelly-like material was identified throughout the pleural cavity, and pleural biopsy was done [Figure 2a, 2b].Figure 1: (a) Hyperpigmentation with hypertrichosis on thighs and buttocks, (b) Hypothyroidism causing goiter, (c) Left massive pleural effusion on presenation, (d) CECT chest with left pleural effusion, pleural thickening and pigtail in situFigure 2: (a) Jelly like translucent material seen in pleural cavity on thoracoscopy, (b) Thoracoscopy guided pleural biopsy and adhesiolysis, (c) Expanded left lung post breaking down septations via thoracoscopy, (d) Pleural Bx with H&E statin showing pinkish glassy material, (e) Pleural biopsy with congo red stain showing apple green birefringenceHistopathology demonstrated fibrillar amyloid material showing Congo red positivity and classic apple-green birefringence under polarised light. Immunohistochemistry confirmed serum amyloid A protein, indicating secondary amyloidosis [Figure 2d, 2e]. Given concurrent renal dysfunction, kidney biopsy revealed similar deposits. Normal serum free light chain ratio, absence of M-spike on serum electrophoresis, and bone marrow with <5% plasma cells excluded primary light chain amyloidosis. The diagnosis of H syndrome with pleural and renal secondary (AA) amyloidosis was thus confirmed. Clinically significant respiratory amyloidosis occurs predominantly in primary (AL) amyloidosis associated with plasma cell dyscrasias, with pleural effusions occurring in just 1–2% of cases.[4,5] Secondary (AA) amyloidosis usually involves kidneys, liver, and spleen, and pleural localisation remains exceedingly rare. In H syndrome, aberrant histiocytic proliferation and persistent cytokine-mediated inflammation drive chronic production of serum amyloid A protein, a precursor to AA amyloid.[2,6] While renal and hepatic involvement have been reported, pleural amyloidosis has not been documented in H syndrome previously. A literature survey reinforces this rarity. Jacquot et al.[7] described a 37-year-old woman with H syndrome who had pleural effusion due to histiocytic infiltration but no amyloid involvement. Lim et al.[8] reported pleural thickening without effusion in an adolescent female diagnosed with H syndrome. In another case, El-Bassyouni et al.[9] reported a child with H syndrome and elevated amyloid A but no thoracic disease. Hence, our case represents the first biopsy-proven dual-site amyloid deposition—pleural and renal—due to secondary amyloidosis in H syndrome in the Indian population. The management of secondary amyloidosis primarily targets control of the underlying inflammatory disease. No specific or definitive therapy exists for H syndrome. In our case, therapeutic thoracoscopy to break pleural septations and optimise pleural drainage [Figure 2c], along with management of endocrine comorbidities (diabetes, hypothyroidism, hypogonadism), provided significant symptomatic improvement. On 1-month follow-up, the patient’s clinical and radiographic findings showed resolution with minimal residual effusion. Treatment protocols for H syndrome are largely empirical. As reported in the literature, biologics, corticosteroids, methotrexate, mycophenolate mofetil, and cyclosporine have shown variable results.[7] The use of IL-6 blockade appears promising in mitigating systemic inflammation, as demonstrated by case-based evidence.[7] Our experience further underscores the necessity of multi-disciplinary management and close follow-up in preventing multi-organ complications. In conclusion, this case represents a novel presentation of secondary pleural amyloidosis in H syndrome, supported by histopathological and immunohistochemical confirmation at two organ sites. Reporting such unusual manifestations expands the clinical understanding of H syndrome and emphasises the need for awareness among clinicians when evaluating atypical pleural effusions in young patients with multi-systemic inflammatory disorders. Author contributions Dr Irfan Shekh and Dr Randeep Guleria Contributed to the conception and design of the work. The acquisition, analysis, and interpretation of data. Drafting and revising the work. Final approval of the version to be published and agreeing to be accountable for all aspects of the work. Dr Aditi singh, Dr Shubhi Singhal, Dr Ashish Kumar Prakash, Dr Dheeraj Gautam Involved in literature search, planning, conduct, writing the original draft of manuscript. Involved in review and editing, agreeing to be accountable for all aspects of the work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.