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Cystic fibrosis with sarcoidosis—genetics vs immunology: a paradigm shift?
  1. H Kamarova1,
  2. K Thattakkat1,
  3. L Mc Cann2
  1. 1Specialist Registrar, Paediatric Rheumatology, Alder Hey Childrens Hospital, Liverpool, UK
  2. 2Consultant Paediatric Rheumatologist, Alder Hey Childrens Hospital, Liverpool, UK

Abstract

Introduction The authors describe coexistence of sarcoid and cystic fibrosis (CF), previously reported in only four childhood cases. Sarcoidosis has a UK annual incidence of 2–4 per 100 000 while CF is seen in 1/2000 live births. Rarity of both conditions makes coexistence by chance unlikely.

Methods A 12-year-old girl, with pseudomonas positive CF (diagnosed age 7 months with positive sweat test and delta F508/1507 genotype), presented with a 2 year history of intermittent skin rash, joint pains, fever and conjunctivitis. Examination revealed petechial rash, hepatosplenomegaly and small joint arthritis.

Results Investigations showed acute renal impairment (creatinine 200 μmol/l, eGFR 31, albumin/creatinine ratio 22.5 mg/mmol), elevated angiotensin converting enzyme levels (120 μ/l), hypercalcaemia (corrected- 4.57 mmol/l) and positive cANCA (non-PR3/MPO). Renal biopsy demonstrated granulomatous tubulo-interstitial nephritis. Conjunctival biopsy showed non-necrotising epitheloid granuloma. Skin biopsy revealed vasculitis and angiography demonstrated small vessel renal vasculitis. Chest x-ray was consistent with CF (normal CT chest, stable lung function). Treatment was given for sarcoid vasculitis using intravenous methylprednisolone, oral prednisolone and azathioprine. Persistent symptoms 7 months later led to substitution of azathioprine with mycophenolate mofetil and regular IVIG. Disease is currently well controlled. Frequent pseudomonas chest infections are problematic.

Conclusion Increased incidence of CFTR mutations has been observed in twenty-six unrelated adults with sarcoidosis. Similarly, familial clustering with recurrence risk 1:100 among first-degree relatives and presence of HLA B8 and DR3 types has raised questions about common genetic aetiology. However, genotype analysis of families with two or more siblings with sarcoidosis failed to find evidence to support CFTR gene mutations. Sarcoid granulomas resemble those associated with mycobacteria, fungi or hypersensitivity. Aetiology remains obscure, but evidence favours chronic immunological response to unidentified environmental factors with possible genetic susceptibility. Both sarcoidosis and CF show defective T cell mediated immune functions and enhanced B cell activation. Children with CF develop frequent chest infections and progressive lung damage. Chronic immune stimulation with persistent antigenaemia and hyperimmunoglobulinaemia could generate large immune complexes resistant to phagocytosis, stimulating granuloma formation. CF may predispose to sarcoidosis through foreign material in the lung or by an altered immunological reaction.

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