Lipoid proteinosis mimicking Sjögren’s syndrome: a diagnostic challenge in rheumatology practice

Dear Editor, Lipoid proteinosis (LP), or Urbach-Wiethe disease, is a rare autosomal recessive disorder caused by variants in the ECM1 gene on chromosome 1q21 [1]. LP, characterized by the deposition of Periodic acid–Schiff (PAS)-positive hyaline in skin and organs, typically presents in early childhood with hoarseness and progresses to involve multiple organ systems, resulting in dermatological, neurological and mucosal symptoms [1]. Due to its rarity, many physicians are unfamiliar with the clinical features, leading to delayed diagnosis or misdiagnosis. Here, we report a case referred with a preliminary diagnosis of Sjögren’s syndrome (SjS) but was subsequently diagnosed as LP. A 30-year-old female, a child of consanguineous parents, presented with dryness symptoms. She had xerostomia and xerophthalmia, but no other features such as arthritis or a skin rash. The patient has experienced progressive dysphonia since childhood. In the physical examination, multiple papular lesions were observed on the eyelid margins, skin and tongue (Fig. 1, Panels A-B, C and D-E). The video-laryngoscopy showed a hyalinized plaque over the posterior commissure and interarytenoid area, with oedema over the left arytenoid joint (Fig. 1, Panel F). In laboratory tests, erythrocyte sedimentation rate was 4 mm/h, and C-reactive protein was 3 mg/l; rheumatoid factor, anti-cyclic citrullinated peptide, anti-nuclear antibody and extractable nuclear antigens panel were negative. No proteinuria and microalbuminuria were detected in the urine analysis. Schirmer’s test showed bilateral values below 5 mm, indicating significantly decreased tear production. An incision was made for a minor salivary gland biopsy to evaluate for SjS; however, the glands could not be visualized, and the obtained specimens consisted of nonspecific fibrotic tissue. Ultrasonographic and magnetic resonance imaging (MRI) assessment of the parotid glands demonstrated parenchymal thinning and diffuse fatty atrophy (Supplementary Figs S1 and S2). Scintigraphy showed absent radiotracer uptake in both parotid glands, consistent with severely impaired secretory function (Supplementary Fig. S3). Histopathological examination of the skin and eyelid biopsies revealed dermal and perivascular deposits of hyaline-like eosinophilic material, showing strong PAS positivity and negativity with Congo red staining, thereby ruling out amyloid deposition (Supplementary Figs S4 and S5). Next-generation sequencing identified a homozygous NM_004425.4: c.806G>A; p.Cys269Tyr ECM1 variant (Supplementary Fig. S6). This biallelic variant that leads to loss of function in the ECM1 gene has been previously reported as pathogenic in the ClinVar database (Variation ID: 1192520). Based on the clinical, histopathological and molecular findings, a definitive diagnosis of LP was established. As intracranial calcifications are among the common conclusions reported in this condition, MRI and computed tomography ordered and showed no calcification (Supplementary Fig. S7). Long-term follow-up by otorhinolaryngology and dermatology teams, with genetic counselling, was planned.