Coexistence of Usher Syndrome,Familial Mediterranean Fever and Psoriatic Arthritis: A Rare Association

Dear Editor,

We report a rare and complex case of a 32-year-old male presenting with suspected Usher syndrome (USH), familial Mediterranean fever (FMF) and psoriatic arthritis (PsA). The co-occurrence of these conditions raises critical questions regarding shared genetic predispositions, inflammatory pathways and therapeutic challenges.

The patient reported a history of recurrent abdominal pain and febrile episodes dating back to childhood. Bilateral progressive sensorineural hearing loss had also begun during early childhood; although he had been using hearing aids for the past five years, the onset of hearing impairment occurred much earlier. Since adolescence, he had experienced recurrent episodes of swelling, pain and warmth predominantly in both knees. These episodes were managed intermittently with nonsteroidal anti-inflammatory drugs (NSAIDs) and topical treatments; however, treatment adherence and follow-up were irregular. The arthritis was confined to the knees, with no reported involvement of other peripheral joints. During flare-ups, he described erythema and warmth around the affected joints and reported having previously received a diagnosis of erysipelas. He also mentioned occasional low back pain that lacked inflammatory characteristics and was partially responsive to NSAIDs. Additionally, psoriatic plaques had been intermittently observed on both elbows since childhood (Figure 1). In early adulthood, the patient developed night blindness and progressive visual deterioration, for which he was diagnosed with retinitis pigmentosa following ophthalmologic evaluation. In the most recent period, he presented to various centres with significant swelling and pain in the left knee, underwent joint aspiration in emergency and orthopaedic outpatient clinics and was subsequently referred to our department for further evaluation and management.

OPEN IN VIEWER Figure 1.

Elbow Psoriatic Lesions (A) and the Pelvis X-ray of the Patient (B).

On physical examination, the patient had painful, swelling, tenderness and limited flexion with pain in the left knee. Tenderness was also present in the metacarpophalangeal (MCP) joints of both hands. Psoriatic plaques were observed on both elbows. The patient did not report any history of dactylitis. He occasionally experienced heel pain, suggestive of intermittent enthesitis, although no clinical signs of active enthesitis were observed. Lumbar spine mobility was preserved, and he did not report any back pain during the examination. Neurological examination was unremarkable, with no signs of balance problems or vestibular dysfunction; the Romberg test was negative. Systemic examination was otherwise within normal limits.

Initial laboratory tests revealed elevated acute-phase reactants, including a C-reactive protein (CRP) level of 2.3 mg/dL, erythrocyte sedimentation rate (ESR) of 32 mm/hour and serum amyloid A (SAA) of 172 mg/L. Urinalysis showed proteinuria (protein ++ on dipstick). Quantitative analysis revealed a spot urine protein-to-creatinine ratio of 1.92, and 24-hour urinary protein excretion of 707 mg/day, with an albumin level of 535 mg/day. Liver and renal function tests were within normal limits. Viral serologies, including hepatitis B and C markers, were negative. Autoimmune panel, including antinuclear antibody (ANA) and extractable nuclear antigen (ENA) profile, was negative. Complement levels (C3, C4) and serum immunoglobulin levels were within normal reference ranges. Genetic testing for FMF confirmed a homozygous M694V mutation in the Mediterranean Fever (MEFV) gene.

Magnetic resonance imaging (MRI) of the sacroiliac joints demonstrated findings consistent with chronic bilateral sacroiliitis. Lumbar spine MRI revealed inflammatory lesions: T2 hyperintense and T1 hypointense signal changes were noted at the anterior upper endplate of the L4 vertebra. Additional T1-T2 hyperintense signals were also detected at the anterior corners of L2, L3 and L5 vertebrae. Due to persistent proteinuria and high SAA levels, the possibility of secondary amyloidosis was investigated, and the patient underwent a rectal biopsy. Rectal biopsy confirmed AA-type amyloid deposition and the findings were attributed to secondary AA amyloidosis due to FMF.

Given the coexistence of proteinuria, hearing loss and retinal involvement, Alport syndrome was initially considered. However, it was excluded based on the absence of haematuria and lack of typical ocular findings (e.g., anterior lenticonus and central fleck retinopathy). ¹ CHARGE syndrome, a well-known genetic condition and a leading cause of congenital deafblindness, was also considered in the differential diagnosis due to the presence of bilateral sensorineural hearing loss and progressive visual impairment. However, the absence of key diagnostic features such as ocular coloboma, choanal atresia and characteristic craniofacial or cardiac anomalies made CHARGE syndrome less likely in this case. ² Additionally, retinitis pigmentosa in conjunction with sensorineural hearing loss is recognised in several other rare genetic syndromes. These include Cockayne syndrome (characterised by intellectual disability and dwarfism), Alström syndrome (associated with diabetes mellitus and obesity), Hallgren syndrome (with neuropsychiatric manifestations and vestibulocerebellar ataxia), Laurence–Moon–Biedl syndrome (featuring intellectual disability, polydactyly, obesity and hypogonadism) and Refsum syndrome (notable for polyneuropathy and ichthyosis). ³ None of these additional systemic features were observed in our patient; therefore, these syndromes were considered clinically incompatible and excluded from the differential diagnosis. Given the lack of additional syndromic manifestations, USH remained the most consistent diagnosis explaining the patient’s dual sensory impairment.

USH is the most common genetic cause of combined deaf-blindness, characterised by progressive sensorineural hearing loss, retinitis pigmentosa and vestibular dysfunction. The three clinical subtypes (USH1, USH2 and USH3) differ in severity and onset.^4,5 Our patient exhibited bilateral progressive sensorineural hearing loss since childhood and retinitis pigmentosa onset in adolescence, strongly suggestive of Type 2 USH. Importantly, USH2 is not associated with vestibular dysfunction, ⁵ which aligns with our patient’s absence of balance issues. However, genetic testing was unavailable due to institutional limitations. While genetic confirmation was not feasible, the clinical phenotype strongly aligned with Type 2 USH, and alternative syndromic causes were systematically excluded.

Concurrently, the patient had FMF gene (M694V homozygous mutation) with recurrent episodes knee arthritis, abdominal pain, fever and proteinuria, confirming FMF. ⁶ MRI revealed bilateral chronic sacroiliitis and inflammatory lesions at L4 anterior vertebral corners, consistent with axial PsA. Additionally, the patient had elbow psoriatic lesions and metacarpophalangeal joint tenderness, confirming peripheral PsA involvement. ⁷

Importantly, HLA-B27 testing was negative, which is a notable finding in axial PsA cases with sacroiliitis. However, this is also consistent with FMF-associated seronegative spondyloarthropathy (SSpA), where HLA-B27 negativity has been well-documented.^6,8 Previous reports, such as Bodur et al. (2008), have described rare cases of FMF and PsA coexisting in HLA-B27-negative patients, further supporting our observations. ⁸

While rare, amyloid deposition in the inner ear has been proposed as a potential cause of hearing loss in secondary amyloidosis. ⁹ Although both hearing loss and FMF symptoms began in childhood, hearing impairment occurred earlier. Therefore, deafness due to secondary amyloidosis was considered less likely in our case.

Colchicine was initially used for FMF but was discontinued due to suspected myelosuppression (lymphopenia, thrombocytopenia). Biologic therapy was introduced, with interleukin-1 (IL-1) blockade (canakinumab) effectively controlling FMF symptoms, but PsA symptoms persisted. As a result, the regimen was adjusted to include etanercept (tumour necrosis factor (TNF) inhibitor) alongside colchicine, which successfully managed both FMF and PsA symptoms. This therapeutic strategy aligns with previous reports suggesting that TNF inhibitors, such as etanercept and infliximab, can be effective in FMF-associated arthritis when conventional treatments fail.^8,10

To the best of our knowledge, this is the first reported case of suspected USH coexisting with FMF and PsA. While each of these conditions has distinct genetic and inflammatory mechanisms, their simultaneous presence raises the possibility of shared immune dysregulation or genetic susceptibility. The potential role of genetic interactions among these conditions also warrants further exploration.

There is evidence in the literature suggesting that inflammatory diseases such as FMF and PsA may share common inflammatory pathways. For instance, FMF patients have been shown to be at increased risk of developing PsA, which raises the possibility of shared mechanisms in the pathogenesis of both conditions. ¹¹ Furthermore, mutations in the MEFV gene have been proposed to predispose individuals to conditions such as psoriatic juvenile idiopathic arthritis, potentially through abnormalities in IL-1β production. ¹²

However, while the genetic basis of USH is well characterised, there is currently no clear evidence in the literature of a direct genetic or inflammatory link between USH and either FMF or PsA. Therefore, further research is required to determine whether a shared genetic or immunoinflammatory mechanism underlies the coexistence of USH, FMF and PsA.

The coexistence of FMF, PsA and USH presents significant diagnostic and therapeutic challenges, requiring a multidisciplinary approach. We believe this case will be of considerable interest to rheumatologists, geneticists, ophthalmologists and otolaryngologists involved in the management of complex multisystem diseases.