Uveitis is a multifactorial condition with variable etiologies, including infections, immune-mediated diseases, and masquerade syndromes secondary to malignancies or other non-neoplastic disorders [12, 13].

Based on the phenotypic presentation of uveitis in the twins, we needed first to establish a differential diagnosis and to initiate systematic investigations guided by their clinical features. As per their ocular condition, Twin A had bilateral anterior granulomatous uveitis, and retinal vasculitis -mainly phlebitis with segmental appearance-, while Twin B presented with bilateral non granulomatous anterior uveitis, few chorioretinal lesions, and peripheral retinal vasculitis. Despite discernible phenotypic divergence in the twins’ clinical presentations, we postulated a shared underlying etiology. Given the bilateral onset, genetic concordance, and absence of overt systemic symptoms, our workup prioritized etiologies spanning autoimmune disorders, and infectious disease, specifically, Syphilis and Tuberculosis (TB). The systemic work-up was only positive in Twin A, showing high serum ACE, bilateral hilar and mediastinal lymphadenopathy, and skin rash with his previous diagnosis with Celiac Artery Compression Syndrome. Following the exclusion of syphilis and tuberculosis, along with a comprehensive ocular and systemic workup—including pathological examination of a mediastinal lymph node—the collective findings supported a diagnosis of ocular sarcoidosis.

Twin A met the criteria for definite ocular sarcoidosis according to the Revised International Workshop on Ocular Sarcoidosis (IWOS) criteria, as well as the criteria for sarcoidosis-associated uveitis established by the Standardization of Uveitis Nomenclature (SUN) working group [14, 15]. On the contrary, Twin B didn’t even fulfil the criteria for probable ocular sarcoidosis. However, absence of positive laboratory or radiological results, pointed to an underlying immune mediated disease. Yang et al. previously reported a familial case of sarcoidosis associated with uveitis in two sisters [6]. The first sister presented with bilateral panuveitis, while the second exhibited anterior and intermediate uveitis. Both patients had mediastinal lymphadenopathy, and biopsies of the lymph nodes confirmed the diagnosis of sarcoidosis.

One of our patients was previously diagnosed with celiac artery compression syndrome (CAC). Stamler et al. reported an acquired form of CAC syndrome in sarcoidosis, resulting from external compression by enlarged lymph nodes [16].

Being monozygotic twins, in addition to the histopathological evidence of non-caseating granuloma, and the skin rash, we considered late onset Blau Syndrome as a possibility. Blau syndrome is an autosomal dominant condition which typically present before the age of 5 with a triad of skin rash, arthritis, and uveitis and is considered as a form of early onset sarcoidosis [17]. Although, our patients were 21 years old, however, minded with their below average IQ, mild symptoms may have passed unnoticed. Sarens et al. conducted a multicenter study investigating ocular manifestations of Blau syndrome [18]. Among 50 patients diagnosed with Blau syndrome, 76% exhibited ocular involvement at baseline. Bilateral uveitis was present in 37 of these 38 patients (97%), while panuveitis affected 51% of the total eyes studied. The most frequent fundus finding was multifocal chorioretinal lesions and no cases of active vasculitis were reported. To the best of our knowledge adult onset Blau like syndrome was reported once by Yao et al. [19]. Unlike, our patients, their patient didn’t show any ocular involvement.

The concurrent bilateral uveitis observed in monozygotic twins, as described in this case, underscores the potential role of genetic predisposition in ocular inflammatory disease and highlights the need to further explore heritable mechanisms in its pathogenesis. Thus, we performed WES; however, the analysis did not identify any causal variants for uveitis, but it did pinpoint a causal variant for their intellectual impairment by identification of a novel, heterozygous likely pathogenic duplication in SYNGAP1 gene (OMIM # 603384 ) which encodes a ras GTPase-activating protein which is essential for cognition and synapse function [20]. Hence, mutations are responsible for autosomal dominant intellectual developmental disorder-5 (OMIM # 612621) [21].

Our inability to detect a clear causal variant for uveitis on WES does not entirely eliminate a genetic etiology, specifically with expansion of the recognized immune disorders. Furthermore, it is possible the culprit variant may be found in a non-coding region undetected by WES.

Though the exact etiology of sarcoidosis remains elusive; however, disease susceptibility is significantly governed by genetic predisposition. Compelling evidence for the presence of a genetic component underlying sarcoidosis has been provided based on familial aggregation, increased risk in siblings and/or relatives, and ability of genome-wide association studies (GWAS), WES or whole-genome sequencing (WGS) studies to identify genetic variants. Proper understanding of this genetic predisposition can enhance a more personalized approach to diagnosis, prognosis and treatment [22].

Most variants linked to sarcoidosis risk are immune genes or genes involved in immunologic pathways. HLA region is the most consistently associated region with sarcoidosis risk. Other implicated genes are involved in the immune response as those related to cytokines (TNF-α and IL-23), cell surface immune receptors (BTNL2), macrophage activation (SLC11A1) and signaling molecules (ANXA11) [22].

In addition to genetic predispositions, environmental factors have been implicated in the development of sarcoidosis [23]. Identified triggers include infectious agents (e.g., Propionibacterium acnes, mycobacteria, and fungi), non-infectious organic antigens (such as organic bioaerosols), combustible byproducts, and metal dust [24,25,26,27]. The presence of these exposures may explain the simultaneous disease onset in the twins described here. Notably, both individuals had recently begun employment at a garment factory, a setting where occupational exposure to airborne antigens, particulates, or fumes could plausibly contribute to disease initiation.

This case report highlights a rare presentation of sarcoidosis-associated uveitis with simultaneous onset in monozygotic twins, underscoring the potential role of genetic predisposition in disease manifestation. While sarcoidosis is known to cluster in families, synchronous uveitis in twins has never been reported, aligning with prior hypotheses about shared genetic and environmental triggers. This case reinforces the importance of screening siblings of affected patients for early signs of sarcoidosis, particularly in the presence of ocular symptoms. Further research into genetic markers in monozygotic twins could elucidate mechanisms underlying simultaneous disease onset, potentially guiding personalized monitoring strategies for at-risk families.