Childhood-onset MMP is a rare condition, documented in only 28 patients reported in the literature, including mostly females (n = 19, 68%) with a median age at diagnosis ranging from 1 to 17 years [6]. However, an estimated delay in diagnosis of 2 months to 5 years has been recorded among children with the disease. The most frequently affected sites in pediatric patients included the oral cavity (n = 18, 64%), followed by the conjunctiva (n = 11, 39%), the genital mucosa (n = 10, 35%), the skin (n = 6, 21%), and the upper respiratory pathway (n = 5, 62.5%) [7,8,9]. Notably, only five patients presented isolated ocular disease [10,11,12,13]. Moreover, all patients with skin affection also presented ocular manifestations [6,7,8,9, 14,15,16]. Two patients with oral mucous, skin, and ocular affection died; the cause of death was not available for one while the other patient died from tracheal stenosis associated with the disease [15, 16]. General characteristics of previously reported cases of childhood-onset MMP are displayed in Tables 1 and 2. Likewise, tissue involvement in adults presents most commonly in the oral cavity (85%), followed by the conjunctiva (65%), nasopharynx (20–40%), skin (20–35%), genitalia (20%), and more rarely the esophagus and trachea (5–15%) [17]. The prevalence of affected sites and features appears to be comparable to that of pediatric patients; however, genital involvement in children seems to be more prevalent than in adults.

The diagnosis is challenging, compounded by the very low prevalence of the disease in pediatric patients. In this population, reaching diagnosis could be hampered by alternative etiologies for cicatricial conjunctivitis such as hemorrhagic adenoviral conjunctivitis with membrane formation, chlamydial /trachoma keratoconjunctivitis, severe vernal keratoconjunctivitis, and pediatric blepharokeratoconjunctivitis, among others [18]. Moreover, patients may present with a long history of using diverse and multiple topical eye drops and potentially be misdiagnosed as drug-induced conjunctivitis. Proper diagnosis requires concordance between clinical signs and the detection of anti-basement zone autoantibodies. These autoantibodies are tissue-bound, detected by DIF microscopy, or circulating when detected by indirect immunofluorescence (IIF) [17]. DIF showing linear IgG, IgA, and/or C3 deposits at the subepithelial BMZ and/or dermal-epidermal junction is strongly recommended as the major single diagnostic test for MMP [17, 19]. Nonetheless, inaccurate tissue management or collection, along with initially negative results during the early stages of the disease, can result in false-negative outcomes, thereby impeding the timely and accurate diagnosis [3, 11, 17]. Likewise, a previously reported case of ocular MMP in a 12-year-old girl presented a negative DIF result at the initial presentation, subsequently turning positive two years later [11]. The mentioned case was the only patient who manifested an episode of PUK, as in our report. Autoimmune diseases are responsible for nearly half of the non-infectious etiologies of PUK, with rheumatoid arthritis and granulomatosis with polyangiitis being the most frequently underlying diagnoses [20, 21]. Moreover, PUK has only been documented in two additional patients with MMP; the before-stated pediatric patient and an older adult woman developing PUK following cataract surgery [11, 22].

After diagnosis has been properly established, prompt treatment should be initiated. Dapsone (1.0-1.5 mg/kg/day) combined with oral cyclophosphamide (2 mg/kg/day), or corticosteroids (0.5–1.5 mg/kg/day) are the recommended treatment options in adults diagnosed with ocular MMP [5, 17]. Cyclophosphamide has been particularly associated with a prompt response and prolonged remission in patients with ocular involvement [17]. Other alternatives include azathioprine (1.5-2.0 mg/kg/day), methotrexate (5–25 mg/week) [23], mycophenolate mofetil (2 g/day), or sodium mycophenolic acid (1,440 mg/day) [17, 24]. Biologic therapy, such as rituximab (375 mg/m2 weekly for 4 weeks or 1,000 mg twice every 2 weeks) is usually reserved for refractory cases of severe MMP [17, 25]. Treatment in children is hindered by the extensive side effects of the drugs mentioned above and the lack of standardized regimens for MMP in this demographic. Prior cases of pediatric MMP included cyclosporine (4 mg/kg/day) in the treatment regimen; however, two out of three patients receiving this drug were unresponsive and required switching to another agent [12, 13, 15]. Interestingly, none of the prior cases were treated with methotrexate, an antimetabolite extensively studied in the pediatric population for other immune-mediated diseases, rendering an acceptable safety profile [23, 24, 26, 27]. The patient in our report presents the first case of pediatric ocular MMP successfully treated with methotrexate (15 mg/week). Importantly, the long-term use of methotrexate in cases associated with a PUK episode should be closely monitored, as this severe complication may demand the use of more potent immunotherapy, such as alkylating or even anti-CD20 agents [20].

Pediatric MMP with ocular involvement is a rare condition that seems to share clinical features with the adult counterpart, albeit with a relatively more indolent evolution. Timely diagnosis and treatment are warranted but remain challenging.