Rare Immune Disorder Masqueraded as MOGAD in a Young Girl, Case Report Reveals

A devastating case report published in Annals of Clinical and Translational Neurology describes how a lethal, progressive neuroinflammatory illness in a young girl spent years hiding behind a misleading laboratory result, only to be unmasked at last as Griscelli syndrome type 2, an ultrarare genetic error of immunity. The letter, written by Chiara Veredice and colleagues at Università Cattolica del Sacro Cuore in Rome, is framed as a cautionary response to a recent paper portraying myelin oligodendrocyte glycoprotein antibody-associated disease, or MOGAD, as the most frequent and relevant cause of first-time optic neuritis in children. The authors do not dispute that epidemiological observation, but they argue, through the arc of a single tragic clinical course, that a positive anti-MOG antibody test should never be treated as a diagnosis in itself. Their message to clinicians is stark: dysregulated immunity can camouflage itself as a familiar autoimmune disease, and the true identity of the illness may only emerge after years of escalating treatment failure.

The story begins when a previously healthy five-year-old girl was referred to the neurology unit with a fixed right mydriasis, a persistently dilated pupil, and complete retinal detachment in the same eye. Notably, she had never experienced fever or eye pain, features that might otherwise have steered clinicians toward an infectious or inflammatory process of a different character. Brain magnetic resonance imaging revealed severe right optic neuritis, appearing as hyperintensity on T2-weighted sequences, and serum testing detected anti-MOG antibodies at a low titer of 1:10. On the strength of these findings, the team diagnosed MOGAD, an autoimmune condition in which antibodies target myelin oligodendrocyte glycoprotein, a protein on the surface of myelin sheaths in the central nervous system, and initiated monthly intravenous immunoglobulin at a dose of 2 grams per kilogram.

The initial treatment did not hold the disease in check. Three months later, the girl suffered a brainstem relapse marked by vomiting, dysarthria, and ataxia. Repeat MRI showed contrast-enhancing lesions in both supra- and infratentorial regions, together with tonsillar herniation and obstructive hydrocephalus, a life-threatening buildup of cerebrospinal fluid pressure that required a third ventriculocisternostomy, a surgical bypass procedure. High-dose intravenous methylprednisolone pulses of 20 milligrams per kilogram per day were administered for seven days and produced only partial improvement. Despite ongoing therapy, a further relapse followed just three months later, this time presenting with cerebellar ataxia, dysarthria, and a right foot drop. The clinical picture was that of a refractory, relentlessly relapsing inflammatory disorder of the central nervous system, and the team escalated accordingly.

Faced with this refractory-relapsing MOGAD phenotype, the clinicians turned to rituximab, a monoclonal antibody that depletes CD20-positive B cells and is increasingly used as second-line therapy in antibody-mediated neuroinflammatory disease. The drug was given at 375 milligrams per square meter of body surface area weekly for four weeks, but it was discontinued after yet another relapse. Mycophenolate mofetil at 1000 milligrams per day was then added to the monthly immunoglobulin cycles, and this combination finally produced a more stable remission lasting three years. Even during this quiescent period, however, a subtle clue persisted: the girl’s anti-MOG antibody titers fluctuated, swinging between positive and negative results. The authors emphasize precisely this point in their critique, arguing that the role of MOG-IgG serum titer changes and oscillations should not be solely used to clarify the nature of neuroinflammatory pictures in children.

The remission shattered when the girl was 9.6 years old. She abruptly developed a crossed brainstem syndrome, a pattern of neurological deficits produced by a lesion interrupting nerve tracts and cranial nerve nuclei within the brainstem, manifesting as right lower limb hypertonia, flaccid paralysis of the left arm, anarthria, or complete loss of speech, lingual akinesia, and a fixed rightward deviation of the head. A new brain MRI revealed multiple hemorrhagic lesions lined through the thalamus, the nucleo-capsular regions, and the pons. Hemorrhagic transformation within inflammatory brain lesions of this severity is distinctly unusual for typical MOGAD and signaled that the underlying process was something far more destructive than a conventional demyelinating disease.

At this critical juncture, the clinicians returned to a physical sign that had been present all along: the girl’s silvery-gray hair and eyebrows. This peculiar pigmentation, easily overlooked or attributed to benign variation in a child with an autoimmune diagnosis, is in fact the hallmark of Griscelli syndrome, a group of autosomal recessive disorders defined by partial albinism. Acting on this reassessment, the team performed a molecular testing panel for hemophagocytic lymphohistiocytosis, or HLH, a hyperinflammatory syndrome in which immune cells attack the body’s own tissues and organs, using peripheral blood mononuclear cells. The panel revealed two variants in the RAB27A gene on chromosome 15q21: c.153+5G>A, a splice site variant that alters pre-mRNA splicing, and c.514_518del, a pathogenic five-base-pair deletion.

The molecular findings confirmed Griscelli syndrome type 2, catalogued as OMIM #607623, an ultrarare condition caused by mutations in RAB27A and characterized by partial albinism together with impaired cytotoxic activity of T cells and natural killer cells, carrying a risk of life-threatening hemophagocytic lymphohistiocytosis. The biology connects the two seemingly unrelated features of the case. The Rab27a protein is essential for the release of melanin from melanocytes into surrounding cells; when it is dysfunctional, melanin accumulates abnormally within melanocytes and is not transferred properly, producing the characteristic silvery-gray hair and skin hypopigmentation. The same protein is required for the release of cytolytic granules by cytotoxic lymphocytes, so its absence leaves the immune system unable to eliminate infected or activated cells, permitting uncontrolled immune activation that can culminate in the cytokine storm of HLH.

Importantly, the authors note that HLH may be virtually absent in some patients who present with a completely neurologic phenotype, even when molecular findings are fully consistent with Griscelli syndrome type 2. This phenotypic expansion, previously described in the literature in an eleven-year-old girl with Rab27A mutations and no hemophagocytosis, helps explain why the diagnosis remained hidden for more than five years in the present case. After the genetic confirmation, the girl was started on ruxolitinib, a Janus kinase inhibitor that dampens inflammatory signaling downstream of cytokine receptors, at a dose of 5 milligrams twice daily, and she was placed on the waiting list for hematopoietic stem cell transplantation, the only curative option for this disease. Sadly, a slowly progressive multiorgan failure developed five months later, and the girl died at the age of ten.

The case carries a pointed lesson for pediatric neurologists and immunologists alike. Rare genetic errors of immunity can coexist with hypopigmentation skin disorders, and the authors urge healthcare providers to recall that dysregulated immunity may be camouflaged by devastating neuroinflammatory pictures that begin with something as common as optic neuritis. Autoimmune test results, including anti-MOG positivity, may taint the true disease identity, because a positive MOG test does not automatically mean MOGAD. Low antibody titers, atypical clinical features such as absent pain, hemorrhagic lesions, relapses refractory to appropriately escalated immunotherapy, and fluctuating serology should all prompt a broader differential diagnosis that includes inborn errors of immunity. In such patients, recognizing subtle dysmorphic or pigmentation cues and pursuing molecular panels early can redirect treatment toward targeted immunomodulation and, ultimately, curative transplantation before irreversible damage accumulates.

Published as a letter in response to Aduru and colleagues’ finding that MOGAD is the most common cause of isolated optic neuritis in children, this report does not overturn that conclusion but complicates it. It stands as a reminder that the most frequent explanation is not always the correct one, and that in medicine, as in this child’s silver-gray hair, the most visible clue to a hidden diagnosis may be the one easiest to dismiss.

Subject of Research: Griscelli syndrome type 2 masquerading as MOG antibody-associated neuroinflammatory disease in a child

Article Title: A Lethal Progressive Neuroinflammation Disguised as MOGAD Revealing a Final Diagnosis of Griscelli Syndrome

Article References: Veredice, C., Arpaia, C., Contaldo, I., Capasso, A., & Rigante, D. (2026). A Lethal Progressive Neuroinflammation Disguised as MOGAD Revealing a Final Diagnosis of Griscelli Syndrome. Annals of Clinical and Translational Neurology, 13(8), 1740-1742. https://doi.org/10.1002/acn3.70470

Image Credits: AI Generated

DOI: 10.1002/acn3.70470

Keywords: Griscelli syndrome, MOGAD, optic neuritis, RAB27A, hemophagocytic lymphohistiocytosis, neuroinflammation, pediatric neurology, anti-MOG antibodies, partial albinism, rituximab, ruxolitinob, genetic diagnosis