Introduction to Late-Onset Genetic Disorders

Griscelli Syndrome Type 2 (GS2) typically emerges as a devastating pediatric condition. However, a recent case report involving a 46-year-old male demonstrates the possibility of Adult-onset Griscelli Syndrome Type 2. This rare autosomal recessive disorder stems from mutations in the RAB27A gene. While children usually face fatal outcomes without treatment within their first decade, this adult case challenges existing clinical paradigms. Specifically, the patient presented with primary neurological deficits rather than the classical early-childhood immunodeficiency and hypopigmentation triad.

Clinical Presentation and Neurological Symptoms

The patient exhibited significant neurological deterioration, including cerebellar dysarthria, ataxia, and nystagmus. Additionally, clinicians observed muscle hypotonia in the lower limbs. These symptoms often mimic more common adult neurodegenerative diseases. Consequently, a high index of suspicion is necessary to identify rare genetic triggers. Notably, while cutaneous hypopigmentation remains a hallmark of GS2, the neurological symptoms dominated the clinical picture in this late-onset scenario.

Genetic Insights into Adult-onset Griscelli Syndrome Type 2

Diagnostic investigations utilized next-generation sequencing (NGS) to pinpoint the genetic cause. Testing revealed two distinct variants in the RAB27A gene. These included the likely pathogenic c.550C>T [p.(Arg184*)] mutation and the c.213G>T [p.(Gln71His)] variant. Initially, researchers classified the latter as a variant of uncertain significance. However, segregation analysis confirmed the trans configuration of these variants. Therefore, based on clinical evidence and melanosome transport defects, experts reclassified p.Gln71His as likely pathogenic according to ACMG criteria.

Systemic Manifestations and HLH Association

Beyond neurological signs, the patient showed laboratory markers consistent with hemophagocytic lymphohistiocytosis (HLH). These markers included elevated serum ferritin, hypertriglyceridemia, and cytopenia. Furthermore, a brain tissue biopsy confirmed hemophagocytosis. This finding cemented the diagnosis of GS2. Clinical evaluation also highlighted irregular hair pigmentation, which occurs due to defective melanosome transport. Consequently, early diagnosis remains vital for effective clinical intervention and management of potential HLH crises in adults.

FAQs on Griscelli Syndrome Type 2

What is the typical age of onset for GS2?

Typically, Griscelli Syndrome Type 2 presents in infancy or early childhood. Adult-onset cases are extremely rare and may present with atypical or primarily neurological symptoms.

How does the RAB27A mutation affect the body?

The RAB27A gene regulates the transport of melanosomes in skin and hair cells, as well as the exocytosis of lytic granules in immune cells. Mutations lead to pigmentary changes and severe immunodeficiency or HLH.

Can Adult-onset Griscelli Syndrome Type 2 be misdiagnosed?

Yes, because it is rare in adults, it may be misdiagnosed as other forms of ataxia or neurological disorders. Genetic testing and looking for systemic markers like high ferritin are crucial for an accurate diagnosis.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or establish a doctor-patient relationship. Refer to the latest local and national guidelines for clinical practice.

References

Papingi D et al. Atypical Clinical Course of Griscelli Syndrome Type 2 With Primarily Neurologic Presentation and Adult-Onset in a 46-Year-Old Male. Am J Med Genet A. 2026 Mar 18. doi: 10.1002/ajmg.a.70140. PMID: 41851022.

Griscelli C, et al. A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978;65(4):691-702.

Menasche G, et al. Mutation of RAB27A causes Griscelli syndrome associated with hemophagocytic syndrome. Nat Genet. 2000;25(2):173-176.