RAB27A plays an essential role in the regulation of exocytosis and intracellular vesicle trafficking. Loss-of-function mutations in the RAB27A gene cause dysfunctional immune cells and Griscelli Syndrome Type 2 (GS-2), whereas upregulation of RAB27A in cancer cells is associated with a worse prognosis and increased metastasis. Here, we wanted to assess the potential side effects of overexpression of RAB27A in different types of healthy stem cells as preparation for the development of gene therapy for GS-2. Bone marrow mesenchymal stem cells (BM-MSCs) were obtained from GS-2 patients and healthy donors. Healthy murine bone marrow-derived and human cord blood-derived hematopoietic stem/progenitor cells (HSPCs) were transduced with different lentiviral vectors carrying a codon-optimized RAB27A (RAB27Aco) transgene. Cells were used for in vitro functional assays and assessed using flow cytometry, Western Blot and RT-PCR. In vivo transplantation assays in mice were used to assess the effect of RAB27A on stem cell function. Engraftment was assessed using flow cytometry, sections of BM-MSC injection sites were analyzed using histological staining. Overexpression of RAB27A resulted in phenotypic changes in BM-MSCs and decreased colony-forming capacity of HSPCs. Transplantation of RAB27A + stem cells was not associated with any tumorigenesis. Despite high expression of RAB27A in HSPCs before transplantation, RAB27A levels in peripheral blood, bone marrow, and spleen cells remained low, indicating overexpression of RAB27A may have affected the long-term reconstitution potential. Development of gene therapy for GS-2 may require fine-tuning of RAB27A expression but is not likely to be complicated by RAB27A-induced tumorigenesis.

Griscelli Syndrome Type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic mutations in the RAB27A gene. Typically, it is characterized by cutaneous hypopigmentation, immunodeficiency, with or without neurological abnormalities secondary to hemophagocytic lymphohistiocytosis (HLH). Without treatment, GS2 often results in fatal outcomes within the first decade of life. Adult-onset GS2 is extremely rare, with few documented cases. We describe a 48-year-old patient with a neurological presentation: cerebellar dysarthria, ataxia, nystagmus, and muscle hypotonia in the lower limbs. Diagnostic workup included next-generation sequencing (NGS panel), clinical investigations, and segregation analysis in the family to confirm the diagnosis of GS2. Genetic testing revealed two variants in RAB27A: The likely pathogenic c.550C>T [p.(Arg184*)] and c.213G>T [p.(Gln71His)], a variant of uncertain significance. Clinical evaluation confirmed irregular hair pigmentation due to melanosome transport defect, low natural killer cell activity, cytopenia, hypertriglyceridemia, elevated serum ferritin, and brain tissue biopsy compatible with hemophagocytosis, thus cementing the clinical diagnosis of GS2. Segregation analysis confirmed the trans configuration of the variants. Based on the clinical and genetic evidence, the p.Gln71His variant was reclassified as likely pathogenic per ACMG criteria. This rare late-onset GS2 case highlights the need to consider GS2 in adult patients with atypical presentations. Early diagnosis is vital for effective intervention. Greater clinical awareness and research are needed to understand its phenotypic spectrum in adults.

Griscelli syndrome (GS) is a rare autosomal recessive disorder marked by partial oculocutaneous albinism, immunodeficiency, and neurological issues. It has 3 types based on genetic mutations. This report focuses on a patient with GS type 2, characterized by immune abnormalities and neurological symptoms, with only 160 cases documented globally. A 1-year-old boy presented with hyperthermia, diarrhea, and vomiting, revealing hypopigmented skin and silvery-gray hair. He exhibited tachycardia, abdominal distension, hepatosplenomegaly, and signs of immunocompromise. Neurologically, he showed developmental delays and hyperreflexia. Lab tests indicated anemia, thrombocytopenia, and elevated triglycerides. Based on clinical history and laboratory tests diagnosed with GS type 2. The patient received symptomatic treatment, antibiotics, and frequent transfusions, with strict infection prevention due to limited resources for stem cell transplantation. GS, identified in 1978, is a rare autosomal recessive disorder marked by partial albinism and immunodeficiency, with around 160 cases primarily from the Mediterranean. It comprises 3 types: GS1, GS2, and GS3, each with unique genetic and clinical features. GS1 exhibits partial albinism and neurological issues without immune effects due to MYO5A mutations. GS2 presents severe immunodeficiency and risks such as hemophagocytic lymphohistiocytosis linked to RAB27A mutations. GS3, caused by melanophilin gene mutations, has a better prognosis. Diagnosis involves hair microscopy and genetic testing, and while supportive treatments exist, early diagnosis is vital for improved outcomes. GS is a rare genetic disorder with varied symptoms, categorized into 3 types, requiring genetic testing for diagnosis and treatment ranging from management to stem cell transplantation.

Griscelli syndrome (GS) is an uncommon disorder characterized by partial albinism, which gives hair a silvery-grey sheen and variable immunodeficiency or neurological impairment, with pancytopenia, immune dysfunction, hepatosplenomegaly, neurological impairment, hypogammaglobulinemia, and variable cellular immunodeficiency. Three variants GS1, GS2 and GS3 have been described in different phenotypes of the disease with varying presentation. We present two neonates, born two years apart, to parents with third-degree consanguinity. Both had features of partial albinism and neutropenia at birth. Microscopy of hair showed characteristic large aggregates of pigment granules dispersed irregularly along the hair shaft. Given their family history and high clinical suspicion, a diagnosis of Griscelli syndrome was made. Early diagnosis of Griscelli syndrome can offer treatment options like Bone Marrow Transplant and prevent fatal complications like hemophagocytic lymphohistiocytosis. Supportive management during transplantation comprises of antimicrobial therapy, immunoglobulin replacement, and vigilant monitoring for complications like graft versus host disease.

Griscelli syndrome type 2 is a rare autosomal recessive disorder caused by mutations in the RAB27A gene. It is characterized by partial albinism, a silvery sheen of the hair, and an immune deficiency. We report cases of two siblings, a seven-year-old boy and his 10-year-old sister, who were admitted to the emergency department with sepsis complicated by macrophage activation syndrome. Their clinical course was rapidly unfavorable. The diagnosis of Griscelli syndrome type 2 was made in the light of a combination of clinical and biological arguments: oculocutaneous hypopigmentation, silvery sheen of the hair, the absence of psychomotor delay, the occurrence of a macrophage activation syndrome following an infection, and especially the pathognomonic appearance on microscopic examination of a hair sample. The absence of giant granulations in the nucleated cells made it possible to eliminate Chediak-Higashi syndrome. Griscelli syndrome type 2 should be considered in children presenting with hypopigmentation, silvery hair, and immune dysregulation, particularly when complicated by macrophage activation syndrome.