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.

Genetic pigmentary disorders represent a diverse group of genetic conditions characterized by alterations in melanin production and transport and melanocyte development, resulting from single-gene pathological variants. These disorders encompass both hypopigmentary and hyperpigmentary phenotypes, affecting not only skin pigmentation but also ocular, auditory, and systemic manifestations. This review examines the molecular mechanisms underlying major genetic pigmentary disorders, including hypopigmentary (e.g., oculocutaneous albinism, piebaldism, and Waardenburg syndrome) and hyperpigmentary (e.g., dyschromatosis symmetrica hereditaria, dyschromatosis universalis hereditaria, reticulate acropigmentation of Kitamura, and Dowling-Degos disease) disorders. Additionally, we discuss RASopathies, in which pigmentary abnormalities occur alongside multisystem developmental anomalies. Comprehensive understanding of these conditions can provide crucial insights into melanocyte biology and guide future clinical management strategies for affected patients.

Griscelli syndrome type 2 (GS-2) is a rare congenital immune dysfunction characterized by partial albinism and recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by a variant in the gene encoding Rab27a leading to a degranulation defect in melanocytes, natural killer (NK)- and T cells. Prognosis of patients with GS-2 is limited by repetitive episodes of life-threatening HLH with onset in early childhood. The only curative treatment is an allogeneic hematopoietic stem cell transplantation (HSCT). Here, we report on an 18 year old female patient with a homozygous missense p.Arg50Glnfs*35 variant in exon 2 of RAB27A who presented with an exceptionally late onset of severe HLH. Her phenotypically inapparent albinism complicated to correctly diagnose GS-2. Immune function assays confirmed a T- and NK cell degranulation deficiency characteristic for patients with primary HLH, while microscopic hair analysis revealed melanin clumps secondary to melanocyte functional impairment. To understand why disease onset occurred unusually late in this patient, we investigated the patient's T cell and polymorphonuclear neutrophil (PMN) function in more detail. We could show that intracellular granzyme B storage in cytotoxic T cells was increased compared to healthy donors and that the patient's T cells maintained some degranulation activity. Both, antigen-specific cytotoxic response and proliferation capacity of the patient's T cells were preserved. We demonstrate for the first time that also PMN degranulation, assessed as stimulation-induced CD66b and CD11b cell membrane expression, is dysfunctional in patients with Rab27a deficiency-associated primary HLH. The patient was treated with steroids and cyclosporine A for immunosuppression to control the HLH. After two severe episodes within only a few months, she eventually received an allogeneic HSCT and has not experienced further HLH episodes for now more than 3 years after the HSCT procedure. This case should raise awareness for the possibility of initial manifestation of primary, genetically-determined HLH even in adult patients.

3M syndrome is an autosomal recessive disorder characterized by short stature and skeletal developmental abnormalities. A Chinese girl with 3M syndrome and a novel OBSL1 (obscurin-like 1 gene) variant is presented. The patient is a 2-year-old girl who presented with short stature and had intrauterine growth retardation and low birth weight. Gene analysis revealed compound heterozygote mutations in the OBSL1 gene: c.458dupG (p.L154Pfs*100) and c.427dupG (p.A143Gfs*111). The c.427dupG mutation is novel. The c.458dupG mutation has been documented in five cases, occurring only in Chinese individuals, suggesting ethnic specificity. In cases of children with short stature presenting with intrauterine growth retardation, low birth weight, and skeletal developmental abnormalities, 3M syndrome should be considered. The c.458dupG mutation may be a hotspot mutation in the Chinese population.

Griscelli syndrome type 2 (GS2) is an autosomal recessive immunodeficiency characterized by hair hypopigmentation, recurrent fever, hepatosplenomegaly and pancytopenia. This study aims to find new genetic changes and clinical features in 18 children with GS2 caused by the RAB27A gene defect. In all, 18 Iranian children with GS2 who presented with silver grey hair and frequent pyogenic infection were included in this study. After recording demographic and clinical data, PCR sequencing of the RAB27A gene was performed for all exons and exon-intron boundaries. Two patients in this study were subjected to whole-exome sequencing followed by Sanger sequencing. Light microscopy study of hair showed large irregular clumps of pigment with the absence of giant granules on the blood smear. Mutation analysis of the RAB27A gene identified two novel missense mutations as homozygous in a patient, one in exon 2, c.140G>C and another in exon 4, c.328G>T. In addition, for 17 other patients, 6 reported mutations were obtained including c.514_518delCAAGC, c.150_151delAGinsC, c.400_401delAA, c.340delA, c.428T>C and c.221A>G. The mutation c.514_518delCAAGC was the most frequent and found in 10 patients; this mutation may be considered a hotspot in Iran. Early diagnosis and treatment of RAB27A deficiency can contribute to better disease outcomes. In affected families, genetic results could be urgently needed to make a timely decision about haematopoietic stem cell transplantation and prenatal diagnosis.