Silvery hair with dyschromatosis: Griscelli syndrome type 3 or familial gigantic melanocytosis.

We herein illustrate a case of an adult male presenting with silvery hair and generalized guttate hypopigmented macules on a background of diffuse cutaneous hyperpigmentation, since birth. Histopathology showed enlarged melanocytes with abundant melanin. Based on these clinicopathological features, differential diagnoses considered were Griscelli syndrome 3 (GS3) and familial giagantic melanocytosis. GS3 belongs to a group of inherited autosomal recessive (AR) disorders of partial albinism, known as silvery hair syndromes, while familial gigantic melanocytosis (FGM) is a putative disorder of dyschromia with silvery hairs. A pertinent literature search revealed hyperpigmentation or dyschromatosis as a rare manifestation of silvery hair syndromes, especially in dark-skin populations. A comparative analysis of previously reported cases depicted close morphological similarities between GS3 and FGM. We discuss the uncertainty pertaining to cases described in literature as FGM, to be truly representative of a distinctive entity, or merely a morphological variation of GS3.

The GTPase-deficient Rab27A(Q78L) mutant inhibits melanosome transport in melanocytes through trapping of Rab27A effector protein Slac2-a/melanophilin in their cytosol: development of a novel melanosome-targetinG tag.

The small GTPase Rab27A is a crucial regulator of actin-based melanosome transport in melanocytes, and functionally defective Rab27A causes human Griscelli syndrome type 2, which is characterized by silvery hair. A GTPase-deficient, constitutively active Rab27A(Q78L) mutant has been shown to act as an inhibitor of melanosome transport and to induce perinuclear aggregation of melanosomes, but the molecular mechanism by which Rab27A(Q78L) inhibits melanosome transport remained to be determined. In this study, we attempted to identify the primary cause of the perinuclear melanosome aggregation induced by Rab27A(Q78L). The results showed that Rab27A(Q78L) is unable to localize on mature melanosomes and that its inhibitory activity on melanosome transport is completely dependent on its binding to the Rab27A effector Slac2-a/melanophilin. When we forcibly expressed Rab27A(Q78L) on mature melanosomes by using a novel melanosome-targeting tag that we developed in this study and named the MST tag, the MST-Rab27A(Q78L) fusion protein behaved in the same manner as wild-type Rab27A. It localized on mature melanosomes without inducing melanosome aggregation and restored normal peripheral melanosome distribution in Rab27A-deficient cells. These findings indicate that the GTPase activity of Rab27A is required for its melanosome localization but is not required for melanosome transport.

Evidence for defective Rab GTPase-dependent cargo traffic in immune disorders.

A fully functional immune system is essential to protect the body against pathogens and other diseases, including cancer. Vesicular trafficking provides the correct localization of proteins within all cell types, but this process is most exquisitely controlled and coordinated in immune cells because of their specialized organelles and their requirement to respond to selected stimuli. More than 60 Rab GTPases play important roles in protein trafficking, but only five Rab-encoding genes have been associated with inherited human disorders, and only one of these (Rab27a) causes an immune defect. Mutations in RAB27A cause Griscelli Syndrome type 2 (GS2), an autosomal recessive disorder of pigmentation and severe immune deficiency. In lymphocytes, Munc13-4 is an effector of Rab27a, and mutations in the gene encoding this protein (UNC13D) cause Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL3). The immunological features of GS2 and FHL3 include neutropenia, thrombocytopenia, and immunodeficiency due to impaired function of cytotoxic lymphocytes. The small number of disorders caused by mutations in genes encoding Rabs could be due to their essential functions, where defects in these genes could be lethal. However, with the increasing use of next generation sequencing technologies, more mutations in genes encoding Rabs may be identified in the near future.

Poliosis circumscripta: overview and underlying causes.

Although traditionally known as "white forelock," poliosis circumscripta, defined as a localized patch of white hair in a group of hair follicles, can involve any hairy area on the body including the scalp, eyebrows, and eyelashes. Microscopically, poliosis demonstrates either decreased or absent melanin and/or melanocytes in the hair bulbs of the affected hair follicles. Classically, poliosis is known to occur in the setting of several genetic syndromes including piebaldism, Waardenburg, and tuberous sclerosis. In addition, poliosis has been described in association with various acquired conditions. These include inflammatory conditions, benign and malignant neoplastic entities that are mainly melanocytic, medications, and others. In this review, we aim to describe the different conditions where poliosis may be encountered, with the aim of helping the clinician to better evaluate any patient presenting with poliosis.

In vivo and in vitro evidence for epidermal H2O2-mediated oxidative stress in piebaldism.

Piebaldism is characterised by the absence of pigment in patches on the skin, usually present at birth. Mutations in the kit gene are documented. Clinically this disorder can mimic vitiligo. Here, we show for the first time the presence of oxidised pteridine-induced fluorescence in association with H2O2-mediated stress in piebald patches employing Wood's light and in vivo FT-Raman spectroscopy. In situ immunofluorescence data revealed low catalase and methionine sulphoxide reductase A (MSRA) levels whereas thioredoxin reductase and methionine sulphoxide reductase B (MSRB) are not affected. We also show low superoxide dismutase levels in these patients. The presence of thioredoxin reductase provides capacity to reduce H2O2, a mechanism which is absent in vitiligo. Importantly, this enzyme reduces biopterin back to the functioning cofactor 6-tetrahydrobiopterin. The absence of MSRA indicates deficient methionine sulphoxide repair in the cytosol, meanwhile the presence of MSRB is helpful to protect the nucleus. Taken together, we have identified H2O2-mediated stress in piebald skin with distinct differences to vitiligo.

Myositis in Griscelli syndrome type 2 treated with hematopoietic cell transplantation.

Griscelli syndrome is an autosomal recessive disorder characterized by pigmentary dilution and is occasionally associated with a hemophagocytic syndrome (type 2). We present a 13-year-old girl with Griscelli syndrome type 2, who developed a hemophagocytic syndrome along with marked muscle weakness and elevated plasma creatine kinase. Muscle biopsy showed massive inflammatory changes in some fascicles, while other fascicles were relatively spared. Clinical symptoms and biopsy changes resolved after immunosuppression and allogeneic hematopoietic cell transplantation. Our results suggest that muscle involvement should be considered in patients with hemophagocytic syndrome to ensure proper treatment.

A novel KIT missense mutation in one Chinese family with piebaldism.

Piebaldism is an autosomal dominant disorder characterized by congenital leukoderma, mostly affecting forehead, abdomen and knee. Previous studies have revealed that piebaldism is caused by mutations of the KIT gene, which encodes the cell surface transmembrane tyrosine kinase receptor for KIT ligand. We reported here a Chinese Han family with piebaldism, and performed mutation detection of KIT gene by direct sequencing. A novel missense mutation C58G was identified in the patients, but not in the healthy individuals from the family and 100 unrelated controls. This study contributes to the database on KIT in piebaldism and enriches the knowledge about the genotype/phenotype correlation.

Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, naevus depigmentosus and vitiligo.

In order to investigate possible alterations in c-kit protein expression on epidermal melanocytes in different hypopigmentary disorders, we have examined skin specimens from one patient with piebaldism, one patient with naevus depigmentosus, and five patients with vitiligo. Cryosections were examined by immunohistochemistry using monoclonal antibodies against the c-kit protein (YB5.B8) and melanosomes (TA99). In piebaldism, hypomelanotic epidermis contained only a few TA99-positive epidermal melanocytes and no detectable c-kit protein, whereas in naevus depigmentosus the expression of c-kit protein was strong, and TA99 immunoreactivity was faint. In vitiligo lesions, no epidermal immunoreactivity for melanosomes or c-kit protein was found. Normally pigmented skin of all patients showed immunoreactivity of epidermal melanocytes for both c-kit protein and melanosomes. Different hypomelanotic lesions can thus be differentiated by absent melanocyte c-kit protein and low or no expression of melanosomal marker in piebaldism, normal c-kit but low melanosome expression in naevus depigmentosus, and the absence of all melanocyte markers in vitiligo.