Subject(s)
Hypopigmentation , Humans , Hypopigmentation/pathology , Piebaldism/pathology , Piebaldism/complications , Female , MaleABSTRACT
A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold its head on its own or to remain in a stable prone position for an extended period. Histopathological examination revealed an accumulation of clumped melanin and deposition of accumulated keratin within the hair follicles, accompanied by dermal pigmentary incontinence. These dermatological changes were compatible with the histopathology described in dogs with an MLPH-related dilute coat color. We sequenced the genome of the affected dog and compared the data to 795 control genomes. MYO5A, coding for myosin VA, was investigated as the top functional candidate gene. This search revealed a private homozygous frameshift variant in MYO5A, XM_022412522.1:c.4973_4974insA, predicted to truncate 269 amino acids (13.8%) of the wild type myosin VA protein, XP_022268230.1:p.(Asn1658Lysfs*28). The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 142 additionally genotyped, unrelated Dachshund dogs. MYO5A loss of function variants cause Griscelli type 1 syndrome in humans, lavender foal in horses and the phenotype of the dilute mouse mutant. Based on the available data, together with current knowledge on other species, we propose the identified MYO5A frameshift insertion as a candidate causative variant for the observed dermatological and neurological signs in the investigated dog.
Subject(s)
Dog Diseases/genetics , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Piebaldism/genetics , Pigmentation Disorders/genetics , Alleles , Animals , Dog Diseases/pathology , Dogs , Frameshift Mutation/genetics , Genotype , Hair Color/genetics , Hearing Loss, Sensorineural/pathology , Homozygote , Humans , Phenotype , Piebaldism/pathology , Pigmentation/genetics , Pigmentation Disorders/pathologySubject(s)
Adaptor Protein Complex 3/genetics , Adaptor Protein Complex beta Subunits/genetics , Hermanski-Pudlak Syndrome/genetics , Hermanski-Pudlak Syndrome/pathology , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Piebaldism/genetics , Piebaldism/pathology , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/pathology , Adolescent , Child , Female , Gene Deletion , Hermanski-Pudlak Syndrome/immunology , Humans , Lymphohistiocytosis, Hemophagocytic/immunology , Male , Piebaldism/immunology , Primary Immunodeficiency Diseases/immunologySubject(s)
Lymphohistiocytosis, Hemophagocytic , Piebaldism , Primary Immunodeficiency Diseases , rab27 GTP-Binding Proteins/genetics , Adolescent , Autografts , Hematopoietic Stem Cell Transplantation , Humans , Lymphohistiocytosis, Hemophagocytic/diagnostic imaging , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Piebaldism/diagnostic imaging , Piebaldism/genetics , Piebaldism/pathology , Primary Immunodeficiency Diseases/diagnostic imaging , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/pathologySubject(s)
Hearing Loss, Sensorineural/genetics , Immunologic Deficiency Syndromes/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Nervous System Diseases/genetics , Piebaldism/genetics , Pigmentation Disorders/genetics , Child , Child, Preschool , Codon, Nonsense , Egypt/epidemiology , Female , Genotype , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/pathology , Humans , Hypopigmentation/diagnosis , Hypopigmentation/etiology , Hypopigmentation/genetics , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/etiology , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Male , Nervous System Diseases/diagnosis , Nervous System Diseases/etiology , Pedigree , Phenotype , Piebaldism/diagnosis , Piebaldism/epidemiology , Piebaldism/pathology , Pigmentation Disorders/diagnosis , Pigmentation Disorders/epidemiology , Pigmentation Disorders/pathology , PrevalenceABSTRACT
Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SNAI2 genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. Herein, we report a 5-month-old Chinese girl with severe piebaldism but no family history thereof. She has white forelock and large patches of depigmentation in the jaw, central anterior trunk, perineum and extremities. We performed whole-exome and Sanger sequencing and identified a de novo KIT mutation (NM_000222.2: c.2657G>A, p.Gly886Val) in exon 18 of KIT in the proband. Currently, this mutation is located in the most extreme C-terminal of the tyrosine kinase domain 2 of the KIT gene amongst all reported mutations and causes a severe clinical phenotype. We further reviewed literature on piebaldism and summarized 79 KIT gene mutations that lead to this disease. Our study may expand knowledge on the genotype-phenotype correlation in piebaldism and serve as a reference for genetic counseling and prenatal diagnosis of affected families.
Subject(s)
Genetic Predisposition to Disease , Piebaldism/genetics , Pigmentation Disorders/genetics , Proto-Oncogene Proteins c-kit/genetics , Child, Preschool , Female , Humans , Mutation/genetics , Pedigree , Piebaldism/pathology , Pigmentation Disorders/pathology , Exome SequencingSubject(s)
Melanocytes/pathology , Piebaldism/pathology , Skin Pigmentation/physiology , Skin/cytology , Cell Lineage , Child, Preschool , Female , Humans , MART-1 Antigen/metabolism , Melanocytes/metabolism , Microphthalmia-Associated Transcription Factor/metabolism , Piebaldism/diagnosis , Piebaldism/genetics , Proto-Oncogene Proteins c-kit/geneticsABSTRACT
Griscelli syndrome type 2 (GS2) is an autosomal recessive condition associated with the development of hemophagocytic lymphohistiocytosis. GS2 is caused by a gene mutation involving RAB27A, which affects a melanosome anchoring complex in melanocytes and releases cytolytic granules from T cells and natural killer cells. GS2 is known to have immunologic compromise and oculocutaneous albinism. We present the case of 2 sisters who had vastly different phenotypic presentations despite having the same genetic frameshift mutation in the RAB27A gene. Patient 1 presented with seizures and neurological compromise, whereas patient 2 presented with pancytopenia and diarrhea. Both patients developed hemophagocytic lymphohistiocytosis.
Subject(s)
Diarrhea/pathology , Frameshift Mutation , Lymphohistiocytosis, Hemophagocytic/pathology , Pancytopenia/pathology , Piebaldism/pathology , Primary Immunodeficiency Diseases/pathology , Seizures/pathology , rab27 GTP-Binding Proteins/genetics , Child, Preschool , Diarrhea/complications , Diarrhea/genetics , Female , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/genetics , Pancytopenia/complications , Pancytopenia/genetics , Piebaldism/complications , Piebaldism/genetics , Primary Immunodeficiency Diseases/complications , Primary Immunodeficiency Diseases/genetics , Prognosis , Seizures/complications , Seizures/genetics , SiblingsABSTRACT
The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediakâ»Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.
Subject(s)
Pigmentation Disorders/diagnosis , Pigmentation Disorders/genetics , Rare Diseases/diagnosis , Rare Diseases/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , Adult , Chediak-Higashi Syndrome/diagnosis , Chediak-Higashi Syndrome/genetics , Chediak-Higashi Syndrome/immunology , Chediak-Higashi Syndrome/pathology , Child, Preschool , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/immunology , Craniofacial Abnormalities/pathology , Diagnosis, Differential , Female , Hair/abnormalities , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/immunology , Hearing Loss, Sensorineural/pathology , Humans , Hypertrichosis/chemically induced , Iris/abnormalities , Male , Mutation , Neurocutaneous Syndromes/diagnosis , Neurocutaneous Syndromes/genetics , Neurocutaneous Syndromes/immunology , Neurocutaneous Syndromes/pathology , Piebaldism/diagnosis , Piebaldism/genetics , Piebaldism/immunology , Piebaldism/pathology , Pigmentation Disorders/immunology , Pigmentation Disorders/pathology , Quality of Life , Rare Diseases/immunology , Rare Diseases/pathology , Skin Abnormalities , rab27 GTP-Binding Proteins/geneticsABSTRACT
Griscelli syndrome is a rare autosomal recessive inherited disorder characterized by hypopigmentation, silver colored hair, and associated immunological deficiency, which proves fatal in the absence of timely intervention. Our patients diagnosed with Griscelli syndrome-2 presented with fever, hepatosplenomegaly, and deranged hematological and biochemical parameters. Both cases underwent detailed investigations comprising of hair mount microscopic examination, degranulation assay, and mutational studies. Our cases showed defective degranulation activity by NK cells and gene mutation analysis revealed RAB27A mutation that causes defect of cytotoxic granule exocytosis from natural killer (NK) and T-cells, manifesting clinically as hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplantation in one of the patients resulted in stable chimerism; however, the second case relapsed within a month after SCT. Stem cell transplantation is the only curative therapeutic option for GS2; thus, improvement in posttransplantation management may reduce mortality and posttransplant complications. Hence, any child who presents with partial albinism and clinical features suggestive of HLH, a peripheral blood, hair shaft mount examination along with basic immunological NK and T-cell cytotoxicity assay by flow cytometry will help clinch the diagnosis early. It can subsequently be confirmed by molecular study. Timely therapeutic intervention can prevent relapses and severe infection and improve outcome in these cases.
Subject(s)
Hematopoietic Stem Cell Transplantation , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/therapy , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/therapy , Piebaldism/genetics , Piebaldism/therapy , Child, Preschool , Female , Hair , Humans , Immunologic Deficiency Syndromes/pathology , Killer Cells, Natural/pathology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Mutation , Piebaldism/pathology , Primary Immunodeficiency Diseases , Treatment Outcome , rab27 GTP-Binding Proteins/geneticsABSTRACT
Here, we present a theoretical investigation with potential insights on developmental mechanisms. Three biological factors, consisting of two diffusing factors and a cell-autonomous immobile transcription factor are combined with different feedback mechanisms. This results in four different situations or fur patterns. Two of them reproduce classical Turing patterns: (1) regularly spaced spots, (2) labyrinth patterns or straight lines with an initial slope in the activation of the transcription factor. The third situation does not lead to patterns, but results in different homogeneous color tones. Finally, the fourth one sheds new light on the possible mechanisms leading to the formation of piebald patterns exemplified by the random patterns on the fur of some cows' strains and Dalmatian dogs. Piebaldism is usually manifested as white areas of fur, hair, or skin due to the absence of pigment-producing cells in those regions. The distribution of the white and colored zones does not reflect the classical Turing patterns. We demonstrate that these piebald patterns are of transient nature, developing from random initial conditions and relying on a system's bistability. We show numerically that the presence of a cell-autonomous factor not only expands the range of reaction diffusion parameters in which a pattern may arise, but also extends the pattern-forming abilities of the reaction-diffusion equations.
Subject(s)
Body Patterning/physiology , Models, Biological , Piebaldism/veterinary , Skin Pigmentation/physiology , Animal Fur/pathology , Animals , Cattle , Cattle Diseases/etiology , Cattle Diseases/pathology , Computer Simulation , Disease Models, Animal , Dog Diseases/etiology , Dog Diseases/pathology , Dogs , Mathematical Concepts , Melanocytes/pathology , Piebaldism/etiology , Piebaldism/pathology , Stochastic ProcessesABSTRACT
INTRODUCTION: Griscelli syndrome (GS) is a rare autosomal-recessive genetic disease characterized by hypopigmentation of skin and hair. We report a case of GS type 3 with late diagnosis. OBSERVATION: A 31-year-old female patient had presented depigmentation of the hair and eyebrows as well as diffuse skin hypopigmentation during childhood. Microscopic analysis of a hair shaft revealed irregularly distributed clumps of melanin. DNA sequencing showed a homozygous C103T (R35W) transition in exon 1 of MLPH, confirming Griscelli syndrome type 3. DISCUSSION: Three clinical phenotypes of GS have been described based on the underlying genetic defect. GS type 1 and 2 are associated respectively with a central nervous system dysfunction and an immune defect. GS type 3 is an isolated cutaneous form. Diagnosis is confirmed on microscopic examination of hair shafts. 15 cases of GS type 3 have been reported: 9 in males and 6 in females. Mean age at diagnosis is around 12 years. Nine of the reported patients were of Arab origin, four of Turkish origin, and one of Indian origin. R35W mutation was described in 9 cases and E98X and R35Q mutations were each found in one case. CONCLUSION: GS should be suspected in patients presenting gray silvery hair, particularly when these patients are of Arab or Turkish origin.
Subject(s)
Piebaldism/genetics , Pigmentation Disorders/genetics , Pregnancy Complications/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Algeria/ethnology , Consanguinity , Delayed Diagnosis , Diagnosis, Differential , Exons/genetics , Female , Hair/chemistry , Hair/pathology , Hair Color/genetics , Humans , Melanins/analysis , Mutation, Missense , Phenotype , Piebaldism/pathology , Pigmentation Disorders/pathology , Point Mutation , Pregnancy , Pregnancy Complications/pathologyABSTRACT
BACKGROUND/OBJECTIVES: Silvery hair syndrome is a rare, autosomal-recessive entity characterized by silvery gray hair, eyebrows, and eyelashes and may be associated or not with immunologic or neurologic alterations. Two main types have been recognized: Chediak-Higashi syndrome and Griscelli syndrome. Hair shaft examination under light microscopy has been a useful tool to differentiate Chediak-Higashi syndrome from Griscelli syndrome, although distribution of melanin varies according to hair color related to ethnicity. The objective was to compare the pattern of melanin in the skin and with the pattern of melanin distribution in the hair shaft. METHODS: Sixteen patients with silvery hair syndrome were selected (Chediak-Higashi syndrome 5, Griscelli syndrome 11). The distribution of melanin granules in skin and hair shafts was compared and correlated with clinical diagnoses. RESULTS: Chediak-Higashi syndrome was characterized by small granules of melanin uniformly distributed throughout the thickness of the epidermis. Griscelli syndrome was characterized by an irregular pigment distribution in the epidermal basal layer with large and dense granules alternating with areas lacking melanin pigment. In two cases, study of the hair was not conclusive, but the skin showed the characteristic pattern of Griscelli syndrome. CONCLUSION: Skin biopsy is a useful tool in differentiating Chediak-Higashi syndrome from Griscelli syndrome and as a complementary study in cases in which hair shaft pigment distribution does not support the diagnosis, especially in patients with fair hair. The distribution of melanin granules in the skin correlates with that observed in the hair shaft, allowing Chediak-Higashi syndrome to be differentiated from Griscelli syndrome, at any age.
Subject(s)
Chediak-Higashi Syndrome/diagnosis , Hair/pathology , Hearing Loss, Sensorineural/diagnosis , Immunologic Deficiency Syndromes/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , Piebaldism/diagnosis , Pigmentation Disorders/diagnosis , Adolescent , Biopsy , Chediak-Higashi Syndrome/pathology , Child , Child, Preschool , Diagnosis, Differential , Female , Hearing Loss, Sensorineural/pathology , Humans , Immunologic Deficiency Syndromes/pathology , Infant , Infant, Newborn , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Piebaldism/pathology , Pigmentation Disorders/pathology , Primary Immunodeficiency Diseases , Retrospective Studies , Skin/pathologyABSTRACT
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.
Subject(s)
Piebaldism/pathology , Pigmentation Disorders/pathology , Skin Pigmentation , Adult , Humans , Male , Piebaldism/metabolism , Pigmentation Disorders/metabolismSubject(s)
Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/pathology , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Piebaldism/genetics , Piebaldism/pathology , rab27 GTP-Binding Proteins/genetics , 5' Untranslated Regions , Adolescent , Child , Female , Humans , Lymphocytes/metabolism , Male , Melanocytes/metabolism , Mutation , Pedigree , Pigmentation/genetics , Primary Immunodeficiency DiseasesABSTRACT
Piebaldism is a rare autosomal dominant genodermatosis. It is due to congenital absence of melanocytes in the affected areas. We report a case. A 5 year old girl born to consanguineous parents and with similar cases in her mother's; she presented since birth achromic lesions on the legs with a steady evolution. clinical examination showed confluent achromic macules and poliosis (A) with no contrast enhancement under Wood lamp and several coffee-with-milk colored spots on the trunk and thighs(B). The diagnosis of piebaldism was made. Piebaldism is a rare genodermatosis. Its incidence is estimated at less than 1/20000 newborns. It is characterized by the congenital absence of melanocytes in the areas affected by mutation of the c-kit gene and by symmetrical achromic macules appeared at birth with a steady and persistent evolution. A white lock of hair on the forehead could be seen in 80% of cases The differential diagnosis includes vitiligo, albinism and Waardenburg syndrome. Associations have been described with neurofibromatosis type I. However, isolated coffee-with-milk colored spots can be observed; as the case of our patient. The treatment is based on split-thickness skin graft. Piebaldism is a rare genodermatosis. This study aims to discuss its clinical aspects and differential diagnoses.
Subject(s)
Melanocytes/pathology , Piebaldism/diagnosis , Proto-Oncogene Proteins c-kit/genetics , Child, Preschool , Diagnosis, Differential , Female , Humans , Mutation , Piebaldism/genetics , Piebaldism/pathologySubject(s)
Hearing Loss, Sensorineural/pathology , Piebaldism/pathology , Pigmentation Disorders/pathology , Diagnosis, Differential , Fatal Outcome , Fever/etiology , Hair/pathology , Hearing Loss, Sensorineural/diagnostic imaging , Hearing Loss, Sensorineural/therapy , Humans , Infant , Magnetic Resonance Imaging , Male , Piebaldism/diagnostic imaging , Piebaldism/therapy , Pigmentation Disorders/diagnostic imaging , Pigmentation Disorders/therapy , Seizures/etiology , Tomography, X-Ray ComputedABSTRACT
Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.