Subject(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/immunologyABSTRACT
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/geneticsSubject(s)
Adaptor Proteins, Signal Transducing/metabolism , Immunologic Deficiency Syndromes/genetics , Membrane Proteins/metabolism , Mutation, Missense , rab27 GTP-Binding Proteins/genetics , rab27 GTP-Binding Proteins/metabolism , Albinism/genetics , Albinism/immunology , Albinism/metabolism , Amino Acid Substitution , Consanguinity , Female , Genes, Recessive , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/metabolism , Male , Pedigree , Piebaldism/genetics , Piebaldism/immunology , Piebaldism/metabolism , Primary Immunodeficiency Diseases , Protein Binding/geneticsABSTRACT
Cytotoxic T lymphocytes, natural killer cells, and NKT cells are effector cells able to kill infected cells. In some inherited human disorders, a defect in selected proteins involved in the cellular cytotoxicity mechanism results in specific clinical syndromes, grouped under the name of familial hemophagocytic lymphohistiocytosis. Recent advances in genetic studies of these patients has allowed the identification of different genetic subsets. Additional genetic immune deficiencies may also induce a similar clinical picture. International cooperation and prospective trials resulted in refining the diagnostic and therapeutic approach to these rare diseases with improved outcome but also with improved knowledge of the mechanisms underlying granule-mediated cellular cytotoxicity in humans.
Subject(s)
Cytotoxicity, Immunologic/physiology , Killer Cells, Natural/immunology , Lymphohistiocytosis, Hemophagocytic , Natural Killer T-Cells/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Chediak-Higashi Syndrome/genetics , Chediak-Higashi Syndrome/immunology , Cytoplasmic Granules/metabolism , Hermanski-Pudlak Syndrome/genetics , Hermanski-Pudlak Syndrome/immunology , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Lymphocyte Subsets/immunology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/therapy , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/immunology , Macrophage Activation Syndrome/genetics , Macrophage Activation Syndrome/immunology , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Munc18 Proteins/genetics , Munc18 Proteins/immunology , Perforin , Piebaldism/genetics , Piebaldism/immunology , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/immunology , Primary Immunodeficiency Diseases , Qa-SNARE Proteins/genetics , Qa-SNARE Proteins/immunologyABSTRACT
INTRODUCTION: Haemophagocytic syndrome (HS) is a common manifestation of several congenital disorders characterised by a disruption of lysosomal secretion, interrupting the cytolytic pathway and triggering a dysfunction in the immune synapse. In this situation, the recognition of certain extra-immunological manifestations may help in the diagnostic process. PATIENTS AND METHODS: We describe the clinical and biological features present in two brothers with familial haemophagocytic lymphohistiocytosis type 3 (FHL-3), two patients with Griscelli syndrome type 2 (GS-2) and one patient with Chédiak-Higashi syndrome (CHS). RESULTS: Mutational assays at UNC13D were carried out on two brothers after diagnosing an early onset HS in the first one, yielding a positive result in both cases with a consequent diagnosis of FHL-3. The diagnosis of GS-2 was supported by positive results of mutational Rab27A studies in one patient with HS and abnormal pigmentation, and in her cousin who was affected by a similar abnormal pigmentation. The diagnosis of CHS was established in one patient with HS, abnormal pigmentation and atypical granules on cytological examination of a bone marrow smear. Diagnosis was confirmed in this patient by the finding of a homozygous LYST mutation. CONCLUSIONS: We point out the importance of recognising the presence of typical extra-immunological manifestations of certain congenital disorders of lysosome secretion in patients diagnosed with HS. The association of albinism and immunodeficiency has played a critical role in the recent identification of the molecular mechanism involved in these disorders.
Subject(s)
Chediak-Higashi Syndrome , Immunologic Deficiency Syndromes , Lymphohistiocytosis, Hemophagocytic , Lysosomal Storage Diseases , Piebaldism , Antigen-Presenting Cells , Chediak-Higashi Syndrome/diagnosis , Chediak-Higashi Syndrome/genetics , Chediak-Higashi Syndrome/immunology , Child , Child, Preschool , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Infant , Lymphocytes , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/immunology , Lysosomal Storage Diseases/diagnosis , Lysosomal Storage Diseases/genetics , Lysosomal Storage Diseases/immunology , Piebaldism/diagnosis , Piebaldism/genetics , Piebaldism/immunology , Primary Immunodeficiency DiseasesABSTRACT
Griscelli syndrome is a rare autosomal recessive disorder characterized by partial albinism with variable immunodeficiency. Silvery gray hair with large, clumped melanosomes on microscopy of hair shafts are diagnostic. The commonest complication leading to mortality includes lymphohistiocytic proliferation in various organs, including the brain. We present a child with classic clinical features and confirmatory findings of clumped melanosomes on microscopy of hair shaft.
Subject(s)
Common Variable Immunodeficiency , Piebaldism/immunology , Common Variable Immunodeficiency/diagnosis , Fatal Outcome , Female , Humans , Infant , SyndromeABSTRACT
UNLABELLED: A 2-month-old girl presented with fever, hepatosplenomegaly, pancytopenia, hypertriglyceridaemia and silvery-greyish hair, suggesting the diagnosis of Griscelli syndrome (partial albinism with immunodeficiency). This diagnosis was confirmed by the characteristic agglomeration of melanin in the hair shaft and accumulation of melanosomes in melanocytes of the skin. The patient was homozygous for polymorphic markers around the myosin-Va gene on chromosome 15q21, which co-localize to the Griscelli disease locus. Natural-killer cells were in the lower range. The stimulation of lymphocytes with antigen and mitogen was normal. The patient's accelerated phase, characterized by haemophagocytosis was treated with prednisolone, rabbit anti-thymocyte globulins, and intrathecal methotrexate. Remission was maintained with cyclosporin A until HLA-compatible peripheral blood stem cell transplantation from her mother. CONCLUSION: The silvery-greyish hair associated with fever, pancytopenia and hypertriglyceridaemia is the clue to early diagnosis of Griscelli syndrome and important to prevent death before stem cell transplantation.
Subject(s)
Hematopoietic Stem Cell Transplantation , Immunologic Deficiency Syndromes/physiopathology , Piebaldism/physiopathology , Chromosomes, Human, Pair 15 , Female , Hair Color , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/pathology , Immunologic Deficiency Syndromes/therapy , Infant , Melanosomes/ultrastructure , Pedigree , Piebaldism/genetics , Piebaldism/immunology , Piebaldism/pathologyABSTRACT
A case of graft-vs.-host disease (GVHD) arising solely within an area affected by piebaldism is described. The patient, a 35-year-old woman with a single hypopigmented patch on the right leg present since birth, had received an allogeneic bone marrow transplant (BMT) from an HLA-identical sibling donor, for treatment of a myelodysplastic syndrome (MDS). Beginning on day +38 post-BMT, the patch developed changes which were histologically consistent with GVHD. Syngeneic mixed epidermal cell-lymphocyte reaction (MECLR) testing of tissue from the patch, and from adjacent normal skin, showed differences which suggest that piebaldism-affected skin is immunologically different from normal skin. These findings may offer new insight into the pathophysiology of this disorder.
