Chédiak-Higashi syndrome
Chédiak-Higashi syndrome
Clinical features Chédiak-Higashi syndrome is an uncommon autosomal recessive multisystem disorder characterized by partial oculocutaneous albinism, severe immunological dysfunction resulting in recurrent bacterial infections, a bleeding tendency, progressive neurological dysfunction, particularly peripheral neuropathy, and severe periodontitis.1–9 Characteristically, many cells (including melanocytes, myeloid cells, and lymphocytes) contain peroxidase-positive giant granules. The majority of patients die early in childhood as a result of either bacterial infection or an accelerated phase characterized by diffuse infiltration of organs (e.g., liver, spleen), lymph nodes, and bone marrow by lymphocytes and histiocytes.1,3 The accelerated phase is only rarely the first manifestation of the disease.10
Hemophagocytosis is common, as are hepatosplenomegaly, anemia, thrombocytopenia, and neutropenia. About 10% of patients survive into
adulthood but usually succumb to progressive neurological disease. Bone marrow transplant has a dramatic effect in preventing recurrent infections; it also prevents the accelerated phase of the disease but not the progressive neurological deterioration.11
The defect in pigmentation may affect skin, hair, and eyes. Affected individuals usually have light silvery hair, and speckled hyper- and hypopigmentation of exposed areas may be seen.12 Patches of hyperpigmentation mainly seen in sun-exposed areas are, however, rare.13
Pathogenesis and histologic features The tendency to develop recurrent infections is due to impaired chemotaxis and abnormal NK-cell function. Chédiak-Higashi syndrome and Hermansky-Pudlak syndrome (see above) are regarded as disorders of vesicle formation and trafficking.3,4,14–16 The gene for Chédiak-Higashi syndrome has been mapped to chromosome 1 and has been designated CHS1/ LYST. The gene encodes a cytosolic protein of 430 kD. The exact function of this protein in vesicle trafficking is as yet unknown.3,4
997 Griscelli syndrome
problems are classified as Griscelli syndrome type 1. Many of the manifestations of the disease are secondary to the presence of hemophagocytic lymphohistiocytosis and severe immunodeficiency – these patients are classified as Griscelli syndrome type 2.1,4,5 The two phenotypes of the disease correlate with the type of genetic mutation (see below). A third type of the syndrome presents only with hypopigmentation: Griscelli syndrome type 3.6,7 All patients with any subtype of the disease share the presence of hypopigmentation and silver-gray hair. Examination of hair shafts reveals prominent accumulation of melanin. An association with myelodysplastic syndrome has also been documented. Most clinical manifestations occur between the age of 4 months and 4 years. Unless bone marrow transplant is performed early in the course of the disease in patients with Griscelli syndrome type 2, death invariably occurs.8
A biopsy from involved skin shows marked reduction in the amount of melanin present in the epidermis and hair follicles. Giant melanosomes may be seen. These – and the giant granules found in other cells – are the result of giant lysosomes formed during fusion and phagocytosis.14,17
Giant melanosomes and smaller granules can be demonstrated in melanocytes by electron microscopy. Giant cytoplasmic granules have also been documented in Langerhans cells.18
Pathogenesis and histologic features The gene maps to chromosome 15q21 and mutations in two genes located in this region – MYO5a (myosin-Va gene) (Griscelli syndrome type 1) and RAB27A (GTP-binding protein) (Griscelli syndrome type 2) – have been described.9 RAB27A protein appears to be involved in the control of the immune system as patients with mutations of this protein (but not those with mutations of myosin-Va gene) develop hemophagocytic lymphohistiocytosis.9 T cells deficient in this protein also show decrease in cytotoxic activity. In Griscelli syndrome type 3 there are mutations of either the melanophilin gene (MLPH) or deletions of MYO5A F-exon.7 Although, in general, there is correlation between genotype and phenotype, a number of cases display genotypic-phenotypic disparity.10,11