The majority of cases (50C85%) have the childhood form of the disease, which is universally fatal without treatment, and should be suspected in a child who has partial albinism and a history of recurrent or severe infections. phase is the most life-threatening clinical feature of CHS, affecting about 85% of CHS patients within the first decade. This manifestation defines the characteristic childhood form of the disease and is characterized by massive HLH. It often occurs following initial exposure to Epstein-Barr virus (EBV), when it may resemble lymphoma [17]. HLH manifests as fever, lymphadenopathy, and hepatosplenomegaly with signs of liver dysfunction, cytopenia, and bleeding. Massive lymphohistiocytic infiltration of virtually all organ systems may also be observed. Most patients with prior history suggestive of CHS undergo a variable period of recurrent infections before entering the accelerated phase, but primary presentation in the accelerated phase has also been reported [17-20]. However, about 10C15% of patients follow a less severe clinical course of CHS, the adolescent and adult forms. These children present with mostly subtle hypopigmentation, a lower frequency of infections during childhood, adolescence, and adulthood, mild bleeding manifestations, and survive until adulthood without experiencing an NXT629 accelerated phase. Nonetheless, during adolescence or adulthood they develop progressive neurologic symptoms including intellectual deficit, dementia, peripheral neuropathy, parkinsonism, balance abnormalities, and tremor. The diagnosis of CHS is usually established when a child presents to a hospital with partial oculocutaneous albinism and recurrent pyogenic infections, and although unusual, as previously stated, primary presentation in the accelerated phase may also occur. Clinical suspicion is confirmed by laboratory evaluation, imaging studies, and by histologic findings. Indeed, the diagnosis of CHS patients is often made because of incidental observations of giant granules in neutrophils, derived from the coalescence of azurophilic and secondary granules on peripheral Rabbit polyclonal to FASTK blood smears (Figure?1). Giant granules are also observed in lymphocytes and natural killer (NK) cells from patients with CHS. Bone marrow aspirates demonstrate numerous large azurophilic or eosinophilic cytoplasmic inclusion bodies in cells of myeloid lineage that react strongly to peroxidase staining. Ultra-structural studies show that the granules contain giant lysosomes and NXT629 fibrillary structures in myeloid cells, with a reduced number and irregular morphology of platelet-dense bodies [18]. Open in a separate window Figure 1 Wright Giemsa staining of a peripheral blood smear from a patient with Chediak-Higashi syndrome showing polymorphonuclear leukocytes with abundant giant intracytoplasmic granules. Microscopic examination of the hair can also reveal clumped melanin granules, larger than those seen in normal hairs, and examination of the skin shows giant melanosomes both in keratinocytes and melanocytes, which can be used as a laboratory test for differential diagnosis with other partial albinism disorders [21]. Murine models of CHS exhibit the neuronal accumulation of giant lysosomes and intra-cytoplasmic inclusions in Purkinje cells of the cerebellum and motor cortex [22]. CHS patients have a profound defect in the function of cytotoxic and NK cells [23]. In addition, defects of neutrophils [24] include ineffective granulopoiesis, moderate neutropenia, and delayed and incomplete degranulation associated with phagocytic, chemotactic, and bacterial killing defects. Platelets are also functionally defective with reduced dense granules and impaired functions. Platelet function studies are consistent with a storage pool deficiency with reduced dense bodies and consequent defects of secretion-dependent aggregation [18,25]. Immunoglobulin levels and complement are generally normal. Computed tomography scans and magnetic resonance imaging might show diffuse atrophy of the brain and spinal cord [26], while electromyography and electroencephalography might reveal delayed nerve conduction time and seizure activity, respectively. Definite diagnosis is based on the molecular genetic testing of or a diagnosis of CHS do not prove the acute clinical syndrome of HLH, but rather a predisposition to develop the condition. Additionally, there are several characteristics that may underscore the clinical suspicion: moderate lymph node enlargement, jaundice, edema, pleural or pericardial effusions, skin rash, hypoproteinemia and hyponatremia, and elevation of liver NXT629 transaminases and lactate dehydrogenase [31]. Although not currently cited in any formal diagnostic algorithm, flow cytometry has been added to the arsenal of screening tools for HLH. The absence or decreased intensity of CD107a measured on the cell surface after degranulation has a high sensitivity and specificity for the diagnosis of a primary (genetic) disorder of granule exocytosis, as opposed to secondary causes.