Chédiak–Higashi syndrome

Chédiak–Higashi syndrome(CHS) is a rareautosomal recessivedisorder that arises from a mutation of a lysosomal trafficking regulator protein,which leads to a decrease inphagocytosis. The decrease in phagocytosis results in recurrentpyogenicinfections,albinism, and peripheralneuropathy.
In Chédiak–Higashi syndrome, the lysosomal trafficking regulator (LYST) gene is mutated, leading to disruption of protein synthesis as well as the storage and secretory function oflysosomalgranules inwhite blood cells.This results in defective white blood cell function with enlargedvesicles. This syndrome also leads toneutropeniaand phagocyte bactericidal dysfunction due to impairedchemotaxis.Deficiency in serotonin and adenosine-phosphate-containing granules inplateletscauses impaired platelet aggregation, leading to prolonged bleeding time. Thus, patients are susceptible to infections and often present with oculo-cutaneous albinism and coagulation defects.Patients often present with early-onset aggressiveperiodontitisassociated with advanced alveolar bone loss and tooth mobility due to neutropenia and defective neutrophil function. Recurrent oral ulcerations are also one of the common oral manifestations in patients with this disease.Dental practitioners who notice child patients who present with recurrent unexplainedgingivitisandperiodontitisalong with hypopigmentation of hair, skin and eyes should consider making a referral to medical practitioners to investigate for the possible diagnosis of Chédiak–Higashi syndrome.
People with CHS have light skin and silvery hair (albinism) and frequently complain of solar sensitivity andphotophobia. Other signs and symptoms vary considerably, but frequent infections and neuropathy are common. The infections involvemucous membranes, skin, and the respiratory tract. Affected children are susceptible to infection byGram-positiveand gram-negative bacteria and fungi, withStaphylococcus aureusbeing the most common infectious cause. Infections in CHS patients tend to be very serious and even life-threatening.Neuropathyoften begins in the teenage years and becomes the most prominent problem. Few patients with this condition live to adulthood.
Most children with Chédiak–Higashi syndrome ultimately reach a stage known as the "accelerated phase", or the "lymphoma-like syndrome", in which defectivewhite blood cellsdivide uncontrollably and invade many of the body's organs. The accelerated phase is associated with fever, episodes of abnormal bleeding, overwhelming infections, and organ failure. These medical problems are usually life-threatening in childhood.
Mutations in theCHS1gene (also calledLYST) located on the chromosome 1q42-q43 have been found to be connected with Chédiak–Higashi syndrome. This gene provides instructions for making a protein known as the lysosomal trafficking regulator. Researchers believe that this protein plays a role in the transport (trafficking) of materials into lysosomes. Lysosomes act as recycling centers within cells. They use digestive enzymes to break down toxic substances, digest bacteria that invade the cell and recycle worn-out cell components. Although the lysosomal trafficking regulator protein is involved in the normal function of lysosomes, its exact role is unknown.
In melanocytic cells, LYST gene expression may be regulated byMITF.Mutations inMITFare known to causeWaardenburg syndrometype 2 andTietz syndrome, which result in depigmentation and deafness.
CHS is a disease causing impairedbacteriolysisdue to failure ofphagolysosomeformation.As a result of disordered intracellular trafficking there is impairedlysosomedegranulationwithphagosomes, so phagocytosedbacteriaare not destroyed by the lysosome'senzymes.
In addition, secretion of lyticsecretory granulebycytotoxic T cellsis affected.
The disease is characterised by large lysosomevesiclesinphagocytes(neutrophils), which thus have poorbactericidalfunction, leading to susceptibility to infections, abnormalities in nuclear structure of leukocytes,anemia, andhepatomegaly.Döhle bodies(remnants ofendoplasmic reticulum) in theneutrophilare also seen.
The diagnosis is confirmed by bone marrow smears that show "giantinclusion bodies" in the cells that develop into white blood cells (leukocyte precursor cells). CHS can be diagnosed prenatally by examining a sample of hair from a fetal scalp biopsy or testingleukocytesfrom a fetal blood sample.
Under light microscopy the hairs present evenly distributed, regular melanin granules, larger than those found in normal hairs. Under polarized light microscopy these hairs exhibit a bright and polychromatic refringence pattern.
There are several manifestations of Chédiak–Higashi syndrome as mentioned above; however,neutropeniaseems to be the most common. The syndrome is associated withoculocutaneous albinism. Patients are prone to infections, especially withStaphylococcus aureus, as well asStreptococci.
It is associated with periodontal disease of the deciduous dentition. Associated features include abnormalities in melanocytes (albinism), nerve defects, and bleeding disorders.
There is no specific treatment for Chédiak–Higashi syndrome. Bone marrow transplants appear to have been successful in several patients. Infections are treated with antibiotics and abscesses are surgically drained when appropriate. Antiviral drugs such as acyclovir have been tried during the
terminal phase of the disease. Cyclophosphamide and prednisone have been tried. Vitamin C therapy has improved immune function and clotting in some patients.
It is named for theCubanphysician and serologist of Lebanese descentMoisés Chédiak Ahuayda(1903–1993) and theJapanesepediatricianOtotaka Higashi(1883–1981).It is often spelled without the accent as Chediak–Higashi syndrome.
It also occurs incattle, bluePersian cats,Australian blue rats,mice,minks,foxes,and the only known captivewhite orca.