Chédiak-Higashi syndrome
Encyclopedia
Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy. It occurs in humans, cattle
, white tiger
s, blue Persian cat
s, Australian blue rats
, mice
, mink
, foxes, and the only known captive albino orca
.
n physician and serologist Alexander Moisés Chédiak and the Japan
ese pediatrician Otokata Higashi. It is often spelled without the accent as Chediak–Higashi syndrome.
formation. As a result of disordered intracellular trafficking there is impaired lysosome
degranulation
with phagosomes, so phagocytosed bacteria
are not destroyed by the lysosome
's enzymes.
In addition, secretion of lytic secretory granules by cytotoxic T cells is affected.
The disease is characterised by large lysosome vesicle
s in phagocytes (neutrophils), which thus have poor bactericidal function, leading to susceptibility to infections, abnormalities in nuclear structure of leukocytes, anemia
, and hepatomegaly
.
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.
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.
. Other signs and symptoms vary considerably, but frequent infections and neuropathy are common. The infections involve mucous membranes, skin, and respiratory tract. Affected children are susceptible to gram-positive and gram-negative bacteria and fungi, with S. aureus being the most common. Neuropathy often begins in the teenage years and becomes the most prominent problem. Infections in CHS tend to be very serious and even life-threatening; few patients with this condition live to adulthood.
Most children with Chédiak–Higashi syndrome ultimately reach a stage known as the accelerated phase — the lymphoma-like-syndrome. This severe phase of the disease is thought to be triggered by a viral infection (usually the Epstein-Barr virus
, EBV). In the accelerated phase, defective white blood cells divide 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 have been found in the CHS1 (also called LYST) gene. The primary defect in this disease is in special granules present in skin pigment cells and certain white blood cells. For example, a granule that contains melanin is not made properly in skin, resulting in decreased skin pigmentation. A
defect in granules found in certain types of white blood cells causes immune system problems. Albinism
is typically partial, and some patients have peripheral neuropathy
.
terminal phase of the disease. Cyclophosphamide and prednisone have been tried. Vitamin C therapy has improved immune function and clotting in some patients.
seems to be the most common. The syndrome is associated with oculocutaneous albinism
. Persons are prone for infections, especially with Staphylococcus aureus.
It is associated with periodontal disease of the deciduous dentition. Associated features include abnormalities in melanocytes (albinism), nerve defects, bleeding disorders.
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
, white tiger
White tiger
The white tiger is a recessive mutant of the Bengal tiger, which was reported in the wild from time to time in Assam, Bengal, Bihar and especially from the former State of Rewa.-Color comparison:...
s, blue Persian cat
Persian cat
The Persian is a longhaired breed of cat characterized by its round face and shortened muzzle. Its name refers to Persia, the former name of Iran, where similar cats are found. Recognized by the cat fancy since the late 19th century, it was developed first by the English, and then mainly by...
s, Australian blue rats
Fancy rat
The fancy rat is a domesticated brown rat , which is the most common type of pet rat. The name fancy rat derives from the idea of animal fancy or the phrase "to fancy" ....
, mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
, mink
Mink
There are two living species referred to as "mink": the European Mink and the American Mink. The extinct Sea Mink is related to the American Mink, but was much larger. All three species are dark-colored, semi-aquatic, carnivorous mammals of the family Mustelidae, which also includes the weasels and...
, foxes, and the only known captive albino orca
Chimo (killer whale)
Chimo , was a young female orca exhibited in Sealand of the Pacific from 1970 to 1972, Chimo was notable for being the only partially albino orca ever exhibited in captivity. Years before her capture, another pure white orca was spotted in what is suspected to be the same pod, this orca was named...
.
Eponym
It is named for the CubaCuba
The Republic of Cuba is an island nation in the Caribbean. The nation of Cuba consists of the main island of Cuba, the Isla de la Juventud, and several archipelagos. Havana is the largest city in Cuba and the country's capital. Santiago de Cuba is the second largest city...
n physician and serologist Alexander Moisés Chédiak and the Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
ese pediatrician Otokata Higashi. It is often spelled without the accent as Chediak–Higashi syndrome.
Pathology
It is a disease with impaired bacteriolysis due to failure of phagolysosomePhagolysosome
A phagolysosome is the membrane-enclosed organelle which forms when a phagosome fuses with a lysosome. After fusion, the food particles or pathogens contained within the phagosome are usually digested by the enzymes contained within the lysosome. Phagolysosome formation follows phagocytosis...
formation. As a result of disordered intracellular trafficking there is impaired lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
degranulation
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...
with phagosomes, so phagocytosed bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
are not destroyed by the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
's enzymes.
In addition, secretion of lytic secretory granules by cytotoxic T cells is affected.
The disease is characterised by large lysosome vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
s in phagocytes (neutrophils), which thus have poor bactericidal function, leading to susceptibility to infections, abnormalities in nuclear structure of leukocytes, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, and hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
.
Diagnosis
The diagnosis is confirmed by bone marrow smears that show "giant inclusion 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 testing leukocytes from 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.
Causes
Chédiak–Higashi syndrome is caused by mutations in the LYST gene. 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 structures called 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.
Symptoms and prognosis
Patients with CHS have light skin and silvery hair, and frequently complain of solar sensitivity and photophobiaPhotophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
. Other signs and symptoms vary considerably, but frequent infections and neuropathy are common. The infections involve mucous membranes, skin, and respiratory tract. Affected children are susceptible to gram-positive and gram-negative bacteria and fungi, with S. aureus being the most common. Neuropathy often begins in the teenage years and becomes the most prominent problem. Infections in CHS tend to be very serious and even life-threatening; few patients with this condition live to adulthood.
Most children with Chédiak–Higashi syndrome ultimately reach a stage known as the accelerated phase — the lymphoma-like-syndrome. This severe phase of the disease is thought to be triggered by a viral infection (usually the Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
, EBV). In the accelerated phase, defective white blood cells divide 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 have been found in the CHS1 (also called LYST) gene. The primary defect in this disease is in special granules present in skin pigment cells and certain white blood cells. For example, a granule that contains melanin is not made properly in skin, resulting in decreased skin pigmentation. A
defect in granules found in certain types of white blood cells causes immune system problems. Albinism
Albinism
Albinism is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes due to absence or defect of an enzyme involved in the production of melanin...
is typically partial, and some patients have peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
.
Treatment
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 theterminal phase of the disease. Cyclophosphamide and prednisone have been tried. Vitamin C therapy has improved immune function and clotting in some patients.
Clinical findings
There are several manifestations of Chédiak–Higashi syndrome as mentioned above; however, neutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
seems to be the most common. The syndrome is associated with oculocutaneous albinism
Albinism
Albinism is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes due to absence or defect of an enzyme involved in the production of melanin...
. Persons are prone for infections, especially with Staphylococcus aureus.
It is associated with periodontal disease of the deciduous dentition. Associated features include abnormalities in melanocytes (albinism), nerve defects, bleeding disorders.