Hermansky-Pudlak syndrome
Encyclopedia
Hermansky–Pudlak syndrome (HPS) is a rare autosomal recessive
disorder which results in oculocutaneous albinism
(decreased pigmentation), bleeding problems due to a platelet
abnormality (platelet storage pool defect), and storage of an abnormal fat-protein compound (lysosomal
accumulation of ceroid lipofuscin).
There are eight classic forms of the disorder, based on the gene
tic mutation
from which the disorder stems.
A ninth type has also been described. This last type is due to a mutation in the gene Pallidin (PLDN).
The disease can cause dysfunctions of the lung
s, intestine
, kidney
s or heart
. The major complication of most forms of the disorder is pulmonary fibrosis
, which typically exhibits in patients ages 40 – 50 years old. This is a fatal complication seen in many forms of HPS, and is the usual cause of death from the disorder.
The disorder is more common in Puerto Rico
, where many of the clinical research studies on the disease have been conducted.
of the skin and hair, characteristic eye findings, and demonstration of absent
dense bodies on whole mount electron microscopy of platelets. Molecular
genetic testing of the HPS1 gene is available on a clinical basis for
individuals from northwestern Puerto Rico. Molecular testing of the HPS3 gene
is available on a clinical basis for individuals of central Puerto Rican or
Ashkenazi Jewish heritage. Sequence analysis is available on a clinical basis
for mutations in HPS1 and HPS4. Diagnosis of individuals with other types of
HPS is available on a research basis only.
s in several gene
s: HPS1
, HPS3
, HPS4
, HPS5
, HPS6
and HPS7.
HPS type 2, which includes immunodeficiency in its phenotype, is caused by mutation in the AP3B1
gene.
HPS type 7 may result from a mutation in the gene coding for dysbindin
protein.
Hermansky–Pudlak Syndrome is thought to be inherited as an autosomal recessive genetic trait. The defective gene, called HSP, responsible for this disorder is located on the long arm of chromosome 10 (10q2). Some research suggests that an abnormality of lysosomal function may be responsible for the development of the disease. HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1 and BLOC1S3 are associated with Hermansky Pudlak syndrome.
In autosomal recessive disorders, the condition does not appear unless a person inherits two copies of the defective gene responsible for the disorder, one copy coming from each parent. If an individual receives one normal gene and one gene for the disorder, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
and the antidiuretic dDAVP.
be aware that patients may have postoperative pulmonary complications as part
of the syndrome.
Preoperative hematology consultation is advisable prior to elective ocular
surgeries. Since patients with the syndrome have bleeding tendencies,
intraoperative, perioperative, and postoperative hemorrhages should be
prevented and treated. If platelet aggregation improves with desmopressin, it
may be administered in the preoperative period. However, sometimes
plasmapheresis is needed in the perioperative period.
Ophthalmologists should try to avoid retrobulbar blocks in patients with the
syndrome. Whenever possible, patients with HPS may benefit from general
endotracheal anesthesia. Phacoemulsification may help prevent intraoperative
and postoperative bleeding in patients with the syndrome. Prolonged bleeding
has been reported following strabismus surgery in patients with the syndrome.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
disorder which results in 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...
(decreased pigmentation), bleeding problems due to a platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
abnormality (platelet storage pool defect), and storage of an abnormal fat-protein compound (lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
accumulation of ceroid lipofuscin).
There are eight classic forms of the disorder, based on the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
tic mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
from which the disorder stems.
A ninth type has also been described. This last type is due to a mutation in the gene Pallidin (PLDN).
Prognosis
The course of HPS has been mild in rare instances of the disorder, however, the general prognosis is still considered to be poor.The disease can cause dysfunctions of the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s or heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
. The major complication of most forms of the disorder is pulmonary fibrosis
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...
, which typically exhibits in patients ages 40 – 50 years old. This is a fatal complication seen in many forms of HPS, and is the usual cause of death from the disorder.
The disorder is more common in Puerto Rico
Puerto Rico
Puerto Rico , officially the Commonwealth of Puerto Rico , is an unincorporated territory of the United States, located in the northeastern Caribbean, east of the Dominican Republic and west of both the United States Virgin Islands and the British Virgin Islands.Puerto Rico comprises an...
, where many of the clinical research studies on the disease have been conducted.
Diagnosis
The diagnosis of HPS is established by clinical findings of hypopigmentationof the skin and hair, characteristic eye findings, and demonstration of absent
dense bodies on whole mount electron microscopy of platelets. Molecular
genetic testing of the HPS1 gene is available on a clinical basis for
individuals from northwestern Puerto Rico. Molecular testing of the HPS3 gene
is available on a clinical basis for individuals of central Puerto Rican or
Ashkenazi Jewish heritage. Sequence analysis is available on a clinical basis
for mutations in HPS1 and HPS4. Diagnosis of individuals with other types of
HPS is available on a research basis only.
Causes
HPS can be caused by mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in several gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s: HPS1
HPS1
Hermansky-Pudlak syndrome 1 protein is a protein that in humans is encoded by the HPS1 gene.-External Links:* -Further reading:...
, HPS3
HPS3
Hermansky-Pudlak syndrome 3 protein is a protein that in humans is encoded by the HPS3 gene.-External Links:* -Further reading:...
, HPS4
HPS4
Hermansky-Pudlak syndrome 4 protein is a protein that in humans is encoded by the HPS4 gene.-External Links:* -Further reading:...
, HPS5
HPS5
Hermansky-Pudlak syndrome 5 protein is a protein that in humans is encoded by the HPS5 gene.-External Links:* -Further reading:...
, HPS6
HPS6
Hermansky-Pudlak syndrome 6 also known as ruby-eye protein homolog is a protein that in humans is encoded by the HPS6 gene.- Function :...
and HPS7.
HPS type 2, which includes immunodeficiency in its phenotype, is caused by mutation in the AP3B1
AP3B1
AP-3 complex subunit beta-1 is a protein that in humans is encoded by the AP3B1 gene.-External Links:* -Further reading:...
gene.
HPS type 7 may result from a mutation in the gene coding for dysbindin
Dysbindin
Dysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbindin was discovered by the research group of Derek Blake...
protein.
Hermansky–Pudlak Syndrome is thought to be inherited as an autosomal recessive genetic trait. The defective gene, called HSP, responsible for this disorder is located on the long arm of chromosome 10 (10q2). Some research suggests that an abnormality of lysosomal function may be responsible for the development of the disease. HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1 and BLOC1S3 are associated with Hermansky Pudlak syndrome.
In autosomal recessive disorders, the condition does not appear unless a person inherits two copies of the defective gene responsible for the disorder, one copy coming from each parent. If an individual receives one normal gene and one gene for the disorder, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Symptoms
There are three main disorders caused by Hermansky–Pudlak syndrome, which result in these symptoms:- Albinism and eye problems: Individuals will have varying amounts of skin pigment (melanin). Because of the albinism there are eye problems such as light sensitivity (photophobia), strabismus (crossed eyes), and nystagmus (involuntary eye movements). Hermansky–Pudlak syndrome also impairs vision.
- Bleeding disorders: Individuals with the syndrome have platelet dysfunction. Since platelets are necessary for blood clotting, individuals will bruise and bleed easily.
- Cellular storage disorders: The syndrome causes a wax-like substance (ceroid) to accumulate in the body tissues and cause damage, especially in the lungs and kidneys.
- Is associated with Granulomatous Colitis.
Treatment
While there is a cure for HPS, treatment for chronic hemorrhages associated with the disorder includes therapy with vitamin EVitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
and the antidiuretic dDAVP.
Considerations for patients with Hermansky-Pudlak
A preoperative pneumologist consultation is needed. The anesthesia team shouldbe aware that patients may have postoperative pulmonary complications as part
of the syndrome.
Preoperative hematology consultation is advisable prior to elective ocular
surgeries. Since patients with the syndrome have bleeding tendencies,
intraoperative, perioperative, and postoperative hemorrhages should be
prevented and treated. If platelet aggregation improves with desmopressin, it
may be administered in the preoperative period. However, sometimes
plasmapheresis is needed in the perioperative period.
Ophthalmologists should try to avoid retrobulbar blocks in patients with the
syndrome. Whenever possible, patients with HPS may benefit from general
endotracheal anesthesia. Phacoemulsification may help prevent intraoperative
and postoperative bleeding in patients with the syndrome. Prolonged bleeding
has been reported following strabismus surgery in patients with the syndrome.
See also
- Biogenesis of lysosome-related organelles complex 1Biogenesis of lysosome-related organelles complex 1BLOC-1 or biogenesis of lysosome-related organelles complex 1 is a ubiquitously expressed multisubunit protein complex. BLOC-1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules...
- List of cutaneous conditions