Hermansky-Pudlak syndrome

Other Names: HPS; Albinism with hemorrhagic diathesis and pigmented reticuloendothelial cells; Delta storage pool disease; Hermansky Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) affects multiple body systems and includes bleeding and visual problems, and abnormally light coloring of the skin, hair, and eyes (oculocutaneous albinism). Other symptoms may include immune problems, lung scarring (pulmonary fibrosis), and colitis.

Other, less common features of Hermansky-Pudlak syndrome include inflammation of the large intestine (granulomatous colitis) and kidney failure.

Types

There are nine different types of Hermansky-Pudlak syndrome, which can be distinguished by their signs and symptoms and underlying genetic cause. Types 1 and 4 are the most severe forms of the disorder. Types 1, 2, and 4 are the only types associated with pulmonary fibrosis. Individuals with type 3, 5, or 6 have the mildest symptoms. Little is known about the signs, symptoms, and severity of types 7, 8, and 9.

Epidemiology

Hermansky-Pudlak syndrome is a rare disorder in most populations and is estimated to affect 1 in 500,000 to 1,000,000 individuals worldwide. Type 1 is more common in Puerto Rico, particularly in the northwestern part of the island where about 1 in 1,800 people are affected. Type 3 is common in people from central Puerto Rico. Groups of affected individuals have been identified in many other regions, including India, Japan, the United Kingdom, and Western Europe.

Cause

Hermansky-Pudlak syndrome (HPS) occurs when there is a gene not working correctly. There are ten different genes associated with HPS. These include AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, and HPS6. DNA changes known as pathogenic variants are responsible for making genes work incorrectly or sometimes, not at all. These genes provide instructions for making proteins that are used to make four distinct protein complexes. These protein complexes play a role in the formation and movement (trafficking) of a group of cell structures called lysosome-related organelles (LROs). LROs are very similar to compartments within the cell called lysosomes, which digest and recycle materials. However, LROs perform specialized functions and are found only in certain cell types. LROs have been identified in pigment-producing cells (melanocytes), blood-clotting cells (platelets), and lung cells.

Mutations in the genes associated with Hermansky-Pudlak syndrome prevent the formation of LROs or impair the functioning of these cell structures. In general, mutations in genes that involve the same protein complex cause similar signs and symptoms. People with this syndrome have oculocutaneous albinism because the LROs within melanocytes cannot produce and distribute the substance that gives skin, hair, and eyes their color (melanin). Bleeding problems are caused by the absence of LROs within platelets, which affects the ability of platelets to stick together and form a blood clot. Mutations in some of the genes that cause Hermansky-Pudlak syndrome affect the normal functioning of LROs in lung cells, leading to pulmonary fibrosis.

Mutations in the HPS1 gene cause approximately 75 percent of the Hermansky-Pudlak syndrome cases from Puerto Rico. About 45 percent of affected individuals from other populations have mutations in the HPS1 gene. Mutations in the HPS3 gene are found in about 25 percent of affected people from Puerto Rico and in approximately 20 percent of affected individuals from other areas. The other genes associated with Hermansky-Pudlak syndrome each account for a small percentage of cases of this condition.

In some people with Hermansky-Pudlak syndrome, the genetic cause of the disorder is unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Symptoms

The following list includes the most common signs and symptoms in people with Hermansky-Pudlak syndrome (HPS).

Symptoms may include:

• Decreased immune function (immunodeficiency)
• Involuntary rapid eye movements (nystagmus)
• Partial absent skin coloring (partial albinism)
• Absent color in the eye (ocular albinism)
• Lung scarring that gets worse with time (pulmonary fibrosis)
• Inflammation of the colon (colitis)
• Poor absorption of nutrients (malabsorption)

The symptoms of HPS are present at birth. Many babies have involuntary eye movements. Children with HPS may have lighter hair, eyes, and skin, than other family members. They may bruise easy and have vision problems. Gastrointestinal problems including stomach pain, diarrhea, and weight loss may occur in the teens. Some people with HPS develop scarring of the lungs over time (pulmonary fibrosis) which can be serious.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Immunodeficiency(Decreased immune function)
• Neutropenia(Low blood neutrophil count)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Partial albinism(Partial absent skin pigmentation)

30%-79% of people have these symptoms

• Abnormality of the optic nerve(Optic nerve issue)
• Abnormality of visual evoked potentials
• Amblyopia(Lazy eye)
• Astigmatism(Abnormal curving of the cornea or lens of the eye)
• Bruising susceptibility(Bruise easily)
• Cataract(Clouding of the lens of the eye)
• Epistaxis(Bloody nose)
• Hypopigmentation of hair(Loss of hair color)
• Menometrorrhagia
• Myopia(Close sighted)
• Ocular albinism(Absent pigmentation in the eye)
• Photophobia(Extreme sensitivity of the eyes to light)
• Pulmonary fibrosis
• Renal insufficiency(Renal failure)
• Strabismus(Cross-eyed)

Diagnosis

The diagnosis of HPS is established by clinical findings of hypopigmentation 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.

Treatment

Treatment for Hermansky-Pudlak syndrome (HPS) is based on preventing and/or managing the symptoms and complications.

Correction of refractive errors and use of low vision aids; humidifier to reduce frequency of epistaxis; oral contraceptives can limit the duration of menstrual periods; thrombin-soaked gelfoam for skin wounds with prolonged bleeding; DDAVP (1-desamino-8-D-arginine vasopressin) for wisdom tooth extraction and invasive procedures; platelet or red blood cell transfusions for surgery or protracted bleeding; supplemental oxygen and, ultimately, lung transplantation for severe pulmonary disease; steroids, other anti-inflammatory agents, and/or Remicade® for granulomatous colitis. Immunodeficiency, when present, is granulocyte colony-stimulating factor (G-CSF) responsive.

Prognosis

The course of HPS has been mild in rare instances of the disorder, however, the general prognosis is still considered to be poor.

NIH genetic and rare disease info

• NIH info on Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome is a rare disease.

Hermansky-Pudlak syndrome Resources
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