Dermatologic Manifestations of Hermansky-Pudlak Syndrome 

Updated: Aug 10, 2018
Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Hermansky-Pudlak syndrome (HPS) is a rare group of autosomal recessive diseases whose manifestations include oculocutaneous albinism, bleeding, and lysosomal ceroid storage.[1] Its etiology has been related to defects in 7 genes: HPS1, HPS2 (AP3B1) , HPS3, HPS4, HPS5, HPS6, and HPS7. Before 2016, only 9 types of Hermansky-Pudlak syndrome were defined; in 2016, a tenth type was defined based on mutations in the AP3D1 gene.[2] See the image below.

The face of a Puerto Rican girl with Hermansky-Pud The face of a Puerto Rican girl with Hermansky-Pudlak syndrome. Note the blond hair and the pale skin.

See 13 Common-to-Rare Infant Skin Conditions, a Critical Images slideshow, to help identify rashes, birthmarks, and other skin conditions encountered in infants.

The type of albinism associated with Hermansky-Pudlak syndrome is a tyrosinase-positive form. Because patients with Hermansky-Pudlak syndrome can produce some melanin, varying amounts of pigmentation may be present; some patients have blond hair and others have brown hair. Secondary to the albinism that results from Hermansky-Pudlak syndrome, visual defects, including photophobia (light sensitivity), strabismus (crossed eyes), and nystagmus (involuntary eye movements), occur.

The bleeding problems of Hermansky-Pudlak syndrome result from platelet dysfunction and manifest with easy bruisability, nose bleeds, and extended bleeding times.

Pulmonary fibrosis, inflammatory bowel disease, and kidney disease are all symptoms linked to ceroid accumulation in the cells of these organs.

Hermansky-Pudlak syndrome was first noted in 1959 by Hermansky and Pudlak, who described 2 unrelated persons with albinism with lifelong bleeding tendencies and peculiar pigmented reticular cells in the bone marrow as well as in biopsy samples of the lymph node and the liver.

Pathophysiology

Hermansky-Pudlak syndrome results from the abnormal formation of intracellular vesicles. The impaired function of specific organelles indicates that the causative genes encode proteins operative in the formation of lysosomes and vesicles. Four such genes, HPS1, ADTB3A, HPS3, and HPS4, are associated with the 4 known subtypes of Hermansky-Pudlak syndrome: Hermansky-Pudlak syndrome type 1 (HPS-1), Hermansky-Pudlak syndrome type 2 (HPS-2), Hermansky-Pudlak syndrome type 3 (HPS-3), and Hermansky-Pudlak syndrome type 4 (HPS-4).

The HPS1 gene is located on band 10q23. The most common mutation in HPS-1 is the most common mutation in Puerto Ricans. In this variant, a 16–base pair frame shift duplication occurs at exon 15 of the HPS1 gene. In the Swiss variant, a frame shift occurs at codon 322 of the HPS1 gene. The gene products of HPS1 remain to be defined.

HPS-2 is caused by a mutation in the gene encoding the beta-3A subunit of the heterotetrameric AP3 complex (ADTB3A), which resides on chromosome 5. ADTB3A is known to assist in vesicle formation from the trans-Golgi network or late endosome.

Because the expression of the beta-3A subunit is normally ubiquitous, deficiency of the beta-3A subunit leads to a precise phenotype in cells with a large number of intracellular granules (eg, neutrophils, natural killer cells, cytotoxic T lymphocytes, platelets, melanocytes).[3] The absence of AP-3 results in a low intracellular content of neutrophil elastase, with the consequence of neutropenia. Abnormal movement of lytic granules and reduced perforin content in cytotoxic T lymphocytes and natural killer cells define their respective defects in cytolytic activity.[3]

Less pronounced severity of immunodeficiency can be due to a novel 2 bp-deletion (c.3222_3223delTG) in the final exon of AP3B1, causing a frameshift and thus a prolonged altered HPS2 protein. The place of the deletion is at the very C-terminal's end, preventing a complete loss of the HPS2 protein.[4]

The HPS3 gene is located on band 3q24. HPS-3 is a biogenesis of the lysosome-related organelles complex (BLOC)–2 component.[5]

HPS4 involves the human homolog of the mouse light-ear gene. It is located at band 22q11.2–q12.2. Its function remains to be defined.

HPS5 (ruby-eye 2) function has been recently defined. Hermansky-Pudlak syndrome type 5 (HPS-5) results from a deficiency of the HPS-5 protein, a component of BLOC-2.[6] Cells deficient in the HPS-5 protein maintain early-stage melanosome formation and Pmel-17 trafficking.[6] However, tyrosinase and TYRP1 are mistrafficked and thus fail to be efficiently delivered to melanosomes of HPS-5 melanocytes.[6] Syrzycka et al[7] demonstrated that the pink gene encodes the Drosophila ortholog of the human HPS5 gene.

HPS6 (ruby-eye) have recently been cloned and linked to Hermansky-Pudlak syndrome.

A seventh type of Hermansky-Pudlak syndrome (HPS-7) has been described. HPS-7 results from mutant dysbindin, a member of BLOC-1. The sdy mutant mouse expresses no dysbindin protein, owing to a deletion in the gene DTNBP1 (encoding dysbindin); this mutation of the human ortholog DTNBP1 causes a novel form of Hermansky-Pudlak syndrome called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex in both muscle and nonmuscle cells. Dysbindin is a component of BLOC-1, which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted, and cappuccino, which are associated with Hermansky-Pudlak syndrome in mice.[8]

Studies have revealed that many Hermansky-Pudlak syndrome gene products are stable components of at least 3 distinct, ubiquitously expressed protein complexes, named BLOC-1, BLOC-2, BLOC-3, and BLOC-4. Hermansky-Pudlak syndrome–associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; BLOC-1, consisting of 4 Hermansky-Pudlak syndrome proteins (pallidin, muted, cappuccino, HPS-7/sandy); BLOC-2, consisting of HPS-6/ruby-eye, HPS-5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS-1/pale ear and HPS-4/light ear. In the cytosol, HPS-1 (but not HPS-4) is part of yet another complex, termed BLOC-5.

In some investigations, rab geranylgeranyl transferase plays a role in Hermansky-Pudlak syndrome.

Systemic manifestations of Hermansky-Pudlak syndrome involve accumulation of a ceroidlike substance in tissue lysosomes. Ceroid is the name given to the waxlike substance. This lysosomal defect has been reported in reticuloendothelial cells, bone marrow, and lung macrophages. In Hermansky-Pudlak syndrome, particularly the cases in Puerto Rico, ceroid-lipofuscin–like pigment accumulates in lysosomal structures, causing tissue damage, and, upon kidney involvement, this leads to increased urinary dolichol excretion. In addition, clinical evidence of storage disease manifesting with restrictive lung disease, granulomatous colitis, kidney failure, and cardiomyopathy is present. The Swiss variant has fewer systemic manifestations.

Platelets in patients with Hermansky-Pudlak syndrome abnormally aggregate with collagen, thrombin, epinephrine, and adenosine diphosphate (ADP). Electron microscopy shows that platelets in patients with Hermansky-Pudlak syndrome either lack dense bodies (DBs) or have smaller or fewer DBs. DBs are required for the second phase of platelet aggregation. DBs are storage sites for serotonin, calcium, and pyrophosphate.

Falcon Perez et al[9] found that the Drosophila ortholog of the HPS-5 subunit of BLOC-2 identically mirrors the granule group gene pink (p) that was first investigated in 1910 but had not been identified at the molecular level. The phenotype of pink mutants was worsened by alterations in AP-3 subunits or in the orthologs of VPS33A and Rab38.

The Hermansky-Pudlak HPS1/pale ear gene regulates epidermal and dermal melanocyte development.[10]

A germline mutation in BLOC1S3/reduced pigmentation results in a novel variation of Hermansky-Pudlak syndrome (HPS8).[11]

Di Pietro et al[12] noted that BLOC-1 interacts with BLOC-2 and the AP-3 complex, facilitating protein trafficking on endosomes, and, when BLOC-1 is defective, Hermansky-Pudlak syndrome results.

A new homozygous nonsense mutation resulting in HPS1 was described in 2014.[13]

Jung et al[14] identified a homozygous deletion in the AP3B1 gene that causes HPS-2.

Hermansky-Pudlak syndrome protein complexes interface with phosphatidylinositol 4-kinase type II-alpha (PI4KII-alpha) in neuronal and non-neuronal cells.[15] Specifically, BLOC-1 deficiencies, but not BLOC-2 or BLOC-3 deficiencies, impact PI4KII-alpha inclusion into AP-3 complexes. BLOC-1, PI4KII-alpha, and AP-3 belong to a tripartite complex involved with down-regulation of PI4KII-alpha, BLOC-1, and AP-3 complexes.

In 2016, a tenth type of Hermansky-Pudlak syndrome was defined based on mutations in the AP3D1gene; this type causes seizures and immunodeficiency.[2]

Receptors of Chitinase 3-like-1 and Chitinase 3-like-1 are associated with lung disease in HPS.[16]

Etiology

Hermansky-Pudlak syndrome is an autosomal recessive disorder. Founder effects (one or several people who originated a population) are believed to cause the clustering of the disease in such places as Puerto Rico. The origin of Hermansky-Pudlak syndrome in Puerto Rico has been traced to a region of southern Spain, and a connection to cases in Holland is possible.

Other researchers have identified a second example of a founder mutation causing Hermansky-Pudlak syndrome in central Puerto Rico. They estimated that the large deletion in the HPS3 gene arose from 1880-1890. At that time, the ancestors of 3 of the 6 families with HPS-3 emigrated from the town of Ciales to the towns of Aibonito, Barranquitas, and Naranjito. Each of the 3 families could also trace their ancestry to 1 individual, Calixto Rivera, who brought his relatives to Aibonito and the surrounding area to deforest his land for tobacco growing.

Consanguinity and geographical isolation contribute to the continued occurrence of the disease.

Pseudodominance has been reported in the northwestern quarter of Puerto Rico and is associated with patients with Hermansky-Pudlak syndrome who marry persons who are carriers.

Epidemiology

Frequency

United States

Hermansky-Pudlak syndrome may be the most frequent single-gene disorder in Puerto Rico. Some have estimated a frequency of about 1 case in 2000 population among Puerto Ricans. Others state that, in Puerto Rico, Hermansky-Pudlak syndrome has a frequency of about 1 case in 1800 population, with an estimated carrier frequency of 1 in 21. Screening programs for Hermansky-Pudlak syndrome have been carried out in Puerto Rico because of the higher prevalence of the disorder in this population.[17]

International

Hermansky-Pudlak syndrome is common in an isolated mountain village in the Swiss Alps in the canton Valais. It has also been reported to be more common in persons of Dutch descent. Turkish and Pakistani kindreds have been reported. Cases have been reported in Japan as well. Hermansky-Pudlak syndrome has now been reported in African Americans, specifically in 2 brothers who carried compound heterozygous mutations in HPS-1: 1 mutation previously noted, p.M325WfsX6 (c.972delC), and a novel silent mutation that resulted in a splice defect at p.E169E (c.507G > A).[18] Hermansky-Pudlak syndrome has also been reported in a patient of Indian descent.[19]

Race

This disease is most common in Puerto Rico, but it has been reported in Switzerland, Japan, and other countries. Ashkenazi Jews with mild symptoms and mutations in the HPS3 gene have been reported.

Sex

Hermansky-Pudlak syndrome affects the sexes equally.

Age

This disease first manifests in childhood. At this time, albinism is evident. Its systemic manifestations unfold over time and are uncommon in childhood. Inflammatory bowel disease symptom onset occurs at age 12-30 years. The onset of pulmonary fibrosis begins in the third and fourth decades of life. Patients die of pulmonary fibrosis in their fourth or fifth decade of life.

Prognosis

Most patients with Hermansky-Pudlak syndrome (about 70%) die from complications related to this syndrome. Pulmonary fibrosis leads to death in almost 50% of patients with Hermansky-Pudlak syndrome, usually in the fourth decade of life. Pulmonary complications are more common in Puerto Rican patients. Bleeding leads to death in about 10% of patients with Hermansky-Pudlak syndrome. Because patients receive blood and platelet transfusions, the occurrence of blood-borne illness transmission is higher in these patients. Some patients have colitis, and about 13% of patients die from complications relating to colitis. Other causes of death include intestinal, liver, and kidney failure. While some cases are treatable, some are intractable such as a case reported in 2014 of a 52-year-old man whose HPS1 was untreatable and resulted in death.[20]

Most patients with Hermansky-Pudlak syndrome are legally blind. Cataracts can also develop at an earlier age than in healthy control subjects. A lack of pigmentation in the eyes can result in photophobia (light sensitivity), strabismus (crossed eyes), and nystagmus (involuntary eye movements). Best-corrected visual acuity in patients with Hermansky-Pudlak syndrome ranges from 20/60 to 20/400.

Patients with Hermansky-Pudlak syndrome manifest with skin pathology related to albinism. Clinical studies report that 80% of patients with Hermansky-Pudlak syndrome have freckles or lentigines. Melanoma, solar keratoses, squamous cell carcinoma, and basal cell carcinoma have been reported.

Patient Education

Patients need extensive education regarding visual impairment and visual enhancement. They need to understand the implications of photophobia, low-vision aids, nystagmus, and strabismus. The benefits of protective sunglasses must be explained to patients. Sunglasses decrease photophobia in patients with Hermansky-Pudlak syndrome. Sunglasses with ultraviolet protection minimize the harmful visual effects of ultraviolet rays. Further, blue blockers, yellow tint, or polarized glasses may decrease photophobia in patients with Hermansky-Pudlak syndrome. Low-vision aids enhance the lives of patients with Hermansky-Pudlak syndrome. These aids can facilitate educational activities. Patients and families need education regarding telescopic lenses, high-contrast school materials, and font magnifiers. Grønskov et al[21] have suggested that people with diseases such as Hermansky-Pudlak syndrome (1) use glasses (possibly bifocals) and dark glasses or photochromic lenses to abate effects of reduced visual activity and photophobia and (2) consider having strabismus and nystagmus corrected if necessary.

Patients need to understand that their skin is sensitive to the sun. They must wear sunblock with a high SPF and avoid sun exposure. They should wear hats and undergo frequent dermatologic evaluation. They should obtain regular skin cancer checks.

Patients and families need to understand the implications of the increased bleeding tendency. Patients must avoid contact sports and physical trauma. Surgery should be undertaken with caution.

Patients need to understand that lung and heart function can be adversely affected by Hermansky-Pudlak syndrome. Therefore, they need to frequently visit doctors to assess and avoid the complications involved.

Because patients with Hermansky-Pudlak syndrome have many health issues, they might require psychological, educational, and social assistance from appropriate specialists.

For patient education resources, see the Ear, Nose, and Throat Center and Nosebleed.

 

Presentation

History

Because patients with Hermansky-Pudlak syndrome have platelet dysfunction, albinism, and ceroid accumulation, clinical history that relates to these complications must be investigated.

When the intestines are infiltrated with ceroid, patients can have diarrhea, weight loss, cramps, and possibly blood in the stool. These manifestations resemble those of inflammatory bowel disease, with the onset of symptoms occurring in patients aged 12-30 years. Most of the patients with Hermansky-Pudlak syndrome–related bowel disease are Puerto Rican. Response to medical therapy is said to be poor. One article reported 2 children, aged 7 years and 3 years, with granulomatous colitis in association with Hermansky-Pudlak syndrome.[22] One of these children was Puerto Rican. Hazzan et al[23] noted Crohn disease–like colitis, enterocolitis, and perianal disease in a patient with Hermansky-Pudlak syndrome, suggesting that the intestinal pathology of Hermansky-Pudlak syndrome results from the development of classic Crohn disease.

Ceroid can infiltrate the pulmonary system as well. When the lungs are impaired in this fashion, shortness of breath and abnormal fatigue with exertion can occur. The disease can progress to pulmonary fibrosis, with scar tissue restricting the inflation of the lungs.[24] Patients should be asked about previous pulmonary function tests and steroid therapy. Thomas de Montpréville et al[25] noted pulmonary fibrosis in a patient with Hermansky-Pudlak syndrome related to a defect in surfactant. This patient had undergone lung transplantation.

Hermansky-Pudlak syndrome impairs vision; thus, patients should be asked about photophobia, previous eyeglasses, bifocals, eyeglass tints, low-vision aids, amblyopia therapy, and strabismus surgery.

Patients with Hermansky-Pudlak syndrome are prone to skin cancers; thus, they should be asked about any new skin growths. A history of sun exposure, sunblock application, skin biopsy, and cancers should be obtained from patients.

Bleeding diathesis must be investigated. Persons with Hermansky-Pudlak syndrome may have a tendency to bruise easily or to experience frequent nosebleeds or prolonged bleeding. Epistaxis is the most frequent hemorrhagic manifestation. Patients with Hermansky-Pudlak syndrome can have unusual bleeding episodes (eg, heavy menstrual bleeding, bleeding with dental procedures). Patients should be asked about medications that affect bleeding and, thus, should be queried about the use of aspirin and aspirin derivatives. Persons should be asked if their children or parents bleed easily.

Women with Hermansky-Pudlak syndrome should be queried about pregnancies and pregnancy complications, menometrorrhagia, abnormal uterine bleeding, and gynecologic surgery. Therapy-refractory menorrhagia has been noted as the first manifestation of Hermansky-Pudlak syndrome.[26]

Family history is important in understanding Hermansky-Pudlak syndrome. Patients should be asked where their families originated. Puerto Rican ancestry is important and must be investigated. Parental consanguinity and family incidence of Hermansky-Pudlak syndrome need to be reviewed with patients.

In 2003, Iannello et al[27] described a new familial Hermansky-Pudlak syndrome clinical variant in 2 sisters, one aged 6 years and the other aged 23 years. They expressed the common symptoms of Hermansky-Pudlak syndrome, but they also had diffuse interstitial pulmonary disease as well as augmented platelet aggregation. They were very susceptible to bacterial infections.

Interestingly, Iannello et al[27] observed a urinary tract abnormality in a younger sister with Hermansky-Pudlak syndrome and a porencephalic cyst in an older sister with Hermansky-Pudlak syndrome. These developmental defects have been reported in persons with Cross syndrome (oculocerebral hypopigmentation syndrome), which is a syndrome that has evaded precise definition. These sisters seemed to have an overlapping of the phenotypic manifestations of different rare syndromes. The presence of ceroidlike autofluorescent material in urinary sediment, combined with the histologic aspects and the autofluorescence of oral mucosa biopsy specimens, was consistent with a ceroidlike lipofuscin storage problem.

Enders et al[28] noted lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II.

Interestingly, Hermansky-Pudlak syndrome is a bleeding defect, in part, but late-onset menstrual bleeding has been noted.[29]

In Hermansky-Pudlak syndrome type IV, which involves (BLOC)-3, impacts healthy subjects' working memory and impacts function deficits in those with schizophrenia; this is not surprising because HPS is a neural disease in part.[30]

Physical Examination

Physical findings relate to albinism, which affects the skin and the eyes. Pulmonary fibrosis can also be evaluated on physical examination.

Skin findings in Hermansky-Pudlak syndrome

Patients with Hermansky-Pudlak syndrome commonly have blond hair and pale skin, as demonstrated in the image below. Some have brown hair and brown eyes.

The face of a Puerto Rican girl with Hermansky-Pud The face of a Puerto Rican girl with Hermansky-Pudlak syndrome. Note the blond hair and the pale skin.

Melanocytic nevi with dysplastic features, acanthosis nigricans–like lesions in the axillae and the neck, and trichomegaly have been reported to occur.

Metastatic skin involvement of granulomatous colitis in Hermansky-Pudlak syndrome has been reported.[31]

Ocular findings in Hermansky-Pudlak syndrome

Ocular findings in Hermansky-Pudlak syndrome include poor visual acuity, refractive errors associated with with-the-rule astigmatism, strabismus, congenital nystagmus, prominent Schwalbe line, iris transillumination, foveal hypoplasia, and albinotic retinal mid periphery, as shown in the image below.[32]

Photo showing light brown eyes and a red reflectio Photo showing light brown eyes and a red reflection in the eyes.

Best-corrected visual acuity in patients with Hermansky-Pudlak syndrome ranges from 20/60 to 20/400 in the Snellen chart. Refractive errors range from high myopia to hyperopia.

Patients with Hermansky-Pudlak syndrome have congenital nystagmus. The most common types of strabismus found in patients with this syndrome are esotropia and exotropia. Vertical deviations have been reported.

Patients with Hermansky-Pudlak syndrome have various anterior segment abnormalities that include the following: a prominent Schwalbe line, iris transillumination, and presenile cataracts. Iris transillumination varies from almost total transillumination (pigment found at the collarette) to minimal peripheral transillumination.

Patients with Hermansky-Pudlak syndrome have pale optic nerves.

Patients with Hermansky-Pudlak syndrome have foveal hypoplasia. Vascular architecture varies. Macular transparency (grading visibility of choroidal vessels) ranges from transparent to opaque. Patients with Hermansky-Pudlak syndrome have albinotic mid periphery.

Patients with Hermansky-Pudlak syndrome can have poor binocular vision.

Patients with this syndrome have no color vision defects on Ishihara testing.

Visual-evoked potentials show excessive decussation of the optic nerve fibers.

Iris heterochromia with Hermansky-Pudlak syndrome has been reported.[33]

Pulmonary and cardiac findings in Hermansky-Pudlak syndrome

Because patients can manifest with impaired lung function, auscultation of patients' lungs is important.

The lung's susceptibility to pulmonary fibrosis in Hermansky-Pudlak syndrome is determined by the alveolar epithelium.[34]

Because accumulation of ceroid in the heart can cause cardiomyopathy, auscultation of the heart is important.

A case of pulmonary alveolar proteinosis has been reported.[35]

Complications

The most common complication is bleeding, and care should be taken to minimize its effects in surgery and to avoid trauma. Ceroid can infiltrate all body organs and can lead to pulmonary failure, kidney failure, cardiomyopathy, colitis, and other organ malfunctions. In particular, pulmonary complications can occur following general endotracheal anesthesia. Because patients with Hermansky-Pudlak syndrome are photosensitive, skin cancers can develop and visual function can worsen.

 

DDx

 

Workup

Laboratory Studies

Genetic testing for the HPS1 gene, which most commonly occurs in Puerto Ricans, exists. A company called GeneDx can perform DNA screening for the 16–base pair duplication found in this variation of Hermansky-Pudlak syndrome (HPS).

Examination of blood platelets under an electron microscope can be performed. The absence of DBs (referred to as chocolate chips) in the platelets is indicative of this syndrome. Drops of platelet-rich plasma separated from blood are placed on Formvar microscope grids for 1 minute. Next, they are rinsed by passing them through drops of distilled water. Fluid is removed from the grid edges with filter paper, and they are air dried and inserted into the electron microscope. DBs are inherently electron opaque and easily visualized in whole mount preparations. They are spherical in form, and, although variable in size, they differ significantly from other electron-dense structures in platelets, including clusters, chains, relatively dense alpha granules, and giant lysosomes. The uranaffin reaction of Richards and DaPrada deposits uranium salts in the inner half of the DB membrane and can help distinguish DBs from other organelles, but it is not useful for whole mount preparations. Determining the number of DBs in platelets before and after exposure to thrombin provides a reasonable estimate of secretable DBs in platelets containing opaque, nondense body structures. The ultrastructure of ceroid-lipofuchsin inclusions in macrophages in bone marrow, gut, and other tissues can be helpful, but the absence of DBs in the platelets in association with albinism is diagnostic for Hermansky-Pudlak syndrome.

Standard blood tests (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], platelet count, bleeding time) do not identify the platelet defect in Hermansky-Pudlak syndrome. Bleeding time of patients with Hermansky-Pudlak syndrome varies from 6-20 minutes. As many as 25% of patients with Hermansky-Pudlak syndrome have bleeding times within the reference range. Many patients with Hermansky-Pudlak syndrome have reduced von Willebrand factor activity in their platelets. Patients with Hermansky-Pudlak syndrome have been reported to lack the CD63 marker on platelets.

Hair bulb incubation test can be used to classify patients with albinism into tyrosinase negative or tyrosinase positive. All patients with Hermansky-Pudlak syndrome have tyrosine-positive albinism. Clinical correlation is necessary because some patients with Hermansky-Pudlak syndrome may have false-negative results.

Imaging Studies

High-resolution CT is more sensitive than chest radiography in evaluating the extent of pulmonary disease in patients with Hermansky-Pudlak syndrome.[36] Mild findings on high-resolution CT scans are paralleled by normal findings on chest radiographs. Common chest radiographic findings include reticulonodular interstitial pattern, perihilar fibrosis, and pleural thickening. High-resolution CT scans can show septal thickening, ground-glass opacities, and peribronchovascular thickening. One study noted that 82% of patients with Hermansky-Pudlak syndrome had abnormalities on high-resolution CT scans.[37]

Because of a propensity to bleed, patients with Hermansky-Pudlak syndrome who experience physical trauma should undergo CT scanning to rule out intra-articular, intracranial, and/or internal bleeding.

Other Tests

Because patients have impaired vision, their vision should be tested and evaluated in a comprehensive fashion. Inspecting the iris for transillumination and the retina for findings compatible with albinism is useful. Visual acuity testing is also useful.

In children with Hermansky-Pudlak syndrome, because their vision can be impaired in a fashion that affects their ability to learn, educational and intellectual testing should be performed.

Patients with Hermansky-Pudlak syndrome should be evaluated by using pulmonary function tests. Forced vital capacity (FVC), forced expiratory volume (FEV), mean total lung capacity, mean vital capacity, and mean diffusing capacity of the lung for carbon monoxide decrease as interstitial lung disease progresses.

Some studies have reported that patients with albinism have a decreased bone density when compared with age-corrected control subjects, but the role of testing for bone density is unclear in Hermansky-Pudlak syndrome.

Procedures

Biopsy should immediately be performed on new skin growths because the potential for the development of skin cancers in these patients is great.

Histologic Findings

Histologic and ultrastructural findings of non–sun-exposed skin showed melanocytes, with short dendritic processes and decreased numbers of melanosomes. Ultrastructural examination of platelets revealed greatly reduced numbers of delta granules. In adults, solar elastosis is usually present on sun-exposed skin.

Izquierdo et al[38] found that patients with HPS-1 have thicker foveae than normal controls, perhaps because of the absence of a foveal pit as part of the foveal hypoplasia associated with Hermansky-Pudlak syndrome. Conversely, persons with Hermansky-Pudlak syndrome have lower macular volumes compared with the general population, perhaps because of a loss of retinal nuclear layers in these patients.

 

Treatment

Medical Care

The care of patients with Hermansky-Pudlak syndrome (HPS) involves many medical specialties. Treatment involves minimizing the complications of bleeding; monitoring organ function, which ceroid deposits can impair; compensating for visual impairment; and evaluating skin that, because of albinism, can easily develop skin cancer.

Medications have been used to try to diminish the bleeding diathesis in patients with Hermansky-Pudlak syndrome. The heart and lung function of these patients can be impaired; thus, physical therapy and means for enhancing heart and lung function are useful. Erzin et al[39] noted complicated granulomatous colitis in a patient with Hermansky-Pudlak syndrome, which was successfully treated with infliximab.

Pregnancy can be complicated by Hermansky-Pudlak syndrome as a result of bleeding-related complications. A report in 2008 notes use of 1-deamino-8-arginine-vasopressin during labor in a patient with Hermansky-Pudlak syndrome during 2 successful vaginal births after cesarean delivery.[40]

Surgical Care

Because patients with Hermansky-Pudlak syndrome bleed easily and have pulmonary compromise, surgery requires the involvement of hematologists and pulmonologists. If platelet aggregation improves with desmopressin, it may be administered in the preoperative period to improve platelet function.

Consultations

The care of patients with Hermansky-Pudlak syndrome requires consultations from many medical specialties because of its complicated nature.

Patients should regularly see a dermatologist to monitor for the development of skin lesions.

Consultation with a hematologist is useful because patients with Hermansky-Pudlak syndrome have impaired platelet function and a resultant bleeding diathesis.

Consultations with a pulmonologist and a cardiologist are needed to manage pulmonary fibrosis and cardiomyopathy and to facilitate pulmonary and cardiac rehabilitation.

Consultation with a gastroenterologist is useful because of gastrointestinal findings associated with ceroid deposition. Some patients may have a granulomatous colitis that resembles Crohn disease.

Consultation with a geneticist may aid families in understanding the disease and its implications for reproduction and health. The genetic defect involved can be investigated as well.

Consultation with a gynecologist is helpful in females with Hermansky-Pudlak syndrome. One study reported menometrorrhagia in 60% of female patients with Hermansky-Pudlak syndrome. In one series, as many as 46% of the female patients with Hermansky-Pudlak syndrome underwent gynecologic surgical procedures as part of treatment of abnormally abundant menstrual bleeding. No maternal mortalities have been reported in female patients with Hermansky-Pudlak syndrome.

Consultation with an ophthalmologist can be useful for evaluating visual defects and acuity and instituting appropriate interventions.

Diet

Osteoporosis has been reported in patients with albinism. Patients may benefit from vitamin D and calcium-enriched diets, but this is not proven or well documented.

Activity

Because of photosensitivity, patients should avoid sun exposure, use sunblock with a high sun protection factor (SPF), and wear photoprotective glasses (sunglasses). Additionally, because of the increased incidence of bleeding, patients should avoid contact sports and physical trauma.

Prevention

Patients can receive genetic counseling. Patients in areas that have a high incidence of carriers of Hermansky-Pudlak syndrome should avoid marrying close relatives. Currently, no gene therapy for Hermansky-Pudlak syndrome exists.

Long-Term Monitoring

A variety of steps in medical care can be useful in helping patients.

A MedicAlert bracelet or other identification can be helpful in notifying caregivers of patients with Hermansky-Pudlak syndrome who have a bleeding disorder.

The avoidance of aspirin, products containing aspirin, and any other products that may compromise platelet function is important for patients.

The importance of good dental care needs to be explained to patients. The dentist must be aware that the patient has Hermansky-Pudlak syndrome because some dental procedures may require special medications and precautions.

Proper treatment of nosebleeds is important for patient care. Nasal packing should only be performed under medical supervision because removal may cause further bleeding.

Damage to the lungs must be avoided; thus, diligent treatment of upper respiratory infections and avoidance of smoking are useful.

The use of gauze with petrolatum and pressure dressings on cuts or abrasions that require coverings is useful.

In the care of patients with Hermansky-Pudlak syndrome, thrombin on Gelfoam has a role in surface bleeding and DDAVP and platelets have a role in serious bleeding.

Feliciano et al[41] noted steps to facilitate dental care for patients with Hermansky-Pudlak syndrome, including (1) use of eyeglasses with 99% ultraviolet filter to protect Hermansky-Pudlak syndrome patients from the unpleasant dental light stimulus, (2) an extra-soft toothbrush and conservative brushing technique, (3) use of medications with antifibrinolytic agents, and (4) local care to ensure hemostasis.

 

Medication

Medication Summary

Medications have been used to try to diminish the bleeding diathesis in patients with Hermansky-Pudlak syndrome. Poor response to desmopressin acetate (DDAVP) in children with Hermansky-Pudlak syndrome has been reported.[42] Hermansky-Pudlak syndrome with severe colitis has responded to infliximab.[43] The pulmonary fibrosis of Hermansky-Pudlak syndrome has been treated with pirfenidone.[44]

Hemostatic Agents

Class Summary

These agents are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

Desmopressin acetate (DDAVP, Stimate, DDAVP injection)

Desmopressin acetate is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. It is indicated for patients with hemophilia A and mild von Willebrand disease to maintain hemostasis. If used preoperatively, administer 30 minutes prior to the scheduled procedure.