Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Includes: Hermansky-Pudlak Syndrome 1, Hermansky-Pudlak Syndrome 2, Hermansky-Pudlak Syndrome 3, Hermansky-Pudlak Syndrome 4, Hermansky-Pudlak Syndrome 5, Hermansky-Pudlak Syndrome 6, Hermansky-Pudlak Syndrome 7, Hermansky-Pudlak Syndrome 8]
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Authors:
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William A Gahl, MD, PhD
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Initial Posting:
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Last Revision:
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Disease characteristics. Hermansky-Pudlak syndrome (HPS) is a multi-system disorder characterized by tyrosinase-positive oculocutaneous albinism, a bleeding diathesis resulting from a platelet storage pool deficiency, and, in some cases, pulmonary fibrosis or granulomatous colitis. The albinism is characterized by hypopigmentation of the skin and hair and the ocular findings of reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in easy bruising, frequent epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and progresses to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals.
Diagnosis/testing. 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.
Management. Treatment of manifestations: correction of refractive errors and use of low vision aids; 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 for severe pulmonary disease; steroids, other anti-inflammatory agents and/or Remicade® for granulomatous colitis. Prevention of secondary complications: protection of the skin from the sun; wearing a medical alert bracelet that explicitly describes the functional platelet defect; maximizing pulmonary function before development of pulmonary fibrosis by prompt treatment of pulmonary infections, immunizing with influenza and pneumococcal vaccines, and regular moderate exercise. Surveillance: annual ophthalmologic examination; at least annual examination of the skin for solar keratoses (premalignant lesions), basal cell carcinoma, squamous cell carcinoma; annual pulmonary function testing in those over age 20 years; routine history for symptoms of colitis (e.g., cramping, increased mucus in the stool, rectal bleeding). Agents/circumstances to avoid: aspirin-containing products, cigarette smoke. Testing of relatives at risk: In rare families with HPS3, HPS5, or HPS6, the evaluation of apparently unaffected siblings may yield a positive diagnosis.
Genetic counseling. HPS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis is available, but only for those families in which mutations have been identified in an affected individual.
The diagnosis of Hermansky-Pudlak syndrome (HPS) is established by clinical findings of oculocutaneous albinism in combination with a bleeding diathesis of variable severity [Gahl et al 1998].
The diagnosis of oculocutaneous albinism is established by finding hypopigmentation of the skin and hair on physical examination associated with the following characteristic ocular findings:
Absence of platelet dense bodies. Currently, the sine qua non for diagnosis of HPS is absence of dense bodies on whole mount electron microscopy of platelets [Witkop et al 1987]. Upon stimulation of platelets, the dense bodies, which contain ADP, ATP, serotonin, calcium, and phosphate, release their contents to attract other platelets. This process constitutes the secondary aggregation response, which cannot occur in the absence of the dense bodies. There are normally four to eight dense bodies per platelet, but there are none in the platelets of individuals with HPS.
Coagulation studies
Ceroid lipofuscin. The demonstration of a yellow, autofluorescent, amorphous lipid-protein complex, called ceroid lipofuscin, in urinary sediment and parenchymal cells is characteristic of HPS, but this laboratory finding is virtually never used in diagnosis.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Genes. The HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, and BLOC1S3 genes are known to be associated with HPS.
Other loci. Most likely, mutations in other genes also result in HPS.
Clinical uses
Clinical testing
HPS1. Homozygosity for a 16-bp duplication is found in approximately 75% of all affected individuals of Puerto Rican ancestry [Santiago Borrero et al 2006] and in virtually all affected individuals from northwestern Puerto Rico [Oh et al 1996 , Huizing & Gahl 2002]. To date, the 16-bp duplication has not been reported in affected individuals not of Puerto Rican ancestry. This duplication is designated c.1470_1486dupCCAGCAGGGGAGGCCC, c.1470_1468dup16.
HPS3. Homozygosity for g.339_4260del3904, GenBank reference sequence AF375663 (also known as the 3.9-kb deletion) has been identified in affected individuals of Puerto Rican ancestry only [Anikster et al 2001].
HPS3. Homozygosity for c.1163+1G>A (also known as 1303+1G>A) splice site mutation has been identified in affected individuals of Ashkenazi Jewish ancestry only [Huizing, Anikster, Fitzpatrick et al 2001].
HPS1. The HPS1 gene is mutated in virtually all affected individuals from northwestern Puerto Rico and in approximately 45% of affected non-Puerto Ricans [Oh et al 1996 , Oh et al 1998 , Shotelersuk et al 1998 , Shotelersuk & Gahl 1998 , Oetting & King 1999 , Hermos et al 2002 , Huizing & Gahl 2002]. Homozygotes as well as compound heterozygotes for HPS1 mutations have been identified.
HPS4. Mutations in the gene HPS4 have been reported in 15 affected individuals [Suzuki et al 2002 , Anderson et al 2003], including a Sri Lankan [Bachli et al 2004].
Research testing
Direct DNA. Molecular genetic testing for AP3B1, HPS3, HPS6, DTNBP1, and BLOC1S3 mutations — with the exception of HPS3 mutations g.339_4260del3904, AF375663 (also known as 3.9-kb deletion) and c.1163+1G>A (also known as 1303+1G>A) — is available on a research basis only and requires mutation scanning or sequence analysis .
AP3B1. Mutations in the AP3B1 gene have been identified in several individuals: two adult brothers [Dell'Angelica et al 1999], a six-year-old boy [Huizing et al 2002], another child [Clark et al 2003], two siblings of a consanguineous Turkish mating [Jung et al 2006], two Italian siblings [Fontana et al 2006], and a child originally diagnosed with Griscelli syndrome [Enders et al 2006].
HPS3. Homozygosity for a unique g.339_4260del3904, AF375663 (also known as 3.9-kb deletion) has been found in 100% of affected individuals from the region of central Puerto Rico near Aibonito [Anikster et al 2001].
Individuals with HPS who are of Ashkenazi Jewish background have a unique c.1163+1G>A, AY033141 (also known as 1301+G>A or IVS5+1G>A) splice site mutation [Huizing, Anikster, Fitzpatrick et al 2001]. Of six individuals with this mutation, four were homozygotes and two were compound heterozygotes.
HPS5. Mutations in HPS5 have been found in five individuals. The mutations include a homozygous four-base deletion in a three-year-old Turkish boy [Zhang et al 2003], homozygous missense mutations in 51- and 43-year-old sisters of Swiss extraction [Huizing et al 2004], compound heterozygous insertions in a 21-year-old woman of English and Irish background [Huizing et al 2004], and compound heterozygous deletion/nonsense mutations in a ten-year-old boy of English, Irish, Dutch, and Swedish background [Huizing et al 2004].
HPS6. Only one mutation in HPS6 has been reported. A 39-year-old Belgian woman carried a homozygous four-base deletion [Zhang et al 2003]. Four other individuals with HPS6 mutations have been identified but not reported.
DTNBP1. A 48-year-old Portuguese woman with HPS7 exhibited a homozygous nonsense mutation in DTNBP1.
BLOC1S3. A single family in Britain was identified with a homozygous frameshift mutation in BLOC1S3 [Morgan et al 2006].
Table 1
summarizes molecular genetic testing for this disorder.
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1. Proportion of affected individuals with a mutation(s) as classified by gene, population group, and/or test method
2. All Ashkenazi Jewish 3. Direct DNA refers to the use of mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with a specific disorder. |
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
No other phenotypes are known to be caused by mutations in HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, or BLOC1S3.
The clinical characteristics of Hermansky-Pudlak syndrome (HPS) consist of oculocutaneous albinism, a bleeding diathesis, a platelet storage pool deficiency, and other organ involvement [Huizing, Anikster, & Gahl 2001 ; Huizing & Gahl 2002]. Signs and symptoms of oculocutaneous albinism in HPS are variable but visual acuity generally remains stable.
Eyes. Nearly all children with the albinism of HPS have nystagmus at birth, often noticed by the parents in the delivery room and by the examining physician. Children with HPS may also have periodic alternating nystagmus [Gradstein et al 2005], wandering eye movements, and lack of visual attention. The initial diagnosis of albinism is sometimes made by the ophthalmologist.
The nystagmus can be very fast early in life, and generally slows with time, but nearly all individuals with albinism have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable when an individual is tired, angry, or anxious, and less marked when s/he is well rested and relaxed.
Photophobia may accompany severe foveal hypoplasia.
Iris color may remain blue or change to a green/hazel or brown/tan color. Globe transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina.
Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood [Iwata et al 2000].
Alternating strabismus is found in most individuals with albinism and is generally not associated with the development of amblyopia.
Skin/hair. The hair color ranges from white to brown, and can occasionally darken with age. Skin color can be white to olive, but is generally at least a shade lighter than that of other family members.
Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare.
Affected Puerto Ricans typically have solar damage manifesting as actinic keratoses and nevi. Ephelids, lentigines, and basal cell carcinoma also occur with increased frequency among Puerto Ricans with HPS [Toro et al 1999].
Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal [Huizing et al 2007]. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, or other surgeries. Typically, cuts bleed longer than usual but heal normally. Bruising generally first appears at the time of ambulation. Epistaxis occurs in childhood and diminishes after adolescence. Menstrual cycles may be heavy and irregular. Prolonged bleeding after tooth extraction can lead to the diagnosis of HPS. Affected individuals with colitis may bleed excessively per rectum. Exsanguination as a complication of childbirth, trauma, or surgery is extremely rare.
Pulmonary fibrosis. The pulmonary fibrosis of HPS typically causes symptoms in the thirties and is fatal within a decade. The pulmonary fibrosis has been described largely in individuals with HPS1 from northwestern Puerto Rico [Brantly et al 2000 , Avila et al 2002], but also occurs in other individuals with HPS1 [Brantly et al 2000 , Hermos et al 2002] or HPS4 [Anderson et al 2003 , Bachli et al 2004]. To date, convincing evidence of pulmonary fibrosis has not been reported for HPS3, HPS5, or HPS6. The fibrosis consists of progressive, restrictive lung disease with an extremely variable time course [Gahl et al 1998 , Brantly et al 2000 , Gahl et al 2002].
Colitis. A bleeding granulomatous colitis resembling Crohn's disease presents, on average, at age 15 years, with wide variability [Gahl et al 1998]. The colitis is severe in 15% of cases and occasionally requires colectomy; affected individuals may have the inflammatory bowel disease of HPS without the explicit diagnosis of colitis. Objective signs of colitis have been found primarily in persons with HPS1 or HPS4 [Hussain et al 2006]. Although the colon is primarily involved in HPS, any part of the alimentary tract, including the gingiva, can be affected.
Other. Cardiomyopathy and renal failure have also been reported in HPS [Witkop et al 1989].
Neutropenia and/or immune defects have been associated with HPS2 [Shotelersuk et al 2000 , Huizing & Gahl 2002 , Clark et al 2003 , Fontana et al 2006].
Pathogenesis. Pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure have been attributed to the lysosomal accumulation of ceroid lipofuscin, but this relationship is speculative.
Correlations between specific HPS-causing mutations and particular clinical presentations are not convincing.
The pulmonary fibrosis of HPS is associated with Puerto Ricans homozygous for the c.1470_1468dup16 mutation in HPS1 [Gahl et al 1998]. However, the occurrence of lethal pulmonary fibrosis in an Irish individual with HPS1 mutations [Brantly et al 2000] and in Sri Lankan [Bachli et al 2004] and Eastern European [Anderson et al 2003] individuals with HPS4 mutations suggests that any HPS1 or HPS4 mutation can cause pulmonary disease. Pulmonary fibrosis did not occur in one study of four individuals with HPS5 [Huizing et al 2007].
Two brothers and a six-year-old boy with compound heterozygosity for AP3B1 mutations had typical HPS but also persistent neutropenia and an increased frequency of infections in childhood [Shotelersuk et al 2000 , Huizing & Gahl 2002]. No clinical information is available on a fourth individual with AP3B1 mutations [Clark et al 2003]. A two-year-old boy diagnosed with HPS2 had fatal hemophagocytic lymphohistiocytosis [Enders et al 2006], and two Italian siblings had an immune defect involving abnormal natural killer cell function [Fontana et al 2006]. Two Turkish siblings with HPS2 manifested developmental delay and dysmorphic features, but consanguinity was also involved [Jung et al 2006].
Individuals with HPS3 mutations have milder symptoms than those with HPS1 mutations [Huizing, Anikster, Fitzpatrick et al 2001]. The albinism in HPS3 is characterized by such minimal hypopigmentation that some individuals have carried the diagnosis of ocular albinism rather than oculocutaneous albinism. Visual acuity often approximates 20/100 or better. Bleeding is also mild and pulmonary involvement has not been observed. Significant granulomatous colitis occurs primarily in HPS1 and HPS4 [Hussain et al 2006]. The severity of clinical symptoms does not appear to correlate with the severity of the molecular defect.
The variability and severity of oculocutaneous albinism and bleeding diathesis found in HPS4 are similar to those of HPS1 [Suzuki et al 2002 , Anderson et al 2003]. Pulmonary fibrosis and granulomatous colitis also occur in HPS4; no correlation has been found between the severity of symptoms and specific mutations.
HPS5 and HPS6 appear to resemble HPS3 in their mildness and lack of pulmonary disease. It is difficult to discern the severity of HPS7 and HPS8 based upon the single case reported for each.
HPS may have been referred to as non-neuronal ceroid-lipofuscinosis to differentiate it from neuronal ceroid-lipofuscinosis or Batten disease. In HPS, the nervous system is spared.
Individuals with HPS with mild hypopigmentation but a bleeding disorder could be referred to as having "delta storage pool deficiency"; however, individuals with isolated delta storage pool deficiency do not have vision defects.
HPS occurs worldwide and has an estimated prevalence of one in 500,000 to one in 1,000,000 in non-Puerto Rican populations.
Prevalence of HPS1 in northwestern Puerto Rico is one in 1800. HPS1 has been reported in a small isolate in a Swiss village and as a genetic isolate in Japan [Ito et al 2005].
HPS3 occurs as a genetic isolate in central Puerto Rico [Anikster et al 2001 , Santiago Borrero et al 2006].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Albinism. The diagnosis of Hermansky-Pudlak syndrome (HPS) should be considered in anyone with oculocutaneous albinism or ocular albinism, as the bleeding diathesis can be mild, unrecognized, or previously disregarded. It may be reasonable to screen all individuals with albinism for HPS by examining their platelets for absent dense bodies. Disorders with albinism included in the differential diagnosis:
Oculocutaneous albinism type 1 (OCA1) is caused by mutations in the TYR gene. Ocular findings include nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity usually in the range of 20/100 to 20/400, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irises that do not darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens with age, white skin that over time develops some generalized pigment and may tan with sun exposure, and blue irises that change to green/hazel or brown/tan with age. Visual acuity may be 20/60 or better in some individuals.
Oculocutaneous albinism type 2 (OCA2) is caused by mutations in the OCA2 gene. Affected individuals usually have pigmented hair at birth and usually do not tan later in life, but some have been identified who have white hair at birth. They may develop pigmented nevi and freckles, but the skin does not develop generalized pigment. The irises usually develop some pigment that can be seen by the hazel/green to tan/brown color or by globe transillumination.
Oculocutaneous albinism type 4 (OCA4) is caused by mutation in the SLC45A2 gene (also known as MAPT, membrane-associated transporter protein). OCA4 was initially identified in one male of Turkish origin. Studies now suggest that this is the second most common type of OCA in Japanese individuals. The phenotype is similar to that of OCA2 in Caucasian individuals.
X-linked ocular albinism (XLOA) is caused by mutations in the GPR143 gene. Affected males have congenital and persistent visual impairment. XLOA is characterized by congenital nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. Skin and hair pigment are normal.
Disorders of platelet dense bodies. Described in a recent review [Gunay-Aygun et al 2004], these disorders include the following:
Chediak-Higashi syndrome. Affected individuals have a significantly increased frequency of infection in childhood, mild oculocutaneous albinism, and a bleeding diathesis [Introne et al 1999]. This entity is characterized by huge, fused, dysfunctional lysosomes and macromelanosomes. Individuals with Chediak-Higashi syndrome always have giant intracellular granules in their neutrophils on a peripheral blood smear; individuals with HPS never exhibit this finding. Also, persons with Chediak-Higashi syndrome often develop a fatal lymphohistiocytosis or the accelerated phase; this has been reported in only a single person with HPS, i.e., one with HPS2 [Enders et al 2006]. Without bone marrow transplantation (BMT), individuals with classic Chediak-Higashi syndrome die in childhood.
Griscelli syndrome. Affected individuals have mild hypopigmentation and immunodeficiency and can have the accelerated phase of lymphohistiocytosis. A distinguishing finding is silvery-gray hair.
Note: Elejalde syndrome is now considered to be a type of Griscelli syndrome in which neurologic involvement, rather than immunodeficiency and lymphohistiocytosis, occurs.
Cross syndrome [Huizing et al 2000b]. Affected individuals have hypopigmentation, ocular anomalies, and severe central nervous system involvement with developmental delay; the latter findings are not part of Hermansky-Pudlak syndrome.
Pulmonary fibrosis. Individuals with familial pulmonary fibrosis do not have hypopigmentation, visual defects, or a bleeding diathesis; the only feature shared with HPS is a diathesis toward interstitial lung disease.
Lymphohistiocytosis. See Familial Hemophagocytic Lymphohistiocytosis and X-Linked Lymphoproliferative Disease (XLP).
To establish the extent of disease in an individual diagnosed with Hermansky-Pudlak syndrome (HPS):
Eyes
Skin. Treatment of skin cancer does not differ from that in the general population.
Bleeding
Pulmonary fibrosis
Colitis. The granulomatous colitis of HPS resembles Crohn's colitis and, as such, may respond to steroids and other anti-inflammatory agents. Remicade® has also been used with benefit [Erzin et al 2006].
Skin. Skin care in HPS is dictated by the amount of pigment in the skin and the cutaneous response to sunlight. Protection from the sun should be provided to prevent burning, other skin damage, and skin cancer. In very sensitive individuals, sun exposure as short as five to ten minutes can be significant, while exposure of 30 minutes or more is usually significant in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, and socks). For extremely sun-sensitive individuals, sun screens with a high SPF value (total blocks with SPF 45-50+) are appropriate; for less sun-sensitive individuals, sun screens with SPF values of 15 or above can be used.
Bleeding. Individuals with HPS should consider obtaining a medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (platelet count, prothrombin time, partial thromboplastin time) are normal in HPS.
Pulmonary fibrosis. Prior to the development of pulmonary fibrosis, attention should be paid to maximizing pulmonary function. This entails avoidance of cigarette smoke, prompt treatment of pulmonary infections, immunization with influenza and pneumococcal vaccines, and regular moderate exercise.
Eyes. Annual ophthalmologic examination, including assessment of refractive error, is indicated.
Skin. Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare. Examination for these findings should be performed at least annually.
Pulmonary fibrosis. Pulmonary function testing should be performed annually in adults.
Colitis. The colitis is suspected in those with a history of cramping, increased mucus in the stool, and rectal bleeding; colonoscopy is used to confirm the diagnosis.
Bleeding. All aspirin-containing products as well as activities that could involve the risk of a bleeding episode should be avoided.
Pulmonary fibrosis. Cigarette smoking decreases pulmonary function and may worsen progression of pulmonary fibrosis.
In families with HPS3, HPS5, or HPS6, the evaluation of apparently unaffected siblings may yield a positive diagnosis.
In individuals with HPS1 and HPS4, the diagnosis of HPS will be apparent because the hypopigmentation and nystagmus are clinically evident.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Recent studies suggest a salutary effect on pulmonary function of the investigational drug pirfenidone in affected individuals with pulmonary function greater than 50% of normal [Gahl et al 2002]. Further clinical trials are ongoing.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because they reduce vision.
No successful therapy for or prophylaxis against the pulmonary fibrosis of HPS exists. Steroids are often tried but have no apparent beneficial effect.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
All types of Hermansky-Pudlak syndrome (HPS) are inherited in an autosomal recessive manner.
Parents of a proband
Sibs of a proband
Offspring of a proband
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for the c.1470_1468dup16 duplication in HPS1 and the g.339_4260del3904, AF375663 deletion and c.1163+1G>A splice site mutation in HPS3 is available on a clinical basis. Carrier testing for other HPS1 sequence variants and mutations in HPS4 is available on a clinical basis once the mutations have been identified in the family.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only and/or the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at 25% risk of inheriting two mutations in HPS1 (i.e., either two copies of c.1470_1468dup16, one of c.1470_1468dup16 and another HPS1 mutation, or two other HPS1 mutations), two copies of g.339_4260del3904 in HPS3, or two mutations in HPS4 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
No laboratories offering molecular genetic testing for prenatal diagnosis of other mutations which cause HPS are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see
.
Preimplantation genetic diagnosis (PGD)
may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
HPS1 | HPS1 | 10q23.1 | Hermansky-Pudlak syndrome 1 protein |
HPS2 | AP3B1 |