Hermansky-Pudlak syndrome (ORPHA:79430)
Hermansky-Pudlak syndrome (HSP) is a multi-system disorder characterized by oculocutaneous albinism, bleeding diathesis and, in some cases, neutropenia, pulmonary fibrosis, or granulomatous colitis. HPS comprises eight known disorders (HPS-1 to HPS-8), the majority of which present with the same clinical phenotype to varying degrees of severity.
Epidemiology
Prevalence is estimated at 1/500,000 - 1/1,000,000 in non-Puerto Rican populations. In northwestern Puerto Rico the prevalence of HPS-1 is 1/1,800.
Clinical description
HPS usually presents in early childhood, but may present at older ages, with oculocutaneous albinism (varying degrees of hypopigmentation), reduced visual acuity (often at/below the level of legal blindness), horizontal nystagmus, easy bruising of soft tissues, epistaxis, prolonged bleeding after dental extraction, surgery or childbirth and, in HPS-2 (see this term), neutropenia and recurrent infections. Women may present with medically significant menstrual bleeding. Complications may include granulomatous colitis and, in HPS-1 or HPS-4, pulmonary fibrosis (PF) (HPS with PF as a complication; see this term). PF is the most serious complication and usually presents in the fourth or fifth decade.
Etiology
HPS is characterized by a storage pool deficiency of platelets and can be caused by mutations in one of several genes: HPS1 (10q23.1), AP3B1 (5q14.1; causing HPS-2), HPS3 (3q24), HPS4 (22q11.2-q12.2), HPS5 (11p15-p13), HPS6 (10q24.32), DTNBP1 (6p22.3; HPS-7), and BLOC1S3 (19q13; HPS-8). The product of AP3B1 codes for the beta 3A subunit of adaptor complex-3 (AP-3), involved in vesicle formation and protein sorting. The function of the other HPS gene products is unknown, but they interact with each other in biogenesis of lysosome related organelle complexes (BLOCs); BLOC-3: HPS1 and HPS4; BLOC-2: HPS3, HPS5 and HPS6; BLOC-1: HPS7 and HPS8. Affected lysosome-related organelles include melanosomes in melanocytes, delta granules in platelets, lamellar bodies in pulmonary type II cells, and secretory granules in T cells.
Diagnostic methods
Diagnosis is based on clinical findings of oculocutaneous albinism in combination with a bleeding diathesis, confirmed by an absence of platelet dense bodies and genetic testing. Accurate diagnosis of the HPS subtype has important prognostic and treatment implications.
Differential diagnosis
Differential diagnoses include other forms/causes of oculocutaneous albinism, i.e., X-linked ocular albinism, Chediak-Higashi syndrome, Griscelli syndrome, Cross syndrome, pulmonary fibrosis and hemophagocytic lymphohistiocytosis.
Antenatal diagnosis
Antenatal testing may be available for families in which disease-causing mutations have been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
There is no known cure. The bleeding diathesis is a major concern during surgery, dental extraction or childbirth and may be treated with transfusion of platelets or whole blood. Desmopressin may be used prophylactically. Recombinant activated factor VII (VIIa) may also be used. Avoidance of aspirin products is essential. Sunscreen and avoidance of sunlight are important to reduce the risk of solar damage and skin malignancies. Lung transplant is the only known treatment for PF (in HPS-1, HPS-2, and HPS-4). Pirfenidone may slow the progression of PF but only in patients who have significant residual lung function. Steroid therapy is not effective. Neutropenia in HPS-2 can be treated with granulocyte-cell stimulating factor (G-CSF).
Prognosis
The course of HPS-3, HPS-5 and HPS-6 (or HPS without PF as a complication; see this term) is mild with no pulmonary involvement. Prognosis of HPS-1 and HPS-4 is poor as PF is fatal. Prognosis for HPS-7 and HPS-8 (only one case of each reported) has not been well characterized.

                            Last update: 
                            March 2010


                            - Expert reviewer(s): 
                            Dr William GAHL  - Dr Marjan HUIZING