Hermansky-Pudlak syndrome (HPS) is a rare heterogeneously inherited autosomal recessive group of disorders presenting with oculocutaneous albinism, bleeding diathesis and pulmonary disease. HPS is thought to occur as a consequence of disturbed formation or trafficking of intracellular vesicles, most importantly, melanosomes, platelet dense granules and lysosomes. The latter finding, in particular, contributes much to the morbidity associated with the disease, as ceroid lipofuscin deposits in lysosomes affect many organ systems. This is especially problematic in the lungs where it is often associated with pulmonary fibrosis and premature death. Currently, there are 7 known HPS genes in humans. In the mouse, at least 16 known HPS genes produce HPS-mutant phenotypes. The HPS gene mutation is considered to be one of the most prevalent single-gene disorders in northwest Puerto Rico, home to the largest cohort of known patients. In HPS, interventions addressing the bleeding diathesis and pulmonary fibrosis are often disappointingly ineffectual. Pirfenidone, a novel compound with documented anti-inflammatory, antioxidant and antifibrotic effects, appears to hold promise in delaying or preventing fibrosis. To date, there has been one successful lung transplant performed on a patient with HPS. We present a patient with HPS and review the current literature on our understanding of this rare disorder.

1.
Hermansky F, Pudlak P: Albinism associated with hemorrhagic diathesis and unusual pigment reticular cells in the bone marrow: report of two cases with histochemical studies. Blood 1959;14:162–169.
2.
Di Pietro SM, Dell’Angelica EC: The cell biology of Hermansky-Pudlak syndrome: recent advances. Traffic 2005;6:525–533.
3.
Dell’Angelica EC: The building BLOC(k)s of lysosomes and related organelles. Curr Opin Cell Biol 2004;16:458–464.
4.
Nguyen T, Wei ML: Characterization of melanosomes in murine Hermansky-Pudlak syndrome: mechanisms of hypopigmentation. J Invest Dermatol 2004;122:452–460.
5.
Bachli EB, Brack T, Eppler E, Stallmach T, Trueb RM, Huizing M, Gahl WA: Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis. Am J Med Genet 2004;127A:201–207.
6.
Boissy RE, Richmond B, Huizing M, Helip-Wooley A, Zhao Y, Koshoffer A, Gahl WA: Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3. Am J Pathol 2005;166:231–240.
7.
Huizing M, Gahl WA: Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Curr Mol Med 2002;2:451–467.
8.
Poletti V, Costabel U, Casoni GL, Bigliazzi C, Drent M, Olivieri D: Rare infiltrative lung diseases: a challenge for clinicians. Respiration 2004;71:431–443.
9.
Hermos CR, Huizing M, Kaiser-Kupfer MI, Gahl WA: Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases. Hum Mutat 2002;20:482.
10.
Dell’Angelica EC, Mullins C, Caplan S, Bonifacino JS: Lysosome-related organelles. FASEB J 2000;14:1265–1278.
11.
Guttentag SH, Akhtar A, Tao JQ, Atochina E, Rusiniak ME, Swank RT, Bates SR: Defective surfactant secretion in a mouse model of Hermansky-Pudlak syndrome. Am J Respir Cell Mol Biol 2005;33:14–21.
12.
Nakatani Y, Nakamura N, Sano J, Inayama Y, Kawano N, Yamanaka S, Miyagi Y, Nagashima Y, Ohbayashi C, Mizushima M, Manabe T, Kuroda M, Yokoi T, Matsubara O: Interstitial pneumonia in Hermansky-Pudlak syndrome: significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type-2 pneumocytes. Virchows Arch 2000;437:304–313.
13.
Huizing M, Boissy RE, Gahl WA: Hermansky-Pudlak syndrome: vesicle formation from yeast to man. Pigment Cell Res 2002;15:405–419.
14.
Li W, Rusiniak ME, Chintala S, Gautam R, Novak EK, Swank RT: Murine Hermansky-Pudlak syndrome genes: regulators of lysosome-related organelles. Bioessays 2004;26:616–628.
15.
Marks MS, Seabra MC: The melanosome: membrane dynamics in black and white. Nat Rev Mol Cell Biol 2001;2:738–748.
16.
Clark R, Griffiths GM: Lytic granules, secretory lysosomes and disease. Curr Opin Immunol 2003;15:516–521.
17.
Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, Hamblin T, Davies EG, Griffiths GM: Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003;4:1111–1120.
18.
Nguyen T, Novak EK, Kermani M, Fluhr J, Peters LL, Swank RT, Wei ML: Melanosome morphologies in murine models of Hermansky-Pudlak syndrome reflect blocks in organelle development. J Invest Dermatol 2002;119:1156–1164.
19.
Anikster Y, Huizing M, White J, Shevchenko YO, Fitzpatrick DL, Touchman JW, Compton JG, Bale SJ, Swank RT, Gahl WA, Toro JR: Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nat Genet 2001;28:376–380.
20.
Wildenberg SC, Oetting WS, Almodovar C, Krumwiede M, White JG, King RA: A gene causing Hermansky-Pudlak syndrome in a Puerto Rican population maps to chromosome 10q2. Am J Hum Genet 1995;57:755–765.
21.
Witkop CJ, Nunez Babcock M, Rao GH, Gaudier F, Summers CG, Shanahan F, Harmon KR, Townsend D, Sedano HO, King RA, et al: Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Bol Asoc Med P R 1990;82:333–339.
22.
Krisp A, Hoffman R, Happle R, König A, Freyschmidt-Paul P: Hermansky-Pudlak syndrome. Eur J Dermatol 2001;11:372–373.
23.
Izquierdo NJ, Royuela MA, Maumenee IH: Possible origins of the gene of Hermansky-Pudlak in Puerto Rico. P R Health Sci J 1993;12:147–148.
24.
Poddar RK, Coley S, Pavord S: Hermansky-Pudlak syndrome in a pregnant patient. Br J Anaesth 2004;93:740–742.
25.
Schallreuter KU, Frenk E, Wolfe LS, Witkop CJ, Wood JM: Hermansky-Pudlak syndrome in a Swiss population. Dermatology 1993;187:248–256.
26.
Avila NA, Brantly M, Premkumar A, Huizing M, Dwyer A, Gahl WA: Hermansky-Pudlak syndrome: radiography and CT of the chest compared with pulmonary function tests and genetic studies. AJR Am J Roentgenol 2002;179:887–892.
27.
Gwynn B, Martina JA, Bonifacino JS, Sviderskaya EV, Lamoreux ML, Bennett DC, Moriyama K, Huizing M, Helip-Wooley A, Gahl WA, Webb LS, Lambert AJ, Peters LL: Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex. Blood 2004;104:3181–3189.
28.
Oh J, Bailin T, Fukai K, Feng GH, Ho L, Mao JI, Frenk E, Tamura N, Spritz RA: Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet 1996;14:300–306.
29.
Oiso N, Riddle SR, Serikawa T, Kuramoto T, Spritz RA: The rat Ruby (R) locus is Rab38: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain. Mamm Genome 2004;15:307–314.
30.
Suzuki T, Ito S, Inagaki K, Suzuki N, Tomita Y, Yoshino M, Hashimoto T: Investigation on the IVS5 +5G → A splice site mutation of HPS1 gene found in Japanese patients with Hermansky-Pudlak syndrome. J Dermatol Sci 2004;36:106–108.
31.
Feng L, Novak EK, Hartnell LM, Bonifacino JS, Collinson LM, Swank RT: The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes. Blood 2002;99:1651–1658.
32.
Gardner JM, Wildenberg SC, Keiper NM, Novak EK, Rusiniak ME, Swank RT, Puri N, Finger JN, Hagiwara N, Lehman AL, Gales TL, Bayer ME, King RA, Brilliant MH: The mouse pale ear (ep) mutation is the homologue of human Hermansky-Pudlak syndrome. Proc Natl Acad Sci USA 1997;94:9238–9243.
33.
Li W, Zhang Q, Oiso N, Novak EK, Gautam R, O’Brien EP, Tinsley CL, et al: Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet 2003;35:84–89.
34.
Zhang Q, Zhao B, Li W, Oiso N, Novak EK, Rusiniak ME, Gautam R, Chintala S, O’Brien EP, Zhang Y, Roe BA, Elliott RW, Eicher EM, Liang P, Kratz C, Legius E, Spritz RA, O’Sullivan TN, Copeland NG, Jenkins NA, Swank RT: Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nat Genet 2003;33:145–153.
35.
Hearing VJ: Biogenesis of pigment granules: a sensitive way to regulate melanocyte function. J Dermatol Sci 2005;37:3–14.
36.
Hazelwood S, Shotelersuk V, Wildenberg SC, Chen D, Iwata F, Kaiser-Kupfer MI, White JG, King RA, Gahl WA: Evidence for locus heterogeneity in Puerto Ricans with Hermansky-Pudlak syndrome. Am J Hum Genet 1997;61:1088–1094.
37.
Introne W, Boissy RE, Gahl WA: Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 1999;68:283–303.
38.
Nowicki R, Szarmach H: Chediak-Higashi syndrome; in James WD, Elston DM (eds): eMedicine Dermatology. St. Petersburg, eMedicine Corporation, 1999.
39.
Tang X, Yamanaka S, Miyagi Y, Nagashima Y, Nakatani Y: Lung pathology of pale ear mouse (model of Hermansky-Pudlak syndrome 1) and beige mouse (model of Chediak-Higashi syndrome): severity of giant lamellar body degeneration of type II pneumocytes correlates with interstitial inflammation. Pathol Int 2005;55:137–143.
40.
Chiang PW, Oiso N, Gautam R, Suzuki T, Swank RT, Spritz RA: The Hermansky-Pudlak syndrome 1 (HPS1) and HPS4 proteins are components of two complexes, BLOC-3 and BLOC-4, involved in the biogenesis of lysosome-related organelles. J Biol Chem 2003;278:20332–20337.
41.
Martina JA, Moriyama K, Bonifacino JS: BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4. J Biol Chem 2003;278:29376–29384.
42.
Nazarian R, Falcon-Perez JM, Dell’Angelica EC: Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4. Proc Natl Acad Sci USA 2003;100:8770–8775.
43.
Gahl WA, Brantly M, Kaiser-Kupfer MI, Iwata F, Hazelwood S, Shotelersuk V, Duffy LF, Kuehl EM, Troendle J, Bernardini I: Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). N Engl J Med 1998;338:1258–1264.
44.
Lyerla TA, Rusiniak ME, Borchers M, Jahreis G, Tan J, Ohtake P, Novak EK, Swank RT: Aberrant lung structure, composition, and function in a murine model of Hermansky-Pudlak syndrome. Am J Physiol Lung Cell Mol Physiol 2003;285:L643–L653.
45.
Dell’Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS: Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999;3:11–21.
46.
Shotelersuk V, Dell’Angelica EC, Hartnell L, Bonifacino JS, Gahl WA: A new variant of Hermansky-Pudlak syndrome due to mutations in a gene responsible for vesicle formation. Am J Med 2000;108:423–427.
47.
Gautam R, Chintala S, Li W, Zhang Z, Tan J, et al: The Hermansky-Pudlak syndrome 3 (cocoa) protein is a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). J Biol Chem 2004;279:12935–12942.
48.
Di Pietro Sm, Falcon-Perez JM, Dell’Angelica EC: Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6. Traffic 2004;5:276–283.
49.
Tsilou ET, Rubin BI, Reed GF, McCain L, Huizing M, White J, Kaiser-Kupfer MI, Gahl W: Milder ocular findings in Hermansky-Pudlak syndrome type 3 compared with Hermansky-Pudlak syndrome type 1. Ophthalmology 2004;111:1599–1603.
50.
Anderson PD, Huizing M, Claassen DA, White J, Gahl WA: Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Hum Genet 2003;113:10–17.
51.
Huizing M, Hess R, Dorward H, Claassen DA, Helip-Wooley A, Kleta R, Kaiser-Kupfer MI, White JG, Gahl WA: Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5. Traffic 2004;5:711–722.
52.
Perry PK, Silverberg NB: Cutaneous malignancy in albinism. Cutis 2001;67:427–430.
53.
Shotelersuk V, Gahl WA: Hermansky-Pudlak syndrome: models for intracellular vesicle formation. Mol Genet Metab 1998;65:85–96.
54.
Cordova A, Barrios NJ, Ortiz I, Rivera E, Cadilla C, Santiago-Borrero PJ: Poor response to desmopressin acetate (DDAVP) in children with Hermansky-Pudlak syndrome. Pediatr Blood Cancer 2005;44:51–54.
55.
Scheinfeld NS, Johnson AM: Hermansky-Pudlak syndrome. E-medicine, updated October 11, 2004.
56.
Zatik J, Poka R, Borsos A, Pfliegler G: Variable response of Hermansky-Pudlak syndrome to prophylactic administration of 1-desamino 8D-arginine in subsequent pregnancies. Eur J Obstet Gynecol Reprod Biol 2002;104:165–166.
57.
Teitel JM: Unexpected bleeding disorders: algorithm for approach to therapy. Clin Lab Haematol 2000;22(suppl 1):26–9; discussion 30–32.
58.
Witkop CJ, Krumwiede M, Sedano H, White JG: Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome. Am J Hematol 1987;26:305–311.
59.
Parker MS, Rosado Shipley W, de Christenson ML, Slutzker AD, Carroll FE, Worrell JA, White JG: The Hermansky-Pudlak syndrome. Ann Diagn Pathol 1997;1:99–103.
60.
Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA: Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest 2000;117:129–136.
61.
Witkop CJ Jr, Wolfe LS, Cal SX, White JG, Townsend D, Keenan KM: Elevated urinary dolichol excretion in the Hermansky-Pudlak syndrome. Indicator of lysosomal dysfunction. Am J Med 1987;82:463–470.
62.
Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, Cardona H, Calis KA, Gochuico B: Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab 2002;76:234–242.
63.
Schinella RA, Greco MA, Cobert BL, Denmark LW, Cox RP: Hermansky-Pudlak syndrome with granulomatous colitis. Ann Intern Med 1980;92:20–23.
64.
Mahadeo R, Markowitz J, Fisher S, Daum F: Hermansky-Pudlak syndrome with granulomatous colitis in children. J Pediatr 1991;118:904–906.
65.
Marshall RP, McAnulty RJ, Laurent GJ: The pathogenesis of pulmonary fibrosis: is there a fibrosis gene? Int J Biochem Cell Biol 1997;29:107–120.
66.
Cook DN, Brass DM, Schwartz DA: A matrix for new ideas in pulmonary fibrosis. Am J Respir Cell Mol Biol 2002;27:122–124.
67.
Yoshioka Y, Kumasaka T, Ishidoh K, Kominami E, Mitani K, Hosokawa Y, Fukuchi Y: Inflammatory response and cathepsins in silica-exposed Hermansky-Pudlak syndrome model pale ear mice. Pathol Int 2004;54:322–331.
68.
Ivy GO, Kanai S, Ohta M, Smith G, Sato Y, Kobayashi M, Kitani K: Lipofuscin-like substances accumulate rapidly in brain, retina and internal organs with cysteine protease inhibition. Adv Exp Med Biol 1989;266:31–45; discussion 45–47.
69.
del Pozo Pozo AI, Jimenez-Yuste V, Villar A, Quintana M, Hernandez-Navarro F: Successful thyroidectomy in a patient with Hermansky-Pudlak syndrome treated with recombinant activated factor VII and platelet concentrates. Blood Coagul Fibrinolysis 2002;13:551–553.
70.
Kaufmann JE, Vischer UM: Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003;1:682–689.
71.
Teitel JM: Unexpected bleeding disorders: algorithm for approach to therapy. Clin Lab Haematol 2000;22(suppl 1):26–29; discussion 30–32.
72.
Kingman CE, Kadir RA, Lee CA, Economides DL: The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG 2004;111:1425–1428.
73.
Van Dorp DB, Wijermans PW, Meire F, Vrensen G: The Hermansky-Pudlak syndrome. Variable reaction to 1-desamino-8D-arginine vasopressin for correction of the bleeding time. Ophthalmic Paediatr Genet 1990;11:237–244.
74.
Wijermans PW, van Dorp DB: Hermansky-Pudlak syndrome: correction of bleeding time by 1-desamino-8D-arginine vasopressin. Am J Hematol 1989;30:154–157.
75.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd: Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs 2004;64:405–430.
76.
Cain WC, Stuart RW, Lefkowitz DL, Starnes JD, Margolin S, Lefkowitz SS: Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone. Int J Immunopharmacol 1998;20:685–695.
77.
Iyer SN, Gurujeyalakshmi G, Giri SN: Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999;291:367–373.
78.
Gurujeyalakshmi G, Hollinger MA, Giri SN: Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. Am J Physiol 1999;276:L311–L318.
79.
Kaneko M, Inoue H, Nakazawa R, Azuma N, Suzuki M, Yamauchi S, Margolin SB, Tsubota K, Saito I: Pirfenidone induces intercellular adhesion molecule-1 (ICAM-1) down-regulation on cultured human synovial fibroblasts. Clin Exp Immunol 1998;113:72–76.
80.
Akira M, Hamada H, Sakatani M, Kobayashi C, Nishioka M, Yamamoto S: CT findings during phase of accelerated deterioration in patients with idiopathic pulmonary fibrosis. AJR Am J Roentgenol 1997;168:79–83.
81.
Kondoh Y, Taniguchi H, Yokoi T, Suzuki R, Suzuki K, Noda Y, Ogawa K, Kato T, Mori T, Kaneko M, Takagi K: Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 1993;103:1808–1812.
82.
Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr: Idiopathic Pulmonary Fibrosis Study Group. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–133.
83.
Azuma A: Shared mechanisms of lung injury and subsequent fibrosis: role of surfactant proteins in the pathogenesis of interstitial pneumonia in Hermansky-Pudlak syndrome. Intern Med 2005;44:529–530.
84.
Lasky J: Pirfenidone. IDrugs 2004;7:166–172.
85.
McKane BW, Fernandez F, Narayanan K, Marshbank S, Margolin SB, Jendrisak M, Mohanakumar T: Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal transplant model. Transplantation 2004;77:664–669.
86.
Padilla M: Medical Director, Lung Transplantation Program Director, ILD/Advanced Lung Disease Program, Mount Sinai Medical Center, New York, N.Y. Personal correspondence.
87.
Appel D: Founder, Hermansky-Pudlak Syndrome Network Inc., Long Island, N.Y. Personal correspondence.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.