DOI: 10.1148/radiol.2452040495
(Radiology 2007;245:595-599.)
© RSNA, 2007
Case 124: Hermansky-Pudlak Syndrome1
Yahya M. Berkmen, MD 
and
Belinda M. Dsouza, MD
1 From the Department of Radiology, Columbia University Medical Center, 630 W 168th St, MC 28, New York, NY 10032-3784. Received March 17, 2004; revision requested May 26; revision received June 30; accepted July 28; final version accepted August 16.
Address correspondence to B.M.D. (e-mail: bmd2111{at}columbia.edu).
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HISTORY
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A 53-year-old Puerto Rican man presented with long-standing and gradually increasing dyspnea. He also reported occasional abdominal pain, easy bruising, and occasional epistaxis. The patient denied smoking. He stated that his sister had died of pulmonary fibrosis many years earlier.
Physical examination revealed bilateral crackles in the lungs and skin hypopigmentation. Oxygen saturation was 82% on room air. Red blood cell, white blood cell, and platelet counts were normal. Lung function tests revealed obstructive and restrictive disease, with severe reduction of carbon monoxide diffusing capacity. Lung biopsy was not performed. The patient was hypertensive and had elevated blood urea nitrogen (32 mg/dL [11 mmol/L]; normal, 10–20 mg/dL [3.6–7.1 mmol/L]) and serum creatinine (1.9 mg/dL [168 µmol/L]; normal, 0.6–1.5 mg/dL [53.0–132.6 µmol/L]) levels. Chest radiography and computed tomography (CT) were performed.
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IMAGING FINDINGS
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Posteroanterior chest radiography was performed at admission (Fig 1) and revealed diffuse bilateral reticular abnormalities that involved mostly the periphery of the lungs, with lower lobe predominance. The diaphragm was elevated, suggesting volume loss in the lungs. High-spatial-resolution CT of the chest was performed subsequently and revealed diffuse subpleural blebs that were relatively large in the upper lobes (Fig 2a) and gradually decreased in size from the middle of the thorax (Fig 2b) to the lung bases (Fig 2c). There was a generalized ground-glass appearance of the lungs, as evidenced by the black bronchus sign, which was described as "increased conspicuity of the bronchi within a ground-glass opacity" (1) (Fig 2b), and by traction bronchiectasis (2), indicating the presence of diffuse fibrosis (Fig 2c).
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Figure 2a: Three high-spatial-resolution transverse CT sections of the chest (collimation, 1 mm) obtained through the (a) upper lobes, (b) carina, and (c) dome of the diaphragm. The lungs appear more opaque (diffuse ground-glass opacity) than normal. There is mild to moderate centrilobular emphysema. (a) Subpleural blebs (arrows) surround the lung parenchyma. They are larger anteriorly. (b) Subpleural blebs are smaller. The black bronchus sign (arrows) of two subsegmental bronchi in the right upper lobe is visible. (c) Subpleural blebs (arrowheads) are smaller. There are several dilated bronchi (arrows). This finding is known as traction bronchiectasis.
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Figure 2b: Three high-spatial-resolution transverse CT sections of the chest (collimation, 1 mm) obtained through the (a) upper lobes, (b) carina, and (c) dome of the diaphragm. The lungs appear more opaque (diffuse ground-glass opacity) than normal. There is mild to moderate centrilobular emphysema. (a) Subpleural blebs (arrows) surround the lung parenchyma. They are larger anteriorly. (b) Subpleural blebs are smaller. The black bronchus sign (arrows) of two subsegmental bronchi in the right upper lobe is visible. (c) Subpleural blebs (arrowheads) are smaller. There are several dilated bronchi (arrows). This finding is known as traction bronchiectasis.
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Figure 2c: Three high-spatial-resolution transverse CT sections of the chest (collimation, 1 mm) obtained through the (a) upper lobes, (b) carina, and (c) dome of the diaphragm. The lungs appear more opaque (diffuse ground-glass opacity) than normal. There is mild to moderate centrilobular emphysema. (a) Subpleural blebs (arrows) surround the lung parenchyma. They are larger anteriorly. (b) Subpleural blebs are smaller. The black bronchus sign (arrows) of two subsegmental bronchi in the right upper lobe is visible. (c) Subpleural blebs (arrowheads) are smaller. There are several dilated bronchi (arrows). This finding is known as traction bronchiectasis.
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DISCUSSION
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The radiologic findings are indicative of the diffuse nonspecific pulmonary fibrosis most commonly seen in patients with idiopathic pulmonary fibrosis or collagen-vascular diseases (ie, scleroderma, rheumatoid lung, mixed connective tissue disease, etc) (3). However, radiologic evidence of fibrosis in association with clinical findings of hypopigmentation (albinism), easy bruising, and occasional epistaxis should lead to the correct diagnosis of Hermansky-Pudlak syndrome (HPS). It is interesting that the patient's sister died of pulmonary fibrosis. This suggests a rare familial form of the disease (4). Intermittent abdominal pain and renal insufficiency in our patient were believed to be caused by gastrointestinal and renal involvement.
HPS consists of oculocutaneous hypopigmentation (albinism), platelet dysfunction (easy bruising, prolonged bleeding), and storage of autofluorescent pigment (ceroid or lipofuscin) in lysosomal organelles of the cells of multiple organs and the reticuloendothelial system. It is a genetically transmitted autosomal recessive disorder. There are six distinct genetic forms (HPS-1 through HPS-6), resulting in somewhat different clinical manifestations (HPS-1 through HPS-6) (5). The HPS-1 gene is the most common variant, whereas the HPS-2 gene is the least common (5).
In North America, most patients with HPS are from Puerto Rico, where an estimated 400 people with HPS are concentrated mostly in the northwest region of the island (6,12,16). Sporadic cases occurring in other countries and ethnic groups have been reported (4,6,7).
The pathogenesis of this syndrome is poorly understood. However, available evidence indicates that in these seemingly unrelated manifestations there is a common aberration at the cellular and molecular level consisting of "abnormal [vesicular] trafficking to and among lysosome-related organelles such as melanosomes, platelet-dense granules, and lysosomes" (5). To a lesser extent, there appears to be abnormal function of the other secretory cells. For instance, type II pneumocytes exhibit excessive accumulation of surfactant (giant lamellar body degeneration), suggesting a basic defect in either formation or secretion of surfactant (8). In patients with HPS-2, large lytic granules are accumulated and trapped in cytotoxic T cells, preventing them from killing their target cells (9,10). Likewise, natural killer cells and vascular endothelial cells (Weibel-Palade bodies) may also be defective (10,11).
Pulmonary fibrosis frequently complicates HPS (12). The incidence and severity of fibrosis is greatest in patients with HPS-1 and HPS-4 (5). Slowly progressive lung fibrosis occurs in individuals aged 20–40 years. Accumulation of ceroid in the pulmonary macrophages is seen at histologic analysis and bronchoalveolar lavage (13) and is believed to be the main pathogenetic factor in the development of pulmonary fibrosis. Platelet-derived growth factor and other cytokines are increased in bronchoalveolar lavage fluid, suggesting that an inflammatory process may also play an important role in this event (11).
Microscopically, there is a fibrosis that resembles usual interstitial pneumonitis (8,14,15). In addition, there is cellular degeneration and proliferation of type II cells containing giant lamellar bodies (surfactant) that may hypothetically contribute to the development of pulmonary fibrosis (8).
The radiologic appearance of HPS is nonspecific. Findings on chest radiographs are variably described as fine or coarse reticular or reticulonodular shadows (14–16) or as interstitial patterns or infiltrates (15,16) that usually involve both lungs symmetrically (14) or display different patterns at different areas (15). Perihilar fibrosis and pleural thickening are also described (16). High-spatial-resolution CT reveals different changes at different stages of disease. Septal thickening, mild reticulations, and ground-glass opacities that predominantly occupy the lung periphery in early stages progress to severe reticulations, perivascular thickening, subpleural cysts, and bronchiectasis in advanced stages and extend to the central portions of the lungs (15,16).
Patients with HPS may occasionally develop granulomatous colitis similar to Crohn disease (14,17). This is believed to be the result of accumulation of ceroid or lipofuscin in the bowel wall. Small-bowel involvement is rare (18). Ceroid accumulation in the kidney results in renal insufficiency and failure (17).
Chédiak-Higashi and Griscelli syndromes are genetically determined disorders associated with oculocutaneous albinism and are similar to but distinctly different from HPS. The major differences between Chédiak-Higashi syndrome and HPS are recurrent childhood infections, peripheral and central neuropathy, and an accelerated phase (nonmalignant lymphohistiocytic infiltration of organs, specifically, the liver and spleen, causing hepatosplenomegaly and resembling lymphoma), which commonly causes death in these patients, usually in early childhood (4). Recurrent infections are caused by neutropenia and dysfunctional neutrophils containing giant cytoplasmic granules that cannot be discharged from the cells. Thus, neutrophils are unable to kill the offending organisms (19). Giant granules also impair the chemotaxis of the granulocytes (19,20).
In patients with Griscelli syndrome, oculocutaneous albinism may be limited to the hair. Deficiency of platelet-dense bodies does not exist; thus, there is no bleeding tendency. There is neutropenia and neutrophil dysfunction, but giant granules are lacking. An accelerated phase exists, and death usually occurs in early childhood (4,19).
In summary, clinical findings of albinism, platelet dysfunction, progressive shortness of breath, laboratory evidence of restrictive lung disease, and the ethnic background of the patient—coupled with chest radiographic and CT manifestations of pulmonary fibrosis—were diagnostic of HPS. The differential diagnosis for two other diseases associated with albinism (Chédiak-Higashi and Griselli syndromes) is not difficult. HPS lacks the neutropenia and recurrent infections in early childhood associated with Chédiak-Higashi and Griselli syndromes and the neuropathy associated with Chédiak-Higashi syndrome; furthermore, there is absence of bleeding tendency in patients with Griselli syndrome.
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FOOTNOTES
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Deceased. 
Authors stated no financial relationship to disclose.
| Part one of this case appeared 4 months previously and may contain larger images.
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References
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- Hansell DM. High-resolution CT of diffuse lung disease: value and limitations. Radiol Clin North Am 2001;39:1091–1113. [CrossRef][Medline]
- Westcott JL, Cole SR. Traction bronchiectasis in end-stage pulmonary fibrosis. Radiology 1986;161:665–669. [Abstract/Free Full Text]
- Franquet T. High-resolution CT of lung disease related to collagen vascular disease. Radiol Clin North Am 2001;39:1171–1187. [CrossRef][Medline]
- Iannello S, Fabbri G, Bosco P, et al. A clinical variant of familial Hermansky-Pudlak syndrome. MedGenMed 2003;5:3. [Medline]
- Lyerla TA, Rusiniak ME, Borchers M, et al. 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. [Abstract/Free Full Text]
- Gahl WA, Brantly M, Troendle J, et al. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab 2002;76:234–242. [CrossRef][Medline]
- Harrison C, Khair K, Baxter B, Russell-Eggitt I, Hann I, Liesner R. Hermansky-Pudlak syndrome: infrequent bleeding and first report of Turkish and Pakistani kindreds. Arch Dis Child 2002;86:297–301. [Abstract/Free Full Text]
- Nakatani Y, Nakamura N, Sano J, et al. 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. [CrossRef][Medline]
- Clark RH, Stinchcombe JC, Day A, et al. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003;4:1111–1120. [CrossRef][Medline]
- Trambas CM, Griffiths GM. Delivering the kiss of death. Nat Immunol 2003;4:399–403. [CrossRef][Medline]
- Starcevic M, Nazarian R, Dell'Angelica EC. Molecular machinery for the biogenesis of lysosome-related organelles: lessons from Hermansky-Pudlak syndrome. Semin Cell Dev Biol 2002;13:271–278. [CrossRef][Medline]
- Garay SM, Gardella JE, Fazzini EP, et al. Hermansky-Pudlak syndrome: pulmonary manifestations of a ceroid storage disorder. Am J Med 1979;66:737–747. [CrossRef][Medline]
- White DA, Smith GJ, Cooper JA Jr, Glickstein M, Rankin JA. Hermansky-Pudlak syndrome and interstitial lung disease: report of a case with lavage findings. Am Rev Respir Dis 1984;130:138–141. [Medline]
- Leitman BS, Balthazar WE, Garay SM, Naidich DP, McCauley DI. The Hermansky-Pudlak syndrome: radiographic features. Can Assoc Radiol J 1986;37:42–45. [Medline]
- Shimizu K, Matsumoto T, Miura G, et al. Hermansky-Pudlak syndrome with diffuse pulmonary fibrosis: radiologic-pathologic correlation. J Comput Assist Tomogr 1998;22:249–251. [CrossRef][Medline]
- Avila NA, Brantly M, Premkumar A, Huizing M, Dwayer 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. [Abstract/Free Full Text]
- Schinella RA, Greco MA, Cobert BL, Denmark LW, Cox RP. Hermansky-Pudlak syndrome with granulomatous colitis. Ann Intern Med 1980;92:20–23. [Abstract/Free Full Text]
- Goswami GK, Sadler MA. Small-bowel stricture in a woman with oculocutaneous albinism (Hermansky-Pudlak syndrome). AJR Am J Roentgenol 2000;174:1163–1164. [Free Full Text]
- Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 1999;68:283–303. [CrossRef][Medline]
- Shiflett SL, Kaplan J, Ward DM. Chediak-Higashi syndrome: a rare disorder of lysosomes and lysosome related organelles. Pigment Cell Res 2002;15:251–257. [CrossRef][Medline]
Congratulations to the 135 individuals and 10 resident groups that submitted the most likely diagnosis (Hermansky-Pudlak syndrome) for Diagnosis Please, Case 124. The names and locations of the individuals and resident groups, as submitted, are as follows:
Individual responses
- Hisashi Abe, MD, Suita, Osaka, Japan
- Gholamali Afshang, MD, Tinley Park, Ill
- Todd Aho, MD, Detroit, Mich
- Erhan Akpinar, Ankara, Turkey
- Albert J. Alter, MD, PhD, Madison, Wis
- Augusto Celso S. Amato Filho, MD, São Paulo, Brazil
- Asim K. Bag, MD, Birmingham, Ala
- Monica Ballesta Moratalla, MD, Valencia, Spain
- Bryan D. Berkey, MD, Tripler AMC, Hawaii
- Eric L. Bressler, MD, Minnetonka, Minn
- Douglas C. Brown, MD, Virginia Beach, Va
- Marcelo Cabrini, Lomas de Zamora, Argentina
- Antonio A. Cavalcanti, MD, São Paulo, Brazil
- Hearns W. Charles, MD, New York, NY
- Alex T. Chuang, MD, Dallas, Tex
- Raymond W. Chyu, MD, Cupertino, Calif
- Daniel N. Costa, MD, Boston, Mass
- Marco A. Cura, MD, San Antonio, Tex
- Marc G. De Baets, MD, Collina d'Oro, Switzerland
- Peter De Baets, Damme, Belgium
- Johannes F. De Villiers, MBChB, MMed, Gisborne, New Zealand
- Thaworn Dendumrongsup, MD, Songkla, Thailand
- Walter T. Depaulaneto III, MD, Rio de Janeiro, Brazil
- Sandeep P. Deshmukh, MD, Hayward, Calif
- Susana Dias, MD, Porto, Portugal
- Jorge Docampo, Buenos Aires, Argentina
- Seyed A. Emamian, MD, PhD, Rockville, Md
- Bing Fabrice, Saint Ismier, France
- Shella Farooki, Dublin, Ohio
- Brett D. Ferdinand, MD, Livingston, NJ
- Angeles Franco Lopez, Madrid, Spain
- Akira Fujikawa, MD, Setagaya, Tokyo, Japan
- Rajneesh Galwa, Jaipur, India
- Ram P. Galwa, MD, Chandigarh, India
- Douglas J. Gardner, MD, Windsor, Ontario, Canada
- Vidisha V. Ghole, MD, Irving, Tex
- Mark G. Goldshein, MD, Andover, Mass
- Francisco Jose Gonzalez, Santander, Spain
- Dan G. Gridley, MD, Phoenix, Ariz
- Flavius F. Guglielmo, MD, Basking Ridge, NJ
- Pramod K. Gupta, MD, Plano, Tex
- Leticia Gutierrez, MD, Madrid, Spain
- Ferris M. Hall, MD, Brookline, Mass
- Srinivasan Harish, MBBS, Burlington, Ontario, Canada
- Thomas S. Helling, Jr, MD, Richardson, Tex
- Yuusuke Hirokawa, MD, Kyoto, Japan
- Waleed M. Ibrahim, MD, Columbus, Ohio
- Rathachai Kaewlai, MD, Boston, Mass
- Masako Kataoka, MD, Cambridge, United Kingdom
- Rujimas Khumtong, MD, Hat-Yai, Songkhla, Thailand
- Takuji Kiryu, MD, PhD, Gifu, Japan
- Stefanos Lachanis, Athens, Greece
- Alexis Lacout, MD, Paris, France
- Mario A. Laguna, MD, Milwaukee, Wis
- Martin Lecompte, MD, Manotick, Ontario, Canada
- Inigo Lecumberri IV, MD, Bilbao, Spain
- Myron M. Levitt, MD, Scotch Plains, NJ
- John T. Lim, MD, Newport Coast, Calif
- David A. Lisle, MBBS, Brisbane, Australia
- Jaime Llauger, MD, Barcelona, Spain
- Patricia A. Lowry, MD, Chattanooga, Tenn
- George D. Lyons, MD, Tulsa, Okla
- Naganathan B. Mani, MD, Miami, Fla
- Alberto A. Marangoni, MD, Cordoba, Argentina
- Michael B. Martin, MD, Austin, Tex
- Daniel L. Martins, MD, São Paulo, Brazil
- Andrew C. Mason, MBBCh, Vancouver, British Columbia, Canada
- Satoshi Matsushima, MD, Tokyo, Japan
- Waldir H. Maymone, MD, Rio de Janeiro, Brazil
- Ronan A. McDermott, MBBCh, Dublin, Ireland
- Jo Meersschaert, Leuven, Belgium
- Michael P. Meyers, MD, Winnipeg, Manitoba, Canada
- Nikolaos Michailidis, Thessaloniki, Greece
- Manabu Minami, MD, PhD, Yokohama, Japan
- Sankar R. Mondal, MD, Nassau, Bahamas
- Jose Mondello, MD, Buenos Aires, Argentina
- Tetsuo Nakayama, MD, Osaka, Japan
- Tammam N. Nehme, MD, East Wenatchee, Wash
- Mizuki Nishino, MD, Boston, Mass
- Bonnie E. O'hayon, MD, Toronto, Ontario, Canada
- Anietie E. Okon, MD, North Liberty, Iowa
- Cinthia D. Ortega, MD, São Paulo, Brazil
- Klaus Orth, Aachen, Germany
- Marc G. Ossip, MD, Toronto, Ontario, Canada
- Ann B. Owen, MD, Murfreesboro, Tenn
- Esther Pallisa, MD, Barcelona, Spain
- David M. Panicek, MD, New York, NY
- Suresh K. Patel, MD, Chicago, Ill
- Yeliz Pekcevik, Izmir, Turkey
- Nicola Pelosi, Palmanova, Italy
- Stacey L. Piche, MD, Summerland, British Columbia, Canada
- Sudhakar N. Pipavath, MD, Seattle, Wash
- Sanjay P. Prabhu, MBBS, Melbourne, Australia
- Ilias Primetis, MD, Athens, Greece
- Prashant Raghavan, MD, Charlottesville, Va
- Daniel C. Rappaport, MD, Toronto, Ontario, Canada
- Matthew C. Rheinboldt, MD, Nashville, Tenn
- Manoel D. Rocha, MD, São Paulo, Brazil
- Tsutomu Sakamoto, MD, Tokyo, Japan
- Steven Schepers, Herent, Belgium
- Steven M. Schultz, MD, Fort Worth, Tex
- Hidekazu Seo, MD, Hamamatsu, Shizuoka, Japan
- Matthew P. Shapiro, MD, Charlottesville, Va
- Hideki Shima, MD, Tokyo, Japan
- Taro Shimono, MD, Osaka, Sayama, Japan
- Ken Simmons, MD, Sydney, Australia
- William L. Simpson, MD, New York, NY
- Annemie Snoeckx, MD, Zandhoven, Belgium
- James D. Sprinkle, Jr, MD, Spotsylvania, Va
- Paul Stark, La Jolla, Calif
- Subramanian Subramanian, MD, New Delhi, India
- Kouichi Sugiyama, Numazu, Japan
- Norio Takahashi, MD, Fukui, Japan
- Yukihisa Takayama, MD, Columbus, Ohio
- Ayako Takeuchi, MD, PhD, Tokyo, Japan
- Ken Tamai, Kyoto, Japan
- Douglas L. Teich, MD, Brookline, Mass
- Osman Temizoz, Edirne, Turkey
- Kazuma Terauchi, Fujieda, Shizuoka, Japan
- Eugene Tong, MD, Austin, Tex
- William C. Torreggiani, MB, Dublin, Ireland
- Ozgur Tosun, Ankara, Turkey
- Ricardo H. Trueba, MD, Buenos Aires, Argentina
- Baris I. Turkbey, MD, Baltimore, Md
- Ercument Unlu, Edirne, Turkey
- Eleni Vafeiadou, Thessaloniki, Greece
- Nanda Venkatanarasimha, MBBS, MRCP, Plymouth, United Kingdom
- Ricardo Luis Videla, Córdoba, Argentina
- Christopher P. Vittore, MD, Belvidere, Ill
- Tim Weber, MD, Heidelberg, Germany
- David C. Wilkes, MD, Dallas, Tex
- Edward W. Williams, MBChB, British Isles, United Kingdom
- Kaneko You, Gifu, Japan
- Joe Yut, Olathe, Kan
- Bas Zonneveld, MD, Deventer, Netherlands
Resident group responses
- Baylor University Medical Center Radiology Residents, Dallas, Tex
- Diagnostico Medico Radiology Residents, Buenos Aires, Argentina
- Fundación Científica del Sur Radiology Residents, Lomas de Zamora, Argentina
- Fundacion Jimenez Diaz Radiology Residents, Madrid, Spain
- Hospital Italiano Cordoba Radiology Residents, Cordoba, Argentina
- Kyoto City Hospital Radiology Residents, Kyoto, Japan
- Prince of Songkla University Radiology Residents, Hat Yai, Songkla, Thailand
- Santa Casa da Misericórdia do Rio de Janeiro Radiology Residents, Rio de Janeiro, Brazil
- University of Pennsylvania Radiology Residents, Philadelphia, Pa
- Virginia Commonwealth University Radiology Residents, Richmond, Va
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HISTORY
IMAGING FINDINGS 
