The Hermansky-Pudlak Syndrome

PATHOLOGICAL-RADIOLOGICALCORRELATIONS

The Hermansky-Pudlak Syndrome Mark S. Parker, MD, William R. Shipley, MD, Melissa L. Rosado de Christenson, Lt Col, USAF, MC, A. David Slutzker, MD, Frank E. Carroll, MD, John A. Worrell,MD, andJames G. White, MD Hermansky-Pudlak Syndrome (HPS) is a rare, inheritable disorder characterized by the classic triad of oculo-cutaneous albinism, platelet dysfunction, and ceroid deposition. An associated complication is pulmonary fibrosis with progressive restrictive lung disease. This report discusses the lung involvement often seen in this condition correlated with radiography, computed tomography, high-resolution computed tomography, and the underlying pathology, by means of two such afflicted siblings. The elder died of respiratory failure while awaiting lung transplantation. The younger sibling is currently undergoing evaluation for transplantation. Ann Diagn Pathol 1: 99-103, 1997. Copyright © 1997by W.B. Saunders Company Index Words: Hermansky-Pudlak Syndrome, albinism, pulmonary fibrosis, restrictive lung disease, ceroid, platelet dense bodies

RMANSKY-PUDLAK SYNDROME (tiPS) is a re, autosomal recessive disorder characterized by the classic triad of oculocutaneous albinism, platelet dysfunction, and ceroid deposition within cells of the mononuclear phagocytic system.l-s An associated complication with a variable expression is pulmonary fibrosis with progressive restrictive lung disease. Emphasizing the radiological and pathological manifestations in the lung, we report two siblings with HPS who developed pulmonary fibrosis. The older sibling's clinical course spanned approximately 4 years. The patient died of respiratory failure while awaiting a single-lung transplant. This case provides illustrative material of the radiological and pathological features of HPS. Her

From UniversJtyof Texas Southwestern Medical Centerat Dallas, Department ~Diagnostic Radiology, Dallas, TX; Vanderbilt University Medical Center, Department of Pathology, Nashville, TN; Armed Forces [astitute of Pathology, Department of Radiologic-Pathology, Wm'hington, DC; Horizon Physidan Group, Knoxville, TN,," Vanderbilt University Medical Center, Department of Diagnostic Radiology, Nashville, TN,. Vanderbilt University Medical Center, Department of Diagnostic Radiology, Nashville, TN; and University of Minnesota Health System, Department of Laborato!y Medicine and Pathology, Minneapolis, MdK. The opinions and assertionscontainedherein are theprivate views of the authors and are not to be construedas offcial or as reflectingthe views of the Department of theAir Force or the Department ofDefenee. Address correspondenceto Mark S. Parker,MD, Universityof Texas Southwestera Medical Center at Dallas, Department of Diagnostic Radiology, 5201 Harry Hines Blvd, Dallm, TX 75235. Copyright 0 1997 by W..B. Saunders Company 1092-9134/97/0102-0004505.00/0

younger brother's respiratory disease has progressed with deteriorating pulmonary function over the last 2 years. Lung transplant evaluation is currently in progress. The latter case demonstrates electron microscopic and high-resolution computed tomography (HRCT) manifestations of liPS. Case Reports Case 1

Case 1 is a 35-year-old albino woman with HPS and no known Puerto Rican or Dutch lineage. Her parents were third or fourth cousins. She had a significant bleeding history with severe, easy bruising, menorrhagia, bleeding after hysterectomy, and marked frequent epistaxis. She also suffered from chronic iron deficiency anemia. Respiratory symptoms first developed in 1991 with the onset of repeated episodes of pleuritic chest pain and cough productive of clear sputum. Eventual open lung biopsy demonstrated evidence.of pulmonary interstitial fibrosis. The patient was subsequently admitted to the hospital in January 1995, for increasing dyspnea. Pulmonary function tests (PFTs) revealed a restrictive pattern with total lung capacity (TLC) 38% of predicted TLC, and diffusing capacity of carbon monoxide (DLCO) 20% of predicted DLCO. Oxygen and steroid therapy were implemented. Chest radiographs on admission (Fig 1) demonstrated significant bilateral volume loss and diffuse, predominantly bibasilar peripheral interstitial parenchy-

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Figure 1. Radiological manifestations of HPS in case 1. (A) PA chest radiograph demonstrates significant volume loss and marked bilateral increased interstitial markings primarily affecting the peripheral mid and lower lungs. (B) Chest CT scan (lung window) at the level of the carina and lung bases (C). Demonstrates Patchy multifocal "ground glass" opacities affecting the right upper lobe, the left upper lobe, and both bases. Fibrosis with "honeycombing," thickened intralobular septa and traction bronchiectasis are also present.

mal disease. Thoracic computerized tomography (CT) (Fig 1) demonstrated diffuse patchy "ground glass" opacities, interstitial fibrosis, traction bronchiectasis, and honeycombing. Lung transplant evaluation was initiated, and the patient was subsequently discharged awaiting a donor lung. Respiratory failure progressed, and she died approximately 6 weeks later. Autopsy revealed chronic interstitial fibrosis and extensive ceroid deposition throughout the mononuclear phagocytic system. Case 2

Case 2 is the 34-year-old younger brother of the patient described case 1. He was diagnosed with albinism at birth and has a long history of excessive bleeding after minor trauma and occasional epistaxis. He also

suffers from diminished visual acuity, ocular nystagmus, and photosensitivity. Respiratory symptoms have progressed over the last 2 years, with complaints of dyspnea with heavy lifting and stair climbing. PFT results have also deteriorated, with a TLC of 72%, a functional residual capacity (FRC) of 82%, a residual volume (RV) of 76%, a forced expiratory volume at 1.0 second of 77% and a DLCO of 70% of predicted. Chest radiographs revealed modest bilateral volume loss and predominantly mid- and lower-lung peripheral interstitial opacities similar to those seen in case 1. HRCT (Fig 2) reveals "ground glass" opacities, interstitial fibrosis, traction bronchiectasis, and honeycombing. Additional laboratory studies demonstrate a prolonged bleeding time of >20 minutes (normal, <9.5 minutes), platelet adhesiveness of 59% (normal, >80%), and a total lack of

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Figure 2. Radiological manifestations of HPS in the younger, less symptomatic sibling, case 2. Selected HRCT images (A) demonstrates patchy peripheral "ground-glass" opacities, subpleural cysts, and honeycomb lung, and traction bronchiectasis of both upper lobes. (B) Inter- and intralobular septal thickening, ground-glass opacities, and extensive honeycombing are present in both lower lobes.

platelet-dense granules on electron microscopy (Fig 3). This constellation of clinical and laboratory findings is diagnostic of liPS. Based on these results and the rapid demise of his sibling, he is currently being evaluated for single-lung transplantation. Discussion

Hermansky and Pudlak first described albinism associated with hemorrhagic diathesis and the presence of unusual pigmented reticular cells in the bone marrow in 1959.4 This syndrome, now known as the HermanskyPudlak Syndrome (HPS), is a rare, autosomal recessive disorder consisting of the classic triad of oculocutaneous tyrosinase-positive albinism, bleeding diathesis secondary to platelet dysfunction, and ceroid deposition within the mononuclear phagocytic system (MPS). 1-3 Associated complications with variable expression include an increased predilection toward respiratory infections, pulmonary fibrosis with progressive restrictive lung disease, and inflammatory- bowel disease. Men and women are equally affected.5 The vast majority of patients are originally from Puerto Rico or southern Holland. A history of consanguinity is not uncommon. 5,G

Approximately 200 cases had been reported by 1985 worldwide.3,5 The most striking feature on physical examination is the oculocutaneous albinism. The albinism is referred to as "tyrosine positive" because of the presence of tyrosine in the melanosomes. This feature is not present in persons with total albinism. Hair follicles of affected individuals will darken when incubated with either L-tyrosine or L-DOPA (levo-dihydroxyphenylalanin@ Because the degree of albinism is variable, it may not be easily recognized. The astute clinician may appreciate a fairer complexion, lighter hair color, or the presence of freckling in the affected person as compared with other family members. Additionally, a given individual's phenotypic expression will vary as a function of both age and ethnicity. Patients with HPS may also manifest a variety of ocular abnormalities including visual impairment, photophobia, nystagmus, and strabismus. The iris is often translucent or blue. The fundus is hypopigmented.7,8 The second major component of the HPS triad is a bleeding diathesis characterized by a delta storage pool platelet defect. Electron microscopy demonstrates a

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dense granules on electron microscopy is the most reliable method of diagnosis of I-[PS.7,9 Extensive ceroid deposition throughout the MPS is the third major component of the HPS triad. Ceroid, theorized to reside within lysosomes, is a complex chromolipid, the origin and chemical structure of which are not completely understood. Ceroid is recognized histologically as a fine granular brown Periodic acidSchiff-positive (PAS-positive), acid-fast pigment (Fig 4). This pigment demonstrates a brilliant yellow-orange fluorescence under ultraviolet light,a,4,1°Ceroid deposits may be identified within the MPS cells of the liver, spleen, large bowel, proximal tubules of the kidney, capillary and venous endothelium and glial cells of the central nervous system, and the alveoli of affected individuals. However, ceroid accumulation in the lung is variable and is not always seen in bronchoalveolar lavage or open lung biopsy specimens.5,a,9 The role of ceroid deposition in the development of pulmonary fibrosis is uncertain. White et a111 demonstrated increased superoxide production by stimulated alveolar macrophages in patients with HPS as opposed to normal controls. They speculated that ceroid-laden macrophages may be more responsive to various exogenous stimuli, resulting in the subsequent release of "toxic" oxygen metabolites. These metabolites may damage the pulmonary interstitium, resulting in interstitial fibrosis and subsequent end-stage lung disease (Fig 5). However, as already discussed, ceroid deposition is not universally found in the lungs of patients with HPS with pulmonary fibrosis. Therefore, ceroid deposition alone is not solely responsible for the resultant fibrosis.5,8,9 Although the syndrome affects males and females Figure 3. Electron photomicrographs. (A) Normal control platelets demonstrating the presence of dense granules. (B) Platelets from case two. The dense granules are characteristically absent in patients with HPS.

total lack of dense granules in the platelets of patients with HPS. Dense granules represent the storage organelles essential for the second phase of platelet aggregation. The granules contain serotonin, adenosine triphosphate (ATP), adenosine diphosphate (ADP), pyrophosphate, and calcium that are released after stimulation by potent aggregating agents such as epinephrine and collagen. Such release results in the aggregation of adjacent platelets. This second phase ofplatelet aggregation is, however, functionally impaired in affected patients, resulting in a prolonged bleeding time with resultant hemorrhagic complications. The absence of

Figure 4. Ceroid deposition. Case 1. PAS-positive ceroidladen macrophages (arrow) and foamy macrophages (arrowhead) are seen within the alveoli.

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Conclusion

Figure 5. Pathologic changes of interstitial fibrosis. Case 1. Dense pulmonary interstitial fibrosis and resultant traction bronchiectasis (arrow).

equally, the pulmonary manifestations are twice as common in females. Lung disease typically manifests in the third to fourth decades of life with the onset of progressive dyspnea, a nonproductive cough and hypoxemia at rest. Pulmonary fibrosis resulting in respiratory failure is the leading cause of death. 8,9 The radiographical features of HPS are not specific enough to allow a diagnosis to be made on the basis of imaging alone. Radiographic abnormalities in HPS tend to occur later in the course of the disease than the changes in pulmonary function do. Radiographical findings range from a fine reticular interstitial pattern to a coarse reticulonodular pattern. There may be little decrease in overall lung volume. The subpleural zone is often spared. Bullae, architectural distortion, and traction bronchiectasis are associated findings that have been described as having an upper lung zone predilection. Interstitial fibrosis and end-stage lung changes may eventually develop in some patients. 8,12,13 The treatment of liPS-related lung disease has mainly been supportive. Corticosteroids and immunosuppressive agents have generally not been successful. Lung transplantation may be the only viable form of therapy available to those patients with progressive respiratory failure. Bilateral lung transplantation might be considered given the propensity patients with HPS have to recurrent pulmonary infections. The pathophysiology of HPS may suggest that even transplantation may prove only palliative, because the disease, at least theoretically, might be expected to recur in the donor organ(s). As of this writing, no patient with HPS has survived long enough to undergo transplantation. 8

The syndrome of Hermansky-Pudlak is added to the seemingly ever-growing list of etiologies of interstitial lung disease. Although a rare entity, the prognosis of HPS with interstitial disease and fibrosis is worse than that of uncomplicated HPS. The former typically progresses despite steroid therapy and the vast majority of patients die within 1 to 6 years after the diagnosis of respiratory failure. Currently, no successful form of therapy exists. Because lung transplantation is potentially curative, knowledge of HPS, its hallmarks, and various manifestations may result in early detection, prompt evaluation for transplant therapy, and improve the survival of this otherwise progressively debilitating and potentially lethal syndrome.

References 1. Reynolds SP, Davies BH, Gibbs AR: Diffuse pulmonary fibrosis and the Hermansky-Pudlak Syndrome: Clinical course and postmortem findings. Thorax 1994;49:617-618 2. Garay SM, Gardella JE, Fazzini EP, et ah Hermansky-Pudlak Syndrome. Pulmonary manifestations ofa ceroid storage disorder. Am J Med 1979;66:737-747 3. Schinella RA, Greco MA, Garay SM, et al: Hermansky-Pudlak Syndrome: A clinicopathologic study. Hum Pathoi 1985;16:366-376 4. Hermansky F, Pudlak P: Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow. Report of two cases with histochemical studies. Blood 1959;14:162-169 5. DePinho RA, Kaplan KL: The Hermansky-Pudlak Syndrome: Report of three cases and review of pathophysiology and management considerations. Medicine 1985;64:192-202 6. Hoste P, Williams j, Devriendt J, et al: Familial diffuse interstitial pulmonary fibrosis associated with oculocutaneous albinism: report of two cases with a family study. ScandJ Resp Dis 1979;60:128 7. Schachne JP, Glaser N, Lee Sanhee, et al: Hermansky-Pudlak Syndrome: Case report and clinicopathologic review. J Am Acad Dermatol 1990;22:926-932 8. Horowitz ID: Dyspnea in a 30-year-old Hispanic man with albinism. Chest 1995;108:1158-1160 9. Wockel W, SultzJ: Diffuse pulmonary fibrosis and HermanskyPudlak syndrome. Thorax 1995;50:591 10. Harmon KR, Witkop CJ, White JG, et ah Pathogenesis of pulmonary fibrosis: Platelet-derived growth factor precedes structural alteration in the Hermansky-Pudlak Syndrome. J Lab Clin Med 1994;123:617-627 11. White DA, Smith GJ, Cooper JA, et al: Hermansky-Pudlak Syndrome and interstitial lung disease: Report of a case with lavage findings. Am Rev Resp Dis 1984;130:138-I41 12. Fraser RG, Pare JAP, Pare PD, et ah Diagnosis of Diseases of the Chest, (3 ed). Philadelphia, PA, Saunders, 1991, pp 2593-2594 13. Leitman BS, Balthazar EJ, Garay SM, et al: The HermanskyPudlak Syndrome: Radiographic features. Can Assoc RadiolJ 1986;37: 42-45