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Hermansky-Pudlak syndrome
Hermansky-Pudlak Syndrome Pulmonary Manifestations
STUART M. GARAY, M.D. JOHN E. GARDELLA, M.D. EUGENE P. FAZZINI. M.D. ROBERTA M. GOLDRING, M.D New York, New York
From the Departments of Medicine and Pathology, New York University School of Medicine: and the Chest Service, Bellevue Hospital Center, New York, New York. Requests for reprints should be addressed to Dr. Roberta M. Goldring, New York University School of Medicine, 550 First Avenue, New York, New York 10016. Manuscript accepted December 27.1978.
of a Ceroid Storage Disorder
The Hermansky-Pudlak syndrome is a form of oculocutaneous alhinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Herman&y-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients. In 1959 Hermansky and Pudlak [l] first described a congenital disorder consisting of oculocutaneous albinism, a hemorrhagic defect and the accumulation of ceroid in the reticuloendothelial system of various tissues. Since the original description, fewer than 50 cases of Hermansky-Pudlak syndrome have been reported in the literature. Most reports have dealt almost exclusively with the albinism and associated bleeding disorder [2-71. During a 16 month interval, seven patients with Herman&y-Pudlak syndrome were diagnosed at the New York University-Bellevue Hospital Center. In contrast to the previously reported cases, diffuse pulmonary fibrosis and/or inflammatory bowel disease were prominent manifestations in five of these patients. This study will focus on the pulmonary aspect of this syndrome. Herman&y-Pudlak syndrome is a storage disorder different from those previously described involving ceroid [8-111. Ceroid, a complex chromolipid, is related to lipofuscin, the aging pigment. Although the storage material in Herman&y-Pudlak syndrome has been labelled ceroid [12], the actual nature of this pigment remains unknown.* Unlike other storage diseases in which specific catabolic, hydrolyzing enzymes are lacking [IS], the defect in ceroid-lipofuscin disorders has not been elucidated. Indeed, ceroid storage diseases have received little attention in the general medical literature and have not been clearly established as abnormalities of lysosomal metabolism. This * Because of this uncertainty on the one hand and the histochemical similarities to ceroid on the other hand, the qualifying phrase “ceroid-like” shall be used throughout this paper.
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TABLE I
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ET AL.
Clinical Features of Five Patients with Hermansky-Pudlak Syndrome Case 1
Age (yr) and sex Birthplace Family history Albinism Colitis Bleeding diathesis
Ceroid deposition
Case 2
Case 3
Case 4
Case 5
28, F Aguadilla
38, M Aguadilla
20, F Aguadilla
43, F Aguadilla
32, F Aguadilla
1 sister 1 brother 1 brother
2 sisters
Upper gastrointestinal bleed
2 sisters 2 brothers 1 brother 1 sister Lower gastrointestinal bleed
1 sister 1 brother -
Postpartum bleed Lower gastrointestinal bleed Urine Colon
1 sister 1 brother 1 brother 1 sister Tooth extraction
Urine Lung
Urine
...
Urine Lung
Postpartum bleed Tooth extraction
Colon Pulmonary interstitial disease Symptoms Chest X-ray Pulmonary function tests Lung biopsy Inflammatory bowel
Moderate dyspnea on exertion Reticulonodular Restrictive ND +
Dyspnea at rest Honeycomb cystic changes Restrictive
Mild dyspnea on exertion Reticulonodular
Fibrosis
Mild dyspnea on exertion Reticulonodular
Restrictive
Dyspnea at rest Honeycomb cystic changes Restrictive
ND -
Fibrosis +
ND
Restrictive
NOTE: ND = not done; i- = present; - = absent. Patients in Cases 1 and 3 and patients in Cases 5 and 2 are siblings.
study suggests that Herman&y-Pudlak syndrome is a storage disorder more common than previously appreciated and that it should be considered in patients who present with pulmonary interstitial fibrosis and/or inflammatory bowel disease.
METHODS The diagnosis of Hermansky-Pudlak syndrome was based upon the finding of tyrosinase-positive oculocutaneous albinism in patients of Puerto Rican extraction, accumulation of ceroid-like material and the demonstration of a qualitative platelet defect. Platelet function studies, including a platelet count, Ivy bleeding time and platelet aggregation, were carried out in each patient. Pulmonary function testing was performed on all patients. Lung volumes were determined by standard spirometry and plethysmography. Predicted values are thqse of Morris et al. (151.The maximum expiratory flow volume (MEFV) curve was recorded on an X-Y recorder. Values in our laboratory for normal nonsmokers of similar age to the patients studied in this paper are comparable to those of Miller et al. [16] and Lapp and Hyatt [17]. Airway resistance, conductance and specific conductance were measured in the body plethysmograph using the methods described by Dubois, Botelho and Comroe [18]. Diffusing capacity (DLco) was measured by the singlebreath method described by Ogilvie et al. [19]. The DLco was partitioned into the membrane diffusion coefficient (DM]and the pulmonary capillary blood volume using methods described by Roughton and Forster [20]. Predicted values are
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those of Bucci et al. [21]. Pulmonary compliance was measured with an esophageal balloon as described by Milic-Emili and associates [22].The static deflation pressure-volume curve was recorded during a slow expiration from total lung capacity (TLC] to functional residual capacity (FRC) in order to obtain the transpulmonary pressure at TLC (which reflects maximum static recoil pressure at TLC) and static compliance at FRC [23]. Compliance was measured at increasing frequencies of breathing at constant tidal volumes to test for frequency dependence of compliance [%I. Two patients underwent lung biopsy; flexible fiberoptic bronchoscopy in one and thoracotomy in the other. Specimens were examined under light microscopy with standard hematoxylin and eosin stains and with special histochemical stains [25]. Electron microscopy was also performed on one lung specimen. The lung biopsy specimens as well as urine from four patients (Cases I. 2,4 and 5) were examined under ultraviolet light for fluorescence [25].
RESULTS The clinical features of the five patients with Hermansky-Pudlak syndrome are outlined in Table I. Two representative clinical summaries follow the conclusion of this paper.
Pulmonary Function Tests. Lung volumes and airway function: The results of pulmonary function studies are shown in Table II. Each patient had a reduction in all lung volumes. Large airway function was normal as evidenced by normal forced expiratory volumes in 1
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TABLE II
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Pulmonary Function Data case2
Case1 6177 Lung volumes’ 2.30 (58) VC (liter) 2.28 (73) FRC (liter) 3.52 (66) TLC (liter) Airway function* 2.12 (66) FEV, (liter) FEV,lFVC 0.87 (1 lo) FEFsO(literlsec)t 3.21 (66) FEFs5(literlsec)t 1.18 (42) 1.32 FEF&FVC§ FEFIBVCiI 0.49 S&, (IiterlsecJ 0.227 cm l+O/liter)~ Diffusion* 12.0 (46) DL,, (ml/min/ mm Hg) DL/AIv vol 3.9 (80) Mechanics Compliance*
r/70
5177
2.18 (55)
1.01 (26)
1.94 (64) 3.42 (64)
i .58 (79)
0177
~Case3
~ Case4
Case5 12178
2.38 (59)
0.93 (30) 1.06 (38) 1.68 (37)
1.64 (54) 1.27 (66) 2.48 (63)
0.82 (34) 1.00 (131) 2.40 (57) 1.a8 (92) 2.92 2.18
1.45 (59) 0.84 (106) 3.66 (85) 0.78 (31) 2.14 0.45 0.314
7/n
2.16 (45)
1.28 (33) 1.44 (72) 2.09 (44)
1.75 (65) 3.43 (66)
1.a0 (57) 0.84 (106) 3.14 (65) 0.71 (25) 1.48 0.33 0.247
1.02 (32) 0.86 (113) 1.65 (31) 0.63 (24) 1.40 0.53 0.309
1.14 (36) 0.85 (111) 1.a0 (34) 0.47 (la) 1.35 0.35 0.226
2.40 (73) 0.71 (87) 4.33 (88) 1.97 (65) 1.73 0.79 0.332
7.0 (27)
3.0 (20)
3.0 (20)
2.6 (53)
1.5 (36)
1.7 (31)
5/n
i 2.9 (48)
..
9 (56) 3.9 (71)
4.76 (92)
l
0.053 (0.120.21) 0.027 (0.040.07) 0.050 (0.120.21) 58 (21-32) 17 (4-6)
Gtatic
Cspecific CdylWiC
P,, at TLC++ P,,ITLCt* Arterial blood gas PH Rest Exercise ~02 (mm Hg) Rest Exercise
7.47 7.48
0.013 ( o.oa0.14) 0.14 ( 0.040.07) 0.022 (o.oa0.14) 42 (24-29) 19 (5-6)
7.38 7.38
0.02 (o.oa0.14) 0.01 (0.040+7) 0.02 (o.oa0.14) 61(24-29) 29 (5-6)
7.46 7.48
0.065 (0.080.13) 0.051 (0.040.07) 0.06 (o.oa0.13) 64 (17-23) 25.8 (4-6)
0.039 (0.040.07) 0.068 (0.1 l0.19) 30 (21-36) 8.8 (4-7)
7.51 7.42
7.48
7.42 7.36
76 55
74 50
60 38
105 a9
68
a9 68
33 26
34 31
33 31
22 30
36
36 39
34 64
35 63
50 75
19 25
39
pCO2(mmHd Rest Exercise (A - a) DO2 (mm Hg) Rest Exercise
la
36
Numbers in parentheses represent percentages predicted. t Forced expiratory flow rate at 50 per cent of the vital capacity determined by the maximum expiratoty flow volume curve (see text). $ Forced expiratory flow rate at 25 per cent of the vital capacity determined by the maximum expiratory flow volume curve (see text). 5 Normal range 1.07 f 0.25 (as determined in our laboratory). ‘1Normal range 0.36 f 0.14 (as determined in our laboratory). # Specific conductance (normal 0.13-0.35). Numbers in parentheses represent predicted normal range [ 231. ++Maximum static elastic recoil pressure. tt Coefficient of retraction. l
l
l
second (FEV1) and specific conductance values in all patients. The maximum expiratory flow-volume curves revealed mild to moderate reduction in flow rates at all lung volumes. The flow-volume loops displayed a uniform pattern of reduction in expiratory flow (Figure 1); the reduction in flow rates was proportional to the decrease in volume in each patient. There was no evidence of dysfunction at low lung volumes. Follow-up studies
in two patients (Case 1 at one year and Case 2 at three months) did not reveal any significant change in airway function or lung volumes. Diffusion: Four patients demonstrated a reduction in DLco. One patient (Case 4) was too dyspneic to cooperate for the single breath diffusion study. In three patients (Cases I, 3 and 5] the initial decrease in diffusion was proportional to the diminution in alveolar volume,
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80-
60-
00 0
20
40
60
80
PRESSURE
(cm l-$0) Figure 2.
I
7
I
I
5 VOLUME
I
I
3
I
I
Volume-pressure curves for four patients (Cases 1, 2,3 and 5). One patient (Case 2) had an initial compliance study (a) repeated three months later (b). The volume data is presented as percentage of predicted total lung capacity, and is plotted against static transpulmonary pressure. The inflation pressures are markedly increased at any given lung volume compared to normal (shaded area [ 231).
I
I
(liters)
,
lgure 1.
Flow related to absolute volume during tidal breathing (small loops) and maximum inspiration and expiration (large loops). The maximum expiratory flow-volume curve reveals a normal pattern on the left and a “restrictive” pattern (Case 2) on the right. Note the normal contour of the latter curve, despite a reduction in flow rates.
whereas in one patient (Case 2) the decrease in diffusion was greater. A diffusion study repeated one year later in one patient (Case 1) revealed a marked deterioration in DLco despite the lack of progression in the clinical and roentgenologic findings. It should be noted that when the diffusion was moderately reduced in this patient, it was proportional to the decrease in alveolar volume (DJAlv vol = 80 per cent of predicted). However, one year later the diffusion was markedly reduced even. when related to alveolar volume (Dr/Alv vol = 53 per cent of predicted). A follow-up diffusion study (three months later) in another patient (Case 2) revealed no change in DLco. When the diffusing capacity was partitioned into the components in Case 1,the D~,,Iwas reduced to 18 ml/mm
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Hg/min (28 per cent of predicted), whereas the pulmonary capillary blood volume dropped to 27 ml (41 per cent of predicted). Similarly, the membrane diffusion coefficient (DM = 22 ml/mm Hg/min) and the pulmonary capillary blood volume (= 41 ml) were reduced in another patient (Case 5). A follow-up diffusion study (three months later) in one patient (Case 2) revealed no change in DLco. Gas exchange: Each patient, except one (Case 3), had mild to moderate hypoxemia at rest. However, all patients (including Case 3) had a widened alveolar-arterial oxygen gradient ([A-a] DOz) at rest. Arterial oxygen desaturation occurred in each patient upon exercise. One patient (Case 4) could not tolerate an exercise study because of dyspnea. Mechanics: Compliance studies (Table II, Figure 2) performed in four patients demonstrated a marked reduction in static, specific and dynamic compliances. There was no frequency dependence of compliance. The maximum static elastic recoil pressure (Pet) and the coefficient of retraction were markedly increased in three patients (Cases 1,2and 5). Only the coefficient of retraction was significantly increased in another (Case 3). In one patient (Case 2) a follow-up compliance study
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(three months later) revealed a marked increase in the P,l and coefficient of retraction without a change in TLC. Pathology. Light microscopy: Specimens of lung tissue were available for pathologic examination in two patients (Cases 2 and 4) (Figures 3 and 4). The biopsy specimen from one (Case 2) (Figure 31revealed diffuse interstitial fibrosis involving the alveolar septums as well as peribronchial fibrosis. Macrophages were filled with finely granular pigment (consistent with ceroid-like material] that stained positively with periodic acidSchiff stain. The biopsy specimen from another patient (Case 4) (Figure 4) showed almost complete replacement of the parenchyma by fibrous tissue within which collagen and elastic fibers were seen. Dilated bronchioles were filled with mucus and occasionally with neutrophils and desquamated epithelial cells. Some bronchioles showed areas of squamous metaplasia, whereas others showed marked hyperplasia. The remaining distal air spaces displayed evidence of epithelial regeneration and foamy macrophages indicating obstruction. Macrophages were scattered in the fibrous tissue around the bronchi. There was no evidence of an increased number of macrophages in the interstitium. Some macrophages contained anthracotic pigment and others contained finely divided brown pigment (ceroid-like material) that stained positively with periodic acid-Schiff stain, and weakly positive Ziehl-Neilsen acid-fast stain. Perl’s stain for iron was negative. Fontana’s stain for melanin was positive. In both patients the finely divided brown pigment in the alveolar macrophages showed intense orange fluorescence when viewed by ultraviolet illumination. Urinary sediment from four patients (Cases 1,2,4and 5) displayed intense orange fluorescence when viewed by ultraviolet light. Electron microscopy: Electron microscopy was performed on the biopsy specimen from one patient (Case 4) [Figure 5). Macrophages were seen containing a mixture of amorphous particulate debris (ceroid-like material) and lipid-filled vacuoles of varying size. In some cells the entire cytoplasm was replaced by ceroid-like material. None of the pigment was enclosed within membranes; however, membranes do not preserve well in deparaffinized tissue. The ceroid-like material was not arranged in a lamellar formation. There was no evidence of melanosomes or ingested cells. A few crystalline deposits were recognized within macrophages. COMMENTS The Hermansky-Pudlak syndrome comprises a subgroup of patients with tyrosinase-positive ocuIocutaneous albinism [26]. Besides the autosomal recessive mode of inheritance and visual disturbances, patients with Hermansky-Pudlak syndrome have deposits of ceroid-like material throughout the reticuloendothelial system, in buccal mucosa and urine. A qualitative
SYNDROME-GARAY
ET AL.
Case 2. Biopsy specimen from patient. Macrdphages filled with finely divided ceroid-like pigment. Hematoxylin and eosin stain, original magnification X 400, reduced by 30 per cent. Figure 3.
platelet defect has been found, which is characterized by electron microscopy as a diminished number of platelet “dense bodies,” i.e., the storage organelles for serotonin, ADP and ATP [27]. The functional defect is the failure of platelets to develop irreversible secondary aggregation, typical of a platelet storage pool deficiency. All patients in this study had a qualitative platelet defect, whereas most suffered serious bleeding complications [cf. Table I). Other serious hemorrhagic events have occurred in patients with this syndrome [26]. Although originally described in two Czechoslovakian patients, subsequent reports have shown a predominance of patients from Southern Holland and the Arecibo region of Puerto Rico [28]. Most patients in North America have been Puerto Ricans, with rare exceptions [26]. The seven patients diagnosed in this Medical Center (including the five described in this study) come from four unrelated families. All were born and raised in Aguadilla, a town northwest of Arecibo. It should be noted that the pigment disorder in Hermansky-Pudlak syndrome has a variable phenotypic expression, depending upon the racial background of the patient. Patients from Puerto Rico may have some pigmentation of their skin and eyes, and their hair is
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Figure 4. Case 4. Biopsy specimens from patient. Top, a bronchiole with metaplastic lining is seen at the upper right. Numerous macrophages contain finely divided ceroid-like pigment. Hematoxylin and eosin stain, original magnification X 120, reduced by 21 per cent. Bottom, pigment laden macrophages in fibrous stroma stain positively with periodic acid-Schiff stain. Original magnification X 400, reduced by 21 per cent.
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often red or reddish brown. Thus, such patients are often not recognized as albinos and may be mistaken for Caucasians. Four of the patients described in this report had been treated by physicians for several years in various teaching hospitals and clinics without being diagnosed as albinos. Following the diagnosis in one (Case 2). physicians at this Medical Center displayed a high index of suspicion for Herman&y-Pudlak syndrome in patients of Puerto Rican extraction who presented with a bleeding diathesis, pulmonary fibrosis or inflammatory bowel disease. This led to the subsequent diagnosis of six additional cases in a relatively short period of time. The original patients of Hermansky and Pudlak had evidence of pulmonary dysfunction. One, who complained of exertional dyspnea, had a chest roentgenogram suggestive of pulmonary fibrosis. The other had several episodes of hemoptysis related to previous tuberculosis. However, the postmortem examination in the latter patient revealed macrophages containing ceroid in various organs including the pulmonary interstitium (12]. There have been other brief descriptions
ET AL.
of the pulmonary findings in this syndrome. Witkop et al. [26] noted some patients with interstitial disease on chest roentgenograms whereas Davies and Tuddenheim [29] described a family in which four siblings had pulmonary disease associated with oculocutaneous albinism and a platelet defect. The clinical picture in these patients is characterized by the insidious onset of dyspnea. The natural history of pulmonary manifestations of Herman&y-Pudlak syndrome is unknown, although the progressive deterioration in two patients (Cases 2 and 4) suggests a course similar to idiopathic fibrosis. Two patients (Cases 2 and 4) had evidence of interstitial disease on chest roentgenograms for a period of four years, although symptoms developed two and four years later, respectively. Three patients (Cases 1,2 and 3) had a gradual onset of symptoms ranging from six months to two years, whereas one patient [Case 4) had an abrupt onset of marked dyspnea one month prior to diagnosis. The severity of the symptoms ranged from mild dyspnea on exertion in one patient (Case 5) to incapacitating dyspnea at rest, malaise and weight loss in two others (Cases 2 and 4). Of interest
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is the paucity of symptoms in one patient (Case 5) despite the severe abnormalities detected upon pulmonary function testing (cf. Table II]. The roentgenographic features of the patients in this report are similar to those found in idiopathic pulmonary fibrosis [30]. Chest films taken previously were compared in an attempt to trace the course of the disease. Early films revealed ill-defined densities giving a “ground-glass” pattern, As lung
involvement advanced clinically and physiologically, the roentgenograms revealed a diffuse interstitial reticulonodular pattern and in two cases progressed to honeycombed, cystic lesions in the upper lobes (Figure 6). Pulmonary function tests revealed the typical pattern for restrictive parenchymal lung disorders [31]; a reduced FEVl but normal FEV1:FVC, diminished lung volumes, decreased DLco, and resting hypoxemia which worsened with exercise. All patients had MEFV curves displaying a contour typical of restrictive interstitial lung disease (Figure 1) [32]. Jayamanne et al. [33] have emphasized that flow rates must be related to lung volumes to properly evaluate airway function in interstitial disease. Thus, although the absolute flow rates were reduced, they were normal or “supernormal” when corrected for the diminished volumes. A “supernormal” flow to volume ratio suggested increased recoil properties of the respiratory system-a characteristic of significant interstitial disease-which was confirmed by compliance studies. In addition, the uniform reduction in flow rates (as evidenced by the flow-volume ratios and the contour of the MEFV curves) suggested normal small airway function, Furthermore, frequency dependence of compliance, a hallmark of small airway disease [24], was not present. These findings contrast with recent studies that demonstrate small airway dysfunction in patients with pulmonary fibrosis [341. Crystal et al. [35] advocate
Figure 6. Case 2. The films of this patient show a progression over three years from nonspecific, ill defined densities to an overt honeycomb pattern with large cystic areas.
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the use of volume-pressure curves to stage the degree of fibrosis in interstitial lung disease. As the degree of fibrosis increases, a greater transpulmonary pressure is required to achieve full inspiration. The “coefficient of retraction,” i.e., the transpulmonary pressure at full inspiration divided by the total lung capacity, correlates best with the degree of fibrosis [36]. Compliance studies revealed a marked increase in the maximum transpulmonary pressure at TLC, as well as a high coefficient of retraction (Table II, Figure 2). This physiologic indication of fibrosis was confirmed by subsequent lung biopsy. Since the original description by Hermansky and Pudlak, there has been no further investigation of the pulmonary pathologic findings. The biopsies in the present cases revealed extensive fibrosis which accounts for the pulmonary dysfunction cited. As in the original case, macrophages filled with ceroid-like material were dispersed throughout the interstitium. Previous studies by White et al. [7] revealed similar inclusion bodies in bone marrow macrophages of patients with Hermansky-Pudlak syndrome. In both the lungs and the bone marrow, ceroid-like material appeared in large masses of particulate debris mixed with vacuoles containing neutral lipids. White et al. [7] demonstrated a sequence of events from phagocytized red cells to the appearance of ceroid-like material in macrophages. Such a sequence may be responsible in the present cases, although it could not be verified in the lung tissue that was examined. This process is analogous to other
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lipidoses such as Gaucher’s and Niemann-Pick’s diseases in which unmetabolized lipid material accumulates in macrophages [37]. Clinical pulmonary disease as well as lipid-laden alveolar macrophages have also been found in these sphingolipidoses [38,39]. However, in contrast to Hermansky-Pudlak syndrome, ceroid-like material is not found in these macrophages. Electron microscopy reveals that the sphingomyelin deposits in these disorders occur as membrane-bound cytoplasmic bodies displaying a lamellar structure, often with periodic spacing [40.41]. Excessive phagocytosis of unsaturated lipids and/or a congenital inadequacy to catabolize unsaturated lipids could result in the accumulation of ceroid or ceroid-like material [42,43].A basic question concerning ceroid-like material is whether it is a passive byproduct or if it induces fibrosis. Early research by Hartroft [44] demonstrated fibrous tissue production in normal canine aortas injected with ceroid. Lipid peroxidation, the process responsible for ceroid production [45], is associated with the formation of free radicals that can damage tissues as in radiation fibrosis [46] and oxygen toxicity [47]. Lysosomal enzymes may also be released inappropriately and induce inflammatory or fibrogenic responses [48]as in silicosis [49] and asbestosis [50]. Several investigators have documented the association of lysosomal enzymes with ceroid and lipofuscin [4&51]. These mechanisms may be responsible for the pulmonary fibrosis in patients with Herman&y-Pudlak syndrome. Aside from the pulmonary disease, two patients presented with a previously unreported clinical feature of Herman&y-Pudlak syndrome. Both patients had episodes of fever, abdominal pain and bloody diarrhea, and they were originally diagnosed as having ulcerative (Case 1)and granulomatous [Case 4)colitis. Upon reviewing the pathologic specimens in both cases, ceroid-like material was found within macrophages and occasional epithelial cells lining the bowel wall. It should be noted that the original description of Hermansky-Pudlak syndrome mentioned this material within macrophages in the colonic wall. However, the patient had no associated symptoms. Histiocytes containing ceroid-like material in the lamina propria of the colon have been reported by Fisher and Hellstrom [52], These patients also had no significant clinical consequences of this finding. Further analysis is being performed on the colonic specimens in these patients and will be reported in the near furture [53]. Together, two patients [Cases 1 and 4)had three siblings who were albinos, had bleeding problems and were thought to have “colitis” as well. Thus, ceroid involvement of colon may mimic ulcerative or granulomatous colitis; however, the treatment and prognosis may be different. CONCLUSION During the past 20 years fewer than 50 cases of Hermansky-Pudlak syndrome have been reported. The rarity of this disorder is surprising in light of the expe-
ET AL.
rience presented herein. The difficulty in recognizing this type of albinism has been discussed and may account for the paucity of cases diagnosed. The new observations of this study relate to the characterization of the pulmonary and previously unrecognized gastrointestinal manifestations of this disorder. Deposition of ceroid-like pigment within the reticuloendothelial system of the lungs and colon is associated with significant disease in these organs. The possibility that Hermansky-Pudlak syndrome represents a disorder of lysosomal metabolism with a potential for fibrosis has been raised. The life-threatening implications of the bleeding diathesis, pulmonary fibrosis and inflammatory bowel disease underscore the need to identify these patients as well as the necessity for genetic counseling.
REPRESENTATIVE
CLINICAL SUMMARIES
Patient 1. This 28 year old Puerto Rican albino woman suffered abdominal pain and diarrhea in 1974 and was diagnosed as having ulcerative colitis. In October 1976, she was admitted to another hospital with dyspnea, and a chest roentgenogram was reported to be consistent with pulmonary fibrosis. In June 1977, abdominal pain, diarrhea and fever recurred, and the patient was admitted to Bellevue Hospital. The patient was born in Aguadilla, Puerto Rico, and two of seven siblings are also albinos. The albino brother had a history of a “bleeding problem” and died at age 18of a bowel disorder. The patient had a history of several severe bleeding episodes including one life-threatening incident which occurred postpartum. Physical examination revealed a marked decrease in cutaneous pigment, blond hair and freckles in sun exposed areas. Examination of the eyes revealed decreased visual acuity, horizontal and rotaw nystagmus, a small amount of pigment in the iris and scant macular pigment on funduscopic examination. There were fine, crackling rales throughout both lung fields, but the remainder of the examination was within normal limits. The hematocrit value on admission was 34 per cent. The remainder of the complete blood count and blood chemistry studies were within normal limits. An arterial blood gas measurement on room air showed pH 7.47, pCOz 33mm Hg, and pOz 76 mm Hg. The chest roentgenogram showed diffuse reticulonodular infiltrates. Platelet function studies demonstrated a prolonged bleeding time (15 minutes], despite a normal platelet count. There was diminished platelet aggregation in response to connective tissue, but normal reactivity when ADP and epinephrine were used. On the basis of the clinical presentation, the diagnosis of Herman&y-Pudlak syndrome was made. The diagnosis of ulcerative colitis was suggested by characteristic findings on barium enema and colonoscopy. Because of repeated episodes of massive gastrointestinal bleeding, a colectomy was ultimately required. Pulmonary function testing was performed prior to the patient’s colectomy, and repeated one year later.
Patient 4. This 43year old Puerto Rican woman had been in good health until 1964, when she was hospitalized for presumed granulomatous colitis for which she required a total colectomy. A chest roentgenogram in 1974 showed bilateral reticulonodular infiltrates, although the patient was asymptomatic. In April 1978, the patient presented to Bellevue
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Hospital complaining of a one month history of dyspnea on exertion, malaise and weight loss of 5 pounds. She was born in Aguadilla and has four albino siblings. The physical examination on admission revealed a thin woman, tachypneic at rest, with reddish brown hair and fair skin with numerous freckles. The eyes were remarkable for strabismus, horizontal and vertical nystagmus, a blue-gray iris with retinal hypopigmentation and severely decreased visual acuity. The chest examination revealed diffuse rales. The laboratory data on admission revealed complete blood count and blood chemistry studies to be within normal limits. An arterial blood gas study with the patient on room air showed the following: pH 7.45, pOz 68 mm Hg and pCOz 36 mm Hg. The chest film revealed bilateral diffuse reticulonodular infiltrates. Platelet function studies revealed a delayed secondary wave of aggregation in response to epinephrine. The impression, therefore, was that the patient had Hermansky-Pudlak syndrome. The patient’s
interstitial lung disease was investigated with pulmonary function testing and an open lung biopsy (cf. Table II and “Results”J.
ACKNOWLEDGMENT
We wish to thank the Bellevue Hospital Center housestaff who helped to care for these patients. We are indebted to Dr. Rody P. Cox for encouraging this study, and to Dr. H. William Harris, for his valuable editorial comments. We are grateful for the excellent technical assistance of Dr. Sandra Wolman for the fluorescence studies, Dr. Henrietta Lackner for the platelet aggregation studies, Ms. Debbie Goldberg for the electron micrographs, Mr. Martin Rotker for the pathology photography, and Ms. Hadassah Epstein and Ms. Orna Schanzer for the pulmonary function studies.
REFERENCES
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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 14: 162. 1959. Muniz FG, Fradera 1, Maldonado PV, et al.: Albinisin, bleeding tendency and abnormal pigmented cells in the bone marrow. A case report. Texas Rep Biol Med 28: 167, 1970. Logan LJ, Rapoport SI, Maher I: Albinism and abnormal platelet function. N Engl J Med 284: 1340,197l. Maurer HM, Wolfe JA, Buckingham S, et al.: Impotent platelets with prolonged bleeding times. Blood 39: 490,
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a. 9.
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11.
12. 13. 14. 15.
16. 17.
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Hardisty RM, Mills DCB: The platelet defect associated with albinism. Ann NY Acad Sci 201: 429,1972. Murakami M, Odake K, Matsuda T, et al.: Bleeding tendency with platelet dysfunction and albinism. A case report. Thromb Diath Haemorrh 27: 461,1972. White IG. Witkoo Cl Ir. Gerritsen SM: The HermanskvPudlek Syndrime.‘cltrastructure of bone marrow ma& roohages. Am 1 Path01 70: 329.1972. Oppenh;?imer Ei?, Andrews EC Jr: Ceroid storage disease in childhood. Pediatrics 23: 1091. 1959. Ford DK. Price GE, Culling CFA, et al.: Familial lipochrome pigmentation of histiocytes with hyperglobulinemia, pulmonary infiltration, splenomegaly, arthritis and susceptibility to infection. Am J Med 33: 478,1962. Levine AS, Lemieux B, Brunning R, et al.: Ceroid accumulation in a oatient with nroeressive neuroloeical disease. Pediatrics i2: 462, 1968.’ ” Winkler HH. Frame B. Saeed SM. et al.: Ceroid storage disease complicated by rupture ofthe spleen. Am J MYed46: 297,1969. Bednar B, Hermansky F, Lojda Z: Vascular pseudohemophilia associated with ceroid pigmentophagia in albinos. Am J Path01 45: 283,1964. Brady R: Heritable catabolic and anabolic disorders of lipid metabolism. Metabolism 26: 329,1977. Weiss H: Platelet aggregation. Hematology (William WJ, Beutler E, Erslev A, Rundels RW, eds). New York, McGraw Hill Book Company, 1971, p 1658. Morris JF, Koski A, Johnson LC: Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 103: 57, 1971. Miller A, Teirstein AS, Jackler I, et al.: Airway function in chronic pulmonarv sarcoidosis with fibrosis. Am Rev Resoir Dis 109: 179:1974. Lapp &JL,Hyatt RE: Some factors affecting the relationship of maximal expiratory flow to lung volume in health and disease. Dis Chest 51: 475.1967.
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Dubois AB, Botelho SY, Comroe JH: A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with resuiratorv disease. 1Clin Invest 35: 327.1956. Ogilvie CM, borster RE: Blakemore WS, et al.: A standardized breath holding techniaue for the clinical measurement of the diffusing iapacity bf the lung for carbon monoxide. J Clin Invest 36: 1,1957. Roughton FJW, Forster RE: Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung. J Appl Physiol 11: 290, 1957. Bucci G, Cook CD, Barrie H: Studies of respiratory physiology in children. V. Total lunr! diffusion. diffusing caoacitv of pulmonary membrane, %d pulmonary ca&la& blood volume in normal subiects from 7 to 40 vears of aee. I Y 1 I Pediatr 58: 820, 1961. ’ Milic-Emili I. Mead 1.Turner IM. et al.: Imnroved technioue for estim&ing pleiral press& for esobhageal ball& J Appl Physiol19: 207.1964. Turner JM, Mead J, Wohl ME: Elasticity of human lungs in relation to age. J Appl Physio125: 664.1968. Woolcock AJ, Vincent NJ, Macklem PT: Frequency dependence of compliance as a test for obstruction in the small airways. J Clin Invest 48: 1097, 1968. Witkop CJ Jr, White JG, Gerrittsen SM, et al.: HermanskyPudlak Syndrome (HPS): a proposed block in glutathione peroxidase. Oral Surg 34: 790.1973. Witkop CJ, Quevedo WC, Fitzpatrick TB: Albinism. The Metabolic Basis of Inherited Disease (Stanbury JB, Wyngaarden JB, Fredrickson DS, eds), New York, McGraw Hill Book Company, 1978, chap 14. White JG, Witkop CJ Jr: Effects of normal and aspirin platelets on defective secondary aggregation in the HermanskyPudlak Syndrome. A test for storage pool deficient platelets. Am J Pathol68: 57.1972. Witkop CJ Jr, White JG, King RA: Oculocutaneous albinism. Heritable Disorders of Amino Acid Metabolism INvhan ’ ’ WL, ed]. New York, Wiley, 1974, chap 11. Davies B. Tuddenham EGD: Familial oulmonarv fibrosis associated with oculocutaneous albinism and platelet function defect. A new svndrome. Q1 Med 45: 219.1976. ,lohnson TH Ir: Radioloev aid honevc&b lune disease. Am J Roentgen01 104: 810,1968. Austrian R. McClement IH. Renzetti AD, et al.: Clinical and physiologic features 01 some types of pulmonary disease with impairment of alveolar-capillary diffusion. The syndrome of alveolar-capillary block. Am J Med 11:667, 1951. Lord GP, Gazioglu K, Kaltreider N: The maximum expiratory VI
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flow-volume in the evaluation of patients with lung disease. Am ] Med 46: 72,1969. Jayamanne DS, Epstein H, Goldring RM: The influence of lung volume on exuiratorv flow rates in diffuse interstitial lung disease. Am j’Med Sci 275: 329.1978. Fulmer JD, Roberts WC, von Gal ER, et al.: Small airways in idiopathic pulmonary fibrosis. J Clin Invest 60: 595,1977. Crystal RG, Fulmer JD, Roberts WC, et al.: Idiopathic pulmonary fibrosis. Ann Intern Med 85: 769,1976. Schlueter DP. Immekus I. Stead WW: Relationshio between maximal inspiratory ‘pressure and total lung capacity (coefficient of retraction) in normal subjects and in patients with emphysema, asthma, and diffuse pulmonary infiltration. Am Rev Respir Dis 96: 656, 1967. Pentchev PG, Barranger JA: Sphingolipidoses: molecular manifestations and biochemical strategies. J Lipid Res 19:
44. 45.
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Brown & Company, 1976, p 145. Hartroft WS: Pathogenesis and significance of Hemoceroid and hyaloceroid; two types of ceroid-like pigment found in human atheromatous lesions. J Gerontol8: 158.1953. Miquel J, Oro J, Bensch KG, et al.: Lipofuscin. Fine structural and biochemical studies. Free Radicals in Biology (Pryor WA, cd]. vol. 3, New York, Academic Press, 1977, chap 4. Desai ID. Sawant PL, Tappel AL: Peroxidative and radiation damage to isolated lysosomes. Bioch Biophs Acta 86: 277, 1964.
47.
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38. Skikne MI, Prinsloo I, Webster I: Electron microscopy of lung in Neimann-Pick disease. J Path01 106: 119,1972. 39. Schneider EL, Epstein CS, Kaback MJ, et al.: Severe pulmonary involvement in adult Gaucher’s disease. Am 1Med 63: 475, 1977. 46. Lynn R, Tenry RD: Lipid histochemistry and electron microscopy in adult Neimann-Pick disease. Am J Med 37: 987, 1964. 41. Peters SP. Lee RE. Glew RH: Gaucher’s disease, a review. Medicine 56: 425, 1977. 42. Porta EA. Hartroft WS: Lipid pigments in relation to aging and dietary factors (lipofuscins]. Pigments in Pathology (Wolman M, ed) New York, Academic Press, 1969, chap 7. 43. Rywlin A: Histopathology of the Bone Marrow, Boston, Little,
ET AI,.
Fridovich I: Oxygen radicals, hydrogen peroxide and oxygen toxicity. Free Radicals in Biology (Pryor WA, ed), vol. I, New York, Academic Press, 1976, p 239. Weissmann G. Zurier RB. Soieler PI. et al.: Mechanisms of lysosomal enzyme release from ‘icukocytes exposed to immune complexes and other particles. J Exp Med 134: L
149s, 1971.
Allison AC, Harington MB, Birbeck M: An examination of the cvtotoxic effects of silica on macrouhages. ] Exp Med 124: i41 1966. 50. Davies P, Allison AC, Ackerman A, et al.: Asbestos induces selective release of lysosomal enzymes from mononuclear phagocytes. Nature 251: 423, 1974. 51. Siakotos AN, Armstrong D: Age pigment, a biochemical indicator of intracellular aging. Neurobiology of aging (Ordy JM, Brizzee KR, eds), New York, Plenum Press, 1975. 52. Fisher ER, Hellstrom HR: Ceroid-like colonic histiocytosis. Am J Clin Path01 42: 581, 1964. 53. Schinella R, Greco MA, Cobert B. et al.: Hermansky-Pudlak syndrome associated with colitis. Manuscript submitted for publication. 49.
The American Journal of Medicine
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STUART M. GARAY, M.D. JOHN E. GARDELLA, M.D. EUGENE P. FAZZINI. M.D. ROBERTA M. GOLDRING, M.D New York, New York
From the Departments of Medicine and Pathology, New York University School of Medicine: and the Chest Service, Bellevue Hospital Center, New York, New York. Requests for reprints should be addressed to Dr. Roberta M. Goldring, New York University School of Medicine, 550 First Avenue, New York, New York 10016. Manuscript accepted December 27.1978.
of a Ceroid Storage Disorder
The Hermansky-Pudlak syndrome is a form of oculocutaneous alhinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Herman&y-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients. In 1959 Hermansky and Pudlak [l] first described a congenital disorder consisting of oculocutaneous albinism, a hemorrhagic defect and the accumulation of ceroid in the reticuloendothelial system of various tissues. Since the original description, fewer than 50 cases of Hermansky-Pudlak syndrome have been reported in the literature. Most reports have dealt almost exclusively with the albinism and associated bleeding disorder [2-71. During a 16 month interval, seven patients with Herman&y-Pudlak syndrome were diagnosed at the New York University-Bellevue Hospital Center. In contrast to the previously reported cases, diffuse pulmonary fibrosis and/or inflammatory bowel disease were prominent manifestations in five of these patients. This study will focus on the pulmonary aspect of this syndrome. Herman&y-Pudlak syndrome is a storage disorder different from those previously described involving ceroid [8-111. Ceroid, a complex chromolipid, is related to lipofuscin, the aging pigment. Although the storage material in Herman&y-Pudlak syndrome has been labelled ceroid [12], the actual nature of this pigment remains unknown.* Unlike other storage diseases in which specific catabolic, hydrolyzing enzymes are lacking [IS], the defect in ceroid-lipofuscin disorders has not been elucidated. Indeed, ceroid storage diseases have received little attention in the general medical literature and have not been clearly established as abnormalities of lysosomal metabolism. This * Because of this uncertainty on the one hand and the histochemical similarities to ceroid on the other hand, the qualifying phrase “ceroid-like” shall be used throughout this paper.
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TABLE I
SYNDROME-GARAY
ET AL.
Clinical Features of Five Patients with Hermansky-Pudlak Syndrome Case 1
Age (yr) and sex Birthplace Family history Albinism Colitis Bleeding diathesis
Ceroid deposition
Case 2
Case 3
Case 4
Case 5
28, F Aguadilla
38, M Aguadilla
20, F Aguadilla
43, F Aguadilla
32, F Aguadilla
1 sister 1 brother 1 brother
2 sisters
Upper gastrointestinal bleed
2 sisters 2 brothers 1 brother 1 sister Lower gastrointestinal bleed
1 sister 1 brother -
Postpartum bleed Lower gastrointestinal bleed Urine Colon
1 sister 1 brother 1 brother 1 sister Tooth extraction
Urine Lung
Urine
...
Urine Lung
Postpartum bleed Tooth extraction
Colon Pulmonary interstitial disease Symptoms Chest X-ray Pulmonary function tests Lung biopsy Inflammatory bowel
Moderate dyspnea on exertion Reticulonodular Restrictive ND +
Dyspnea at rest Honeycomb cystic changes Restrictive
Mild dyspnea on exertion Reticulonodular
Fibrosis
Mild dyspnea on exertion Reticulonodular
Restrictive
Dyspnea at rest Honeycomb cystic changes Restrictive
ND -
Fibrosis +
ND
Restrictive
NOTE: ND = not done; i- = present; - = absent. Patients in Cases 1 and 3 and patients in Cases 5 and 2 are siblings.
study suggests that Herman&y-Pudlak syndrome is a storage disorder more common than previously appreciated and that it should be considered in patients who present with pulmonary interstitial fibrosis and/or inflammatory bowel disease.
METHODS The diagnosis of Hermansky-Pudlak syndrome was based upon the finding of tyrosinase-positive oculocutaneous albinism in patients of Puerto Rican extraction, accumulation of ceroid-like material and the demonstration of a qualitative platelet defect. Platelet function studies, including a platelet count, Ivy bleeding time and platelet aggregation, were carried out in each patient. Pulmonary function testing was performed on all patients. Lung volumes were determined by standard spirometry and plethysmography. Predicted values are thqse of Morris et al. (151.The maximum expiratory flow volume (MEFV) curve was recorded on an X-Y recorder. Values in our laboratory for normal nonsmokers of similar age to the patients studied in this paper are comparable to those of Miller et al. [16] and Lapp and Hyatt [17]. Airway resistance, conductance and specific conductance were measured in the body plethysmograph using the methods described by Dubois, Botelho and Comroe [18]. Diffusing capacity (DLco) was measured by the singlebreath method described by Ogilvie et al. [19]. The DLco was partitioned into the membrane diffusion coefficient (DM]and the pulmonary capillary blood volume using methods described by Roughton and Forster [20]. Predicted values are
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those of Bucci et al. [21]. Pulmonary compliance was measured with an esophageal balloon as described by Milic-Emili and associates [22].The static deflation pressure-volume curve was recorded during a slow expiration from total lung capacity (TLC] to functional residual capacity (FRC) in order to obtain the transpulmonary pressure at TLC (which reflects maximum static recoil pressure at TLC) and static compliance at FRC [23]. Compliance was measured at increasing frequencies of breathing at constant tidal volumes to test for frequency dependence of compliance [%I. Two patients underwent lung biopsy; flexible fiberoptic bronchoscopy in one and thoracotomy in the other. Specimens were examined under light microscopy with standard hematoxylin and eosin stains and with special histochemical stains [25]. Electron microscopy was also performed on one lung specimen. The lung biopsy specimens as well as urine from four patients (Cases I. 2,4 and 5) were examined under ultraviolet light for fluorescence [25].
RESULTS The clinical features of the five patients with Hermansky-Pudlak syndrome are outlined in Table I. Two representative clinical summaries follow the conclusion of this paper.
Pulmonary Function Tests. Lung volumes and airway function: The results of pulmonary function studies are shown in Table II. Each patient had a reduction in all lung volumes. Large airway function was normal as evidenced by normal forced expiratory volumes in 1
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TABLE II
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Pulmonary Function Data case2
Case1 6177 Lung volumes’ 2.30 (58) VC (liter) 2.28 (73) FRC (liter) 3.52 (66) TLC (liter) Airway function* 2.12 (66) FEV, (liter) FEV,lFVC 0.87 (1 lo) FEFsO(literlsec)t 3.21 (66) FEFs5(literlsec)t 1.18 (42) 1.32 FEF&FVC§ FEFIBVCiI 0.49 S&, (IiterlsecJ 0.227 cm l+O/liter)~ Diffusion* 12.0 (46) DL,, (ml/min/ mm Hg) DL/AIv vol 3.9 (80) Mechanics Compliance*
r/70
5177
2.18 (55)
1.01 (26)
1.94 (64) 3.42 (64)
i .58 (79)
0177
~Case3
~ Case4
Case5 12178
2.38 (59)
0.93 (30) 1.06 (38) 1.68 (37)
1.64 (54) 1.27 (66) 2.48 (63)
0.82 (34) 1.00 (131) 2.40 (57) 1.a8 (92) 2.92 2.18
1.45 (59) 0.84 (106) 3.66 (85) 0.78 (31) 2.14 0.45 0.314
7/n
2.16 (45)
1.28 (33) 1.44 (72) 2.09 (44)
1.75 (65) 3.43 (66)
1.a0 (57) 0.84 (106) 3.14 (65) 0.71 (25) 1.48 0.33 0.247
1.02 (32) 0.86 (113) 1.65 (31) 0.63 (24) 1.40 0.53 0.309
1.14 (36) 0.85 (111) 1.a0 (34) 0.47 (la) 1.35 0.35 0.226
2.40 (73) 0.71 (87) 4.33 (88) 1.97 (65) 1.73 0.79 0.332
7.0 (27)
3.0 (20)
3.0 (20)
2.6 (53)
1.5 (36)
1.7 (31)
5/n
i 2.9 (48)
..
9 (56) 3.9 (71)
4.76 (92)
l
0.053 (0.120.21) 0.027 (0.040.07) 0.050 (0.120.21) 58 (21-32) 17 (4-6)
Gtatic
Cspecific CdylWiC
P,, at TLC++ P,,ITLCt* Arterial blood gas PH Rest Exercise ~02 (mm Hg) Rest Exercise
7.47 7.48
0.013 ( o.oa0.14) 0.14 ( 0.040.07) 0.022 (o.oa0.14) 42 (24-29) 19 (5-6)
7.38 7.38
0.02 (o.oa0.14) 0.01 (0.040+7) 0.02 (o.oa0.14) 61(24-29) 29 (5-6)
7.46 7.48
0.065 (0.080.13) 0.051 (0.040.07) 0.06 (o.oa0.13) 64 (17-23) 25.8 (4-6)
0.039 (0.040.07) 0.068 (0.1 l0.19) 30 (21-36) 8.8 (4-7)
7.51 7.42
7.48
7.42 7.36
76 55
74 50
60 38
105 a9
68
a9 68
33 26
34 31
33 31
22 30
36
36 39
34 64
35 63
50 75
19 25
39
pCO2(mmHd Rest Exercise (A - a) DO2 (mm Hg) Rest Exercise
la
36
Numbers in parentheses represent percentages predicted. t Forced expiratory flow rate at 50 per cent of the vital capacity determined by the maximum expiratoty flow volume curve (see text). $ Forced expiratory flow rate at 25 per cent of the vital capacity determined by the maximum expiratory flow volume curve (see text). 5 Normal range 1.07 f 0.25 (as determined in our laboratory). ‘1Normal range 0.36 f 0.14 (as determined in our laboratory). # Specific conductance (normal 0.13-0.35). Numbers in parentheses represent predicted normal range [ 231. ++Maximum static elastic recoil pressure. tt Coefficient of retraction. l
l
l
second (FEV1) and specific conductance values in all patients. The maximum expiratory flow-volume curves revealed mild to moderate reduction in flow rates at all lung volumes. The flow-volume loops displayed a uniform pattern of reduction in expiratory flow (Figure 1); the reduction in flow rates was proportional to the decrease in volume in each patient. There was no evidence of dysfunction at low lung volumes. Follow-up studies
in two patients (Case 1 at one year and Case 2 at three months) did not reveal any significant change in airway function or lung volumes. Diffusion: Four patients demonstrated a reduction in DLco. One patient (Case 4) was too dyspneic to cooperate for the single breath diffusion study. In three patients (Cases I, 3 and 5] the initial decrease in diffusion was proportional to the diminution in alveolar volume,
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80-
60-
00 0
20
40
60
80
PRESSURE
(cm l-$0) Figure 2.
I
7
I
I
5 VOLUME
I
I
3
I
I
Volume-pressure curves for four patients (Cases 1, 2,3 and 5). One patient (Case 2) had an initial compliance study (a) repeated three months later (b). The volume data is presented as percentage of predicted total lung capacity, and is plotted against static transpulmonary pressure. The inflation pressures are markedly increased at any given lung volume compared to normal (shaded area [ 231).
I
I
(liters)
,
lgure 1.
Flow related to absolute volume during tidal breathing (small loops) and maximum inspiration and expiration (large loops). The maximum expiratory flow-volume curve reveals a normal pattern on the left and a “restrictive” pattern (Case 2) on the right. Note the normal contour of the latter curve, despite a reduction in flow rates.
whereas in one patient (Case 2) the decrease in diffusion was greater. A diffusion study repeated one year later in one patient (Case 1) revealed a marked deterioration in DLco despite the lack of progression in the clinical and roentgenologic findings. It should be noted that when the diffusion was moderately reduced in this patient, it was proportional to the decrease in alveolar volume (DJAlv vol = 80 per cent of predicted). However, one year later the diffusion was markedly reduced even. when related to alveolar volume (Dr/Alv vol = 53 per cent of predicted). A follow-up diffusion study (three months later) in another patient (Case 2) revealed no change in DLco. When the diffusing capacity was partitioned into the components in Case 1,the D~,,Iwas reduced to 18 ml/mm
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May 1979 The American Journal of Medicine
Hg/min (28 per cent of predicted), whereas the pulmonary capillary blood volume dropped to 27 ml (41 per cent of predicted). Similarly, the membrane diffusion coefficient (DM = 22 ml/mm Hg/min) and the pulmonary capillary blood volume (= 41 ml) were reduced in another patient (Case 5). A follow-up diffusion study (three months later) in one patient (Case 2) revealed no change in DLco. Gas exchange: Each patient, except one (Case 3), had mild to moderate hypoxemia at rest. However, all patients (including Case 3) had a widened alveolar-arterial oxygen gradient ([A-a] DOz) at rest. Arterial oxygen desaturation occurred in each patient upon exercise. One patient (Case 4) could not tolerate an exercise study because of dyspnea. Mechanics: Compliance studies (Table II, Figure 2) performed in four patients demonstrated a marked reduction in static, specific and dynamic compliances. There was no frequency dependence of compliance. The maximum static elastic recoil pressure (Pet) and the coefficient of retraction were markedly increased in three patients (Cases 1,2and 5). Only the coefficient of retraction was significantly increased in another (Case 3). In one patient (Case 2) a follow-up compliance study
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(three months later) revealed a marked increase in the P,l and coefficient of retraction without a change in TLC. Pathology. Light microscopy: Specimens of lung tissue were available for pathologic examination in two patients (Cases 2 and 4) (Figures 3 and 4). The biopsy specimen from one (Case 2) (Figure 31revealed diffuse interstitial fibrosis involving the alveolar septums as well as peribronchial fibrosis. Macrophages were filled with finely granular pigment (consistent with ceroid-like material] that stained positively with periodic acidSchiff stain. The biopsy specimen from another patient (Case 4) (Figure 4) showed almost complete replacement of the parenchyma by fibrous tissue within which collagen and elastic fibers were seen. Dilated bronchioles were filled with mucus and occasionally with neutrophils and desquamated epithelial cells. Some bronchioles showed areas of squamous metaplasia, whereas others showed marked hyperplasia. The remaining distal air spaces displayed evidence of epithelial regeneration and foamy macrophages indicating obstruction. Macrophages were scattered in the fibrous tissue around the bronchi. There was no evidence of an increased number of macrophages in the interstitium. Some macrophages contained anthracotic pigment and others contained finely divided brown pigment (ceroid-like material) that stained positively with periodic acid-Schiff stain, and weakly positive Ziehl-Neilsen acid-fast stain. Perl’s stain for iron was negative. Fontana’s stain for melanin was positive. In both patients the finely divided brown pigment in the alveolar macrophages showed intense orange fluorescence when viewed by ultraviolet illumination. Urinary sediment from four patients (Cases 1,2,4and 5) displayed intense orange fluorescence when viewed by ultraviolet light. Electron microscopy: Electron microscopy was performed on the biopsy specimen from one patient (Case 4) [Figure 5). Macrophages were seen containing a mixture of amorphous particulate debris (ceroid-like material) and lipid-filled vacuoles of varying size. In some cells the entire cytoplasm was replaced by ceroid-like material. None of the pigment was enclosed within membranes; however, membranes do not preserve well in deparaffinized tissue. The ceroid-like material was not arranged in a lamellar formation. There was no evidence of melanosomes or ingested cells. A few crystalline deposits were recognized within macrophages. COMMENTS The Hermansky-Pudlak syndrome comprises a subgroup of patients with tyrosinase-positive ocuIocutaneous albinism [26]. Besides the autosomal recessive mode of inheritance and visual disturbances, patients with Hermansky-Pudlak syndrome have deposits of ceroid-like material throughout the reticuloendothelial system, in buccal mucosa and urine. A qualitative
SYNDROME-GARAY
ET AL.
Case 2. Biopsy specimen from patient. Macrdphages filled with finely divided ceroid-like pigment. Hematoxylin and eosin stain, original magnification X 400, reduced by 30 per cent. Figure 3.
platelet defect has been found, which is characterized by electron microscopy as a diminished number of platelet “dense bodies,” i.e., the storage organelles for serotonin, ADP and ATP [27]. The functional defect is the failure of platelets to develop irreversible secondary aggregation, typical of a platelet storage pool deficiency. All patients in this study had a qualitative platelet defect, whereas most suffered serious bleeding complications [cf. Table I). Other serious hemorrhagic events have occurred in patients with this syndrome [26]. Although originally described in two Czechoslovakian patients, subsequent reports have shown a predominance of patients from Southern Holland and the Arecibo region of Puerto Rico [28]. Most patients in North America have been Puerto Ricans, with rare exceptions [26]. The seven patients diagnosed in this Medical Center (including the five described in this study) come from four unrelated families. All were born and raised in Aguadilla, a town northwest of Arecibo. It should be noted that the pigment disorder in Hermansky-Pudlak syndrome has a variable phenotypic expression, depending upon the racial background of the patient. Patients from Puerto Rico may have some pigmentation of their skin and eyes, and their hair is
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Figure 4. Case 4. Biopsy specimens from patient. Top, a bronchiole with metaplastic lining is seen at the upper right. Numerous macrophages contain finely divided ceroid-like pigment. Hematoxylin and eosin stain, original magnification X 120, reduced by 21 per cent. Bottom, pigment laden macrophages in fibrous stroma stain positively with periodic acid-Schiff stain. Original magnification X 400, reduced by 21 per cent.
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often red or reddish brown. Thus, such patients are often not recognized as albinos and may be mistaken for Caucasians. Four of the patients described in this report had been treated by physicians for several years in various teaching hospitals and clinics without being diagnosed as albinos. Following the diagnosis in one (Case 2). physicians at this Medical Center displayed a high index of suspicion for Herman&y-Pudlak syndrome in patients of Puerto Rican extraction who presented with a bleeding diathesis, pulmonary fibrosis or inflammatory bowel disease. This led to the subsequent diagnosis of six additional cases in a relatively short period of time. The original patients of Hermansky and Pudlak had evidence of pulmonary dysfunction. One, who complained of exertional dyspnea, had a chest roentgenogram suggestive of pulmonary fibrosis. The other had several episodes of hemoptysis related to previous tuberculosis. However, the postmortem examination in the latter patient revealed macrophages containing ceroid in various organs including the pulmonary interstitium (12]. There have been other brief descriptions
ET AL.
of the pulmonary findings in this syndrome. Witkop et al. [26] noted some patients with interstitial disease on chest roentgenograms whereas Davies and Tuddenheim [29] described a family in which four siblings had pulmonary disease associated with oculocutaneous albinism and a platelet defect. The clinical picture in these patients is characterized by the insidious onset of dyspnea. The natural history of pulmonary manifestations of Herman&y-Pudlak syndrome is unknown, although the progressive deterioration in two patients (Cases 2 and 4) suggests a course similar to idiopathic fibrosis. Two patients (Cases 2 and 4) had evidence of interstitial disease on chest roentgenograms for a period of four years, although symptoms developed two and four years later, respectively. Three patients (Cases 1,2 and 3) had a gradual onset of symptoms ranging from six months to two years, whereas one patient [Case 4) had an abrupt onset of marked dyspnea one month prior to diagnosis. The severity of the symptoms ranged from mild dyspnea on exertion in one patient (Case 5) to incapacitating dyspnea at rest, malaise and weight loss in two others (Cases 2 and 4). Of interest
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is the paucity of symptoms in one patient (Case 5) despite the severe abnormalities detected upon pulmonary function testing (cf. Table II]. The roentgenographic features of the patients in this report are similar to those found in idiopathic pulmonary fibrosis [30]. Chest films taken previously were compared in an attempt to trace the course of the disease. Early films revealed ill-defined densities giving a “ground-glass” pattern, As lung
involvement advanced clinically and physiologically, the roentgenograms revealed a diffuse interstitial reticulonodular pattern and in two cases progressed to honeycombed, cystic lesions in the upper lobes (Figure 6). Pulmonary function tests revealed the typical pattern for restrictive parenchymal lung disorders [31]; a reduced FEVl but normal FEV1:FVC, diminished lung volumes, decreased DLco, and resting hypoxemia which worsened with exercise. All patients had MEFV curves displaying a contour typical of restrictive interstitial lung disease (Figure 1) [32]. Jayamanne et al. [33] have emphasized that flow rates must be related to lung volumes to properly evaluate airway function in interstitial disease. Thus, although the absolute flow rates were reduced, they were normal or “supernormal” when corrected for the diminished volumes. A “supernormal” flow to volume ratio suggested increased recoil properties of the respiratory system-a characteristic of significant interstitial disease-which was confirmed by compliance studies. In addition, the uniform reduction in flow rates (as evidenced by the flow-volume ratios and the contour of the MEFV curves) suggested normal small airway function, Furthermore, frequency dependence of compliance, a hallmark of small airway disease [24], was not present. These findings contrast with recent studies that demonstrate small airway dysfunction in patients with pulmonary fibrosis [341. Crystal et al. [35] advocate
Figure 6. Case 2. The films of this patient show a progression over three years from nonspecific, ill defined densities to an overt honeycomb pattern with large cystic areas.
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the use of volume-pressure curves to stage the degree of fibrosis in interstitial lung disease. As the degree of fibrosis increases, a greater transpulmonary pressure is required to achieve full inspiration. The “coefficient of retraction,” i.e., the transpulmonary pressure at full inspiration divided by the total lung capacity, correlates best with the degree of fibrosis [36]. Compliance studies revealed a marked increase in the maximum transpulmonary pressure at TLC, as well as a high coefficient of retraction (Table II, Figure 2). This physiologic indication of fibrosis was confirmed by subsequent lung biopsy. Since the original description by Hermansky and Pudlak, there has been no further investigation of the pulmonary pathologic findings. The biopsies in the present cases revealed extensive fibrosis which accounts for the pulmonary dysfunction cited. As in the original case, macrophages filled with ceroid-like material were dispersed throughout the interstitium. Previous studies by White et al. [7] revealed similar inclusion bodies in bone marrow macrophages of patients with Hermansky-Pudlak syndrome. In both the lungs and the bone marrow, ceroid-like material appeared in large masses of particulate debris mixed with vacuoles containing neutral lipids. White et al. [7] demonstrated a sequence of events from phagocytized red cells to the appearance of ceroid-like material in macrophages. Such a sequence may be responsible in the present cases, although it could not be verified in the lung tissue that was examined. This process is analogous to other
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lipidoses such as Gaucher’s and Niemann-Pick’s diseases in which unmetabolized lipid material accumulates in macrophages [37]. Clinical pulmonary disease as well as lipid-laden alveolar macrophages have also been found in these sphingolipidoses [38,39]. However, in contrast to Hermansky-Pudlak syndrome, ceroid-like material is not found in these macrophages. Electron microscopy reveals that the sphingomyelin deposits in these disorders occur as membrane-bound cytoplasmic bodies displaying a lamellar structure, often with periodic spacing [40.41]. Excessive phagocytosis of unsaturated lipids and/or a congenital inadequacy to catabolize unsaturated lipids could result in the accumulation of ceroid or ceroid-like material [42,43].A basic question concerning ceroid-like material is whether it is a passive byproduct or if it induces fibrosis. Early research by Hartroft [44] demonstrated fibrous tissue production in normal canine aortas injected with ceroid. Lipid peroxidation, the process responsible for ceroid production [45], is associated with the formation of free radicals that can damage tissues as in radiation fibrosis [46] and oxygen toxicity [47]. Lysosomal enzymes may also be released inappropriately and induce inflammatory or fibrogenic responses [48]as in silicosis [49] and asbestosis [50]. Several investigators have documented the association of lysosomal enzymes with ceroid and lipofuscin [4&51]. These mechanisms may be responsible for the pulmonary fibrosis in patients with Herman&y-Pudlak syndrome. Aside from the pulmonary disease, two patients presented with a previously unreported clinical feature of Herman&y-Pudlak syndrome. Both patients had episodes of fever, abdominal pain and bloody diarrhea, and they were originally diagnosed as having ulcerative (Case 1)and granulomatous [Case 4)colitis. Upon reviewing the pathologic specimens in both cases, ceroid-like material was found within macrophages and occasional epithelial cells lining the bowel wall. It should be noted that the original description of Hermansky-Pudlak syndrome mentioned this material within macrophages in the colonic wall. However, the patient had no associated symptoms. Histiocytes containing ceroid-like material in the lamina propria of the colon have been reported by Fisher and Hellstrom [52], These patients also had no significant clinical consequences of this finding. Further analysis is being performed on the colonic specimens in these patients and will be reported in the near furture [53]. Together, two patients [Cases 1 and 4)had three siblings who were albinos, had bleeding problems and were thought to have “colitis” as well. Thus, ceroid involvement of colon may mimic ulcerative or granulomatous colitis; however, the treatment and prognosis may be different. CONCLUSION During the past 20 years fewer than 50 cases of Hermansky-Pudlak syndrome have been reported. The rarity of this disorder is surprising in light of the expe-
ET AL.
rience presented herein. The difficulty in recognizing this type of albinism has been discussed and may account for the paucity of cases diagnosed. The new observations of this study relate to the characterization of the pulmonary and previously unrecognized gastrointestinal manifestations of this disorder. Deposition of ceroid-like pigment within the reticuloendothelial system of the lungs and colon is associated with significant disease in these organs. The possibility that Hermansky-Pudlak syndrome represents a disorder of lysosomal metabolism with a potential for fibrosis has been raised. The life-threatening implications of the bleeding diathesis, pulmonary fibrosis and inflammatory bowel disease underscore the need to identify these patients as well as the necessity for genetic counseling.
REPRESENTATIVE
CLINICAL SUMMARIES
Patient 1. This 28 year old Puerto Rican albino woman suffered abdominal pain and diarrhea in 1974 and was diagnosed as having ulcerative colitis. In October 1976, she was admitted to another hospital with dyspnea, and a chest roentgenogram was reported to be consistent with pulmonary fibrosis. In June 1977, abdominal pain, diarrhea and fever recurred, and the patient was admitted to Bellevue Hospital. The patient was born in Aguadilla, Puerto Rico, and two of seven siblings are also albinos. The albino brother had a history of a “bleeding problem” and died at age 18of a bowel disorder. The patient had a history of several severe bleeding episodes including one life-threatening incident which occurred postpartum. Physical examination revealed a marked decrease in cutaneous pigment, blond hair and freckles in sun exposed areas. Examination of the eyes revealed decreased visual acuity, horizontal and rotaw nystagmus, a small amount of pigment in the iris and scant macular pigment on funduscopic examination. There were fine, crackling rales throughout both lung fields, but the remainder of the examination was within normal limits. The hematocrit value on admission was 34 per cent. The remainder of the complete blood count and blood chemistry studies were within normal limits. An arterial blood gas measurement on room air showed pH 7.47, pCOz 33mm Hg, and pOz 76 mm Hg. The chest roentgenogram showed diffuse reticulonodular infiltrates. Platelet function studies demonstrated a prolonged bleeding time (15 minutes], despite a normal platelet count. There was diminished platelet aggregation in response to connective tissue, but normal reactivity when ADP and epinephrine were used. On the basis of the clinical presentation, the diagnosis of Herman&y-Pudlak syndrome was made. The diagnosis of ulcerative colitis was suggested by characteristic findings on barium enema and colonoscopy. Because of repeated episodes of massive gastrointestinal bleeding, a colectomy was ultimately required. Pulmonary function testing was performed prior to the patient’s colectomy, and repeated one year later.
Patient 4. This 43year old Puerto Rican woman had been in good health until 1964, when she was hospitalized for presumed granulomatous colitis for which she required a total colectomy. A chest roentgenogram in 1974 showed bilateral reticulonodular infiltrates, although the patient was asymptomatic. In April 1978, the patient presented to Bellevue
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Hospital complaining of a one month history of dyspnea on exertion, malaise and weight loss of 5 pounds. She was born in Aguadilla and has four albino siblings. The physical examination on admission revealed a thin woman, tachypneic at rest, with reddish brown hair and fair skin with numerous freckles. The eyes were remarkable for strabismus, horizontal and vertical nystagmus, a blue-gray iris with retinal hypopigmentation and severely decreased visual acuity. The chest examination revealed diffuse rales. The laboratory data on admission revealed complete blood count and blood chemistry studies to be within normal limits. An arterial blood gas study with the patient on room air showed the following: pH 7.45, pOz 68 mm Hg and pCOz 36 mm Hg. The chest film revealed bilateral diffuse reticulonodular infiltrates. Platelet function studies revealed a delayed secondary wave of aggregation in response to epinephrine. The impression, therefore, was that the patient had Hermansky-Pudlak syndrome. The patient’s
interstitial lung disease was investigated with pulmonary function testing and an open lung biopsy (cf. Table II and “Results”J.
ACKNOWLEDGMENT
We wish to thank the Bellevue Hospital Center housestaff who helped to care for these patients. We are indebted to Dr. Rody P. Cox for encouraging this study, and to Dr. H. William Harris, for his valuable editorial comments. We are grateful for the excellent technical assistance of Dr. Sandra Wolman for the fluorescence studies, Dr. Henrietta Lackner for the platelet aggregation studies, Ms. Debbie Goldberg for the electron micrographs, Mr. Martin Rotker for the pathology photography, and Ms. Hadassah Epstein and Ms. Orna Schanzer for the pulmonary function studies.
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