Kageshima Y, et al: Pulmonary fibrosis and Hermansky-Pudlak Syndrome

Case Reports

Juntendo Medical Journal 2021. 67(3), 282-286 Hermansky-Pudlak Syndrome with Acute Hatred Idiopathic Pulmonary Fibrosis: All of the Patients of Oculocutaneous for Past 20 Years in Juntendo University Hospital

) ) ) ) Yukako KAGESHIMA1 , Eiichi INADA1 , Ken OKAMURA2 , Tamio SUZUKI2 ,

) ) Motoyasu KATO3 , Kazuhisa TAKAHASHI3

1)Department of Anesthesiology, Juntendo University Graduate School of Medicine, Tokyo, Japan 2)Department of Dermatology, Yamagata University Graduate School of Medicine, Yamagata, Japan 3)Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

Hermansky-Pudlak syndrome (HPS) is genodermatosis, which is one of syndromic (OCA). OCA categorizes 9 genes, and patients with mutations in HPS1 gene have greater likelihood of pulmonary fibrosis and granulomatous colitis for their 40s. A 49-year-old man was referred to our hospital as his chest CT image indicated abnormal shadow for his age. At birth, he had white skin, blond hair, and blue iris. And he had not visual power. He was also easy to bleed and had disfunction of platelet. Skin biopsy and genetic test indicated he was diagnosed as HPS definitely and had mutations in HPS1 variation on DNA (c.398+5 G>A, homozygote), which is already known. After 4 months from his hospitalization, his respiratory function became worsen. Otherwise he took pirfenidone, pulmonary fibrosis progressed and he died of dyspnea. In our university, 39 patients had diagnosed as OCA during past 20 years. Only 5 patients were conducted gene analysis. 3 patients were OCA1B, and 2 patients were HPS1. In OCA patients, there are some gene mutations which onset serious complications. Early detection by gene test and early treatment is important. Key words: oculocutaneous albinism, Hermansky-Pudlak syndrome, HPS1, pirfenidone, pulmonary fibrosis

simply called OCA, and 7 genes have been reported. Introduction Syndromic types divide into HPS, Chediak-Higashi Hermansky-Pudlak syndrome (HPS) is firstly Syndrome (CHS), and Griscelli syndrome (GS). In reported by Hermansky and Pudlak1) in 1959 and 160 OCA patients, 54 patients (34%) are OCA1, 38 autosomal recessive genodermatosis consisted of patients (26%) are OCA4, 16 patients (10%) are oculocutaneous albinism (OCA), platelet storage HPS15), 12 patients (8%) are OCA26), 2 patients are pool deficiency, and lysosomal accumulation of OCA37, 8), and 1 patient is HPS49). ceroid lipofuscin2). The symptom was thought to be Patients with mutations in the HPS1 gene tend developed by disfunction of , and 9 genes to have greater likelihood of pulmonary fibrosis have been reported3). and granulomatous colitis for their 40s. Especially, In Japan, 8107 albino patients have come to progressive interstitial pneumoniae (IP) link to the hospitals every year, and 160 patients (2%) exhibit prognostic factor. We report here a case of HPS OCA4). OCA can categorize syndromic or non-syn- which developed acute progressive idiopathic dromic types (Table 1). Non-syndromic type is pulmonary fibrosis (IPF). This case was approved

Corresponding author: Yukako Kageshima Department of Anesthesiology, Juntendo University Graduate School of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan TEL: +81-3-3813-3111 E-mail: [email protected] 〔Received Nov. 19, 2020〕〔Accepted Mar. 8, 2021〕 J-STAGE Advance published date: Jun. 7, 2021

Copyright © 2021 The Juntendo Medical Society. This is an open access article distributed under the terms of Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited. doi: 10.14789/jmj.JMJ20-CR03

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Table 1 OCA is categorized by disease gene. A. Non-syndromic type OCA1: Tyrosinase gene-related type 1A: Tyrosinase negative type 1B: Yellow mutant type 1MP: Minimum pigment type 1TS: temperature sensitive type OCA2: P gene-related type OCA3: Tyrosinase Related Protein gene-1 (TYRP1) related type OCA4: Solute carrier family 45 member 2 gene (SLC45A2) related type OCA5: not known (mapped at chromosome 4q24) OCA6: Solute carrier family 24 member 5 gene (SLC24A5) related type OCA7: Chromosome 10 open reading frame 11 gene (C10orf11) related type B. Syndromic type Hermansky-Pudlak syndrome (HPS) HPS1: mutation of pale ear homological gene (HPS1) HPS2: mutation of pearl homological gene (AP3B1) HPS3: mutation of cocoa homological gene (HPS3) HPS4: mutation of light ear homological gene (HPS4) HPS5: mutation of ruby eye 2 homological gene (HPS5) HPS6: mutation of ruby eye homological gene (HPS6) HPS7: mutation of sandy homological gene (DTNBP1) HPS8: mutation of reduced pigmentation homological gene (BLOC1S3) HPS9: mutation of palid homological gene (PLDN) Chediak-Higashi syndrome (CHS) Mutation of LYST gene Griscelli syndrome (GS) GS1: mutation of MYO5A gene GS2: mutation of RAB27A gene GS3: mutation of MLPH gene C. Not categorized by the Institutional Review Board of the Hospital nystagmus, and easy to bleed at nose every other (approval number JHS 20-031), with a patient’s day. By fundus mirror, he had low pigments on written informed consent. eyeground, low growth on yellow spot. Visual acuity test, he had not any visual power (Right: Report of a case 0.08, Left: 0.1). Clinical findings at presentation indi- A 49-year-old man with a history of ulcerative cated his skin was completely white, his hair was colitis was pointed out abnormal shadow on chest CT image by medical checkup three years ago, and he was referred to department of respiratory medi- cine at our hospital for further examination. Since he had not any symptoms, he had been followed up examinations as a day-patient. As he had coughed for one year and breathed difficulty on working for one month, he was put into the hospital for survey and treatment. His chest CT image shadow indi- cated abnormal IP for his age (Figure 1). Involving other symptoms such as bleeding tendency and albinism, he was suspected of HPS and referred to ophthalmology, dermatology, and hematology department. From childhood, his eyes are also blue, showed Figure 1 Chest computed tomography scans

283 Kageshima Y, et al: Pulmonary fibrosis and Hermansky-Pudlak Syndrome

DNA (c.398+5 G>A, homozygote), which is already known, at HPS1, whereas his mother was heterozy- gote. Blood test indicated disfunction of platelet, and easy to bleed. According to the Japanese oculo- cutaneous albinism guidelines, he was diagnosed as HPS definitely and his symptom was serious. Table 2 shows his respiratory function had come to been worsen, but considering hemorrhagic tendency, treatment using bronchoscope was diffi- cult. He was young and resident to be taken opera- tion, he was thought to be adjusted for lung implant. After two months, he had Pulmonary hypertension (PH) and took home oxygen therapy (HOT). After one month, he had chest pain causing by pneumo- thorax on right side. Treating by drain into thoracic cavity had no effect. In order to inhibit the prog- ress of IP, pirfenidone started but worsen. As lung Figure 2 Patient with white skin and blond hair. transplant was not in time of waiting and his family blond, and his iris were blue since being at birth rejected to give their lung to him, he decided to (Figure 2). Skin biopsy indicated no take palliative medicine such as morphine. He died at epidermal basal layer. Genetic test was conducted of dyspnea, but we don’t know the cause of death, at Yamagata University, and it showed variation on how affect the drain into the lung. His family reject

Table 2 Vertical axis shows pneumonia marker( KL-6, SP-D ), and horizontal axis shows the date, patients put into the hospital on day X.

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Table 3 Categorize which first department each OCA patients came. Gene analysis was done at other university, and the patients were 5(OCA1B = 3 patients, HPS1 = 2 patients).

the autopsy, so the reason why he died was unknown. and they were recommended to receive gene anal- ysis at other hospital. In our university, five patients Discussion were already conducted gene analysis. three were HPS1 often complicates with IP and granuloma- OCA1B, and two were HPS1. These patients were tous colitis for their forties. Especially, progressive followed by ophthalmologists and/or dermatolo- IP is the prognostic factor. In Japan, 70% of HPS gists during their courses. These two patients had patients complicated with IP10). Almost all patients no symptoms at skin on birth. White skin and blond were there thirty-forties and came to hospitals hair were noted in one patient at the age of thirty. with chief complaint of difficulty in breathing on Two patients developed pulmonary fibrosis at the working or dry cough. They died 1-6years after age of forty and two died of complications of OCA occurring the IP11). As the reason why they develop in their early fifties. IP in their thirties is unknown, recent studies show Diagnose of HPS is so difficult that we often rule this is linked to environmental factors such as out by not showing any other symptoms. In this exposition and inspiration poisonous substances12). case, we learned the importance of genetic diag- They had been treated by steroid or immunosup- nosis, and take treatments as soon as possible such pressive agent, but not achieved. Since 2008, we as lung transplant which needs wait in order. We can use pirfenidone as we expect not to be fibrotic13). expect 1st department where patients visit to In 2002, RCT report at Puerto Rico indicated that consider the possibilities of HPS as doctors at respi- pirfenidone could delay the developing IPF14). ratory medicine noticed. However, later study showed that pirfenidone did ) Conflict of interest not have availability for IPF15 . In our university, we included all the patients None declared. with OCA in our hospital from 1st June in 1989 to Acknowledgments 2nd September in 2019. 39 patients had diagnosed as OCA during past 20 years. Of the 39 patients, 10 The authors wish to acknowledge Mr. Suzuki were female and 29 were male. The mean age was and Mr. Okamura for gene analysis at Yamagata 14.2. Then, 5 had some allergy, and 15 had same University Hospital. symptoms in relatives. Table 3 shows which depart- References ment OCA patients came at first. Most of patients came to the department of ophthalmology at first, 1) Hermansky F, Pudlak P: Albinism associated with

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