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      Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood

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          Abstract

          Background

          Hermansky-Pudlak syndrome (HPS), a hereditary multisystem disorder with oculocutaneous albinism, may be caused by mutations in one of at least 10 separate genes. The HPS-2 subtype is distinguished by the presence of neutropenia and knowledge of its pulmonary phenotype in children is scarce.

          Methods

          Six children with genetically proven HPS-2 presented to the chILD-EU register between 2009 and 2017; the data were collected systematically and imaging studies were scored blinded.

          Results

          Pulmonary symptoms including dyspnea, coughing, need for oxygen, and clubbing started 3.3 years before the diagnosis was made at the mean age of 8.83 years (range 2-15). All children had recurrent pulmonary infections, 3 had a spontaneous pneumothorax, and 4 developed scoliosis. The frequency of pulmonary complaints increased over time. The leading radiographic pattern was ground-glass opacities with a rapid increase in reticular pattern and traction bronchiectasis between initial and follow-up Computer tomography (CT) in all subjects. Honeycombing and cysts were newly detectable in 3 patients. Half of the patients received a lung biopsy for diagnosis; histological patterns were cellular non-specific interstitial pneumonia, usual interstitial pneumonia-like, and desquamative interstitial pneumonia.

          Conclusions

          HPS-2 is characterized by a rapidly fibrosing lung disease during early childhood. Effective treatments are required.

          Electronic supplementary material

          The online version of this article (10.1186/s13023-018-0780-z) contains supplementary material, which is available to authorized users.

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          European protocols for the diagnosis and initial treatment of interstitial lung disease in children.

          Andrew Bush, Steve Cunningham, Jacques de Blic … (2015)
          Interstitial lung disease in children (chILD) is rare, and most centres will only see a few cases/year. There are numerous possible underlying diagnoses, with specific and non-specific treatment possibilities. The chILD-EU collaboration has brought together centres from across Europe to advance understanding of these considerations, and as part of this process, has created standard operating procedures and protocols for the investigation of chILD. Where established consensus documents exist already, for example, for the performance of bronchoalveolar lavage and processing of lung biopsies, these have been adopted. This manuscript reports our proposals for a staged investigation of chILD, starting from when the condition is suspected to defining the diagnosis, using pathways dependent on the clinical condition and the degree of illness of the child. These include the performance of genetic testing, echocardiography, high-resolution CT, bronchoscopy when appropriate and the definitive investigation of lung biopsy, in order to establish a precise diagnosis. Since no randomised controlled trials of treatment have ever been performed, we also report a Delphi consensus process to try to harmonise treatment protocols such as the use of intravenous and oral corticosteroids, and add-on therapies such as hydroxychloroquine and azithromycin. The aim is not to dictate to clinicians when a therapeutic trial should be performed, but to offer the possibility to collaborators of having a unified approach when a decision to treat has been made.
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            Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).

            Gary M Kupfer, I Bernardini, W Gahl … (1998)
            Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, a storage-pool deficiency, and lysosomal accumulation of ceroid lipofuscin, which causes pulmonary fibrosis and granulomatous colitis in some cases. All identified affected patients in northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of a recently cloned gene, HPS. We compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. Forty-nine patients -- 27 Puerto Ricans and 22 patients from the mainland United States who were not of Puerto Rican descent -- were given a diagnosis on the basis of albinism and the absence of platelet dense bodies. We used the polymerase chain reaction to determine which patients carried the 16-bp duplication. Twenty-five of the Puerto Rican patients were homozygous for the 16-bp duplication, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80 percent of the predicted value. High-resolution computed tomography in 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in eight patients without the duplication revealed minimal fibrosis in three and no fibrosis in the rest. Inflammatory bowel disease developed in eight patients (four in each group) between 3 and 25 years of age. The 16-bp duplication in exon 15 of HPS, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.
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              A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

              Ilaria Campo, Michele Zorzetto, Francesca Mariani … (2014)
              Background Interstitial lung disease occurring in children is a condition characterized by high frequency of cases due to genetic aberrations of pulmonary surfactant homeostasis, that are also believed to be responsible of a fraction of familial pulmonary fibrosis. To our knowledge, ABCA3 gene was not previously reported as causative agent of fibrosis affecting both children and adults in the same kindred. Methods We investigated a large kindred in which two members, a girl whose interstitial lung disease was first recognized at age of 13, and an adult, showed a diffuse pulmonary fibrosis with marked differences in terms of morphology and imaging. An additional, asymptomatic family member was detected by genetic analysis. Surfactant abnormalities were investigated at biochemical, and genetic level, as well as by cell transfection experiments. Results Bronchoalveolar lavage fluid analysis of the patients revealed absence of surfactant protein C, whereas the gene sequence was normal. By contrast, sequence of the ABCA3 gene showed a novel homozygous G > A transition at nucleotide 2891, localized within exon 21, resulting in a glycine to aspartic acid change at codon 964. Interestingly, the lung specimens from the girl displayed a morphologic usual interstitial pneumonitis-like pattern, whereas the specimens from one of the two adult patients showed rather a non specific interstitial pneumonitis-like pattern. Conclusions We have detected a large kindred with a novel ABCA3 mutation likely causing interstitial lung fibrosis affecting either young and adult family members. We suggest that ABCA3 gene should be considered in genetic testing in the occurrence of familial pulmonary fibrosis.
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                Author and article information

                Contributors
                Meike Hengst: Meike.Hengst@med.uni-muenchen.de
                Lutz Naehrlich: Lutz.Naehrlich@paediat.med.uni-giessen.de
                Poornima Mahavadi: Poornima.Mahavadi@innere.med.uni-giessen.de
                Joerg Grosse-Onnebrink: joerg.grosse-onnebrink@ukmuenster.de
                Suzanne Terheggen-Lagro: S.Terheggen@umcutrecht.nl
                Lars Høsøien Skanke: Lars.Hosoien.Skanke@stolav.no
                Luise A. Schuch: Luise.Schuch@med.uni-muenchen.de
                Frank Brasch: Frank.Brasch@klinikumbielefeld.de
                Andreas Guenther: andreas.guenther@innere.med.uni-giessen.de
                Simone Reu: Simone.Reu@med.uni-muenchen.de
                Julia Ley-Zaporozhan: Julia.LeyZaporozhan@med.uni-muenchen.de
                Matthias Griese:
                ORCID: http://orcid.org/0000-0003-0113-912X
                ++49 89 44005 7870 , Matthias.Griese@med.uni-muenchen.de
                Journal
                Journal ID (nlm-ta): Orphanet J Rare Dis
                Journal ID (iso-abbrev): Orphanet J Rare Dis
                Title: Orphanet Journal of Rare Diseases
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1750-1172
                Publication date (Electronic): 27 March 2018
                Publication date PMC-release: 27 March 2018
                Publication date Collection: 2018
                Volume: 13
                Electronic Location Identifier: 42
                Affiliations
                [1 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Ludwig-Maximilians University, Dr von Haunersches Kinderspital, German Center for Lung Research (DZL), ; Lindwurmstr. 4, 80337 Munich, Germany
                [2 ]ISNI 0000 0000 8584 9230, GRID grid.411067.5, University Hospital Gießen and Marburg, German Center for Lung Research, ; Feulgenstr. 12, 35385 Gießen, Germany
                [3 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Department of Internal Medicine, , Justus-Liebig University, German Center for Lung Research, ; Klinikstrasse 36, 35392 Giessen, Germany
                [4 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, University Hospital Münster, ; Albert-Schweitzer-Campus 1, 48149 Münster, Germany
                [5 ]ISNI 000000040459992X, GRID grid.5645.2, Erasmuc MC, , University Medical Center Rotterdam, ; S’Gravendijkwal 230, 3015 Rotterdam, The Netherlands
                [6 ]ISNI 0000 0004 0627 3560, GRID grid.52522.32, St.Olav’s University Hospital, ; Trondheim, Norway
                [7 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Klinikum Bielefeld Mitte, , Institut für Pathologie, ; Teutoburger Straße 50, 33604 Bielefeld, Germany
                [8 ]Member of the European IPF Network, Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany
                [9 ]Ludwig-Maximilians University, Institute of Pathology, Thalkirchnerstr. 36, 80337 Munich, Germany
                [10 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Department of Radiology, , Ludwig-Maximilians University, ; Lindwurmstr. 4, 80337 Munich, Germany
                Author information
                http://orcid.org/0000-0003-0113-912X
                Article
                Publisher ID: 780
                DOI: 10.1186/s13023-018-0780-z
                PMC ID: 5870397
                PubMed ID: 29580292
                SO-VID: d17f402a-9f3d-4e72-a5ab-3c2060eb3553
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 13 November 2017
                Date accepted : 1 March 2018
                Funding
                Funded by: European Union’s Seventh Framework Program
                Award ID: 305653
                Award Recipient :
                Funded by: German Center for lung research (DZL)
                Funded by: German Center for lung research (DZL)
                Funded by: European Cooperation in Science and Technology ()
                Award ID: A16125
                Award Recipient :
                Funded by: Curetis, Holzgerlingen, Germany
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: hermansky-pudlak syndrome type 2,childhood,pulmonary fibrosis,tachydyspnea,pulmonary phenotype
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: hermansky-pudlak syndrome type 2, childhood, pulmonary fibrosis, tachydyspnea, pulmonary phenotype

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