Clinical Case Pulmonary Fibrosis in HermanskyPudlak Syndrome History
Clinical Case Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
History • A 28 -year-old Mexican man presented with exertional dyspnea and chronic dry cough • He also complained of arthralgia and morning stiffness • Clubbing of extremities was not present • He denied a history of fever, hemoptysis, or smoking
History (cont) • Albinism diagnosed in childhood • Nystagmus and decreased visual acuity • Frequent nose bleeds, easy bruising and several episodes of protracted hemorrhagic colitis since the age of 17 • Albino sister with ecchymosis, but no pulmonary symptoms. A paternal “great-great” grandmother was said to be albino, but history of pulmonary disease and age of death were unknown
History (cont) • Father reportedly of Mexican descent, unrelated to his Mexican mother • No known Puerto Rican ancestry • Neither parents nor 2 other siblings affected • Patient is childless • Family history of diabetes mellitus and hypertension
Chest Radiography • A chest radiograph was abnormal showing diffuse reticulonodular interstitial infiltrates • HRCT demonstrated prominent diffuse reticular opacities and ground-glass opacity (indicated on next slide) • Distribution: bases and right middle lobe, also lingual and anterior portions of upper lobes
High Resolution CT
Tests • Pulmonary function tests showed a restrictive pattern • Video-assisted thoracic surgery revealed minimal pleural effusion and mild pleural adhesions – Lung parenchyma was pink and diffusely thickened • Wedge resection of the left lingula was obtained for cultures and histopathologic evaluation (cultures negative)
NL mb F
Pathology Summary • Microscopic sections showed advanced lung remodeling with architectural distortion and fibrosis appreciated • Chronic inflammatory cells were numerous and peculiar patchy clusters of clear vacuolated cells were distinctive
Diagnosis • On the basis of these findings, a diagnosis of Hermansky-Pudlak Syndrome (HPS) was made
What is Hermansky-Pudlak Syndrome? • Findings – – – Oculocutaneous albinism Bleeding diathesis Pulmonary disease Visual impairment Systemic ceroid lipofuscin deposition • Mutated proteins function in organelle biogenesis and transport; lysosomes, lysosome-related organelles (LRO’s), melanosomes, and platelet dense bodies are affected • HPS has GI features of both Crohn’s disease and ulcerative colitis with frequent GI bleeds • Majority of HPS patients with pulmonary findings have HPS-1 and usually have Puerto Rican ancestry
HPS Genetics Gene Symbol Mouse Model Human Disease HPS 1 pale ear HPS 1 AP 3 B 1 pearl HPS 2 HPS 3 cocoa HPS 3 HPS 4 light ear HPS 4 HPS 5 ruby-eye 2 HPS 5 HPS 6 ruby-eye HPS 6 DTNBP 1 sandy HSP 7 AP 3 D 1 mocha PLDN pallid MUTED muted CNO BLOC 1 S 3 cappuccino reduced pigmentation VPS 33 buff RAB 38 ruby (rat) Pierson DM, et al. Respiration. 2006; 73: 382– 395. unknown
HPS Mechanism • There is limited understanding of the mechanisms involved in secretory and endocytic lysosomal pathways • Human mutations such as those associated with HPS may aid elucidation of vesicle biology • Mice bearing similar mutations may also help investigation of basic mechanisms and analysis of drug candidates
Clinical Update • Sister has experienced no pulmonary symptoms • At the age of 30, the patient’s pulmonary status has progressively decompensated; low flow continuous oxygen by nasal cannula was required • Patient is hopeful of receiving a lung transplant • Before transplantation, patient suffers pneumothorax, inanition, respiratory failure and death
Conclusions • Pulmonary radiographs of HPS may mimic findings of UIP/IPF, especially when HPS is end-stage • Histopathologic findings such as clear cells do not support a diagnosis of IPF despite other features of UIP • Not all HPS patients manifest the classical features of albinism, GI symptoms and frequent bleeding • History of bruisability, epistaxis, metrorrhagia (females), family history and provenance may provide clues to diagnosing HPS • Surgical lung biopsy can cause fatal bleeding in HPS patients
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