Rare Lung Disease

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General Information about Rare Lung Disease

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Hermansky-Pudlak syndrome (HPS) is a rare multisystemic hereditary disease manifested by oculocutaneous albinism (OCA), visual impairment, and bleeding diathesis. First described in 1959 by Czechoslovakians Hermansky and Pudlak, HPS represents a heterogeneous group of autosomal recessive disorders with several types described and 9 genes identified to date (Figure 1).

Although the disease is seen around the world, there is considerable variation in gene frequency between countries. Likely this is due to underrecognition of the disease. In contrast, the prevalence of HPS-1 in Puerto Rico is 1:1800 and 1 out of 21 persons carries the gene encoding for HPS type 1 due to a Founder's effect. This high prevalence allows the clinical disease to be more known among individuals of Puerto Rican ancestry. Survival is reduced in the disease with deaths from pulmonary fibrosis accounting for 50% of the morbidity. For relatives in affected families, genetic testing is recommended.

Occulocutaneous albinism may present with any combination of skin and hair hypopigmentation, iris and retinal pigment loss with resulting red reflex, and foveal hypoplasia with marked decrease in visual acuity. Although most patients are phenotypically albino, hair color ranges from white to brown and skin color varies from white to olive being a shade lighter than that of other relatives. Nystagmus from an optic nerve source may be the only obvious feature of the disease in some individuals. Because of these abnormalities, HPS is frequently diagnosed in childhood.

Bleeding manifestations include easy bruising, epistaxis, gingival bleeding, menometrorhagia, postpartum hemorrhage, and prolonged bleeding with tooth extraction and other surgeries. Patients have normal platelet counts and 25% of patients have normal bleeding time, hence platelet electron microscopy showing virtual absence of dense bodies remains a clinical method of HPS diagnosis since not all of the genes are identified at this time. The platelet dense bodies contain granules of ADP, ATP, serotonin, calcium and phosphate. All of these substances are essential elements of the clotting cascade. Hemorrhage during surgical procedures can be successfully managed with platelet transfusions, desmopressin and recombinant factor VII.

Systemic complications including inflammatory bowel disease and pulmonary fibrosis are common and result from ceroid lipofuscin, an amorphous lipid-protein complex accumulated in lysosomes.

Approximately 50 percent of the HPS patients develop interstitial lung disease (ILD). Gene types HPS 1 and HPS 4 cause ILD in virtually all affected patients. Pulmonary fibrosis is linked to foamy accumulation of ceroid in alveolar macrophages leading to chronic inflammation and extensive fibrosis of the alveolar septa and peribronchial stroma ensuing in disrupted gas exchange. Pulmonary radiographs and high-resolution CTs in HPS may mimic UIP/IPF findings (See Figure 2).

In contrast to IPF, the onset of pulmonary fibrosis in HPS is usually in the third or fourth decade and women are affected twice as often as men. HPS pulmonary fibrosis has been seen as young as 20 years and presents with dyspnea on exertion and restrictive lung disease with reduced diffusion capacity on pulmonary function tests. According to recent studies, up to 82% of the patients with the HPS have an abnormal CT of the chest. However, this often occurs with a normal chest radiograph and contributes to disease underestimation. CT findings vary from septal thickening, ground-glass opacities, and mild reticulation in earlier stages to bronchiectasis, severe reticulation, subpleural cysts, and peribronchial thickening in advanced phases of the disease. Pulmonary evaluation should include annual Spirometry and DLCO, vaccination for influenza, whooping cough, and pneumococcus, cardiopulmonary rehabilitation, and tobacco avoidance.

Although feared initially, lung transplantation has been successful in 8 patients with HPS and remains the only known treatment for pulmonary fibrosis thus far. Surgical lung biopsy can cause fatal bleeding and is not necessary to make the diagnosis when the clinical features of this disease are apparent.

Several drugs were studied for pulmonary fibrosis in HPS including pirfenidone, pravastatin, Losartan, Zileuton, N-acetylcysteine, and erythromycin. There are no clinical randomized trials for HPS at present and treatment remains a conundrum.

Although HPS is a rare cause of pulmonary fibrosis, the disease is important to recognize. The biochemical pathways responsible for ILD disease progression may assist more common causes of ILD and are worthy of our study. Early identification of individuals at risk will assist the development of novel therapeutic interventions. Please take the time to learn about this important disease.

Figure 1
Figure 1. HPS genes1

Figure 2

Figure 2. CT scan from a patient with HPS syndrome.


Bibliography

  1. GeneReviews™ [Internet].Pagon RA, Bird TD, Dolan CR, et al., editors. Seattle (WA): University of Washington, Seattle 1993-2012.Gahl WA, Huizing M. Hermansky-Pudlak Syndrome. Bookself ID NBK1287, PMID 20301464.
  2. Garcia, Christine K. Inherited interstitial lung disease. Clin Chest Med. 2004 Sep;25(3):421-33.
  3. Avila, Nilo A, et al. Hermansky-Pudlak syndrome: radiography and CT of the chest compared with pulmonary function tests and genetic studies. AJR Am J Roentgenol. 2002 Oct;179(4):887-92.

Tatsiana Beiko, MD
Rahul Argula, MBBS, MPH
Charlie Strange, MD
Division of Pulmonary and Critical Care Medicine
Medical University of South Carolina