English Version
C. Gaik · T. Wiesmann

Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome

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Keywords Hermansky-Pudlak syndrome; ICD 10: E70.3
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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterised by abnormal intracellular vesicle formation and trafficking [7,17]. It was first described in 1959 [11]. There are a few hot spots of HPS in many regions of the world [6]. Generally, there is a lack of data regarding the disease’s real frequency. Its prevalence is estimated with 1 in 500,000 to 1 in 1,000,000 [14,21]. For unknown reasons, , an unusual high incidence of up to 1:1,800 persons has been identified in the northwestern part of Puerto Rico [6]. 

There are 11 known genetically distinct subtypes of HPS (HPS-1 to HPS-11) [6,7]. Mutations result in defects in intracellular protein trafficking and in the biogenesis of lysosomes as well as the biogenesis of lysosome-related organelles (BLOCs), such as melanosomes and platelet-dense granules [6,23]. 

Oculocutaneous albinism (OCA) is characterised by various degrees of hypopigmentation of hair, skin retina and iris. A decline in visual acuity may be accompanied by retinal hypopigmentation, horizontal nystagmus, photophobia, and strabismus [2,6,21,23]. HPS-2 patients may also result in immunodeficiency from severe neutropenia, often treated with G-CSF [10]. 

In addition, HPS-1 and HPS-4 are at high risk to develop pulmonary fibrosis in adults as well as HPS-2 in children. Fibrosis is supposed to be promoted by lysosomal accumulation of ceroid-lipofuscin in alveolar macrophages, disruption of type-II pneumocytes and a consecutive inflammation cascade [1,7,23,28]. In adults, interstitial, irreversible and progressive lung diseases usually develop in the third decade of life.

Due to a dysfunction in platelet aggregation in HPS, anamnesis often reveals a history of bruising, nose bleeding, menorrhagia or (unexpected) prolonged bleeding after dental extractions or other surgical procedures [6,20,22,23]. However, the severity of the bleeding tendency may widely vary between patients with HPS [5]. In the absence of dense bodies, the bleeding time may be prolonged despite a regular number of platelets and inconspicuous coagulation factors [5,12,18,29].

Moreover, in about 15% of HPS (type 1–4) a patient’s phenotypic presentation may include granulomatous colitis with crampy abdominal pain, weight loss, malabsorption, and frequent watery, bloody diarrhoea [6,9,12,23]. Cardiomyopathy and renal glomerular dysfunction secondary to ceroid deposition have been reported as rare complications of HPS [12].

The diagnosis of the disease is based on clinical features including the typical triad of OCA accompanied by a bleeding disorder due to platelet dysfunction [6,11]. The latter is demonstrated by th absence of platelet dense bodies (δ granules) on whole-mount electron microscopy of platelets, which represents the “gold standard” test for platelet abnormality in HPS [6,7,28]. 

Molecular genetic analysis is recommended to determine the specific subtypes of HPS in order to plan follow-up procedures and better estimate the prognosis in affected patients [6]. However, detailed diagnostics are complex and genetic testing and confirmation are expensive and usually only available on a research basis [2]. Furthermore, the diagnosis of an intestinal lung disease is established with a high-resolution computed tomography of the chest (HRCT), which also provides good radiologic monitoring of disease status and progression [1]. Alung biopsy is not necessary for diagnosis and may merely provoke bleeding complications [6,28].

There are currently no definitive therapeutic or even preventative approaches for HPS [6]. Therefore, therapy is solely symptomatic.

The prognosis of HPS usually depends on the progression of lung fibrosis and in patients with HPS-2 on the immunological defect. The course of pulmonary fibrosis is variable but universally progressive and a major cause of mortality in adults, especially in HPS-1 [7,8,9]. Generally, because of absent efficacy, a corticosteroid or immunosuppressive therapy is not recommended in HPS patients with pulmonary fibrosis [28]. Administration of pirfenidone as a new therapy approach is assumed to slow down the progression of fibrosis, but its use is controversial and not yet generally recommended [8,15]. Patients with HPS-1, HPS-2 and HPS-4 may be referred for lung transplant evaluation to prolong life expectancy [6,7]. Finally, lung transplantation is the only curative therapy for pulmonary fibrosis now [17]. However, the treatment of a Crohn’s disease-like gastrointestinal disorder in HPS has been reported to respond well to immunosuppressive therapy [9]. Unfortunately, the average life expectancy of patients with HPS is 40–50 years (especially in cases of pulmonary impairment) [28].