Table 2:
Hermansky-Pudlak Syndrome Main Clinical Features
| Clinical Feature | Manifestations | LRO Defect (Cell Type) | Deficiency of HPS Complex | Prevention/Therapy |
|---|---|---|---|---|
| Cutaneous Albinism | white/light hair, hypopigmented and sun-sensitive skin 1 | melanosome (skin melanocytes) | AP-3, BLOC-1, -2, -3 |
Preventive care: sun avoidance, sun protection (sunscreen, hat, clothing), periodic skin cancer screening |
| Ocular Albinism | horizontal nystagmus, decreased visual acuity, pale fundus, foveal hypoplasia, iris transillumination 2 | melanosome (retinal pigment epithelial cells) | AP-3, BLOC-1, -2, -3 |
Preventive care: sun avoidance, eye protection (sunglasses, hat) Symptomatic care: vision corrective glasses, ophthalmologic care |
| Bleeding Diathesis | easy bruising, epistaxis, menorrhagia, gingival bleeding, colonic bleeding, prolonged bleeding after trauma or surgery or postpartum 3 | delta granule 3 (platelets) | AP-3, BLOC-1, -2, -3 |
Symptomatic care: local pressure on wounds, topical thrombin, 1-desamino-8D-arginine vasopressin (DDAVP) and other pro-coagulant drugs Therapeutic: platelet transfusion |
| Pulmonary Fibrosis (PF) | nonproductive cough, exertional dyspnea, diffuse rales, hypoxia | lamellar body 4 (type II alveolar epithelial cells) | BLOC-3, AP-3 4 |
Preventive care: avoidance of tobacco products Symptomatic care: supplemental oxygen for hypoxemia, pulmonary rehabilitation Therapeutic: lung transplantation |
| Enterocolitis | abdominal pain, cramps, fever, weight loss, malabsorption, frequent watery and bloody diarrhea. | unknown LRO-membrane formation 5 | BLOC-3, BLOC-2, (BLOC-1) 5 | Therapeutic: corticosteroids, non-steroidal immunomodulator drugs, anti-tumor necrosis factor-alpha drugs (effective for only some subjects) |
| Neutropenia | immunodeficiency | lytic and azurophil granules (neutrophils) | AP-3 (BLOC-1) 6 | Therapeutic: granulocyte colony-stimulating factor (G-CSF) 7 |
| Recurrent Infections | frequent viral and bacterial infections | LRO-related granules (dendritic cells, natural killer cells) | AP-3 | Therapeutic: Not prevented by G-CSF therapy 7 |
Sunburn, photo-aging of the skin, solar keratosis and melanocyte nevi are common in HPS and patients are at risk of developing squamous cell carcinoma, basal cell carcinoma, and melanoma (Toro et al., 1999).
HPS visual acuity is generally stable at 20/200 (legally blind in the United States) or worse. Most HPS patients exhibit nystagmus resulting from abnormal crossing of the optic nerve fibers. Iris transillumination is when a light is shone into the pupil is transmitted back through the iris because of a lack of iris pigmentation (Schneier & Fulton, 2013; Summers et al., 1988).
Absent platelet delta granules (determined by whole mount electron microscopy) is a diagnostic hallmark of HPS. Bleeding tendency varies widely between HPS patients. Due to absent delta granules, a secondary platelet aggregation response cannot occur (Huizing et al, 2017 Oct 26 [Updated 2000 July 24]).
Apart from type II epithelial cell defect, aberrant alveolar macrophage or mast cell function has been suggested to underlie HPS-PF (Kirshenbaum et al., 2016; Mahavadi et al., 2010; Nakatani et al., 2000; Rouhani et al., 2009). Onset of PF is in childhood in AP-3 deficiency (Gochuico et al., 2012) and middle age (30–50 years) in BLOC-3 deficiency (Huizing et al, 2017 Oct 26 [Updated 2000 July 24]). AP-3 related PF has not been described in HPS-10 patients (Ammann et al., 2016; Mohammed et al., 2018). There is no approved medical therapy for HPS PF. Lung transplantation may be considered (El-Chemaly et al., 2018; Gahl et al., 2002; Huizing et al, 2017 Oct 26 [Updated 2000 July 24]; Lederer et al., 2005).
HPS colitis involves intestinal granulomas, erosions and inflammatory cells, and resembles Crohn’s disease. The underlying cause remains unknown. Abnormal endosomal (LRO-related) membrane formation was suggested, leading to ceroid lipofuscin formation, abnormal autophagy and phagocytosis, inflammation (Felipez et al., 2010; Sofia et al., 2017). Some BLOC-2 or BLOC-3 deficient cases develop colitis (Huizing et al, 2017 Oct 26 [Updated 2000 July 24]; Hussain et al., 2006). One BLOC-1 deficient case (HPS-7) developed Crohn’s colitis in adulthood (Lowe et al., 2013). It is unknown if colitis occurs in AP-3 deficiency.
Immunodeficiency was reported in two unrelated individuals with HPS-9 (BLOC-1 deficiency) (Badolato et al., 2012; Okamura et al., 2018) and needs consideration in future BLOC-1 deficient individuals.
G-CSF therapy was only used in HPS-2 patients (AP3B1 deficiency) (Ammann et al., 2016; Fontana et al., 2006). While G-CSF restores neutrophil numbers, it does not prevent recurrent infections caused by defects in innate immunity in HPS-2 (Fontana et al., 2006).