Hermansky–Pudlak Syndrome

Definition and Clinical Characteristics

Figure X-1. Phenotypic heterogeneity of the HPS-1 genotype. Note differences in degree of hair and skin pigmentation | Photo courtesy of The American Academy of Pediatrics Opens in new window

The Hermansky–Pudlak Syndrome (HPS) comprises a group of rare autosomal-recessive Opens in new window disorders of organelle biogenesis Opens in new window characterized by various degrees of oculocutaneous albinism Opens in new window (hypopigmentation of the skin, hair, and eyes), reduced visual acuity Opens in new window, congenital nystagmus Opens in new window, platelet dysfunction Opens in new window resulting in bleeding diathesis, and lysosomal accumulation of ceroid lipofuscin Opens in new window in reticuloendothelial cells Opens in new window.

Other clinical characteristics such as pulmonary fibrosis Opens in new window, granulomatous colitis Opens in new window and immune defects may also occur in some forms.

The first description of the disease originates in 1959, from the Czechoslavakian physicians Frantisek Hermansky and Paulus Pudlak, who described two Czech patients with oculocutaneous albinism, bleeding diathesis and unusual pigmented reticular cells in the bone marrow.

Subtypes of HPS

To date 10 genetic subtypes (Table X-1) of the disease have been identified (genes HPS1–HPS10); all exhibit oculocutaneous albinism and absent platelet dense bodies.

Additional features are present in each subtype, which may include pulmonary fibrosis and immunodeficiency. Several subtypes are limited to single case reports.

Lipid and ceroid pigment are present in macrophages in various organs, including the skin. Pulmonary ceroid deposition leading to respiratory failure is a common cause of death in HPS-1 and HPS-4.

Epidemiology

While rare, Hermansky–Pudlak syndrome (HPS) may be the most common singe gene disorder in Puerto Rico, where 1/20 people carry the gene and the disease is found in 1/1800.

Most HPS in Puerto Ricans is caused by mutations in the HPS1 gene, which have been identified in about 450 patients in the northwest part of the country.

Mutations in HPS3 have also been identified in Puerto Rico, but are much less common.

Outside Puerto Rico, HPS-1 has been identified in approximately 40 additional patients.

Nakatani et al. identified 65 total cases of HPS reported in Japan, and HPS has now been reported in individuals of almost every nationality.

The total number of individuals with HPS is unknown and is likely underestimated based on the low index of suspicion for the disorder, but HPS is thought to affect 1000 patients worldwide.

Approximately 400 patients are registered with Hermansky–Pudlak Syndrome Network Opens in new window, a not-for-profit patient advocacy and support organization (Donna Appell, RN, personal communication).

Gene Description

HPS genes encode protein complexes called biogenesis of lysosome-related organelles (BLOCs), which are expressed in many cell types.

BLOCs Opens in new window are essential in intracellular trafficking and the formation of lysosome-related organelles such as melanosomes and platelet-dense granules and lamellar bodies (responsible for surfactant synthesis and secretion in alveolar type II cells).

All manifestations of Hermansky–Pudlak syndrome appear to arise from defects in the HPS genes encoding BLOCs.

Pathogenesis

The pathogenesis of organ damage in Hermansky-Pudlak syndrome is unclear. However, lysosomal accumulation of ceroid lipofuscin (an amorphous, autofluorescent lipid-protein material) is believed to cause granulomatous colitis in HPS1 and lung fibrosis in HPS1, HPS2 and HPS4.

All subtypes are associated with OCA, which includes hypopigmentation of the hair, skin and eyes.

However, the degree of hypopigmentation is variable, with skin and hair color ranging from white to brown but significantly paler than family members.

Besides retinal and iris hypopigmentation, a reduction in vision and horizontal nystagmus can also be found. Bleeding diathesis is also present in all patients and can vary clinically from easy bruising and epistaxis to post-partum hemorrhage and serious bleeding during surgery.

Pulmonary fibrosis is seen in virtually all patients with HPS1 disease and in a subgroup of those with HPS2 and HPS4 disease but not in the other subtypes.

The onset of pulmonary fibrosis is reported as early as adolescence but more typically occurs at 30–40 years of age.

Chest HRCT reveals peripheral reticulation, thickened interlobular septa and fibrotic changes such as traction bronchiectasis and bronchiolectasis, sometimes associated with ground-grass opacities.

Progression of pulmonary fibrosis is variable, even in patients carrying the same HPS mutations Opens in new window.

Diagnosis

In many patients with Hermansky–Pudlak syndrome, albinism Opens in new window is the first clue to diagnosis, although it can be subtle and missed; ophthalmological examination and excessive bleeding and bruising may also indicate the diagnosis.

Platelet election microscopy is recommended to evaluate the absence of dense bodies in platelets, which is the hallmark of Hermansky–Pudlak syndrome.

Conversely, bleeding time assessment is not reliable and is not recommended in the diagnostic work-up of this disease.

Genetic testing is indicated to determine the different subtypes of HPS, which may help predict clinical manifestations, thus informing on timing of follow-up and prognosis.

Clinical features can also guide genetic testing (Table X-1) and, if negative, a multi-HPS gene panel can be tested.

If genetic testing is not available, a patient with classical disease manifestations (i.e. OCA with bleeding diathesis, pulmonary fibrosis or colitis) should be considered as having HPS.

Furthermore, not all patients with clinical features of this disease carry known pathogenic mutations, suggesting the existence of additional genetic variants.

In patients with pulmonary fibrosis and (suspicion of) Hermansky–Pudlak syndrome, diagnostic lung biopsies should be avoided because of the risk of bleeding.

Therapeutics

Limited therapy exists for individuals with Hermansky–Pudlak syndrome, but prevention and management of bleeding complications is a priority.

HPS patients are counseled to wear medical alert bracelets, and medications such as asprin, ibuprofen, and warfarin are generally avoided.

Platelet transfusions may be required in the setting of trauma, bleeding episodes, or surgical procedures.

Desmopressin (DDAVP) Opens in new window has been administered to many patients, but with inconsistent efficacy. Cordova et al. reported that DDAVP had no effect on bleeding time in 19 pediatric Puerto Rican patients.

No definitive treatment exists for the pulmonary fibrosis associated with Hermansky–Pudlak syndrome and respiratory failure is the most common cause of death after bleeding complications.

Steroids and other immunomodulating agents have been used, but there are no controlled studies to guide therapy and no definite benefits have been reported.

Vigilance and early intervention for respiratory infections may be beneficial in patients with Hermansky–Pudlak syndrome, in addition to prophylaxis with influenza and pneumococcal vaccinations.

Smoking cessation should be recommended for all patients with Hermansky–Pudlak syndrome.

While bleeding complications are a significant consideration, lung transplantation may be an option for some HPS patients with advanced pulmonary fibrosis.