Clinical Description
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement in specific subtypes [Huizing et al 2008]. Signs and symptoms of oculocutaneous albinism in HPS are variable but visual acuity generally remains stable.
Eyes. Nearly all children with the albinism of HPS have nystagmus at birth, often noticed by the parents in the delivery room and by the examining physician. Children with HPS may also have periodic alternating nystagmus [Gradstein et al 2005], wandering eye movements, and lack of visual attention. The initial diagnosis of albinism is sometimes made by the ophthalmologist.
The nystagmus can be very fast early in life, and generally slows with time, but nearly all individuals with albinism have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable when an individual is tired or anxious. Individuals with HPS have increased crossing of the optic nerve fibers [King et al 2001].
Photophobia may accompany severe foveal hypoplasia.
Iris color may remain blue or change to a green/hazel or brown/tan color. Globe transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina.
Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood [Iwata et al 2000].
Alternating strabismus is found in many individuals with albinism and is generally not associated with the development of amblyopia.
Skin/hair. The hair color ranges from white to brown, and can occasionally darken with age. Skin color can be white to olive, but is generally at least a shade lighter than that of other family members.
Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare.
Affected Puerto Ricans typically have solar damage manifesting as actinic keratoses and nevi. Ephelids, lentigines, and basal cell carcinoma also occur with increased frequency among Puerto Ricans with HPS [Toro et al 1999].
Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal [Huizing et al 2007]. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, or other surgeries. Typically, cuts bleed longer than usual but heal normally. Bruising generally first appears at the time of ambulation. Epistaxis occurs in childhood and diminishes after adolescence. Menstrual cycles may be heavy and irregular. Prolonged bleeding after tooth extraction can lead to the diagnosis of HPS. Affected individuals with colitis may bleed excessively per rectum. Exsanguination as a complication of childbirth, trauma, or surgery is extremely rare.
Pulmonary fibrosis. The fibrosis consists of progressive restrictive lung disease with an extremely variable time course [Gahl et al 2002]. Symptoms usually begin in the thirties and are fatal within a decade. Pulmonary fibrosis has been described largely in affected individuals from northwestern Puerto Rico [Brantly et al 2000, Avila et al 2002], but also occurs in other individuals with pathogenic variants in HPS1, HPS4, and AP3B1 [Gochuico et al 2012]. To date, convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes (see , ).
Colitis. A bleeding granulomatous colitis resembling Crohn's disease presents on average at age 17 years, with wide variability [Gahl et al 1998, O'Brien et al 2021]. The colitis is severe in 15% of affected individuals and occasionally requires colectomy; affected individuals may have the inflammatory bowel disease of HPS without the explicit diagnosis of colitis. Objective signs of colitis have been found in persons with pathogenic variants in HPS1, HPS3, HPS4, or HPS6 [Hussain et al 2006, O'Brien et al 2021]. Although the colon is primarily involved in HPS, any part of the alimentary tract, including the gingiva, can be affected.
Neutropenia. Neutropenia and/or immune defects have been associated with AP-3-deficient HPS, including individuals with pathogenic variants in AP3B1 [Fontana et al 2006, de Boer et al 2017] or AP3D1 [Ammann et al 2016].
Other. Cardiomyopathy and renal failure have also been reported in individuals with HPS [Witkop et al 1989].
Pathogenesis. The mechanism of pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure remains unknown. It is likely associated with aberrant biogenesis of lysosome-related organelles in specialized cells [Huizing et al 2008]. Ceroid lipofuscin, a poorly defined, amorphous, granular, electron-dense, autofluorescent lipid-protein material, has been found to accumulate in the lysosomes of HPS cells, including renal tubular cells, alveolar macrophages, and cells of the gastrointestinal tract, bone marrow, liver, spleen, lymph nodes, and heart. The clinical consequences of lipofuscin accumulation in HPS remain greatly unexplored, as does the underlying cellular cause [Gahl et al 1998].
Phenotype Correlations by Gene
All individuals with HPS exhibit oculocutaneous albinism (as a result of aberrant melanosome formation) and a bleeding diathesis (as a result of absent platelet delta granules). Other clinical features occur per subtype and are listed below; individuals with pathogenic variants in the same HPS protein complex of AP-3, BLOC-1, BLOC-2, or BLOC-3 exhibit similar clinical characteristics [Huizing et al 2008, Huizing et al 2020]. These complexes are described in Molecular Pathogenesis.
AP3B1, AP3D1 (AP-3 Deficiency)
As of March 2021, 40 individuals with pathogenic variants in AP3B1 or AP3D1 have been reported. These individuals differ from those with other forms of HPS in that they exhibit immunodeficiency. They have an increased susceptibility to infections as a result of congenital neutropenia and impaired NK-cell cytotoxicity. It has been suggested that the neutropenia is caused by mislocalization of granule proteins in neutrophils [de Boer et al 2017], including elastase [Di Pietro et al 2006, Jung et al 2006].
The one individual reported with AP3D1-related HPS, a boy of consanguineous Turkish parents, also exhibited neurodevelopmental delay, generalized seizures, and impaired hearing, features not commonly seen in individuals with AP3B1-related HPS. The boy died at age 3.5 years of septic pneumonia [Ammann et al 2016]. See Less Common Genetic Causes, AP3D1 (pdf) for variant details.
BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1 (BLOC-1 Deficiency)
As of March 2021, 29 individuals with pathogenic variants in genes encoding subunits of BLOC-1 have been described, including BLOC1S3 (13 individuals), BLOC1S5 (2 individuals), BLOC1S6 (6 individuals), or DTNBP1 (8 individuals) have been described [Huizing et al 2020, Pennamen et al 2020, Liu et al 2021, Michaud et al 2021, Pennamen et al 2021]. Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism and a bleeding diathesis. These individuals appear to have a silvery/blond/gold hair color at birth that may turn darker with age [Cullinane et al 2012, Lowe et al 2013, Pennamen et al 2020].
No pulmonary defects have been reported in these individuals. One Italian individual with BLOC1S6-related HPS presented with immunodeficiency [Badolato et al 2012]; therefore, close follow up of other individuals is required to determine if immunodeficiency is a feature of BLOC-1 deficiency.
HPS3, HPS5, HPS6 (BLOC-2 Deficiency)
As of March 2021, about 212 individuals with pathogenic variants in HPS3, HPS5, or HPS6 have been reported (including ~72 Puerto Rican individuals homozygous for a 3.9-kb deletion in HPS3 and 20 Israeli Bedouin individuals homozygous for a frameshift variant in HPS6) [Huizing et al 2020]. Individuals with pathogenic variants in HPS3, HPS5, or HPS6 are BLOC-2 deficient and generally have milder symptoms than those with BLOC-3 deficiency (pathogenic variants in HPS1 or HPS4) [Huizing et al 2008]. The albinism in individuals with BLOC-2-related HPS can present with such minimal hypopigmentation that some individuals may be diagnosed with ocular albinism rather than oculocutaneous albinism. Visual acuity often approximates 20/100 or better.
Bleeding is also mild and pulmonary involvement has not been observed in individuals with BLOC-2 deficiency.
Individuals with BLOC-2 deficiency can go undiagnosed for decades: a new diagnosis of HPS5-related HPS was described in a man age 92 years with light skin and hair, nystagmus, decreasing visual acuity with age, and a bleeding history. He is the oldest reported individual with HPS [Ringeisen et al 2013].
HPS1, HPS4 (BLOC-3 Deficiency)
As of March 2021, approximately 452 individuals with pathogenic variants in HPS1 or HPS4 have been reported (including ~261 Puerto Rican individuals homozygous for a 16-bp duplication in HPS1) [Huizing et al 2020]. These individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [Huizing et al 2008].
BLOC-3 deficiency is associated with lethal pulmonary fibrosis. The lung fibrosis is a restrictive lung disease and individuals with BLOC-3-deficiency typically begin to display symptoms in their early thirties and progress to death within a decade, unless lung transplantation is achieved [Gahl et al 2002, Huizing et al 2008].
Significant granulomatous colitis occurs primarily in individuals with HPS1, HPS3, HPS4, or HPS6 pathogenic variants [Hussain et al 2006, O'Brien et al 2021].
Prevalence
HPS is a rare disorder with an estimated worldwide prevalence of 1-9 per 1,000,000 individuals (www.orpha.net).
The prevalence per subtype can differ because of founder variants. The prevalence of HPS1-related HPS in northwestern Puerto Rico is 1:1,800 [Witkop et al 1989].
HPS1-related HPS has also been reported in a small isolate in a Swiss village [Schallreuter et al 1993] and as a genetic isolate in Japan [Ito et al 2005].
HPS3-related HPS occurs as a genetic isolate in central Puerto Rico, where about 1:16,000 individuals are affected [Anikster et al 2001, Santiago Borrero et al 2006]. Newborn screening of 12% of the Puerto Rican population detected two homozygotes and 73 heterozygotes with the common variant (also referred to as the 3.9-kb deletion) [Torres-Serrant et al 2010].
Individuals with HPS have been identified in many other regions, including China, India, South America, and Western Europe.