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 HPS have nystagmus at birth, often noticed by the parents and the examining physician in infancy. Children with HPS may also have periodic alternating nystagmus, wandering eye movements, and lack of visual attention. The nystagmus can be very fast early in life and generally slows with time, but nearly all individuals have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable in lateral eye gaze, or when an individual is tired or anxious.
Iris color may remain blue or change to a green/hazel or brown/tan color. Iris 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.
Photophobia may accompany severe foveal hypoplasia.
Foveal hypoplasia is associated with significant visual acuity loss. Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood.
Individuals with HPS have increased crossing of the optic nerve fibers.
Alternating strabismus is found in many individuals with HPS and is generally not associated with the development of amblyopia.
Hair/skin. 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 of lightly pigmented skin to the sun 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.
Some affected individuals have solar damage manifesting as actinic keratoses and nevi. Freckles, solar lentigines, and basal cell carcinoma also occur with increased frequency among individuals with HPS.
Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, and/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. 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. Symptoms usually begin in the 30s and may be fatal within a decade. Pulmonary fibrosis has been described largely in affected individuals from northwestern Puerto Rico (HPS1-related HPS), but also occurs in other individuals with pathogenic variants in AP3B1, HPS1, and HPS4 [Gahl et al 2002, Gochuico et al 2012, Velázquez-Díaz et al 2021, Yokoyama & Gochuico 2021]. Some individuals with HPS1-related pulmonary fibrosis successfully underwent bilateral or single-lung transplantations [Yokoyama & Gochuico 2021, Benvenuto et al 2022]. Convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes.
Colitis. A bleeding granulomatous colitis resembling Crohn 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. 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. HPS-related colitis may be responsive to corticosteroids, anti-inflammatory drugs, immune modulators, or anti-tumor necrosis factor alpha drugs [Schinella et al 1980, O'Brien et al 2021]. Partial or total colectomy was performed in some individuals with severe disease unresponsive to therapy [Schinella et al 1980, Gahl et al 1998, Hussain et al 2006].
Neutropenia. Neutropenia and/or additional immune defects (e.g., impaired NK cell cytotoxicity) 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, Mohammed et al 2019].
Other. Other features have been reported rarely in individuals with HPS, including cardiomyopathy and renal failure [Gahl et al 1998], thrombocytopenia and leukemia [Badolato et al 2012, Okamura et al 2018], or neurologic involvement [Okamura et al 2018, Michaud et al 2021].
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)
Individuals with pathogenic variants in AP3B1 or AP3D1 exhibit immunodeficiency. They have an increased susceptibility to infections due to congenital neutropenia and impaired NK cell cytotoxicity. In vitro evidence suggests that the neutropenia is caused by mislocalization of granule proteins in neutrophils [de Boer et al 2017].
Some individuals with AP3D1-related HPS exhibited additional features not commonly seen in individuals with AP3B1-related HPS, including neurodevelopmental delay, seizures, or impaired hearing [Ammann et al 2016, Mohammed et al 2019, Frohne et al 2022]. It is not clear if these features are related to AP-3 complex subunit delta-1 deficiency.
BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1 (BLOC-1 Deficiency)
Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism, a bleeding diathesis, and colitis.
BLOC-1-deficient individuals appear to have a silver/blond/gold hair color at birth that may turn darker with age [Lowe et al 2013, Pennamen et al 2020]. No pulmonary defects have been reported in these individuals.
Some individuals exhibited additional features that should be monitored in other affected individuals. A female of northern European descent with DTNBP1-related HPS exhibited granulomatous colitis [Lowe et al 2013], a Portuguese female with DTNBP1-related HPS had recurrent bacterial infections with slightly reduced NK degranulation [Boeckelmann et al 2022]. Of the five reported individuals with BLOC1S6-related HPS, an Italian and a Japanese female had thrombocytopenia and leukemia [Badolato et al 2012, Okamura et al 2018], the Japanese female developed schizophrenia in her late 40s [Okamura et al 2018], a Chinese boy had abnormal brain waves by electroencephalogram [Liu et al 2021], and a Syrian girl had recurrent infections, abnormal psychomotor development, and dextrocardia [Michaud et al 2021].
HPS3, HPS5, HPS6 (BLOC-2 Deficiency)
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 fibrosis 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)
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 potentially lethal pulmonary fibrosis, a progressive restrictive lung disease. Individuals typically become symptomatic in their 30s and may die within a decade, unless transplanted [Gochuico et al 2012, Velázquez-Díaz et al 2021, Yokoyama & Gochuico 2021, Benvenuto et al 2022].
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 one to nine in 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 [Santiago Borrero et al 2006].
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 g.339_4260del3904 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, the Middle East, South America, and Western and Eastern Europe.