To the Editor:
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic condition characterized by oculocutaneous albinism, bleeding diathesis caused by platelet dysfunction, nystagmus, colitis, and other manifestations.1 The disease is associated with genetic mutations that cause defects in the function of lysosome-related organelles and the abnormal cellular trafficking of selected proteins.2 Eleven genetic mutations have been described (HPS-1, HPS-2, HPS-3, etc.), of which at least 3 mutations have been associated with lung involvement (HPS-1, HPS-2, and HPS-4). HPS-1, a severe form of HPS, is associated almost invariably with pulmonary fibrosis that often progresses to respiratory failure at a relatively young age.3 Some HPS mutations are associated with neurologic defects, chronic renal failure, and immunodeficiency.4 HPS is believed to affect 1 to 9 of 500,000 to 1,000,000 individuals worldwide,1 but the condition is most prevalent in the Caribbean Island of Puerto Rico where its prevalence has been estimated at 1 in 1,820 individuals. HPS-1 is the most common mutation in Puerto Rico, but HPS-3 is also prevalent.5
Formal HPS national registries are not available; therefore, the incidence and prevalence of HPS in most countries including the United States, the demographics of those people affected, and the impact of the condition on health care systems around the world are unknown.
Methods
To characterize the prevalence and comorbidities of HPS in the United States, we analyzed the TriNetX and EPIC Cosmos databases searching for patients with an HPS diagnosis based on International Classification of Diseases (ICD-10) codes (ICD-10 E70.331). The TriNetX database contains data from 116,090,587 patients who were identified within more than 120 organizations6; we limited the investigation to health care organizations within the United States. The EPIC Cosmos database includes more than 250,000,000 patients from more than 250 participating institutions.7 The search included data collected between June 13, 2019, and June 12, 2024. Cohorts were identified with the use of ICD-10, RxNorm, TriNetX-curated, and LOINC codes to identify patients with HPS, medications, and comorbidities. The work did not require institution review board approval.
Results
The EPIC Cosmos database contained 787 patients with HPS diagnosis, which suggests a prevalence of 2.9 affected individuals per 1,000,000 people. The average age was 35 years; 59% of the patients were female (Table 1). Sixty-three percent of patients were between the ages of 18 and 65 years; 25.6% of them were 18 years or younger, and 11.9% of them were 65 years or older. Sixty-eight percent of patients with HPS were White, followed by Black patients (6%), Asian patients (4%), and Native American patients (2%). Forty-five percent of the patients were Hispanic; 15.6% of the patients did not list ethnicity. Consistent with the diagnosis of HPS, a significant percentage of patients had a diagnosis of albinism (26.9%; 18.6% with oculocutaneous albinism), qualitative platelet defects (26.3%), unspecified abdominal pain (26.6%) and diarrhea (16%), and nystagmus (20.1%) and legal blindness (16.6%) (Table 2). Respiratory conditions and symptoms were also common and included shortness of breath (24.9%), cough (24.7%), asthma (19.7%), and upper respiratory infection (18.3%). Additionally, gastroesophageal reflux disease, hypertension, hyperlipidemia, anemia, obesity, and vitamin D deficiency were prevalent. Anxiety disorders, chronic pain, and fatigue affected 10% to 22% of patients with HPS. The incidence and prevalence of unspecified pulmonary fibrosis (codified as J84.10) in patients with HPS ranged from 5.24% to 14.9%, respectively, but higher percentages of patients had respiratory symptoms of cough and shortness of breath (approximately 24%); approximately 3% of patients were prescribed the antifibrotic pirfenidone, with very few patients prescribed nintedanib. Most patients with HPS were in states on the East Coast of the United States, which included Florida, Pennsylvania, New York, Connecticut, Massachusetts, North Carolina, and New Jersey. Texas, Ohio, and Illinois also had a significant percentage of patients with HPS. The geographic distribution of patients with HPS was different to that of the overall population, which was suggested by results of chi-squared test of independence (X2 = 559.3; degrees of freedom = 14; P < 2.2 × 10-16). Note that the evaluation of the TriNetX database revealed nearly identical findings (Tables 1, 2).
Table 1.
Prevalence of Hermansky-Pudlak Syndrome in the United States Based on TrinetX and EPIC Cosmos Databases
| Variable | Database |
|
|---|---|---|
| TriNetX | EPIC Cosmos | |
| General | ||
| No. | 379 | 787 |
| Prevalence, per 1 million | 3 | 3 |
| Age, mean ± SE, y | 33 ± 22.1 | 35 ± 22 |
| Sex | ||
| Female | 213 (56.2) | 464 (59) |
| Male | 156 (41.2) | 323 (41) |
| Race | ||
| White | 185 (48.8) | 538 (68.3) |
| Black | 17 (4.5) | 49 (6.2) |
| Asian | 14 (3.7) | 29 (3.7) |
| Other races | 51 (13.5) | 267 (33.9) |
| Unknown | 104 (27.4) | 43 (5.4) |
| Ethnicity | ||
| Hispanic | 139 (36.7) | 356 (45.2) |
| Non-Hispanic | 161 (42.5) | 332 (42.2) |
| Unlisted | 74 (19.5) | 99 (15.6) |
| Antifibrotics | ||
| Pirfenidone | ≤ 10 (2.7) | 19 (2.5) |
| Nintedanib | … | < 10 (1.3) |
Data are presented as No. (%) unless otherwise indicated.
Table 2.
Comorbidities in Persons With Hermansky-Pudlak Syndrome Who Were Identified in in TrinetX and EPIC Cosmos Databases
| Condition | Database |
|
|---|---|---|
| TriNetX | EPIC Cosmos | |
| GI | ||
| Gastroesophageal reflux disease | 88 (23.2) | 225 (28.6) |
| Abdominal pain | 76 (20.0) | 209 (26.6) |
| Constipation | 64 (16.9) | 135 (17.2) |
| Colitis | 48 (12.7) | < 10 (1.3) |
| GI bleeding | 19 (5.0) | 34 (4.3) |
| Diarrhea | 54 (14.2) | 126 (16.0) |
| Skin | ||
| Albinism | 123 (32.4) | 212 (26.9) |
| Oculocutaneous albinism | 69 (18.2) | 146 (18.6) |
| Ocular | ||
| Nystagmus | 106 (28.0) | 158 (20.1) |
| Legal blindness | 35 (9.2) | 131 (16.6) |
| Hematology | ||
| Anemia | 65 (17.2) | 185 (23.5) |
| Platelet defects | 101 (26.6) | 207 (26.3) |
| Respiratory | ||
| Cough | 49 (12.9) | 194 (24.7) |
| Shortness of breath | 68 (17.9) | 196 (24.9) |
| Asthma | 67 (17.7) | 155 (19.7) |
| Acute upper respiratory infection | 59 (15.6) | 144 (18.3) |
| Fatigue | 59 (17.6) | 124 (15.8) |
| Cardiovascular/ metabolic | ||
| Hypertension | 75 (19.8) | 190 (24.1) |
| Hyperlipidemia | 44 (11.6) | 135 (17.2) |
| Obesity | 50 (13.2) | 133 (16.9) |
| Vitamin D deficiency | 45 (11.9) | 128 (16.2) |
| Other | ||
| Headache | 33 (8.7) | 145 (18.4) |
| Anxiety | 49 (12.9) | 171 (21.7) |
| Chronic pain | 40 (10.6) | 123 (15.6) |
Data are presented as No. (%) unless otherwise indicated.
Discussion
To our knowledge, this work represents the first attempt at evaluation of the epidemiology, demographic data, and health care factors in individuals with a diagnosis of HPS in the United States. Several important observations were made. First, as expected, most patients were less than 65 years old, and many had conditions consistent with the well-known characteristics of HPS. Second, the prevalence of HPS in the US population appears to be similar to that ascribed globally (1 to 9 per 1,000,000 people)1,4; a higher proportion of female patients are affected, which is an intriguing finding considering that there is no known sex predominance of the condition. Third, most patients were self-described as White or Hispanic, while 4% to 6% were self-described as Black. HPS has been described in Black individuals8; the prevalence of oculocutaneous albinism is relatively high in some populations in Africa. However, the prevalence of HPS in those populations is not clear. We also observed that HPS may be overrepresented in certain groups, such as Native American individuals, which suggests the potential presence of an undescribed “founder” mutation.
The prevalence of asthma in the HPS population that was identified was approximately 20%, which is relatively high and points to the possible contribution of Hispanic patients, especially Puerto Rican patients, who have a high prevalence of asthma.9 We were also intrigued to learn about the prevalence of anxiety disorder and chronic pain, which indicates a significant psychologic burden of the disease and suggests that HPS may also impact musculoskeletal and nervous systems, which frequently contribute to chronic pain.10 Finally, we observed that most patients with HPS reside in states located on the East Coast of the United States, followed by Texas, Ohio, and Illinois, which aligns with the number of Puerto Rican patients living in those areas.
This study has limitations that reflect the nature of working with national databases. Possible inaccuracies in the diagnosis, double counting of patients (relevant only to TriNetX), possible patient overlap between the TriNetX and EPIC Cosmos databases, the identification of comorbidities, lack of data on specific mutations, and limited information about socioeconomic and other factors are important limitations. Despite this, the analysis allowed for a better understanding of the prevalence and distribution of patients with HPS in the United States and their comorbidities and provided a window into the potential impact of the condition on state and federal health-care systems.
Financial/Nonfinancial Disclosures
None declared.
Acknowledgments
Other contributions: The authors thank Michael Li, PhD, Director of Data Sciences at Jefferson Health, for reviewing the manuscript and corroborating the analysis. The authors also want to acknowledge the efforts of the HPS Network for their unwavering efforts to improve awareness of the condition, for promoting research, and for assisting patients with HPS with health care decisions.
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