STUDY Dermatologic Manifestations of Hermansky-Pudlak Syndrome in Patients With and Without a 16–Base Pair Duplication in the HPS1 Gene Jorge Toro, MD; Maria Turner, MD; William A. Gahl, MD, PhD Background: Hermansky-Pudlak syndrome (HPS) con- without the duplication were non–Puerto Rican except sists of oculocutaneous albinism, a platelet storage pool de- 4 from central Puerto Rico. ficiency, and lysosomal accumulation of ceroid lipofuscin. Patients with HPS from northwest Puerto Rico are homozy- Results: Both patients homozygous for the 16-bp du- gous for a 16–base pair (bp) duplication in exon 15 of HPS1, plication and patients without the duplication dis- a gene on chromosome 10q23 known to cause the disorder. played skin color ranging from white to light brown. Pa- tients with the duplication, as well as those lacking the Objective: To determine the dermatologic findings of duplication, had hair color ranging from white to brown patients with HPS. and eye color ranging from blue to brown. New findings in both groups of patients with HPS were melanocytic Design: Survey of inpatients with HPS by physical ex- nevi with dysplastic features, acanthosis nigricans–like amination. lesions in the axilla and neck, and trichomegaly. Eighty percent of patients with the duplication exhibited fea- Setting: National Institutes of Health Clinical Center, tures of solar damage, including multiple freckles, stel- Bethesda, Md (a tertiary referral hospital). late lentigines, actinic keratoses, and, occasionally, basal cell or squamous cell carcinomas. Only 8% of patients Patients: Sixty-five patients aged 3 to 54 years were di- lacking the 16-bp duplication displayed these findings. agnosed on the basis of the absence of platelet dense bod- As a group, the patients with the duplication lived closer ies in individuals with albinism and a bleeding diathe- to the equator than those without the duplication. sis. The presence of a 16-bp duplication in HPS1 was determined by polymerase chain reaction amplifica- Conclusion: Patients with HPS exhibit wide variation tion; 40 patients were homozygous for the duplication in pigmentation and dermatologic findings. and 25 lacked the duplication. All patients with the du- plication were from northwest Puerto Rico; all patients Arch Dermatol. 1999;135:774-780 ERMANSKY-PUDLAK syn- procedures. The accumulation of ceroid li- drome (HPS), an autoso- pofuscin is associated with primary pul- mal recessive disorder, monary fibrosis in a large number of pa- consists of oculocutane- tients and with granulomatous colitis in ous albinism, a platelet 10% to 20% of patients.5-7 The pulmonary storage pool deficiency, and lysosomal ac- fibrosis usually proves fatal by the fourth H 1-3 8,9 cumulation of ceroid lipofuscin. The ocu- or fifth decade. locutaneous albinism results in variable pig- Hermansky-Pudlak syndrome oc- ment dilution, congenital nystagmus, a curs with a high frequency in northwest visual acuity approximating 20/200, and Puerto Rico, where 1 in 21 individuals is marked iris transillumination in the ma- a carrier and more than 400 people are af- From the Dermatology Branch, jority of patients. The storage pool defi- fected because of an apparent founder ef- National Cancer Institute ciency and lack of a secondary platelet ag- fect.10 Recent studies have uncovered an (Drs Toro and Turner), and gregation response arise from the absence HPS-causing gene on chromosome Section on Human Biochemical of platelet dense bodies, diagnosable on wet- 10q23,11 and subsequent cloning of that Genetics, Heritable Disorders 4 12 Branch, National Institute of mount electron microscopy. Patients with gene, now called HPS1, demonstrated a Child Health and Human HPS generally exhibit easy bruising and epi- coding sequence containing 2100 base 13 Development (Dr Gahl), staxis in childhood, excessive menstrual and pairs (bp) composed of 20 exons. HPS1 National Institutes of Health, postpartum bleeding, and prolonged bleed- is predicted to produce a protein with a Bethesda, Md. ing during dental extraction and surgical molecular weight of 79.3 kd. Although the ARCH DERMATOL / VOL 135, JULY 1999 774 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS AND METHODS uniform dark-brown to black stellate macules smaller than 1 cm on sun-exposed areas.25 Freckles were small (,5 mm), PATIENTS light-brown to medium-brown round macules with even pigmentation on sun-exposed areas.25 Dysplastic nevi were All patients were admitted to the National Institutes of Health defined as irregularly contoured, pigmented papules with Clinical Center, Bethesda, Md, and were enrolled in an in- a diameter greater than 5 mm, a macular component, and stitutional review board–approved study on the clinical and variation in color.25 Cutis rhomboidalis nuchae was defined molecular characteristics of HPS. Forty-nine of the patients as thickening and furrowing of the skin of the nape of the were included in a previous publication comparing groups neck in a rhomboidal pattern.25 Solar elastolytic bands of of patients with HPS with and without the 16-bp duplica- the forearms were cordlike plaques across the surface of tion.7 Informed consent was obtained from all patients or the forearms.26 All squamous cell carcinomas and basal cell their parents. The diagnosis of HPS was based on the find- carcinomas were histologically confirmed. A total of 15 me- ing of oculocutaneous albinism, a history of increased bruis- lanocytic nevi and 2 dysplastic nevi had histological veri- ing, and either absence of platelet dense bodies docu- fication. mented by electron microscopy4 or the presence of a 16-bp duplication in exon 15 of the HPS1 gene, documented by MOLECULAR ANALYSIS molecular analysis.7,13 Twenty-one non–Puerto Ricans from the mainland United States and 44 Puerto Rican patients rang- DNA was extracted from peripheral blood leukocytes of each ing in age from 3 to 54 years were examined between No- patient, and the presence of the 16-bp duplication in exon vember 1, 1995, and March 31, 1998. The 40 patients (21 15 of the HPS1 gene was analyzed by polymerase chain re- females and 19 males) homozygous for the 16-bp duplica- action amplification, as previously described.7,13 Patients tion were older than the 25 patients (14 females and 11 males) with the duplication gave a 285-bp fragment, with normal without the 16-bp duplication (mean ± SD, 30 ± 14 vs 24 ± 10 DNA yielding a 269-bp fragment. For patients lacking the years; P = .05). All patients underwent a complete skin ex- duplication, single-strand conformational polymorphism amination, and all were photographed. A skin biopsy was analysis was performed, followed by sequencing of suspi- performed when clinically indicated. cious exons, as described.18 DERMATOLOGIC LESIONS STATISTICAL ANALYSES The degree of skin pigmentation was defined according to Student t test and the x2 distribution, with P values, were the Fitzpatrick classification.24 Lentigines were defined as used to analyze the data.27 14 genomic structure of HPS1 has been described, the func- RESULTS tion of the gene product remains unknown. In the origi- nal report on HPS1,13 all 22 Puerto Rican patients with HPS proved homozygous for a 16-bp duplication in exon MOLECULAR STUDIES 15; this mutation has subsequently been shown to be as- sociated with a significantly increased risk of restrictive Of 65 patients with HPS admitted to the National Insti- lung disease and pulmonary fibrosis.7 Oh et al13 de- tutes of Health, 40 were homozygous for the 16-bp du- scribed a homozygous single base pair insertion in codon plication in exon 15 of HPS1. All of these patients had Pro324 of 1 Irish patient and of 6 members of a Swiss immediate ancestry in northwest Puerto Rico. Twenty- genetic isolate15,16; they also reported a homozygous single five patients exhibited no allele bearing the 16-bp dupli- base pair duplication in codon Ala441 of a Japanese pa- cation; only 4 of these had Puerto Rican heritage, and they tient. Six other mutations have recently been described, were from the center of the island.21 Four non–Puerto but approximately two thirds of patients with bona fide Rican patients displayed a mutation in HPS1 different from HPS do not have an identifiable mutation in the HPS1 the 16-bp duplication.18 One patient carried a T322insC gene.17,18 mutation, leading to termination at codon 452, and the Several strains of mice have both pigment dilution nonsense mutation E133X. Two affected siblings exhib- and a platelet storage pool deficiency and serve as mod- ited an S396delC mutation, resulting in termination at els for HPS in humans.19,20 One mutant, called pale ear, codon 398, and a T322delC mutation, causing termina- has been mapped to mouse chromosome 19 in a region tion at codon 330. One of these patients was either ho- of conserved synteny with human chromosome 10q23, mozygous or heterozygous for the S396 mutation.18 In the location of HPS1.21 Pale ear is homologous to the hu- the remaining 21 patients, no mutation was found in the man gene.22,23 HPS1 gene. The dermatologic manifestations of HPS have not been extensively documented, nor has correlation be- GENERAL DERMATOLOGIC FEATURES tween genotype and phenotype been attempted. In this article, we describe the array of skin findings that char- The Puerto Rican patients homozygous for the 16-bp du- acterizes HPS, and we compare the dermatologic find- plication exhibited hair color ranging from white to light ings in patients with and without the 16-bp duplication brown; 50% were blond. In contrast, only 28% of pa- in HPS1. tients lacking the 16-bp duplication were blond, and 40% ARCH DERMATOL / VOL 135, JULY 1999 775 ©1999 American Medical Association. All rights reserved.