Dermatologic Manifestations of Hermansky-Pudlak Syndrome in Patients with and Without a 16–Base Pair Duplication in the HPS1 Gene

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 duplication 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

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©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 (Ͻ5 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 ␹2 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 associated 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%

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Dermatologic Findings in Patients With HPS With and Without the 16–Base Pair Duplication in HPS1*

No. (%)†

Duplication Nonduplication (n = 40) (n = 25) P Hair color White with or without 10 (25) 8 (32) yellow tinge Blond 20 (50) 7 (28) .02 Brown 5 (12) 10 (40) Gray 5 (12) 0 Figure 1. Trichomegaly of eyelashes and bushy eyebrows in a 9-year-old boy Eye color homozygous for the 16–base pair duplication. (Reprinted in part with 7 Blue 29 (72) 14 (56) permission from Gahl et al. Copyright ஽1998 Massachusetts Medical Society. All rights reserved.) Hazel 10 (25) 3 (12) .003 Brown 1 (2) 8 (32) Fitzpatrick skin type I 40 (100) 19 (76) .002 Nevi Type None 7 (18) 2 (8) Regular 31 (78) 16 (64) .03 Atypical 2 (5) 7 (28) No. 1-10 26 (65) 10 (40) .008 Ͼ10 7 (18) 13 (52) Freckles 32 (80) 2 (8) Ͻ.001 Lentigines 31 (78) 2 (8) Ͻ.001 Severe sun damage 26 (65) 1 (4) Ͻ.001 Solar keratoses 20 (50) 0 Ͻ.001 Basal cell carcinoma 3 (8) 0 .15 Squamous cell carcinoma 3 (8) 0 .15 Acanthosis nigricans 11 (28) 8 (32) .24 Hypertrichosis-trichomegaly 28 (70) 9 (36) Ͻ.001 Bruising 33 (83) 23 (92) .47

*HPS indicates Hermansky-Pudlak syndrome. †Because of rounding, percentages may not all total 100.

had brown hair (Table 1). Two patients with the 16-bp duplication exhibited a reddish brown hair color. Eye color in the patients with HPS ranged from blue to brown, with Figure 2. Ecchymoses at different stages of development on the legs of a 73% of the patients with the duplication and 56% of those 4-year-old boy homozygous for the 16–base pair duplication. without it having blue irises. All of the patients with the duplication displayed light skin color, but 5 patients without the duplication (20%) had skin with pigmentation similar to that of other family members. By history, hair and skin pigmentation increased as patients aged. Sev- enty percent of patients with the duplication and 36% of those without it had hypertrichosis of the eyelashes and trichomegaly of the arms and legs (Figure 1). A history of prolonged bleeding and bruising was present in patients with and without the 16-bp duplication. Mul- tiple bruises were present in 86% of all the patients with HPS examined, whether or not they carried the 16-bp duplication. An illustrative patient with ecchymoses in different stages of development is shown in Figure 2. Twenty-nine percent of all our patients with HPS had ac- Figure 3. Acanthosis nigricans–like lesion in the axilla of an adult patient anthosis nigricans–like lesions (without pigment) on their bearing the duplication in Hermansky-Pudlak syndrome. necks and axillae (Figure 3). These patients lacked a history of diabetes, hyperandrogenemia, or intake of nico- tinic acid or triazinate. Serum glucose level was within PIGMENTED LESIONS normal limits, and luteinizing hormone, follicle- stimulating hormone, and testosterone levels were nor- Melanocytic nevi were present in 33 (83%) of the 40 pa- mal in all cases. tients with the duplication and in 23 (92%) of the 25 pa-

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C D

1 mm

Figure 4. Melanocytic lesions in Hermansky-Pudlak syndrome. A, Nevus with a pink hue. B, Intradermal nevus. C and D, Pigmented nevi with dysplastic features.

tients without the duplication. Affected individuals had a variety of melanocytic nevi with different degrees of pigmentation, from skin colored to pink to black (Figure 4). Junctional, compound, intradermal, and halo nevi were found. Two patients with the duplication (5%) and 7 without it (28%) had atypical nevi, defined clinically as those with dysplastic features. Both groups of patients with HPS had multiple melanocytic lesions, and 1 patient in the duplication group and 1 in the nonduplication group had more than 50 lesions.

SOLAR DAMAGE

Every patient with sun-damaged skin manifested freck- Figure 5. Three of the most common features of severe sun damage in a les and lentigines. Freckles and stellate black lentigines Puerto Rican patient with Hermansky-Pudlak syndrome, ie, freckles (double were present in 80% of patients bearing the 16-bp arrow), stellate lentigines (thick arrow), and solar keratoses (thin arrow). duplication, although the children examined (Ͻ18 years old) had not yet demonstrated this feature. Only 2 patients in the nonduplication group displayed these observed in 15 patients with the duplication (38%). So- findings (Table 1). Six pairs of siblings with the 16-bp lar elastolytic bands of the forearms were found in 10 pa- duplication and 5 pairs of siblings without it exhibited tients with the duplication (25%). concordance for the presence of freckles, lentigines, and Multiple solar keratoses were present in 20 (50%) nevi. of 40 Puerto Rican patients with HPS bearing the 16-bp Cutaneous manifestations of chronic and severe sun duplication. Squamous cell carcinoma and basal cell car- exposure (Figure 5) were present in approximately two cinoma were each present in 3 patients in the duplica- thirds of the patients with the 16-bp duplication but were tion group. absent from patients without the 16-bp duplication. Sun- Could some of the findings related to solar damage exposed areas, including the face, nuchae, arms, and an- have been worse in the 16-bp duplication group be- terior part of the neck, showed wrinkling and furrow- cause this group was, on average, older than the nondu- ing. Telangiectasias were also present, and the distribution plication group? To investigate this possibility, we ana- of pigment was irregular. Cutis rhomboidalis nuchae was lyzed the findings related to solar damage separately in

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 2. Dermatologic Findings in Adult Patients With HPS A With and Without the 16–Base Pair Duplication in HPS1*

No. (%)

Duplication Nonduplication (n = 33) (n = 12) P Nevi 26 (79) 12 (100) .16 Freckles 30 (91) 2 (17) Ͻ.001 Lentigines 30 (91) 2 (17) Ͻ.001 Severe sun damage 24 (73) 1 (8) Ͻ.001 Solar keratoses 22 (67) 0 Ͻ.001 Basal cell carcinoma 3 (9) 0 .55 Squamous cell carcinoma 3 (9) 0 .55

*HPS indicates Hermansky-Pudlak syndrome. B

all the adults with HPS (Table 2). The 33 adults with the 16-bp duplication had a mean ± SD age (35.9 ± 11.4 years) similar to that of the 12 adult patients with HPS without the 16-bp duplication (35.4 ± 8.6 years; P = .94). Even in this comparably aged group, the patients with the duplication had significantly more signs of solar damage, including freckles, lentigines, and solar keratoses (Table 2).

OPHTHALMOLOGIC FEATURES

All 65 patients with HPS examined had decreased visual C acuity, photophobia, horizontal nystagmus, and some degree of iris hypopigmentation. Iris pigment correlated poorly with skin and hair pigment. Two Puerto Rican patients without the 16-bp duplication showed negligible to moderate transillumination,28 but patients with the duplication showed marked iris transillumination. Ex- amples of hair, skin, iris, and fundus pigmentation are shown in Figure 6.

COMMENT Although the basic defect in HPS remains unknown, it is recognized that HPS melanocytes contain many mor- phologically normal melanosomes up to stage III. The Figure 6. Pigmentation in a Puerto Rican patient homozygous for the 16–base pair duplication. A, White hair, brows, and lashes. B, Iris HPS melanosomes are unusual in that they are spherical transillumination (orange). Dark areas represent normal pigment rather than oval and contain disorganized matrix in the iris, obstructing passage of light. C, Pale areas of the fundus fibers.29 Although giant melanosomes have been indicating hypopigmentation (iris and fundus photographs courtesy of reported by 1 group,30 they were not found by several Muriel I. Kaiser-Kupfer, MD, National Eye Institute, Bethesda, Md). other investigators,31,32 nor were they present in 8 cases we examined by electron microscopy (data not shown). mentation. The HPS1 gene product itself has no known Albinism associated with HPS is considered to be tyrosi- function, but it contains 2 putative transmembrane do- nase positive, based on a positive reaction (melanin pro- mains and a presumed melanosomal localization signal. duction) when hair bulbs are incubated with tyrosine or It is located within the cytoplasm of nonmelanotic cells dopamine.30 and within the granular fraction of melanotic cells. HPS1 Clinically, the dermatologic features of HPS are ex- also has a small block of homology to the Che´diak- tremely variable. Patients exhibit different degrees of cu- Higashi gene product.13 Che´diak-Higashi disease is an- taneous and ocular pigmentation, ranging from nearly other hypopigmentation–platelet store pool deficiency none to almost normal. This phenotypic variability oc- characterized by giant lysosomes and a susceptibility to curs even within a group of patients with HPS that is en- infection.2,3 The molecular characteristics of HPS1, as well tirely homogeneous with respect to the HPS-causing gene. as the multiorganellar involvement in HPS, suggest that This finding reflects the enormously complicated path- the HPS1 gene product is integrally involved in the traf- way that leads to melanin production. Clearly, many genes ficking of melanosomes, platelet dense bodies, and ly- besides HPS1 contribute to the ultimate extent of pig- sosomes.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Our patients homozygous for the 16-bp duplica- They noted that UV-B induced histological changes, such tion manifested some dermatologic signs previously re- as epidermal thickening, dermal inflammation, and elas- ported in Puerto Rican patients with HPS. For example, tic tissue changes. These histological changes were sig- Witkop et al10 found that 100 (49%) of 203 patients with nificantly reduced by UV-B sunscreen alone and further HPS aged 10 years and older had solar keratoses; we found diminished by UV-A/UV-B sunscreen. A similar study in 20 (50%) of 40 patients with solar keratoses (Table 1). humans39 found that UV-A/UV-B sunscreen was effec- Like Witkop et al, we found a small percentage of squa- tive in diminishing solar elastosis in human skin. This mous cell and basal cell carcinomas. Witkop et al re- finding suggests a beneficial effect of sunscreen in the pro- ported that more than 80% of patients with HPS older phylaxis and reversal of photodamage in patients with than 10 years had freckles or lentigines; we described simi- HPS. However, it is unclear whether humans demon- lar findings in this group of Puerto Rican patients. How- strate the same extent of repair seen in mice. ever, we also expanded the dermatologic findings of Pu- Many of our patients (37 of 65) had hypertrichosis erto Rican patients with HPS, since we found a very high and trichomegaly. Hypertrichosis occurs in porphyria, frequency of nevi among individuals homozygous for the acromegaly, Cushing disease, Stein-Leventhal syn- 16-bp duplication. Furthermore, we report new find- drome, and tumors of adrenal, testicular, and ovarian ori- ings seen in both groups of patients with HPS, such as a gin. However, none of our patients had clinical features significant frequency of acanthosis nigricans–like le- suggestive of these disorders. We also found that 56 of sions, hypertrichosis or trichomegaly, and dysplastic nevi. 65 patients with HPS had regular or dysplastic nevi. This Our group of patients without the 16-bp duplica- high frequency is not characteristic of tyrosinase- tion arose from a wide variety of ethnic backgrounds and negative oculocutaneous albinism, in which pigmented regions. Twenty-one of the 25 had no detectable muta- nevi40,41 and dysplastic nevus syndrome with amela- tion anywhere in the HPS gene. Hence, this syndrome is notic melanoma42 have been described only rarely. How- expected to be a molecularly heterogeneous one, con- ever, it is not unusual for tyrosinase-positive oculocuta- sistent with the many genetically distinct mouse models neous albinism. The reason for this difference remains displaying both pigment dilution and platelet storage pool unknown. deficiency.19,20 Several issues related to the dermatologic findings in As a group, the nonduplication group of patients with HPS pertain to the welfare of affected children. First, most HPS displayed the same variability in cutaneous and ocu- children with HPS exhibit excessive bruises when they be- lar pigment as the duplication group, and a similar fre- gin walking. This bruising can be mistaken for child abuse, quency of nevi. However, freckles and lentigines, solar so the correct and early diagnosis of HPS is essential. In keratoses, and squamous cell carcinomas were rare or ab- northwest Puerto Rican patients, the diagnosis of HPS can sent in the nonduplication group (Table 1). This differ- be made molecularly, based on the presence of the 16-bp ence in solar damage between the duplication and nonduplication. However, in patients lacking this mutation, the duplication groups was maintained when only adult diagnosis is made by electron microscopy showing ab- patients (with equivalent mean ages) were analyzed (Table sence of platelet dense bodies, or by platelet studies show- 2), so it was not simply an age effect. However, the dif- ing absence of a secondary aggregation response in a hy- ferences may be partly attributed to the less intense ul- popigmented individual. Another reason to make the traviolet radiation to which patients from the mainland diagnosis of HPS early is to initiate avoidance of aspirin- United States (ie, nonduplication group) were sub- like products and prophylactic use of desmopressin to jected in comparison with the patients in the duplica- shorten the bleeding time,43 thus reducing the likelihood tion group, most of whom were exposed to tropical ul- of severe bleeding episodes. In cases of emergency trauma traviolet radiation on a daily basis. Four Puerto Rican or surgery, families and physicians should be aware of the patients lacked the 16-bp duplication and did not show platelet aggregation defect, and medical alert bracelets can manifestations of severe solar damage. Two of these in- be beneficial. Children are at particular risk of nonmela- dividuals, aged 4 and 47 years,28 had resided in Phila- noma skin cancer, since sun exposure during childhood delphia, Pa, and New York, NY, for all or most of their accounts for an estimated 80% of total lifetime expo- lives and did not have the same degree of sun exposure sure.44 Early sun protection will prevent the future devel- as the island residents. However, 2 other patients, aged opment of premalignant and malignant skin cancer and will 41 and 42 years, resided in Puerto Rico and had only mild protect against the occurrence of severe photoaging. In ad- lentigines and freckles. dition to prompting surveillance for dermatologic compli- The use of sunscreens to prevent33-36 or dimin- cations, the early diagnosis of HPS encourages patients to ish37,38 photodamage in animal models has been re- avoid cigarettes and other lung irritants, which could has- ported.33-36 Kligman et al37 irradiated hairless albino mice ten deterioration of pulmonary function. Finally, chil- with sunlamps emitting both UV-A and UV-B light and dren with HPS have decreased visual acuity, which can im- then applied sun protection factor 15 and sun protec- pede learning, so parents and teachers should be informed tion factor 2 sunscreen to different groups of animals. about the availability of aids for the visually impaired. Repair of collagen degeneration, glycosaminoglycan depo- Future research into HPS will undoubtedly make use sition, and solar elastosis were found with sunscreen use of mouse models of this disorder.20 Clearly, the cloning and were noted to occur to a greater extent with the prod- of the murine genes responsible for these HPS pheno- uct that had the higher sun protection factor. In addi- copies will facilitate isolation of more human genes caus- tion, Harrison et al36 irradiated hairless albino mice with ing the disease. Currently, ep (for pale ear) is recog- UV-A and UV-A/UV-B after applying sunscreen agents. nized as the mouse homolog of HPS, and the pale ear

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 mouse can serve as a model for pathologic and thera- 18. Shotelersuk V, Larson D, Hazelwood S, et al. Three new mutations in a gene caus- peutic studies of the complications of HPS, including der- ing Hermansky-Pudlak syndrome: clinical correlations. Mol Gen Metab. 1998; 64:99-107. matologic involvement. Another example is pearl, whose 19. Jackson IJ. Homologous pigmentation mutations in human, mouse and other gene has been identified as the b3A subunit of adaptor model organisms. Hum Mol Genet. 1997;6:1613-1624. complex-345 and whose human counterpart has been re- 20. Swank RT, Novak EK, McGarry MP, Rusiniak ME, Feng L. Mouse models of Her- cently identified.46 mansky-Pudlak syndrome: a review. Pigment Cell Res. 1998;11:60-80. 21. Novak EK, Hui S-W, Swank RT. The mouse pale ear pigment mutant as a pos- sible animal model for human platelet storage pool deficiency. Blood. 1981;57: Accepted for publication January 15, 1999. 38-43. Presented at the annual meeting of the Society for Pe- 22. Gardner JM, Wildenberg SC, Keiper NM, et al. The mouse pale ear (ep) mutation diatric Dermatology, Orlando, Fla, February 26, 1998. is the homologue of human Hermansky-Pudlak syndrome. Proc Natl Acad Sci We appreciate the excellent ophthalmologic care pro- USA. 1997;94:9238-9243. 23. Feng GH, Bailin T, Oh J, Spritz RA. Mouse pale ear (ep) is homologous to human vided by Muriel I. Kaiser-Kupfer, MD, and Fumino Iwata, Hermansky-Pudlak syndrome and contains a rare “AT-AC” intron. Hum Mol Genet. MD, and the superb ophthalmic photography of Ernest Kuehl 1997;6:793-979. of the National Eye Institute, Bethesda, Md. We also thank 24. Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF. Dermatology in Gen- Vorasuk Shotelersuk, MD, and Senator Hazelwood for per- eral Medicine. 4th ed. New York, NY: McGraw-Hill International Book Co; 1993: 1694. forming mutation analysis on many of the patients. Jim- 25. Lever WF, Schaumberg-Lever G. Degenerative diseases. In: Lever WF, Schaumberg- ping Lin, MD, provided the statistical analysis. Lever G, eds. Histopathology of the Skin. Philadelphia, Pa: JB Lippincott Co; 1990: Reprints: Maria Turner, MD, Dermatology Branch, Na- 298-317. tional Cancer Institute, Bldg 10, Room 12N-238, 10 Cen- 26. Raimer SS, Sanchez RL, Hubler WR Jr, et al. Solar elastotic bands of the fore- ter Dr, MSC 1908, Bethesda, MD 20892-1908 (e-mail: arm: an unusual clinical presentation of actinic keratosis. J Am Acad Dermatol. 1986;15:650-656. [email protected]). 27. Rosner B. Fundamentals of Biostatistics. 2nd ed. Boston, Mass: Duxbury Press; 1986. REFERENCES 28. Hazelwood S, Shotelersuk V, Wildenberg SC, et al. Evidence for locus hetero- geneity in Puerto Ricans with Hermansky-Pudlak syndrome. Am J Hum Genet. 1997;61:1088-1094. 1. Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and un- 29. Orlow SJ. Congenital and genetic disorders associated with hypopigmentation. usual pigmented reticular cells in the bone marrow: report of two cases with his- Curr Probl Dermatol. 1994;6:157-184. tochemical studies. Blood. 1959;14:162-169. 30. Frenk E, Lattion F. The melanin pigmentary disorder in a family with Hermansky- 2. King RA, Hearing VJ, Creel DJ, Oetting WS. Albinism. In: Scriver CR, Beaudet Pudlak syndrome. J Invest Dermatol. 1982;78:141-143. AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Dis- 31. Schachne JP, Glaser N, Lee S, Kress Y, Fisher M. Hermansky-Pudlak syndrome: ease. 7th ed. New York, NY: McGraw-Hill International Book Co; 1995:4353- case report and clinicopathologic review. J Am Acad Dermatol. 1990;22:926-932. 4392. 32. Husain S, Marsh E, Saenz-Santamaria MC, McNutt NS. Hermansky-Pudlak syn- 3. Witkop CJ, Quevedo WC, Fitzpatrick TB, King RA. Albinism. In: Scriver CR, Beau- drome: report of a case with histological, immunohistochemical and ultrastruc- det AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. 6th ed. tural findings. J Cutan Pathol. 1998;25:380-385. New York, NY: McGraw-Hill International Book Co; 1990:2905-2947. 33. Gurish MF, Roberts LK, Krueger GG, et al. The effect of various sunscreen agents 4. Witkop CJ, Krumwiede M, Sedano H, White JG. The reliability of absent platelet on skin damage and the induction of tumor susceptibility in mice subjected to dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome. Am J ultraviolet irradiation. J Invest Dermatol. 1981;76:246-251. Hematol. 1987;26:305-311. 34. Kligman LH, Akin FJ, Kligman AM. Prevention of ultraviolet damage to the der- 5. Schinella RA, Greco MA, Cobert BL, Denmark LW, Cox RP. Hermansky-Pudlak mis of hairless mice by sunscreens. J Invest Dermatol. 1982;78:181-189. syndrome with granulomatous colitis. Ann Intern Med. 1980;92:20-23. 35. Kligman LH, Akin FJ, Kligman AM. Contributions of UVA and UVB to connective 6. Mahadeo R, Markowitz J, Fisher S, Daum F. Hermansky-Pudlak syndrome with tissue damage in hairless mice. J Invest Dermatol. 1985;84:272-276. granulomatous colitis in children. J Pediatr. 1991;118:904-906. 36. Harrison JA, Walker SL, Plastow SR, et al. Sunscreens with low sun protection 7. Gahl WA, Brantly M, Kaiser-Kupfer MI, et al. Genetic defects and clinical char- factor inhibit ultraviolet B and A photoaging in the skin of the hairless albino mouse. acteristics of patients with a form of oculocutaneous albinism (Hermansky- Photodermatol Photoimmunol Photomed. 1991;8:12-20. Pudlak syndrome). N Engl J Med. 1998;338:1258-1264. 37. Kligman LH, Akin FJ, Kligman AM. Sunscreen promote repair of ultraviolet radiation- 8. Garay SM, Gardella JE, Fazzini EP, Goldring RM. Hermansky-Pudlak syndrome: induced dermal damage. J Invest Dermatol. 1983;81:98-102. pulmonary manifestations of a ceroid storage disorder. Am J Med. 1979;66:737- 38. Kligman LH. Connective tissue photodamage in the hairless mouse is partially 747. reversible. J Invest Dermatol. 1987;88(suppl):12S-17S. 9. Davies BH, Tuddenham EGD. Familial pulmonary fibrosis associated with ocu- 39. Boyd AS, Naylor M, Cameron GS, et al. The effects of chronic sunscreen use on locutaneous albinism and platelet function defect: a new syndrome. QJM. 1976; the histologic changes of dermatoheliosis. J Am Acad Dermatol. 1995;33:941- 45:219-232. 946. 10. Witkop CJ, Babcock MN, Rao GHR, et al. Albinism and Hermansky-Pudlak syn- 40. Tsuji T, Saito T. Multiple naevocellular naevi in brothers with albinism. Br J Der- drome in Puerto Rico. Bol Asoc Med P R. 1990;82:333-339. matol. 1978;78:685-692. 11. Wildenberg SC, Oetting WS, Almadovar C, Krumwiede M, White JG, King RA. A 41. Roller JA, Hahn M. Oculocutaneous albinism and multiple pigmented naevi. Br J gene causing Hermansky-Pudlak syndrome in a Puerto Rican population maps Dermatol. 1977;97:698. to chromosome 10q2. Am J Hum Genet. 1995;57:755-765. 42. Pehamberger H, Honigsmann H, Wolff K. Dysplastic nevus syndrome with mul- 12. Shotelersuk V, Gahl WA. Hermansky-Pudlak syndrome: models for intracellular tiple primary amelanotic melanomas in oculocutaneous albinism. J Am Acad Der- vesicle formation. Mol Genet Metab. 1998;65:85-96. matol. 1984;11:731-735. 13. Oh J, Bailin T, Fukai K, et al. Positional cloning of a gene for Hermansky-Pudlak 43. Van Dorp DB, Wijermans PW, Meire F, Vrensen G. The Hermansky-Pudlak syn- syndrome, a disorder of cytoplasmic organelles. Nat Genet. 1996;14:300-306. drome: variable reaction to 1-desamino-8D-arginine vasopressin for correction 14. Bailin T, Oh J, Feng GH, Fukai K, Spritz RA. Organization and nucleotide se- of the bleeding time. Ophthalmic Paediatr Genet. 1990;11:237-244. quence of the human Hermansky-Pudlak syndrome (HPS) gene. J Invest Der- 44. Preston D, Stern R. Nonmelanoma cancers of the skin. N Engl J Med. 1992;327: matol. 1997;108:923-927. 1649-1662. 15. Lattion F, Schneider PH, DaPrada M, et al. Syndrome d’Hermansky-Pudlak dans 45. Feng L, Seymour AB, Jiang S, et al. The beta3A subunit gene (Ap3b1) of the AP-3 un village valaisan. Helv Paediatr Acta. 1983;38:495-512. adaptor complex is altered in the mouse hypopigmentation mutant pearl: a model 16. Schallreuter KU, Frenk E, Wolfe LS, Witkop CJ, Wood JM. Hermansky-Pudlak for Hermansky Pudlak syndrome and night blindness. Hum Mol Genet. 1999;8: syndrome in a Swiss population. Dermatology. 1993;187:248-256. 323-330. 17. Oh J, Ho L, Ala-Mello S, et al. Mutation analysis of patients with Hermansky- 46. Dell’Angelica EC, Shotelersuk V, Agilar RC, et al. Altered trafficking of lysosomal Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus het- proteins in Hermansky-Pudlak syndrome due to mutations in the ␤3A subunit erogeneity. Am J Hum Genet. 1998;62:593-598. of the Ap-3 adaptor. Mol Cell. 1999;3:11-21.

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