Hermansky-Pudlak syndrome

ARTICLE

A 55-year-old man was referred to our department by a geneticist to answer the question whether there are additional dermatological features which could help to predict the risk for his children of being affected by his form of oculocutaneous albinism (Fig.1). An ophthalmological examination had previously revealed a reduced visual acuity with photophobia and a hypopigmentated fundus. Additionally, a horizontal nystagmus was found, which was first noticed after measles in childhood (Fig. 2). His beard showed an unusual yellow tinge (Fig. 3). Bruising following minimal trauma after working in a vineyard as an adolescent was reported. Laboratory examination revealed a storage pool deficiency of thrombocyte function.

These findings are characteristic of the Hermansky-Pudlak syndrome (HPS; MIM 203300), which was first described in 1959 [1] and includes hypopigmentation, prolonged bleeding time due to platelet storage pool deficiency and accumulation of ceroid pigment in lysosomal organelles.

Discussion

HPS is an autosomal recessive trait that is most frequently found in Puerto Rico and in an isolated high mountain village in the Swiss alps [2]. In the Puerto Rican population the frequency was estimated to be 1:1,800. It is caused by a mutation within the gene HPS1 consisting of a 16Bp duplication and localized on chromosome 10q23. HPS1 itself consists of 2,100 bp which includes 20 exons. It encodes a 79.3 kd transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and is apparently crucial for their normal development and function [3]. It contains 2 putative transmembrane domains and a presumed melanosomal localization signal. It is located within the cytoplasm of nonmelanotic cells and within the granular fraction of melanocytes [4]. Feng et al. [5] characterized the mouse HPS cDNA and genomic locus, and identified pathologic HPS gene mutations in ep but not in ru mice, establishing mouse 'pale ear', a murine homolog for human Hermansky-Pudlak syndrome.

Dermatological features

In patients affected with Hermansky-Pudlak syndrome the hair color ranges from white to light brown and the eye color from blue to brown. A light skin colour with signs of solar damage (freckles), hypertrichosis of the eyelashes and trichomegaly on the arms and legs are found in 36% of the patients. Acanthosis nigricans-like lesions (without pigmentation) are found in 29% of HPS1-postive patients. Bruising can be observed in 86% of the patients [6].

Additional clinical features

Ophthalmological findings include reduced visual acuity, horizontal nystagmus and photophobia due to hypopigmentation of the iris and fundus. Other serious features are pulmonary fibrosis and granulomatous colitis [7].

Differential diagnosis

Tyrosinase-negative albinism can be excluded by incubation of extracted hair follicles with the melanin precursor DOPA [8]. Among the tyrosinase-positive forms of oculocutaneous albinism, the Chediak-Higashi syndrome (MIM 214500) can be excluded because of absence of eosinophilic inclusion bodies of myeloblasts and promyelocytes of the bone marrow, absence of malignant lymphoma and normal susceptibility to bacterial infections [9]. Prader-Willi syndrome (MIM 176270) can be excluded because of normal mental and physical development and absence of hypogonadism [10]. With regard to the tendency to bruising, other disorders of thrombocyte function such as Werlhoff disease and drug-induced forms have to be considered for the differential diagnosis.

REFERENCES

1. Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with histochemical studies. Blood 1959; 14: 162-9.

2. Fukai K, Oh J, Frenk E, Almodovar C, Spritz RA. Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23.1-q23.3. Hum Molec Genet 1995; 4: 1665-9.

3. Oh J, Ho L, Ala-Mello S, Amato D, Armstrong L, Bellucci S, Carakushansky G, Ellis JP, Fong C-T, Green JS, Heon E, Legius E, Levin AV, Nieuwenhuis HK, Pinckers A, Tamura N, Whiteford ML, Yamasaki H, Spritz RA. Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity. Am J Hum Genet 1998; 62: 593-8.

4. Oh J, Bailin T, Fukai K, et al. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmatic organelles. Nat Genet 1996; 14: 300-6.

5. Feng GH, Bailin T, Oh J, Spritz RA. Mouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare 'AT-AC' intron Hum Molec Genet 1997; 6: 793-7.

6. Toro J, Turner M, Gahl WA. Dermatologic manifestations of Hermansky-Pudlak Syndrome in patients with or without a 16-base pair duplication in the HPS1 gene. Arch Dermatol 1999; 135: 774-80.

7. Sandberg-Gertzen H, Eid R, Jarnerot G. Hermansky-Pudlak syndrome with colitis and pulmonary fibrosis. Scand J Gastroenterol 1999; 34: 1055-6.

8. King RA, Witkop CJ Jr. Detection of heterozygotes for tyrosinase-negative oculocutaneous albinism by hairbulb tyrosinase assay. Am J Hum Genet 1977; 29: 164-8.

9. Kritzler RA, Terner JY, Lindenbaum J, Magidson J, Williams R, Preisig R, Phillips GB. Chediak-Higashi syndrome: cytologic and serum lipid observations in a case and family. Am J Med 1964; 36: 583-94.

10. Prader A, Labhart A, Willi H. Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach myatonieartigem Zustand im Neugeborenenalter. Schweiz Med Wochenschr 1956; 86: 1260-1.