From the Departments of Internal Medicine (AJV, ET, MHHK, CAJMG), and Surgery (AJCM), Eemland Hospital, Amersfoort, The Netherlands. Correspondence should be addressed to Carlo A.J.M. Gaillard, MD, PhD, Department of Internal Medicine, Eemland Hospital, 3818 ES Amersfoort, The Netherlands. Manuscript submitted March 12, 1999, and accepted in revised form August 31, 1999. A New Variant of Hermansky-Pudlak Syndrome due to Mutations in a Gene Responsible for Vesicle Formation Vorasuk Shotelersuk, MD, Esteban C. Dell’Angelica, PhD, Lisa Hartnell, BS, Juan S. Bonifacino, PhD, William A. Gahl, MD, PhD H ermansky-Pudlak syndrome is a recessive type of oculocutaneous albinism that is prevalent in northwest Puerto Rico due to a founder effect (1–3). In this syndrome, bleeding and bruising occur be- cause of the absence of platelet dense bodies, which nor- mally release serotonin, calcium, and adenosine diphos- phate to trigger a secondary aggregation response (4). In addition, the accumulation of a lipid-protein complex called ceroid lipofuscin (5,6) is thought to cause the pul- monary fibrosis (7) and granulomatous colitis (8) seen in this disease. One gene causing Hermansky-Pudlak syndrome, HPS-1, encodes a 700 amino acid protein of unknown function (9 –11). Northwest Puerto Rican patients are homozygous for a 16 base pair (bp) duplication in HPS-1, but most non-Puerto Rican patients have no mutations in this gene (12,13). Consequently, it has become ac- cepted that several different genes, when mutated, can cause Hermansky-Pudlak syndrome (12–14). This phe- nomenon, called locus heterogeneity, is also found in mice: 14 different mouse strains manifest a type of Her- mansky-Pudlak syndrome (pigment dilution and platelet storage pool deficiency), each due to a different gene (15). To date, three of these genes have been cloned. Pale ear is the murine analogue of patients with HPS-1 mutations (16,17), and pearl (18) and mocha (19) have defects in adaptor complex-3 (AP-3). One protein subunit of adap- tor complex-3, called 3A, is mutated in the pearl mouse, while another protein subunit, called , is mutated in the mocha mouse. Adaptor complex-3 is an aggregate of four different peptides and serves as a “coat” protein that concentrates in a donor membrane and recruits other membrane com- ponents to become part of a newly formed vesicle. These vesicles, such as lysosomes and peroxisomes, are func- tional compartments that provide an optimal environ- ment for specialized biochemical processes. Adaptor complex-3 is thought to be responsible for the formation of pigment-forming vesicles (melanosomes) and platelet storage vesicles (dense bodies) (20,21). We describe two brothers with Hermansky-Pudlak syndrome with mutations in the 3A subunit of adaptor complex-3 (22,23). CASE REPORTS We admitted 49 Hermansky-Pudlak syndrome patients to the NIH Clinical Center under an Institutional Review Board-approved protocol (24). Patient 40, aged 20 years, and patient 42, aged 25 years, were brothers who had normal gestations, deliveries, and birth weights. Bilateral congenital hip dislocations, due to dysplastic acetabulae, required closed reduction in patient 40 and splinting in patient 42. The family was of Dutch origin with no known consanguinity or miscarriages. The brothers’ healthy par- ents had two normal, unaffected sons. Nystagmus was observed in the newborn period. Skin color was light, and the brothers’ white hair gradually turned blond. Bruising occurred in early childhood, with recurrent epistaxis decreasing in frequency by adoles- cence. In patient 42, extraction of several teeth was per- formed with minimal bleeding. Neither brother experi- enced hemoptysis, hematemesis, hematochezia, or me- lena. Hermansky-Pudlak syndrome was suspected when the patients were 8 and 13 years old, and absence of plate- let dense bodies was documented by Dr. James White of the University of Minnesota. From infancy to adolescence, the brothers had recur- rent upper respiratory tract infections and episodes of otitis media that responded to antibiotic treatment. Neu- tropenia was consistently noted. The patients’ unaffected siblings did not have recurrent upper respiratory tract infections. Developmentally, the brothers achieved major mile- stones on time, but complained of poor balance causing stumbling and falling. They completed 11th grade and work on a family farm and nearby factory. Patient 42 smoked one half to 1 pack of cigarettes daily since age 13 years; patient 40 never smoked. Patient 40 had a physio- logic cardiac murmur noted since age 3 years, with nor- mal echocardiograms. Patient 40 had a height of 172.3 cm, weight of 86.5 kg, and head circumference of 56.8 cm. Patient 42 had a height of 173.1 cm, weight of 67.9 kg, and head circum- ference of 56.5 cm. The brothers’ hair was dark blond. Brief Observations April 1, 2000 THE AMERICAN JOURNAL OF MEDICINE Volume 108 423