A number sign (#) is used with this entry because Hermansky-Pudlak syndrome-6 (HPS6) is caused by homozygous or compound heterozygous mutation in the HPS6 gene (607522) on chromosome 10q24.

Hermansky-Pudlak syndrome-6 (HPS6) is characterized by a presentation of oculocutaneous albinism and bleeding diathesis. Nystagmus is usually present and bleeding problems may be mild (Zhang et al., 2003, Schreyer-Shafir et al., 2006).

For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).

Zhang et al. (2003) described a 39-year-old Belgian woman with Hermansky-Pudlak syndrome. She had oculocutaneous albinism and frequent prolonged nosebleeds, as well as prolonged bleeding after dental extractions and surgery. She had no pulmonary or gastrointestinal symptoms. Her platelet count was normal, and her bleeding time was moderately prolonged. Platelet function test showed reduced secretion in response to ATP. Electron microscopy of her platelets showed only very rare dense granules. Her parents had no known consanguinity, but both were from the same small region of east Flanders. A brother was similarly affected.

Schreyer-Shafir et al. (2006) studied a large consanguineous Israeli Bedouin family in which the Hermansky-Pudlak syndrome phenotype was characterized mainly by oculocutaneous albinism. Electron microscopic studies of platelets showed absence of dense bodies, consistent with HPS, and confocal microscopy revealed abnormal distribution of LAMP3 (605883) in patient fibroblasts, indicating abnormal trafficking of lysosomal-related organelles. The findings expanded the phenotype associated with mutations in the HPS6 gene.

Huizing et al. (2009) described 4 patients with HPS6. The first was a 36-year-old woman of Irish and German descent who was found to have partial albinism and nystagmus at age 5 months, but diagnosis was not made until age 26 when bleeding complications were followed up, revealing an absence of platelet dense bodies. She also had multiple abdominal surgeries for hernia, imperforate anus, and gluteal flap repairs. She had other medical problems, including 4 miscarriages, endometriosis, frequent upper respiratory and urinary tract infections, incontinence, migraine headaches, and hearing loss. However, she did not have granulomatous colitis, and renal and pulmonary functions were normal. The second patient was a 22-year-old man of northern European descent who had nystagmus at birth and was diagnosed with oculocutaneous albinism at age 3 months. Although bruising and bleeding after trauma were noted in childhood, he was not diagnosed with HPS until age 16 years, when laboratory studies showed absence of platelet dense granules. There was no renal or lung disease. The third was a 13-year-old girl of German and Dutch descent who had rotary nystagmus in infancy and was diagnosed with oculocutaneous albinism. She had global delayed development and easy bruising. Platelet storage pool deficiency and absence of dense bodies were noted at age 4 years. The fourth patient, a 52-year-old Italian man, also had rotary nystagmus at birth and bruising in childhood. He was diagnosed at age 44 years only when he was found to have gastrointestinal symptoms and oculocutaneous albinism. Laboratory studies showed iron-deficiency anemia and low vitamin B12. There was no interstitial lung disease or renal involvement. Huizing et al. (2009) concluded that patients with HPS6 appear to have clinical features similar to those of other BLOC2-deficient patients, that is, patients with HPS3 (614072) and HPS5 (614074).

Miyamichi et al. (2016) reported a 4-year-old Japanese girl and her 6-month-old sister who had oculocutaneous albinism and absence of platelet dense bodies. Both sisters had light brown hair and fair skin, and both showed congenital nystagmus and exotropia, as well as iris transillumination. Their ocular fundi were hypopigmented, with lack of macular ring reflexes, and optical coherence tomography (OCT) showed bilateral foveal hypoplasia. Although electron microscopy of their platelets showed absence of dense bodies, their platelet counts and bleeding times were normal, as were von Willebrand factor (613160) levels and prothrombin (176930) and partial thromboplastin (134390) times. There was no history of prolonged bleeding and no bleeding manifestations occurred over a 5-year follow-up period. In addition, chest x-rays showed no abnormalities, and heart was normal by ultrasound.

The transmission pattern of HPS6 in the family reported by Schreyer-Shafir et al. (2006) was consistent with autosomal recessive inheritance.

Zhang et al. (2003) mapped the HPS6 gene to chromosome 10q24.32.

In a 39-year-old Belgian woman with HPS, Zhang et al. (2003) identified a homozygous 4-bp deletion (607522.0001) in the HPS6 gene.

In affected members of a large consanguineous Israeli Bedouin family with Hermansky-Pudlak syndrome, who exhibited primarily oculocutaneous albinism, Schreyer-Shafir et al. (2006) identified homozygosity for a 1-bp insertion in the HPS6 gene (607522.0002).

Huizing et al. (2009) identified homozygous or compound heterozygous mutations (607522.0003-607522.0007) in the HPS6 gene in 4 unrelated patients with Hermansky-Pudlak syndrome. All mutations except 1 resulted in a truncated protein. The phenotype was characterized by early-onset nystagmus, oculocutaneous albinism, and a mild bleeding diathesis, but no pulmonary fibrosis, granulomatous colitis, or renal involvement. However, 2 patients had gastrointestinal symptoms. In vitro cellular studies performed on patient melanocytes indicated aberrant cytoplasmic distribution patterns of melanogenic proteins and increased trafficking of TYRP1 (115501) through the plasma membrane, indicating a defect in lysosomal-related organelles.

In 2 Japanese sisters with oculocutaneous albinism (OCA) and absence of platelet dense bodies, who were negative for mutation in known OCA-associated genes, Miyamichi et al. (2016) performed whole-exome sequencing and identified compound heterozygosity for a 1-bp deletion (607522.0009) and a nonsense mutation (Q680X; 607522.0010) in the HPS6 gene. The authors stated that these patients broadened the phenotypic definition of HPS, and noted that this was the first report of HPS in Japanese patients.