ORPHA: 231531, 280663, 79430; DO: 0060547;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.1 | Hermansky-Pudlak syndrome 9 | 614171 | Autosomal recessive | 3 | BLOC1S6 | 604310 |
A number sign (#) is used with this entry because of evidence that Hermansky-Pudlak syndrome-9 (HPS9) is caused by homozygous or compound heterozygous mutation in the PLDN gene (BLOC1S6; 604310), which encodes pallidin, on chromosome 15q21.
For a general phenotypic description and discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).
Hermansky-Pudlak syndrome-9 (HPS9) is characterized by oculocutaneous albinism, with patients exhibiting hypopigmented hair, skin, and irises. Ocular symptoms include nystagmus, photophobia, and reduced visual acuity. Patients may also experience recurrent infections associated with leukopenia, as well as bruising or bleeding due to thrombocytopenia and platelet dysfunction (Badolato et al., 2012; Yousaf et al., 2016).
Badolato et al. (2012) studied a 17-year-old northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. Her medical history included a prolonged episode of fever with seizures at 6 years of age. At presentation, she had thrombocytopenia and leukopenia, with normal platelet aggregation. An increased proportion of both resting and IL2 (147680)-activated NK cells from the patient expressed CD107A (LAMP1; 153330) on the surface compared to controls, and patient NK cells also showed moderately increased cell surface expression of CD63 (155740). In addition, IL2-activated NK cells from the patient had decreased granulation, and both resting and activated NK cells showed reduced cytolytic activity compared to controls. Badolato et al. (2012) noted that the abnormal lysosomal markers on this patient's NK cells were similar to, but distinct from, those observed in patients with HPS2 (608233).
Yousaf et al. (2016) reported a 4-year-old Pakistani girl (family LUAB11) with HPS and mutation in the BLOC1S6 gene. The proband exhibited oculocutaneous albinism, photophobia, nystagmus, low platelet count, and prolonged bleeding and clotting times consistent with platelet dysfunction. A maternal uncle was also shown as affected in the family pedigree, but his clinical features were not reported.
Okamura et al. (2018) reported a 52-year-old Japanese woman (patient 3) who had HPS and mutation in the BLOC1S6 gene. She had white skin, blond hair, and brown irises, exhibited nystagmus and mild amblyopia, and was diagnosed with oculocutaneous albinism. A patient hair sample showed an approximately 80 to 90% reduction in total melanin content compared to control. Although she did not experience recurrent infections, she was leukopenic. She lacked platelet dense granules and had impaired platelet function, and also showed mild thrombocytopenia. She developed schizophrenia when she was in her late forties. The authors noted that due to the high frequency of schizophrenia in the general population, its occurrence in a patient with HPS might be coincidental rather than causal.
Michaud et al. (2021) reported a 2.5-year-old girl of Syrian origin with HPS and mutation in the BLOC1S6 gene. She presented at age 4 months with white skin, yellow hair, and nystagmus. Ophthalmologic examination showed gray-blue irises, horizontal pendular nystagmus, photophobia, myopia, strabismus, complete iris transillumination, retinal hypopigmentation, and pale optic nerves. Other features included asthma and recurrent respiratory infections, but she did not have leukopenia or neutropenia, and IgG, IgA, and IgM counts were normal. She experienced bruising and hematomas, and hematologic evaluation at age 2 years showed a platelet number at the lower limit of the normal range, abnormal platelet aggregation, and absent dense granules. Psychomotor delays (language and walking) and dextrocardia were also present in the proband; the authors stated that it was unclear whether these features were related to the HPS.
Liu et al. (2021) reported a 6-year-old Chinese boy with HPS and mutation in the BLOC1S6 gene. He had brownish-yellow hair, white skin, brown irises, and experienced photophobia, strabismus, and nystagmus. He had bruising on his left thigh. Ophthalmologic evaluation showed horizontal nystagmus, reduced visual acuity, hypopigmented fundus, and underdeveloped foveae, which appeared flat on optical coherence tomography. Electroretinography and visual evoked potentials showed almost normal function of retinal cells bilaterally, but severely blocked transmission function of the optic nerves. Platelet aggregation rates were normal, but some coagulation tests were slightly longer than normal, and electron microscopy revealed absence of platelet dense granules.
The transmission pattern of HPS9 in the family reported by Badolato et al. (2012) was consistent with autosomal recessive inheritance.
In a 17-year-old Italian girl with an HPS-like primary immunodeficiency syndrome, Badolato et al. (2012) performed whole-exome sequencing (WES) and identified homozygosity for a Q78X mutation in the PLDN gene (604310.0001). No mutations were found in other immunodeficiency-associated genes. Sanger sequencing confirmed the Q78X PLDN mutation, which was also present in heterozygosity in her unaffected parents.
By WES in a 4-year-old Pakistani girl (family LUAB11) with HPS, Yousaf et al. (2016) identified homozygosity for the previously reported Q78X nonsense mutation in the BLOC1S6 gene. Her unaffected consanguineous parents were heterozygous for the mutation. A maternal uncle, born of a consanguineous marriage, was also shown as affected in the family pedigree, but his mutation status was not reported.
Okamura et al. (2018) performed WES in Japanese patients diagnosed with oculocutaneous albinism (OCA) who were negative for mutation in OCA-associated genes and the HPS1 gene, and identified a 52-year-old Japanese woman (patient 3) who was homozygous for a 2-bp duplication in the BLOC1S6 gene (604310.0002). Her unaffected mother and sister were heterozygous for the mutation; DNA was unavailable from her father, who was her mother's third cousin.
In a 2.5-year-old girl of Syrian origin with HPS, Michaud et al. (2021) performed next-generation sequencing of 19 albinism-associated genes and identified compound heterozygous mutations in the BLOC1S6 gene: a nonsense mutation (S67X; 604310.0003) and a 2-bp deletion/insertion (604310.0004). Her unaffected parents were each heterozygous for 1 of the mutations. The insertion/deletion was not found in the gnomAD database, whereas the nonsense mutation was present once, in heterozygosity.
By WES in a 6-year-old Chinese boy with HPS, Liu et al. (2021) identified compound heterozygosity for mutations in the BLOC1S6 gene: a nonsense mutation (E50X; 604310.0005) and a 1-bp duplication (604310.0006). Sanger sequencing confirmed the mutations and their presence in heterozygosity in his unaffected parents.
Cullinane et al. (2011) reported a child with an HPS-like syndrome and a homozygous Q78X mutation in the PLDN gene; however, this article was retracted based on the finding of the United States Office of Research Integrity that Andrew R. Cullinane, Ph.D., 'falsified and/or fabricated the results in Figure 3C, by using the same gel images to represent expression of PLDN in fibroblasts and melanocytes.'
Badolato, R., Prandini, A., Caracciolo, S., Colombo, F., Tabellini, G., Giacomelli, M., Cantarini, M. E., Pession, A., Bell, C. J., Dinwiddie, D. L., Miller, N. A., Hateley, S. L., Saunders, C. J., Zhang, L., Schroth, G. P., Plebani, A., Parolini, S., Kingsmore, S. F. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome. (Letter) Blood 119: 3185-3187, 2012. [PubMed: 22461475] [Full Text: https://doi.org/10.1182/blood-2012-01-404350]
Cullinane, A. R., Curry, J. A., Carmona-Rivera, C., Summers, C. G., Ciccone, C., Cardillo, N. D., Dorward, H., Hess, R. A., White, J. G., Adams, D., Huizing, M., Gahl, W. A. A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak syndrome type 9. Am. J. Hum. Genet. 88: 778-787, 2011. Note: Retraction: Am. J. Hum. Genet. 100: 837 only, 2017. [PubMed: 21665000] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.009]
Liu, T., Yuan, Y., Bai, D., Yao, X., Zhang, T., Huang, Q., Qi, Z., Yang, L., Yang, X., Li, W., Wei, A. The first Hermansky-Pudlak syndrome type 9 patient with two novel variants in Chinese population. J. Derm. 48: 676-680, 2021. [PubMed: 33543539] [Full Text: https://doi.org/10.1111/1346-8138.15762]
Michaud, V., Fiore, M., Coste, V., Huguenin, Y., Bordet, J.-C., Plaisant, C., Lasseaux, E., Morice-Picard, F., Arveiler, B. A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies. Platelets 32: 420-423, 2021. [PubMed: 32245340] [Full Text: https://doi.org/10.1080/09537104.2020.1742315]
Okamura, K., Abe, Y., Araki, Y., Wakamatsu, K., Seishima, M., Umetsu, T., Kato, A., Kawaguchi, M., Hayashi, M., Hozumi, Y., Suzuki, T. Characterization of melanosomes and melanin in Japanese patients with Hermansky-Pudlak syndrome types 1, 4, 6, and 9. Pigment Cell Melanoma Res. 31: 267-276, 2018. [PubMed: 29054114] [Full Text: https://doi.org/10.1111/pcmr.12662]
Yousaf, S., Shahzad, M., Kausar, T., Sheikh, S. A., Tariq, N., Shabbir, A. S., University of Washington Center for Mendelian Genomics, Ali, M., Waryah, A. M., Shaikh, R. S., Riazuddin, S., Ahmed, Z. M. Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population. Pigment Cell Melanoma Res. 29: 231-235, 2016. [PubMed: 26575419] [Full Text: https://doi.org/10.1111/pcmr.12438]