ORPHA: 231500, 79430; DO: 0060542;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q12.1 | Hermansky-Pudlak syndrome 4 | 614073 | Autosomal recessive | 3 | HPS4 | 606682 |
A number sign (#) is used with this entry because Hermansky-Pudlak syndrome (HPS4) is caused by homozygous or compound heterozygous mutation in the HPS4 gene (606682) on chromosome 22q12.
Hermansky-Pudlak syndrome-4 (HPS4) is characterized by oculocutaneous albinism in association with easy bruising or a bleeding tendency and absence of platelet dense bodies. Some patients also exhibit pulmonary fibrosis and/or granulomatous colitis (Anderson et al., 2003).
For a general phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).
Anderson et al. (2003) reported 7 patients with HPS and mutations in the HPS4 gene. The patients ranged in age from 3 to 61 years and were primarily of European ancestry, although there were 2 Indian sisters among them. Hair and skin were mildly to severely hypopigmented relative to other family members. Visual acuity ranged from 20/60 to 20/200. All patients lacked platelet dense bodies and had a history of excessive bruising; most experienced nosebleeds, and the 3 female patients also reported menorrhagia. Granulomatous colitis was present in 1 patient, with associated vaginal and rectal fistulas. Restrictive lung disease was found in 3 patients, and 1 had severe pulmonary fibrosis.
Bachli et al. (2004) described a 46-year-old Sri Lankan man, born of first-cousin parents, who had debilitating visual impairment since childhood, with ocular albinism and horizontal nystagmus. Eye examination showed iris transillumination, poorly pigmented fundi, and bilateral foveal hypoplasia. Bleeding history was unremarkable. The patient presented with progressive shortness of breath and had clubbing of the fingers; pulmonary function testing revealed a severe restrictive ventilatory disorder. CT scan of the lungs showed moderate fibrosis, with thickening of the interlobular septae, traction bronchiectasis, and focal peripheral reticulation. His bleeding history was unremarkable and platelet count was normal, but functional analysis showed that the patient's platelets failed to aggregate normally and had no second wave of aggregation. Delta granule storage pool deficiency was confirmed by electron microscopy showing a lack of dense bodies. On skin biopsy, the basal cell layer was weakly pigmented considering that the patient was a Sri Lankan of Tamil (southern India) origin; a normal number of melanocytes was observed, but there was a paucity of melanin pigment in those cells. In addition, there was accumulation of ceroid pigment in perivascular macrophages, and pulmonary biopsy also showed ceroid-laden macrophages.
In the mouse, more than 15 loci manifest mutant phenotypes similar to human Hermansky-Pudlak syndrome (HPS), including 'pale ear' (ep), the mouse homolog of Hermansky-Pudlak syndrome caused by mutation in the HPS1 gene (604982). Mouse ep has a phenotype identical to that of another mutant, 'light ear' (le), which suggested that the human homolog of le is a possible human HPS locus. The mouse le locus had been mapped to chromosome 5 of that species. Suzuki et al. (2002) subjected BACs spanning the le region to exon-trapping and compared sequences with genomic and expressed sequence tag (EST) databases. With availability of the complete DNA sequence of human chromosome 22, it was shown that the organization of the le region of mouse chromosome 5 and human 22q11.2-q12.2 is essentially identical.
The transmission pattern of HPS4 in the families reported by Suzuki et al. (2002) was consistent with autosomal recessive inheritance.
In 23 patients with HPS who were negative for mutation in the HPS1 gene, Suzuki et al. (2002) screened the human 'le' homolog, HPS4, and identified homozygous mutations in 7 European patients (606682.0001-606682.0005). The authors stated that all 7 patients exhibited 'typical clinical findings' of HPS.
In 22 patients with HPS who were negative for mutation in 3 HPS-associated genes, Anderson et al. (2003) screened for mutations in the HPS4 gene by SSCP analysis and/or direct sequencing and identified homozygous or compound heterozygous mutations in 7 patients (606682.0002, 606682.0006-606682.0008, and 606682.0010).
Bachli et al. (2004) reported a patient from Sri Lanka who had oculocutaneous albinism and severe pulmonary fibrosis without granulomatous colitis in whom they identified a homozygous 1-bp deletion (606682.0009) in the HPS4 gene.
Anderson, P. D., Huizing, M., Claassen, D. A., White, J., Gahl, W. A. Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Hum. Genet. 113: 10-17, 2003. [PubMed: 12664304] [Full Text: https://doi.org/10.1007/s00439-003-0933-5]
Bachli, E. B., Brack, T., Eppler, E., Stallmach, T., Trueb, R. M., Huizing, M., Gahl, W. A. Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis. Am. J. Med. Genet. 127A: 201-207, 2004. [PubMed: 15108212] [Full Text: https://doi.org/10.1002/ajmg.a.20683]
Suzuki, T., Li, W., Zhang, Q., Karim, A., Novak, E. K., Sviderskaya, E. V., Hill, S. P., Bennett, D. C., Levin, A. V., Nieuwenhuis, H. K., Fong, C.-T., Castellan, C., Miterski, B., Swank, R. T., Spritz, R. A. Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene. Nature Genet. 30: 321-324, 2002. [PubMed: 11836498] [Full Text: https://doi.org/10.1038/ng835]