Clinical Characteristics
Ocular Features
Oculocutaneous hypopigmentation is common to all types of HPS. The ocular manifestations are similar to that of other types of albinism. Iris transillumination defects, nystagmus, and strabismus are common features. Visual acuity is usually stable in the range of 20/40-20/300 and often accompanied by photophobia. Foveal hypoplasia and fundus hypopigmentation are present similar to that found in other hypopigmentation disorders. The same is true of excessive decussation of retinal neuron axons at the chiasm. Many patients have significant refractive errors.
Systemic Features
In addition to decreased hair, ocular, and skin pigmentation, HPS patients suffer from bleeding diathesis, platelet deficiencies, and accumulation of ceroid material in lysosomes. Pigment can be found in large amounts in reticuloendothelial cells and in the walls of small blood vessels. Some of the same features are found in Chediak-Higashi syndrome (214500) which, however, has additional qualitative changes in leukocytes. HPS2 differs from other forms of HPS in having immunodeficiency and congenital neutropenia. Some patients, especially those with HPS1 and HPS4 mutations, have restrictive lung disease secondary to pulmonary fibrosis often causing symptoms in the third and fourth decades of life. Others have granulomatous colitis, kidney failure, and cardiomyopathy. Solar skin damage is a risk with actinic keratosis, nevi, lentigines and basal cell carcinoma seen in many patients.
Bleeding time is prolonged secondary to an impairment of the normal aggregation response of platelets. Easy bruising, epistaxis, prolonged bleeding during menstruation, after tooth extraction, and after minor surgical procedures are often reported. Platelets lack the normal number of ‘dense bodies’. Coagulation factor activity and platelet counts are normal.
The amount of hair and skin pigmentation is highly variable. Some patients are so lightly pigmented that they are misdiagnosed as having tyrosinase-negative albinism while others have yellow to brown hair with irides blue to hazel. Some darkening of hair is common.
Genetics
Inheritance
This is an autosomal recessive genetically heterogeneous condition resulting from mutations in at least 12 loci: HPS1 (203300) at 10q23.1-q23.2, AP3B1 causing HPS2 (608233) at 5q14.1, and AP3D1 (617050) at 19p13.3 causing HPS 10, whereas in types HPS3 (606118) at 3q24, HPS4 (606682) at 22q11.2-q12.2, HPS5 (607521) at 11p15-p13, HPS6 (607522) at 10q24.32 the mutations themselves have not been characterized. HPS7 is caused by mutations in the DTNBP1 gene (607145) located at locus 6p22.3 and HPS8 by mutations in the BLOC1S3 gene (609762) at 19q13. The nature of the mutations is variable and often unique to the population in which they are found.
Chediak-Higashi syndrome (214500) is a somewhat similar disorder but with leukocyte abnormalities and results from a different gene mutation.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.