A Clinical Variant of Familial Hermansky-Pudlak Syndrome

Silvia Iannello, MD, Giuseppe Fabbri, MD, Paolo Bosco, MD, Antonina Cavaleri, MD, Santi Cantarella, MD, Massimo Camuto, Paolina Milazzo, Francesco Romeo, MD, and Francesco Belfiore, MD

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Literature Review/Discussion

General aspects. In a classic study in Puerto Rico, of 693 persons with albinism, HPS was found in 495 (approximately 5/6 albino Puerto Ricans).[9] In the affected subjects, the consistent finding was storage pool deficient platelets (lack of dense bodies on electron microscopy).[9] The highest prevalence (apparently due to a founder effect) reported for HPS in Puerto Rico was in the northwestern quarter of the island, where at least 1/1800 persons had HPS and 1/21 were carriers.[4,9,13,34] Another group of patients with HPS has been reported in an isolated Valais village of the Swiss Alps.[55,56] Approximately 100 non-Puerto Rican patients are known in the United States, but perhaps there is underestimation due to a low index of suspicion and a poor ascertainment.[20] A recent Belgian study reported that HPS was diagnosed in 13.5% (8/59) of autosomal recessive albinos.[57]

HPS albinos phenotypically resemble other types of oculocutaneous albinos.[9] With regard to hairbulb tyrosinase activity, we must remember that 5 types of oculocutaneous albinism exist: type IA (tyrosinase-negative), type IB (yellow mutant), type II (tyrosinase-positive), type III (minimal pigment) and type IV (the HPS type with moderate to no measurable tyrosinase activity).[58,59] Recently, mutations and polymorphisms in 6 pigmentation genes have been reported to be responsible for different types of oculocutaneous and ocular albinism.[60] The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves.[60] These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism.[60] Patients with HPS exhibit moderate to mild hypopigmentation of the skin, hair, and eyes with extreme variability. To understand the inherent basis for this reduced pigmentation, pure cultures of melanocytes were derived using skin biopsies obtained from patients with HPS.[61] The patients' cells appeared microscopically hypopigmented, and melanin content ranged from 0% to 50% of that for normal melanocytes.[61] In cell lysates of HPS melanocytes, tyrosine hydroxylase activity was within the normal range, but in intact HPS cells, it was almost half that of normal melanocytes.[61]

Genetic data. Human HPS cDNA has been characterized, and several pathologic mutations have been reported.[13,15,20,21,25,29,30,33,34,35,62,63] The HPS gene was identified by positional cloning and homozygous frameshifts. This gene was found in Irish, Japanese, Puerto Rican, and Swiss patients.[13] In a study performed to rapidly screen the genome for candidate loci (collecting blood samples from a relatively homogenous population in Puerto Rico), significant evidence was detected for a marker on chromosome 10q.[34] This aplotype analysis places the HPS gene in a region of approximately 14 centiMorgan that contains D10S198 and D10S1239.[34] The HPS gene on chromosome 10 is complex and may have more than 1 biologically active transcript.[64] Using a linkage disequilibrium mapping approach in Puerto Rican and Swiss Alp albino patients with particular frequency of HPS, the HPS gene was localized to a 0.6-centiMorgan interval in chromosome segment 10q23-q23.3.[33] This suggests that both Puerto Rican and Swiss forms of HPS are either allelic or result from mutations in very closely linked genes in this region.[33] The gene appears to consist of 20 exons spanning about 30.5 Kb in chromosome segment 10q23.1-q23.3, and one of the intervening sequences is a member of the novel, very rare class of so-called "AT-AC" introns.[15] In recent studies, almost all HPS patients in northwest Puerto Rico were homozygous for a 16-bp frameshift duplication in exon 15 of a recently cloned gene.[19,35,65] Only 2 patients lacked the 16-bp duplication, whereas none of the non-Puerto Rican patients (from the mainland United States) carried this mutation.[19,35,65] Recently, a correlation of visual acuity and ocular pigmentation with the 16-bp duplication of the HPS-1 gene was reported.[66] In addition, Puerto Rican HPS most likely displays locus heterogeneity.[19,34,65] A frameshift at codon 322 may be the most frequent HPS mutation in Europeans, and 6 novel HPS mutations define an apparent frameshift hot spot at codon 321-322.[19]

The first gene responsible for HPS (HPS1) and all the HPS1 mutations result in truncated proteins.[21] HPS polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and apparently crucial for their normal development and function.[13,15] Differentially truncated HPS polypeptides may have important consequences for subcellular functions.[13,15] Recently, the HPS protein was reported to be part of a high-molecular-weight complex involved in melanosome biogenesis.[23] A mutation in the _3A subunit gene of the AP-3 adaptor complex (which likely regulates protein trafficking in the trans-Golgi network/endosomal compartment) was demonstrated in a mouse model.[40,67,68] A similar mutation was also reported in 2 HPS patients, with reduced levels of AP-3 in fibroblasts.[69] AP-3 functions in protein sorting to lysosomes, and its mutation can induce an altered trafficking of integral membrane proteins.[69] The molecular characterization of the protein encoded by the HPS-type gene has been performed.[62] An abnormal translocation of tyrosinase and tyrosinase-related protein-1 in cutaneous melanocytes of HPS has been reported.[70] AP-3 seems to mediate tyrosinase but not tyrosinase-related protein-1 in human melanocytes.[71]

HPS as a storage pool disease. Adenine nucleotide and serotonin are normally stored in a specific type of platelet storage organelles (the dense bodies). The most consistent diagnostic feature of HPS albino patients seems to be the lack of platelet-dense bodies with deficient storage pool of adenine nucleotides and serotonin.[41,72,73,74] HPS platelets appear unable to form these organelles or cannot concentrate the products in them due to an organelle membrane defect.[73,75] These findings suggest that the basic defect in these patients is a specific abnormality in organelle development which prevents the formation of an intact granule structure. A mepacrine labeling test (mepacrine is rapidly taken up and localized in dense granules of platelets) was performed in a patient with HPS; results showed that 74% of this patient's megakaryocytes contained no granules.[76] A similar finding was obtained in platelets of the same patient.[76] This suggests that mepacrine also stains the dense bodies in the megakaryocytes and that in HPS, the platelet anomaly is secondary to a megakaryocyte abnormality.[76] By means of flow cytometry for analysis of platelet-dense granule content uptake and release (using mepacrine as the fluorescent marker), a decreased mepacrine uptake was demonstrated in platelets of a patient with HPS, mepacrine uptake being proportional to platelet size.[77] Recently, the mepacrine-based cytofluorimetry was confirmed as a useful test in the diagnosis of delta granule deficiency in HPS.[24] Dutch researchers evidenced lowered platelet 5-hydroxy-tryptamine (5-HT) content in heterozygotes, whereas homozygous HPS patients were characterized by decreased availability of factor 3, aggregation pattern with absent second wave in presence of ADP or adrenaline, and absent collagen aggregation.[78] In all homozygous patients, platelet ADP and 5-HT were strongly decreased, whereas ATP was lowered only in 3 out of 6 HPS patients.[78] A subnormal platelet aggregation with arachidonic acid could be obtained using a high concentration of arachidonic acid (2 mM).[79] On the contrary, normal malondialdehyde levels were recorded, suggesting a normal prostaglandin synthesis in HPS platelets.[79] Lysosomal enzymes were found to be normal in these patients.[79] HPS platelets in platelet-rich plasma do not respond to collagen, and the _-granule release was found impaired and remained subnormal even with high doses of inducers.[74] Only a combination of ADP plus thrombin could restore a normal aggregation.[74] Storage pool deficient platelets develop only single waves of clumping when stimulated by threshold concentrations of aggregating agents (which cause irreversible biphasic aggregation of normal platelets).[74]

Bleeding problems. The absence of dense bodies and their content does not present a serious threat to hemostasis in HPS patients,[80] but the bleeding tendency in HPS is a very complicated problem. In a recent study involving 30 HPS albinos, apart from the abnormalities in platelet aggregation, significantly lower levels of von Willebrand factor (vWF) activity in platelets (P < .0001) together with slightly lower values of plasma vWF activity (P = .03) were reported.[81] A decreased level of vWF in HPS has been reported by others.[82] Some HPS patients have severe bleeding despite normal levels of plasma vWF, suggesting that at least 1 additional factor is responsible for their bleeding diathesis.[81] Finally, a predictable relationship between platelet and plasma vWF values and the bleeding history was not observed in the majority of the patients studied.[81] Aspirin-treated HPS platelets cannot form thromboxane, but placing HPS patients on aspirin did not cause spontaneous hemorrhage, suggesting that secretion of dense body contents is not essential for platelet function.[80] However, other data from literature seem to strongly suggest that many HPS patients are at risk for fatal bleeding and recurrent hemorrhages (including epistaxis, gingival bleeding, and bleeding during menstruation).[35,80] Accordingly, hemorrhagic episodes were first considered a cardinal feature of the syndrome.[35,80] Menometrorrhagia is common in patients with HPS,[9] and massive bleeding following delivery was reported in women with the disorder.[2] However, despite the prior reports of postpartum hemorrhage in the affected patients, 2 pregnant HPS patients showed good outcomes.[83] Recently, the DNA diagnosis and the management of HPS in pregnancy were considered.[84] Major changes in platelet aggregation were not seen in other studies,[85] so that thrombopathy of HPS is generally considered to be without frank clinical consequences, apart from some unusual cases.[86] Nevertheless, the suspected patients should be screened with platelet aggregation studies, as suggested by Reiss and coworkers,[83] or with specific tests of platelet function.[53]

HPS pathogenesis. The basic defect of HPS remains unknown. A defective calcium (Ca) uptake system and low activities for membrane-associated thioredoxin reductase (a possible regulator of melanin biosynthesis via the inhibition of tyrosinase by reduced thioredoxin) were shown in HPS.[87,88] Cell cultures of keratinocytes from HPS-homozygous and HPS-heterozygous patients bind more extracellular Ca than cells from noncarriers, and HPS-homozygous cells appear to have a defective Ca-transport system.[88] The decreased thioredoxin reductase assayed in 3-mm skin punch biopsies is a useful tool for detecting carriers of the HPS gene.[87] In a recent study of HPS, a defective biopterin (6BH4) de novo synthesis/recycling was reported.[89] Thioredoxin/thioredoxin reductase can directly control the redox status of this cofactor, and these activities are allosterically controlled by Ca.[89] Therefore, Ca would directly affect this redox status, and the low enzyme activity in HPS is concomitant with a defective Ca uptake, suggesting an extracellular accumulation of this relevant second messenger.[89]

In a patient with HPS, a platelet-dense granule membrane protein was identified (homologous but not identical to the synaptosomal protein, synaptophysin) and was found to be markedly deficient.[90] An antigen-capture sandwich enzyme-linked immunosorbent assay (ELISA) was developed for the protein granulophysin (a constituent of the platelet-dense granule membrane) and used to characterize the patients with dense granule storage pool deficiency.[91] Granulophysin levels in platelet homogenates of 30 HPS patients were 1/4-1/5 the levels in controls or obligate heterozygotes.[91] CD63 (a membrane protein described originally in platelet lysosomes) was reported to be dramatically decreased in the lysosomes and dense bodies of patients with HPS, and was proposed as a candidate for the primary defect of HPS.[92] Immunoblotting studies demonstrated that anti-CD63 and anti-granulophysin antibodies apparently recognize the same protein.[93] Granulophysin and CD63 are possibly identical proteins, which are present in platelet-dense granules or lysosomes or melanosomes and are deficient in patients with HPS syndrome.[93] Since the CD63 structural gene, promoter and untranslated regions are normal in HPS, the disease is probably not caused by a mutation in the CD63 gene.[92]

HPS variants. Several HPS variants have been described in literature. Hermansky and Cieslar[94] reported the presence of a large amount of an unidentified metabolite after 5-HT incorporation (which differed from 5-HT and 5-hydroxythyptophol) in the platelets of some HPS patients and an abnormal incorporation of labeled glycerol in their triglycerides. Rendu and coworkers[95] reported a patient with reduction in the number of platelet-dense bodies (which were much bigger than normally observed and localized in a peripheral ring). In this patient, serotonin uptake by platelets was much decreased, as was the uptake of free 14C-arachidonic acid and thrombin-induced liberation from phosphatidyl-choline and phosphatidyl-inositol. Moreover, platelet phospholipase A1 activity was much reduced and phospholipase A2 activity was undetectable.[95] Finally, in a male with HPS, an acrofacial dysostosis with growth and mental retardation was reported.[96]

The ceroid-like lipofuscin pigment. In HPS there is a failure of "ceroid" metabolism, and a ceroid-like pigment (a poorly defined lipid-protein complex) accumulates within reticuloendothelial cells or macrophages of the body tissues in affected patients.[2] The amount of ceroid-like material recovered from tissue or urinary sources varies from tissue to tissue and from patient to patient.[2] It is noteworthy that, in a patient with complete oculocutaneous albinism without characteristics of HPS, a histopathologic study revealed few non-membrane-bound electron-dense granules of lipofuscin present in the iris and retinal pigment epithelial cells.[97] An electron microscopic study of peripheral leukocytes obtained from a 39-year-old woman with HPS showed ceroid pigment granules within the lysosomes in 3.5% of monocytes and 5.4% of lymphocytes (T cells).[98] It was speculated that intralysosomal ceroid accumulation in HPS may be due to lysosomal dysfunction.[98] The autofluorescent material stored in HPS is histochemically similar to the pigment stored in the neuronal ceroid lipofuscinoses (NCLs) , a group of inherited (autosomal recessive) progressive neurodegenerative diseases in children and adults.[99,100] The childhood forms of NCLs represent the most frequent progressive encephalopathies in western countries.[99,100] They are characterized by accumulation of lipopigments (lipofuscin and ceroid) within the lysosomes in neuronal and extraneuronal cells, with clinical development of early progressive visual loss, epilepsy, psychomotor deterioration, progressive dementia, and premature death.[99,100] This material contains dolichols (which are components of lysosomes).[101] HPS patients also show increased urinary excretion of dolichols.[27] The recent view is that dolichol metabolism alteration is a nonspecific phenomenon related to some lysosomal dysfunctions and secondary to various neurodegenerative disorders.[27,99,102] In 49 HPS patients, urinary dolichol levels were found to be increased with evidence of ceroid storage in kidneys, but urinary dolichols are not elevated when storage occurs in tissues other than kidney.[27] In an autopsy case (a 39-year-old male HPS patient who died of pulmonary fibrosis and hemorrhage), by means of analysis of autofluorescent ceroid-like storage in several tissues, the presence of pigmented macrophages was seen in almost all organs, especially in bone marrow, spleen, liver, colon, lymph nodes, and kidneys.[103] Ultrastructurally, this ceroid-like material was an intracytoplasmic electron-dense and lucent congeries histochemically similar to ceroid.[103] A substance that revealed brilliant lemon-yellow autofluorescence was extracted from splenic homogenized tissue with chloroform/methanol (2:1), then separated by thin-layer chromatography.[103] This fluorescent substance had an excitation maximum at 360 nm and a fluorescence maximum at 440 nm, which are the same characteristics of the fluorescent lipid peroxidation products in vitro.[103]

HPS complications or associated diseases. Various important complications may occur in HPS, which seem to result from the tissue storage of ceroid pigment.

Pulmonary manifestations of HPS, such as pulmonary fibrosis with progressive restrictive lung disease, constitute the most frequently associated type of disease in several different ethnic populations.[10,17,42,46,47,48,49,104,105,106,107] HPS is one of the few genetic disorders associated with severe pulmonary fibrosis, which is a cause of reduced survival in this disease.[92] Fibrosis is thought to be caused by the accumulation of ceroid both extracellularly and in the lysosomes of alveolar macrophages.[92] In some HPS patients with symptoms, chest film and pulmonary function studies were consistent with restrictive pulmonary disease.[42] Lung biopsies classically revealed diffuse interstitial fibrosis with ceroid-like material within alveolar macrophages (demonstrated by light and electron microscopy).[42] This pulmonary disorder of HPS appears to be more common than is currently recognized, and should be considered in the differential diagnosis of diffuse interstitial pulmonary diseases.[42] Two cases of familial diffuse interstitial pulmonary fibrosis with oculocutaneous albinism were reported, as well as a case of dyspnea in a 30-year-old Hispanic man with simple albinism[108,109] (perhaps forms of undiagnosed HPS). In a study, the clinical course and postmortem findings of an HPS patient with diffuse pulmonary fibrosis mimicked cryptogenic fibrosing alveolitis.[110] Histologic examination revealed a chronic inflammatory infiltrate of pigment-laden macrophages.[110] Further data on immunologic mechanisms operating in lung disease of HPS were obtained by recovering alveolar macrophages from bronchoalveolar lavage. These cells contained the characteristic ceroid-like material, the picture being similar to that seen in idiopathic pulmonary fibrosis (increased levels of Ig or numbers of IgG-and IgA-secreting cells, and normal percentages of putative helper and suppressor T-cell subsets).[111] A pathogenetic hypothesis was based on the platelet-derived growth factor (PDGF), a potent peptide that modulates mesenchymal cell function. This peptide would be present at the alveolar surface before the onset of the physiologic dysfunction in patients in whom pulmonary fibrosis subsequently develops.[49] Bronchoalveolar lavage was performed in 30 asymptomatic patients with HPS, in 9 HPS heterozygotes, and in some normal volunteers, and the characteristic autofluorescence and the ultrastructural features of ceroid were found in the alveolar macrophages of HPS patients.[49] Lavage fluid from HPS patients contained 2 PDGF-related peptides in concentration 6 times greater than control values.[49] Similar results were obtained in HPS heterozygotes.[49] Macrophage-derived PDGF peptides are thought to be important molecules in the initiation of alveolar remodeling in the fibrotic lung disorder of HPS patients.[49]

Another HPS-associated complication is bleeding chronic granulomatous colitis, which has been documented in several families with HPS.[35,50,112,113,114] This colitis occurs in approximately 15% of HPS patients.[35] It is a unique type of inflammatory bowel disease, showing clinical findings suggestive of idiopathic ulcerative colitis and pathologic features suggestive of Crohn's disease.[54,112] Perianal disease with perirectal abscess was described in a 29-year-old woman with HPS.[112] Two HPS patients, affected by inflammatory bowel disease with deposition of ceroid material in the colon, were simultaneously affected by pulmonary fibrosis.[42] Recently, a small-bowel stricture has been reported in a woman with HPS.[115]

Secondary or associated disorders of the immune system are suggested by reports of association between HPS and lupus or frequent bacterial infections, probably linked to the reduced activity of "natural killer" cells.[12] However, a true immune deficiency was not found in HPS patients.[12] A study performed in a large group of HPS patients demonstrated that there is no generalized defect of peripheral blood lymphocyte or neutrophil function in HPS.[5] Reported autoimmune disorders probably arise from a defect within the monocyte-macrophage system, perhaps secondary to ceroid accumulation.[5]

Other HPS-associated disorders, such as Pseudomelanosis coli and deeply pigmented renal cortex, have been reported, as well as the presence of a number of pigment-laden Kupffer cells and macrophages in the Glisson capsule, or the occurrence of intralysosomal accumulation of pigment within the hepatocytes (detected by electron microscopy).[10]Renal failure and cardiomyopathy were also described as HPS-associated disorders.[27] Recently, an IgA nephropathy with antineutrophil cytoplasmic antibodies and crescentic glomerulonephritis was reported in an HPS patient.[116]

Ocular disorders. HPS albinos were found to lack binocular vision due to nearly complete crossing of optic tracts and excessive decussation of optic fibers.[9,14] Ophthalmic findings in HPS are extremely variable,[14,117] and 20 individuals with HPS showed nystagmus and reduced visual acuity (from 20/60 to 20/400), with mild improvement in vision by correction of refractive errors.[14] Foveal hypoplasia was found in all patients, but variability in macular transparency and vascular architecture was reported.[14] In 55 Puerto Rican patients (mean age of 19.7 years), visual acuity was reduced (from 20/50 to 5/200), and all patients had congenital nystagmus, 33/55 had strabismus, 24/55 esotropia, 18/55 exotropia, and 3/55 cataract.[118] In these patients, retina was typically albinotic with macular hypoplasia.[118] Ophthalmoscopic detection of melanin pigment in the macula in albino patients is associated with better vision.[14] The correlation between visual acuity and nystagmus was particularly strong, probably because nystagmus imposes a visual deficit beyond that related to foveal hypoplasia alone.[119] In HPS patients, the electroretinography (ERG) findings were abnormal, and the ERG responses were decreased and similar to the known abnormalities in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten's disease.[120] However, other studies reported normal ERG results in some HPS patients, ERG was found to be normal by others.[121]

Malignant melanomas in HPS. The development of cutaneous malignant melanomas (sometimes amelanotic) is possible, but infrequent, in HPS patients,[121] as well as in other albino patients.[122,123,124,125] For this reason, especially in sunny climates, albino subjects should prevent the skin-damaging effects of the sun by means of protective clothing, sun-screening agents, and indoor occupations.[126] It is extremely important to educate albino patients (with or without HPS) about the need for early detection and treatment of premalignant lesions.[126]

Prognosis in HPS. Visual deficits and pulmonary fibrosis are progressive and irreversible. Death occurs in HPS patients in the fourth or fifth decade, the major causes being fibrotic restrictive pulmonary disease (50% of affected patients die as result of respiratory insufficiency), hemorrhagic episodes, and sequelae of granulomatous enteropathic disease.[9,57,92] The high risk for hemorrhage in some patients emphasizes the importance of screening for patients with albinism and HPS.[117] Although usually mild, bleeding in affected patients can be life-threatening, especially after aspirin administration.[117] A French study reported a case of HPS with spontaneous meningeal hemorrhage and emphasized the risk of failure to recognize the syndrome and the benefit of a systematic detection of coagulation tests in order to prevent drug-induced hemorrhagic accidents.[86,127] Recently, HPS presenting in infancy with subdural hematoma and retinal hemorrhages has been reviewed.[128]

Therapy. No curative therapy for HPS exists; symptomatic treatment is available only for the serious complications.[12] In a study published in 1978, infusion of cryoprecipitate (obtained from donors) decreased bleeding time by almost one third of initial values (within 2 hours of transfusion) in some HPS patients.[129] Twice-daily infusion protected HPS patients from bleeding during surgery.[129] The mechanism of action of cryoprecipitate in this situation is unknown.[129] Improvements in bleeding time were observed with synthetic vasopressin-derivative (1-deamino-8D-arginine vasopressin or desmopressin) in Belgian and Dutch patients with HPS.[130,131] Some of the HPS patients were treated with oral vitamin E therapy that markedly reduced bleeding symptoms but did not affect progression of fatal restrictive lung disease.[85]Large recession of horizontal recti was proposed for treatment of HPS nystagmus with anomalous head posture.[132] In these patients, diagnosis should be made preoperatively to minimize the complications associated with bleeding at the time of extraocular muscle and intraocular surgery.[118]

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