HPS4 Research Articles

Masks of Albinism: Clinical Spectrum of Hermansky–Pudlak Syndrome

Hermansky–Pudlak syndrome (HPS) is a rare disease inherited in the autosomal recessive mode, including 11 clinical genetic subtypes. They are associated with impaired function of the BLOC protein complex (Biogenesis of Lysosome-related Organelles Complexes), and the subunits of the AP-3 complex (adaptor protein complex). Each has its own clinical features, but they are all characterized by albinism, bleeding disorder, and visual abnormalities. Eleven patients from eight unrelated families with an incoming diagnosis of albinism were examined and novel and previously described genetic variants in HPS1, HPS6, and BLOC1S6 genes (types HPS1, HPS6, and HPS9) were found. To determine the optimal therapy and recommendations for further follow up, it is necessary to consider the entire clinical spectrum and genetic polymorphism of the disease. An interdisciplinary approach, combined with the use of non-routine diagnostic techniques such as RNA analysis, is essential for achieving accurate diagnoses in certain complex cases.

Genomic analysis links the American mink Royal pastel coat phenotype to retroviral element type 1 insertion in the HPS3 gene.

To date, only 10 of the more than 30 fur colours that had been observed in American mink (Neogale vison) have been linked to specific genes. The Royal pastel fur colour is part of a large family of brownish colours that are quite similar to one another, making breeding and selecting processes more difficult. Here we carried out whole-genome sequencing of five American minks with Royal pastel (b/b) phenotypes originating from two distinct mink populations. We identified an insertion of endogenous retroviral element type 1 (ERV1) into the first intron of the gene encoding the HPS3 protein, which regulates the trafficking of tyrosinase-containing vesicles to maturing melanosomes. With Cas9-targeted nanopore sequencing, we reconstructed the full-length sequence of the 11.7 Kb ERV1 insertion and observed hypermethylation that spread to the HPS3 gene promoter region. These findings highlight the role of HPS3 in the formation of melanosomes and melanin, as well as the genetic process regulating the intensity and spectrum of hair colour. Moreover, in mink breeding projects, these data are also useful for tracking economically important fur qualities.

After an initial Hermansky-Pudlak syndrome clinical diagnosis, molecular testing reveals variants for oculocutaneous albinism type 1B: A case report.

Albinism is a heterogeneous condition in which patients present complete absence, reduction, or normal pigmentation in skin, hair and eyes in addition to ocular defects. One of the heterogeneous forms of albinism is observed in Hermansky-Pudlak syndrome (HPS) patients. HPS is characterized by albinism and hemorrhagic diathesis due to the absence of dense bodies in platelets. In this report, we describe a case of a pair of Puerto Rican siblings with albinism that were clinically diagnosed with HPS during childhood. Since they did not harbor the founder changes in the HPS1 and HPS3 genes common in Puerto Ricans, as adults they wanted to know the type of albinism they had. We performed exome sequencing, validation by PCR, and cloning of PCR products followed by Sanger sequencing in the family members. We discovered no mutations that could explain an HPS diagnosis. Instead, we found the siblings were compound heterozygotes for 4 variants in the Tyrosinase gene: c.-301C>T, c.140G>A (rs61753180; p.G47D), c.575C>A (rs1042602; p.S192Y), and c.1205G>A (rs1126809; p.R402Q). Our results show that the correct diagnosis for the siblings is OCA1B. Our study shows the importance of molecular testing when diagnosing a rare genetic disorder, especially in populations were the disease prevalence is higher.

Interdisciplinary approach to diagnosis of life-threatening form of albinism: Germanic-Pudlac syndrome case type 1

The Hermansky-Pudlak syndrome (OMIM#203300) is a hereditary genetically heterogeneous disease with an autosomal recessive type of inheritance. There are 11 clinical-genetic subtypes with similar clinical manifestations, but some type may difference with each other clinically. The most common is type 1 Hermansky-Pudlak syndrome. Purpose: Describe the features of the clinical picture and diagnosis of Hermansky-Pudlak syndrome type 1. Materials and methods: complex clinic-instrumental and molecular-genetic results from 2 patients from one family with incoming diagnosis of albinism are used. Result: An interdisciplinary approach to the diagnosis of albinism and a step-by-step molecular-genetic study help to verify the clinical-genetic diagnosis in a family. The clinical case demonstrated clinical polymorphism within one family. Two patients have similar dermatological and ophthalmological clinical picture, but have difference in bronchopulmonary system and the blood system. Probang-female has a history of prolonged repeated bleeding, coagulogram changes, obstructive bronchitis, albino phenotype and eyes failure. Her brother has a similar albino phenotype and eyes failure. The pathogenic variant NM_000195.5: c.1189del was revealed in a homozygous state in 13 exon of the HPS1 gene and Hermansky-Pudlak syndrome type 1 was confirmed by molecular analysis. Conclusion: On the example of this clinical observation of a family with Hermansky-Pudlak syndrome 1 type features of differential diagnosis of albinic states are shown, it is noted that complex examination of patients is necessary, molecular-diagnostics genetic analysis and constant follow up of a hematologist, ophthalmologist, pulmonologist, allergologist, dermatologist, gastroenterologist, geneticist and pediatrician.

HERMANSKY-PUDLAK SYNDROME-ASSOCIATED INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW ON CLINICAL MANIFESTATIONS AND INVESTIGATIONS INTO OPTIMAL MANAGEMENT

Abstract Hermansky-Pudlak Syndrome (HPS) is a rare autosomal condition resulting from a mutation in 1 of at least 7 different genes leading to the triad of tyrosine-positive oculocutaneous albinism, platelet dysfunction leading to prolonged bleeding time, and ceroid lipofuscin within the reticuloendothelial system. The latter of these can result in systemic derangements including renal failure, pulmonary fibrosis, cardiomyopathy, and a disabling granulomatous colitis. This colitis is a unique type of inflammatory bowel disease (IBD) with complications such as intestinal fistulization, ileitis, enterocolitis and perianal disease. There is data to suggest that HPS colitis is due to the development of classical IBD. However, optimal management remains undetermined. Our systematic review aims to analyze the clinical presentation behind HPS colitis, endoscopic versus histopathological findings, and ultimate treatment plans required for optimal management of this disease among HPS genotypes. A comprehensive literature review was conducted on patients with HPS and its associated colitis manifestations from inception to August 2023. Analyses on patient demographics, clinical presentation, HPS genotype, endoscopic versus histopathological findings, medical versus surgical interventions were thoroughly performed. Six cohort studies on HPS patients with coexisting colitis were identified. A total of 84 patients comprised these studies with mean age 32 +/- 9.65. Racial breakdowns were 68% Puerto Rican, 23% white, 4% Indian, 2% Mexican, 1% Honduran, and 1% African American. 59 patients had the HPS-1 genotype, 8 with HPS-3, 3 with HPS-4, and 1 with HPS-6. The most common presenting symptoms were hematochezia (37%), diarrhea (23%), abdominal pain (16%), and constipation (10%). Endoscopic evaluation showed normal gross findings in 65% of cases and abnormalities in only 35%. However, IBD-associated histopathological positivity was more prevalent with the most common findings being granulomas (33%), macrophages without colitis (19%), macrophages with colitis (15%), and lymphoid aggregates (10%). Medical therapy was initiated in 48 cases with the most common medications being steroids (46%), followed by anti-TNFa agents (40%), and immunomodulators (35%). 28 cases required surgical intervention with the most common operation performed being a (subtotal) colectomy and ileostomy. There were scattered cases of laparoscopic loop ileostomies, total colectomies, and proctocolectomies too. Interestingly, 10 patients received no intervention whatsoever. HPS-associated colitis is a debilitating condition that remarkably resembles IBD. There is no consensus on optimal therapy and many patients ultimately require operative intervention. The HPS-1 gene appears to be highly prevalent in this condition and younger patients are more affected, however more research is needed.

Hermansky-Pudlak Syndrome with an Improvement in the Respiratory Symptoms after the Administration of Pirfenidone: A Case Report.

Herein, we report a case of Hermansky-Pudlak syndrome (HPS) in which respiratory symptoms improved with pirfenidone treatment. A 43-year-old Japanese woman with oculocutaneous albinism presented with a cough and dyspnea. High-resolution computed tomography revealed areas of reticular and frosted lung opacities. The diagnosis of HPS was confirmed by a prolonged bleeding time and HPS1 gene mutation. Generally, there is no effective treatment for interstitial pneumonia associated with HPS except for lung transplantation. In the present case, the cough and dyspnea improved with pirfenidone administration. Therefore, clinicians should administer pirfenidone in challenging transplantation cases and during the waiting period for transplantation.

Genetic Study of Patients with Severe Dense Granule Deficiency: Unraveling the Underlying Genetic Complexity of Hermansky-Pudlak Syndrome

Background: Severe platelet (plt) dense granule (DG) deficiency is a hallmark of Hermansky-Pudlak syndrome (HPS), a rare, heterogeneous group of genetic disorders characterized by oculocutaneous albinism, bleeding diathesis, and lysosomal storage defects. A subset of HPS patients (pt) who has HPS1, HPS2, and HPS4 may also experience pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency (syndromic HPS). Platelet transmission electron microscopy (PTEM) has been considered a valuable tool to screen such patients, and molecular testing aids in confirming te diagnosis, subclassifying the HPS and providing information on prognosis in pt. To elucidate the effectiveness of PTEM and next-generation sequencing (NGS) to identify and subclassify HPS pt, we conducted a comprehensive study on a cohort of pt with severe plt DG deficiency. Methods: After IRB approval, consecutive samples submitted to our reference laboratory for PTEM testing were analyzed. Whole mount (WM) PTEM tests were performed on all pt. Targeted NGS of the ISTH tier 1 genes (including 11 HPS-related genes) was performed on a cohort of patients who had < 0.3 mean DG/plt (200 plt counted) by PTEM. Data collected included demographics, PTEM findings, and genetic variants classified based on the 2015 ACMG criteria. Results: A total of 38 pt met our study criteria, the median age at PTEM testing was 39 years (range, 5 months to 76 years), and 22 (58%) were female. Ethnic backgrounds included Caucasian, Albanian, Puerto Rican, and other (unavailable). The mean DG/plt was 0 (0-0.2). A variant in an HPS-related gene was found in 26/38 patients (68%). The spectrum of variants in HPS-related genes is shown in Table 1, encompassing single-nucleotide substitutions, insertions, deletions, and frameshift mutations involving HPS1, HPS3, HPS5, HPS6, and HPS7 ( DTNBP1) genes. In addition to the previously reported pathogenic variants, several novel/previously unreported variants were discovered (Table 1). Interestingly, some patients presented with multiple variants, suggesting potential compound heterozygosity. No variants were found for the remaining 12 patients (32%). Conclusion: Our NGS-based genetic study of 38 patients with severe DG deficiency provides valuable insights into the complexity of this rare disorder. The high yield of finding variants in HPS-related genes verified that WM-PTEM is a useful screening tool for identifying HPS patients. The identification of known variants in HPS-associated genes confirms the importance of genetic testing not only in the diagnosis of HPS but also provides information on prognosis in syndromic HPS. Pathogenicity of novel variants remains to be elucidated. Moreover, the observed 32% of patients who had negative NGS results suggest the existence of as yet undiscovered genetic mechanisms for the severe platelet DG deficiency.

Compound Homozygous Rare Mutations in PLCE1 and HPS1 Genes Associated with Autosomal Recessive Retinitis Pigmentosa in Pakistani Families.

Retinitis pigmentosa (RP) belongs to pigmentary retinopathies, a generic name for all retinal dystrophies with a major phenotypical and genotypical variation, characterized by progressive reduction of photo-receptor functionality of the rod and cone. Global prevalence of RP is ~ 1/4000 and it can be inherited as autosomal dominant (adRP), autosomal recessive (arRP) or X- linked (xlRP). We designed this study to identify causative mutations in Pakistani families affected with arRP. In 2019, we recruited two unrelated Pakistani consanguineous families affected with progressive vision loss and night blindness from Punjab region. Clinical diagnosis confirmed the; bone spicule pigmentation of the retina, and an altered electroretinogram (EGR) response. Proband and healthy individual from each family were subjected for whole-exome sequencing (WES). Various computational tools were used to analyze the Next Generation Sequencing (NGS) data and to predict the pathogenicity of the identified mutations. WES data analysis highlighted two missense homozygous variants at position c.T1405A (p.S469T) in PLCE1 and c.T11C (p.V4A) in HPS1 genes in proband of both families. Healthy individuals of two families were tested negative for p.S469T and p.V4A mutations. The variant analysis study including molecular dynamic simulations predicted mutations as disease causing. Compound effect of mutations in rarely linked PLCE1 and HPS1 genes could also cause RP. This study highlights the potential application of WES for a rapid and precise molecular diagnosis for heterogeneous genetic diseases such as RP.

Hermansky-Pudlak syndrome: Gene therapy for pulmonary fibrosis.

Pulmonary fibrosis is a progressive and often fatal lung disease that manifests in most patients with Hermansky-Pudlak syndrome (HPS) type 1. Although the pathobiology of HPS pulmonary fibrosis is unknown, several studies highlight the pathogenic roles of different cell types, including type 2 alveolar epithelial cells, alveolar macrophages, fibroblasts, myofibroblasts, and immune cells. Despite the identification of the HPS1 gene and progress in understanding the pathobiology of HPS pulmonary fibrosis, specific treatment for HPS pulmonary fibrosis is not available, emphasizing the need to identify cellular and molecular targets and to develop therapeutic strategies for this devastating disease. This commentary summarizes recent advances and aims to provide insights into gene therapy for HPS pulmonary fibrosis.

Oculocutaneous albinism and bleeding diathesis due to a novel deletion in the HPS3 gene.

Hermansky–Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism (OCA) and bleeding diathesis. To date, 11 HPS types have been reported (HPS-1 to HPS-11), each defined by disease-causing variants in specific genes. Variants in the HPS1 gene were found in approximately 15% of HPS patients, most of whom harbor the Puerto Rican founder mutation. In this study, we report six affected individuals from three nonconsanguineous families of Ashkenazi Jewish descent, who presented with OCA and multiple ecchymoses and had normal platelet number and size. Linkage analysis indicated complete segregation to HPS3. Sequencing of the whole coding region and the intron boundaries of HPS3 revealed a heterozygous c.1163+1G>A variant in all six patients. Long-range PCR amplification revealed that all affected individuals also carry a 14,761bp deletion that includes the 5′UTR and exon 1 of HPS3, encompassing regions with long interspersed nuclear elements. The frequency of the c.1163+1G>A splice site variant was found to be 1:200 in the Ashkenazi Jewish population, whereas the large deletion was not detected in 300 Ashkenazi Jewish controls. These results present a novel HPS3 deletion mutation and suggest that the prevalence of HPS-3 in Ashkenazi Jews is more common than previously thought.

Genetic analyses of Vietnamese patients with oculocutaneous albinism.

BackgroundOculocutaneous albinism (OCA) is an autosomal recessive disease with hypopigmentation in skin, hair, and eyes, causing by the complete absence or reduction of melanin in melanocytes. Many types of OCA were observed based on the mutation in different causing genes relating to albinism. OCA can occur in non‐syndromic and syndromic forms, where syndromic OCA coexists with additional systemic consequences beyond hypopigmentation and visual‐associated symptoms.MethodsWe performed whole exome sequencing in seven affected individuals (P1‐P7) for mutation identification, and then, Sanger sequencing was used for verifications.ResultsAmong them, five patients (P1‐P5) have mutations on TYR gene including c.346C > T, c.929insC, c.115 T > C, and c.559_560ins25. The mutation on OCA2 and HPS1 genes was found in patient 6 (P6, OCA2 c.2323G > A) and patient 7 (P7, HPS1 c.972delC), respectively. Confirmation in parents (except the family of the elderly patient, P5) showed that the mother and the father in each family carried one of the variants that were detected in patients. Additionally, the effective genetic counseling was applied in the third pregnancy of a family with two OCA children (P1 and P2).ConclusionTo our best knowledge, this is the first case with a novel homozygous missense mutation (c.115 T > C, p.W39R) in the TYR gene. This study provides a broader spectrum of mutations linked to the oculocutaneous albinism, an additional scientific basis for diagnosis, and appropriate genetic counseling for risk couples.

Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families.

Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA.

Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7).

Hermansky-Pudlak syndrome (HPS), a rare heterogeneous autosomal recessive disorder, is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis due to a defect regarding melanosomes and platelet delta (δ)-granule secretion. Interestingly, patients with HPS type 2 (HPS-2) or HPS type 10 (HPS-10) present additionally with an immunological defect. We investigated three patients (IP1, IP2, and IP3) who suffer from a bleeding diathesis. Platelet aggregometry showed impaired platelet function and flow cytometry revealed a severely reduced platelet CD63 expression hinting to either a defect of platelet delta granule secretion or a decreased number of delta granules in these patients. However, only IP3 presents with an apparent OCA. We performed panel sequencing and identified a homozygous deletion of exon 6 in DTNBP1 for IP3. Western analysis confirmed the absence of the encoded protein dysbindin confirming the diagnosis of HPS-7. Interestingly, this patient reported additionally recurrent bacterial infections. Analysis of lymphocyte cytotoxicity showed a slightly reduced NK-degranulation previously documented in a more severe form in patients with HPS-2 or HPS-10. IP1 is carrier of two compound heterozygous variants in the HPS3 gene (c.65C > G and c.1193G > A). A homozygous variant in HPS5 (c.760G > T) was identified in IP2. The novel missense variants were classified as VUS (variant of uncertain significance) according to ACMG guidelines. For IP1 with the compound heterozygous variants in HPS3 a specialized ophthalmological examination showed ocular albinism. HPS3 and HPS5 encode subunits of the BLOC-2 complex and patients with HPS-3 or HPS-5 are known to present with variable/mild hypopigmentation.

Genetic Variability in Slovenian Cohort of Patients with Oculocutaneous Albinism

Oculocutaneous albinism (OCA) is an inherited disorder affecting the visual system and skin pigmentation. Our aim was to evaluate genetic and clinical heterogeneity in a cohort of Slovenian paediatric patients with clinically suspected OCA using advanced molecular-genetics approach. In as much as 20 out of 25 patients, genetic variants explaining their clinical phenotype were identified. The great majority of patients (15/25) had genetic variants in TYR gene associated with OCA type 1, followed by variants in TYRP1, SLC45A2 and HPS1 genes causative for OCA3, OCA4 and Hermansky-Pudlak syndrome type 1, respectively. We concluded that OCA phenotype could not predict genotype and vice versa. Nevertheless, the diagnostic yield after targeted next generation sequencing (NGS) was 80% and proved to be affective in our paediatric cohort of patients with various degree of OCA. Even in 16 patients with normal complexion the diagnostic yield was 62,5%. Interestingly, we have identified a patient of white European ancestry with OCA3, which is an extremely rare report, and one patient with OCA due to the Hermansky-Pudlak syndrome type 1.

P360 Aggressive Inflammatory Bowel Disease is associated to Hermansky-Pudlak Syndrome: Characterization of a Puerto Rican Cohort

Abstract Background Hermansky-Pudlak Syndrome (HPS), a rare autosomal recessive disorder, is the most common single-gene disorder in Puerto Rico. It is characterized by an aberrant biogenesis of lysosome-related organelles inducing oculocutaneous albinism, bleeding diathesis, and damage to other organs. Around 30% of patients with HPS develop granulomatous enterocolitis, a Crohn’s-like inflammatory bowel disease (IBD). The mutant HPS1 gene is associated with a more severe Early Onset IBD (EO-IBD). We wish to describe a group of patients with HPS-associated IBD. Methods Puerto Ricans with HPS and concomitant IBD were recruited in our IBD clinic for a prospective cohort study. After informed consent, demographic and medical data were collected from the patient and the medical record. Variables included sex, HPS genotype, age at the time of IBD diagnosis, IBD location and behavior according to Montreal and Paris Classification, surgical interventions, medications, and extra-intestinal manifestations (EIM). Descriptive analysis was performed calculating mean and standard deviations. This study is approved by the MSC IRB. Results 13 patients with HPS and IBD, 9 with confirmed genotype 1, were identified: 8 males and 5 females. The mean age at the time of IBD diagnosis was 22 ± 11 years. 6 were diagnosed at ≤ 16 y/o (A1), 6 were diagnosed between 17-40 years (A2) and 1 patient was in the range of EO-IBD (7 y/o). 9 patients had advanced penetrating behavior (B3) of which 7 had concomitant perianal involvement. Most patients (9) had a surgical intervention; 8 have an ostomy. The majority (10) are using biologics (4 with concurrent immunomodulators). The most frequent EIM was peripheral arthropathy seen in 45%. Conclusion HPS patients had a severe course of IBD, as shown by age at diagnosis, phenotype, the prevalence of perianal disease, surgery and use of biologics. In comparison to a database of 836 Puerto Ricans with non HPS Crohn’s Disease, those with HPS were more likely to have surgeries (69% vs 55%, P=.303) and use biologics (77% vs 43%, P=.015). Gastrointestinal symptoms including bleeding may be overlooked by the primary physician. Proactive vigilance in patients with HPS to make an early diagnosis of IBD and aggressive medical treatment may result in better outcomes for these patients.

Hermansky-Pudlak Syndrome and Genetic Diagnosis

Hermansky-Pudlak Syndrome (HPS) is genodermatosis, which is one of syndromic Oculo-Cutaneous Albinism (OCA). OCA categorizes 9 genes, and patients with mutations in HPS1 gene have greater likelihood of pulmonary fibrosis and granulomatous colitis for their 40s. In Juntendo university hospital, 39 patients had diagnosed as OCA during past 20 years. Only 5 patients were conducted gene analysis. 3 patients were OCA1B, and 2 patients were HPS1. In OCA patients, there are some gene mutations which onset serious complications. Early diagnosis by genetic test and early treatment is important.

Hermansky-Pudlak syndrome-associated pneumothorax with rapid progression of respiratory failure: a case report

BackgroundHermansky-Pudlak syndrome (HPS) is an extremely rare disease with pulmonary fibrosis (PF), oculocutaneous albinism, induced platelet dysfunction, and granulomatous colitis. Although patients with HPS-associated PF (HPS-PF) often receive treatment with anti-fibrotic agents, including pirfenidone, many HPS-PF cases are progressive. The development of pneumothorax is known to be rare in HPS-PF. Pneumothorax development is generally important for prognosis in patients with interstitial pneumonia. However, there are few reports regarding the development of pneumothorax in patients with HPS-PF.Case presentationA 50-year-old Japanese man with chestnut hair, white skin, and light brown squint eyes visited our hospital for interstitial pneumonia examination. Chest high-resolution computed tomography (HRCT) demonstrated diffuse bilateral reticular opacities along the bronchovascular bundles and traction bronchiectasis predominantly in the upper lung fields. He was definitively diagnosed with HPS because genetic analysis showed that he had a homozygous mutation, c.398 + 5G > A, in the HPS-1 gene. After diagnosis with HPS-PF, he initiated home oxygen therapy due to gradually progressive hypoxemia.Three months after the HPS-PF diagnosis, the patient suddenly developed severe chest pain and dyspnea and was admitted to our hospital on emergency. He was diagnosed with pneumothorax by chest radiological findings. He immediately received chest drainage; however, his pneumothorax did not improve. Therefore, he underwent video-assisted surgery by thoracic surgeons. The leak point was not detected, but multiple bullae were found, mainly in the upper lung lobes. Thus, the surgeons did not perform bullectomy and only covered the apical areas. Fifteen days after the surgery, the patient developed high fever and dyspnea with a new diffuse reticular shadow found through HRCT. We first initiated the patient on broad-spectrum antibiotics; however, the symptoms and radiological findings worsened. Therefore, we started treatment with pirfenidone for inhibition of PF progression. The patient re-developed pneumothorax with severe respiratory failure. Although he re-underwent chest drainage, he died of progressive respiratory failure.ConclusionsWe herein report the case of a rare HPS patient who developed pneumothorax with progressive PF. Pneumothorax may cause rapid progressive respiratory failure and may be associated with PF progression in HPS-PF.

Novel Brown Coat Color (Cocoa) in French Bulldogs Results from a Nonsense Variant in HPS3.

Brown or chocolate coat color in many mammalian species is frequently due to variants at the B locus or TYRP1 gene. In dogs, five different TYRP1 loss-of-function alleles have been described, which explain the vast majority of dogs with brown coat color. Recently, breeders and genetic testing laboratories identified brown French Bulldogs that did not carry any of the known mutant TYRP1 alleles. We sequenced the genome of a TYRP1+/+ brown French Bulldog and compared the data to 655 other canine genomes. A search for private variants revealed a nonsense variant in HPS3, c.2420G>A or p.(Trp807*). The brown dog was homozygous for the mutant allele at this variant. The HPS3 gene encodes a protein required for the correct biogenesis of lysosome-related organelles, including melanosomes. Variants in the human HPS3 gene cause Hermansky–Pudlak syndrome 3, which involves a mild form of oculocutaneous albinism and prolonged bleeding time. A variant in the murine Hps3 gene causes brown coat color in the cocoa mouse mutant. We genotyped a cohort of 373 French Bulldogs and found a strong association of the homozygous mutant HPS3 genotype with the brown coat color. The genotype–phenotype association and the comprehensive knowledge on HPS3 function from other species strongly suggests that HPS3:c.2420G>A is the causative variant for the observed brown coat color in French Bulldogs. In order to clearly distinguish HPS3-related from the TYRP1-related brown coat color, and in line with the murine nomenclature, we propose to designate this dog phenotype as “cocoa”, and the mutant allele as HPS3co.

A Novel Non-Sense Mutation in a Senegalese Patient with Hermansky-Pudlak Type 1 Syndrome

Hermansky-Pudlak syndrome (HPS) is a rare inherited multisystem disorder characterized by oculocutaneous albinism and diathesis, and in some patients with pulmonary fibrosis. It is caused by defective biogenesis and trafficking of lysosome-related organelles. Genetically HPS is heterogeneous, and ten loci have been identified as causative genes. The majority of these genes encode subunits of multi-protein complexes named biogenesis of lysosomes-related organelles complex. Mutations within HPS1 and HPS4 genes lead to pulmonary fibrosis in HPS type1 and type 4 patients respectively and are the leading cause of mortality. A 14 years Senegalese boy who was initially diagnosed with oculocutaneous albinism was recruited with his father after informed consent for genetic analysis. In his clinical history, there was no bleeding tendency or clinical episodes of hemorrhagic diathesis. One of his sisters had albinism and died from lung complications at the age of 15 years. The patient was referred to the pneumology department of Fann Hospital in Dakar for further explorations. The high-resolution computed tomography (HRCT) scans of the lungs revealed no evidence of diffuse interstitial lung disease, pleuropericardial effusion, bronchiectasis, pulmonary hypertension, intra pulmonary/mediastinal mass or lymphadenopathy. Mutation screening by Albinism NGS panel identified a homozygous mutation located in exon 6 of the HPS1 gene, c.421C>T (p.Gln141*), in the Proband while his father showed heterozygosity for this mutation. The parents of the proband are not consanguineous and this may suggest a common allele of HPS1 among Senegalese people. Patients with oculocutaneous albinism should therefore be evaluated for Hermansky-Pudlak syndrome by mutational screening within the ten HPS genes.

Novel genetic variant of HPS1 gene in Hermansky-Pudlak syndrome with fulminant progression of pulmonary fibrosis: a case report

BackgroundHermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease.Case presentationA 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics.ConclusionsCompound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.