Hermansky–Pudlak Syndrome Type 6 Accompanied with Bowel Vascular Malformation: Clinical Case

Background. Hermansky–Pudlak syndrome type 6 is rare hereditary disease caused by pathogenic variants in base sequence, deletions, and insertions in the HPS6 gene encoding the transmembrane protein of the same name. This disease occurs with hemorrhagic syndrome, oculocutaneous albinism, and inflammatory bowel diseases (in some cases). The clinical picture of the disease, including the gastrointestinal tract pathology, has not been studied completely due to the syndrome rarity.Clinical case description. We would like to present the description of clinical case of the patient with Hermansky–Pudlak syndrome type 6 accompanied with bowel vascular malformation. The patient diagnosed with “oculocutaneous albinism” at the age of 4.5 has shown recurrent intestinal bleedings, blood hemoglobin concentration decrease to 45 g/l; platelet count, mean platelet volume and platelet distribution width remained within the reference values. Slight decrease of Quick’s value to 68% (normal range 70–120%) was revealed. The study of platelet morphology has revealed a decrease in the number of dense granules: < 3 in 25% platelets, < 6 — in 64%. Ultrasound investigation has revealed signs of vascular malformation in ascending colon: significant changes of diameter (widening) and shape of intestinal wall vessels. Molecular genetic analysis (NGS) has revealed the nucleotide variant c.1133T>G (p.Leu378Arg) in homozygous state in the HPS6 gene. The same variant in homozygous state was revealed in the younger proband sister who also had vascular changes in the ascending colon wall.Conclusion. Differential diagnosis of Germanic–Pudlak syndrome type 6 should be performed with other types of this syndrome as well as with syndrome and non-syndrome forms of oculocutaneous albinism. Molecular genetic confirmation of the diagnosis is suggested via massive parallel sequencing (NGS) methods (exome sequencing included) due to the rarity of Hermansky–Pudlak syndrome.

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New Deletions in the Hermansky-Pudlak Syndrome Type 5 Gene in a Japanese Patient

Reports ◽

10.3390/reports2020015 ◽

2019 ◽

Vol 2 (2) ◽

pp. 15

Author(s):

Shinya Kato ◽

Tsugumi Aoe ◽

Akie Hamamoto ◽

Hiroshi Takemori ◽

Toshiya Nishikubo

Keyword(s):

Visual Acuity ◽

Rare Disease ◽

Japanese Patient ◽

Oculocutaneous Albinism ◽

Syndrome Type ◽

Adapter Protein ◽

Prolonged Bleeding ◽

First Case ◽

Hermansky Pudlak Syndrome ◽

Lysosome Related Organelles

The Hermansky-Pudlak syndrome (HPS) is a rare disease characterized by oculocutaneous albinism and prolonged bleeding. HPS is caused by alterations in HPS1-10 and their related genes, comprising the biogenesis of lysosome-related organelles complex 1–3 and adapter protein 3. Here, we report a Japanese patient with HPS associated with mild hypopigmentation, nystagmus, and impaired visual acuity. Sequencing analyses of the mRNA of this patient revealed new deletions (ΔGA and ΔG) in the HPS5 gene. This was the first case of HPS5 gene deficiency in Japan, and the two above-mentioned deletions have not yet been reported among patients with HPS5.

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Patients with Hermansky-Pudlak Syndrome Show Various Phenotypes Caused by Novel Mutations,

Blood ◽

10.1182/blood.v118.21.3286.3286 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3286-3286

Author(s):

Kirstin Sandrock ◽

Karin Kurnik ◽

Stephan Ehl ◽

Christoph Bidlingmaier ◽

Lea Nakamura ◽

...

Keyword(s):

Flow Cytometry ◽

Mental Retardation ◽

Molecular Genetic ◽

Oculocutaneous Albinism ◽

The Other ◽

Chromosome 17 ◽

Flow Cytometry Analysis ◽

Platelet Aggregometry ◽

Hermansky Pudlak Syndrome ◽

Granule Secretion

Abstract Abstract 3286 Background: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder causing oculocutaneous albinism, bleeding disorder and ceroid lipofuscinosis. Platelets from HPS patients are characterized by impaired secretion of dense (δ)-bodies (CD63). Neutropenia and susceptibility to recurrent infections were exclusively observed in HPS2 patients so far. There are eight known human HPS genes (HPS1-HPS8), each leading to a particular clinical HPS subtype (HPS1-HPS8). Patients/Results: The patients show a typical HPS phenotype concerning oculocutaneous albinism and bleeding symptoms. In vivo-, in vitro bleeding time and platelet aggregometry analyses revealed impaired platelet function. We identified HPS3 in two Turkish brothers and HPS2 in a girl from the United Emirates. Both brothers with HPS3 demonstrated absence of platelet δ-granule secretion measured by flow cytometry analysis. A novel 1 bp-deletion in the HPS3 gene was identified in both brothers. In addition, one brother with HPS3 demonstrated psychomotoric retardation. MRI scan revealed cranial gliosis. Interestingly, array-CGH analysis revealed a 0.7 Mb deletion on chromosome 17 which had not been identified in the other brother and which seems to have caused the cranial gliosis. The girl with HPS2 suffered from life-threatening bleeding after tonsillectomy leading to severe asphyxia, resuscitation and finally, to mental retardation. Flow cytometry analysis demonstrated impaired platelet δ-granule secretion with a typical pattern for HPS2. CD63 expression was already increased on resting platelets, but there was only little increase after thrombin stimulation. Interestingly, only a NK-CD107 partial degranulation defect was diagnosed. So far, clinical symptoms of immunodeficiency are not obvious. Molecular genetic analyses revealed a novel 2 bp-deletion in the last exon of HPS2 leading to a frameshift and a prolonged altered protein. The location of the deletion at the very C-terminal end may prevent a complete loss of the HPS2 protein leading to a less pronounced severity of immunodeficiency as in other HPS2 patients. Conclusion: Patients with oculocutaneous albinism should be investigated for increased clinical bleeding symptoms. In case of increased bleeding symptoms, analyses of primary hemostasis should be initiated to confirm HPS. Using flow cytometry analyses HPS2 can be distinguished from the other subtypes of HPS. Molecular genetic investigations should be performed to differentiate the various subtypes of HPS which is important for therapy and prognosis. The HPS3 patient`s mental retardation seemed to be caused by an additional deletion. The identification of the molecular genetic defect helps to understand the patients` various clinical phenotypes. Disclosures: Zieger: Novo Nordisk: Research Funding.

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A Case of Hermansky Pudlak Syndrome Type 2

Blood ◽

10.1182/blood.v118.21.4919.4919 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4919-4919

Author(s):

Vandana Bharadwaj ◽

Andrew Mumford ◽

Josu de la Fuente ◽

Subarna Chakravorty

Keyword(s):

Molecular Genetic ◽

Female Infant ◽

Severe Neutropenia ◽

Target Cells ◽

Lymphocyte Function ◽

Syndrome Type ◽

Chromosome 5 ◽

Immune Disorder ◽

Hermansky Pudlak Syndrome

Abstract Abstract 4919 Hermansky Pudlak Syndrome (HPS) is a genetically heterogeneous group of rare disorders that are classified as ‘lysosome biogenesis disorders’ and are characterized by variegated pigmentation, variable immune deficiencies, and platelet dysfunction. There are 8 known variants of HPS in humans. Lysosomes are membrane-bound organelles that contain hydrolytic enzymes necessary for intracellular degradation and represent the main cellular degradation compartment within the vacuolar system of the eukaryotic cell 1. Biogenesis of lysosomes partly depends on the function of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), −2, and −3 proteins2. The mutated proteins known to give rise to the HPS variants occur in one or more of the cytosolic BLOC complexes, each being composed of different proteins, including the Adaptor Proteins 1–4 (AP1-4) 3. Also, since mutations in the AP3B1 gene encoding the b subunit of the AP3 complex cause the only HPS subtype which is associated with an immune disorder along with other lysosomal abnormalities 4, this indicates that AP3 is important for lysosome function within the immune system. In the absence of AP3, cytotoxic T lymphocyte (CTL) mediated killing is severely impaired and cytotoxic lysosomal granules are unable to move along microtubules when the CTL recognizes target cells 5. We report a case of Hermansky Pudlak Syndrome Type 2 in a consanguineous female infant of Arabic origin who presented with severe sepsis, occulocutaneous albinism, platelet nucleotide deficiency, neutropaenia and a homozygous balanced inversion of chromosome 5; inv(5)(p15q13). Further molecular genetic analysis revealed a breakpoint in the AP3B1 gene, thereby confirming a genetic diagnosis of HPS2. Case Report: A five month old female infant presented with respiratory sepsis requiring ventilation. Clinical examination revealed occulocutaneous albinism (Figure 1) and hepatosplenomegaly. Laboratory data revealed severe neutropenia (0.2×109/l), CD4 lymphopaenia (446/microlitre), normal immunoglobulins, marked reduction of platelet nucleotides and abnormal platelet aggregation studies. There was no evidence of haemophagocytic syndrome at presentation. Neutrophil activity was normal and there was no evidence of B-cell dysfunction. Unexpectedly, her CTLs demonstrated normal lysosomal granule release on activation. Karyotyping showed pericentric balanced inversion in chromosome 5, inv (5)(p15q13). Parental karyotyping revealed heterozygous inversion of chromosome 5 at the same breakpoint. Array comparative genomic hybridization confirmed absence of copy number gain or loss in the inversion. Bacterial artificial chromosome cloning using Fluorescent in situ hybridization confirmed the breakpoint to be within the APB3B1 gene. She made a good recovery from her initial sepsis and continues to remain neutropaenic and CD4 lymphopaenic on follow up for 12 months, and has required a number of admissions with viral sepsis (adenovirus and respiratory syncitial virus). In summary, this is a first report of homozygous pericentric balanced inversion of chromosome 5 inv(5)(p15q13), leading to disruption of the AP3B1 gene, giving rise to a clinical phenotype of Hermansky Pudlak Syndrome Type 2. The normal cytotoxic lymphocyte function remains unexplained. Further molecular genetic work is in progress to map the breakpoint in the AP3B1 gene and the corresponding gene(s) involved in the inversion. Disclosures: No relevant conflicts of interest to declare.

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Genetic Variability in Slovenian Cohort of Patients with Oculocutaneous Albinism

Acta Chimica Slovenica ◽

10.17344/acsi.2021.6690 ◽

2021 ◽

Vol 68 (3) ◽

pp. 683-692

Author(s):

Tinka Hovnik ◽

Maruša Debeljak ◽

Manca Tekavčič Pompe ◽

Sara Bertok ◽

Tadej Battelino ◽

...

Keyword(s):

Genetic Variants ◽

Diagnostic Yield ◽

Skin Pigmentation ◽

Great Majority ◽

Oculocutaneous Albinism ◽

European Ancestry ◽

Syndrome Type ◽

Targeted Next Generation Sequencing ◽

Hermansky Pudlak Syndrome

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.

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Genetic Testing for Oculocutaneous Albinism Type 1 and 2 and Hermansky–Pudlak Syndrome Type 1 and 3 Mutations in Puerto Rico

Journal of Investigative Dermatology ◽

10.1038/sj.jid.5700034 ◽

2006 ◽

Vol 126 (1) ◽

pp. 85-90 ◽

Cited By ~ 35

Author(s):

Pedro J. Santiago Borrero ◽

Yolanda Rodríguez-Pérez ◽

Jessicca Y. Renta ◽

Natalio J. Izquierdo ◽

Laura del Fierro ◽

...

Keyword(s):

Puerto Rico ◽

Genetic Testing ◽

Oculocutaneous Albinism ◽

Syndrome Type ◽

Hermansky Pudlak Syndrome

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Myotonic dystrophy Rossolimo-Churchman-Steinert-Batten (clinical case)

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.04.71-72 ◽

2020 ◽

pp. 71-72

Author(s):

И.А. Синельникова ◽

И.В. Сопрунова ◽

О.П. Николаева

Keyword(s):

Case Report ◽

Myotonic Dystrophy ◽

Clinical Case ◽

Molecular Genetic ◽

Ctg Repeats ◽

Molecular Genetic Method ◽

Genetic Method ◽

Family Case ◽

Dmpk Gene

В статье представлено описание семейного случая миотонической дистрофии Россолимо-Штейнерта-Куршмана-Баттена. Диагноз подтвержден в результате ДНК-диагностики: выявлено увеличенное число копий CTG-повтора гена DMPK, ответственного за развитие миотонической дистрофии. A family case report of Rossolimo-Steinert-Curschmann myotonic dystrophy is presented. An increased number of copies of CTG-repeats of the DMPK gene responsible for the development of MD, i.e., the diagnosis was confirmed by molecular genetic method.

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