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Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
Hemophagocytic lymphohistiocytosis associated with hypopigmentation are a cluster of disorders resulting in defects in lysosomal trafficking modulators. These conditions include Chediak-Higashi syndrome, Griscelli syndrome, and Hermansky Pudlak syndrome. All are the result in abnormal assembly of cytoplasmic granules and fusion with phagosomes leading to abnormal NK, cytotoxic T cell, and granulocyte function due to failure to form the phagolysosome. Clinical manifestations include mucocutaneous albinism (Chediak-Higashi syndrome), abnormal hair structure and color (Griscelli syndrome), recurrent neutropenia, fever, hepatosplenomegaly and lymphadenopathy, and hemophagocytic lymphohistiocytosis following infections. Patients with Chediak-Higashi syndrome have morphological abnormalities in the PMN leukocytes (giant lysosomes), a finding that supports the diagnosis. Patients with Hermansky-Pudlak syndrome have partial albinism, nystagmus, and optic nerve abnormalities.
The skin
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
In the latter type, the pigmentation of hair and iris gradually increases, and mild cases may easily be missed. Marriages between albinos of different types will result in all normal offspring as long as the disorders really are not allelic (i.e. are between one person with mutations in TYR and another with mutations in OCA2). A very rare type, associated with a bleeding diathesis (Hermansky-Pudlak syndrome), is also autosomal recessive. Prenatal detection of severe oculocutaneous albinism may be relevant in tropical countries where the morbidity is high. DNA analysis is much simpler (and can be performed much earlier in pregnancy) than the use of fetal skin biopsy, although molecular testing may not be so easy to access in some of the tropical countries where albinism is especially difficult to manage. It also seems likely that some of the more common genetic variants of pigmentation will be relevant to skin cancer susceptibility.
Hermansky-Pudlak syndrome, Chediak-Chigasi syndrome, and Griscelli syndrome
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Vesna Pljakoska, Silvija Duma, Andrej Petrov
Hermansky-Pudlak syndrome is a rare hereditary disorder, with a worldwide prevalence of 1–9 in 1,000,000 individuals,4 though prevalence differs per subtype and region. The disorder is more commonly found in certain populations of the world. For example, the prevalence of certain subtypes of HPS is significantly higher in Puerto Rico.5 Individuals with HPS have also been identified in other regions, including China, India, South America, and Western Europe. Although initial symptoms usually appear in infancy or early childhood, they may develop at an older age as well. The prognosis for patients with HPS varies depending on the subtype. The course of subtypes 3, 5, and 6, or HPS without pulmonary fibrosis as a complication, is mild with no pulmonary involvement. Prognosis of subtypes 1, 2, and 4 is poor, as pulmonary fibrosis is fatal.4
Novel variant in HPS3 gene in a patient with Hermansky Pudlak syndrome (HPS) type 3
Published in Platelets, 2020
Anna Lecchi, Silvia La Marca, Eti A Femia, Antonia Lenz, Doris Boeckelmann, Andrea Artoni, Flora Peyvandi, Barbara Zieger
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder first described in 1959 [1] associated with variants in 10 known human genetic loci (HPS1-10). The proteins encoded by these genes are part of four known multi-protein complexes called Biogenesis of Lysosome-related Organelles Complexes (BLOC-1, −2, −3) and Adapter Protein (AP-3). Clinical presentation varies and depends on which of HPS genes is mutated [2–9]. Patients with defects in proteins building the same multi-protein complex are likely to have a similar clinical phenotype (e.g., BLOC-3: HPS1, HPS4; BLOC-2: HPS3, HPS5, HPS6) [10]. HPS is characterized by impaired biogenesis and function of specialized/secretory lysosomes and lysosome-related organelles like melanosomes and platelet δ-granules leading to defective trafficking of intracellular vesicles [2,11]. The classical symptoms of HPS comprise oculocutaneous albinism (OCA) (with iris transillumination, congenital nystagmus, lower visual acuity, and skin pigmentation loss), mild to severe bleeding diathesis, sometimes associated with serious complications, such as granulomatous colitis and/or pulmonary fibrosis [12–15], immunodeficiency (only for HPS2 and HPS10) [4,16].
Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing
Published in Annals of Medicine, 2019
Jose María Bastida, Sara Morais, Veronica Palma-Barqueros, Rocio Benito, Nuria Bermejo, Mutlu Karkucak, Maria Trapero-Marugan, Natalia Bohdan, Mónica Pereira, Ana Marin-Quilez, Jorge Oliveira, Yusuf Yucel, Rosario Santos, Jose Padilla, Kamila Janusz, Catarina Lau, Marta Martin-Izquierdo, Eduarda Couto, Juan Francisco Ruiz-Pividal, Vicente Vicente, Jesus Maria Hernández-Rivas, Jose Ramon González-Porras, Maria Luisa Lozano, Margarida Lima, Jose Rivera
Hermansky-Pudlak syndrome is a rare genetic disorder presenting with hypopigmentation, bleeding diathesis, and organ dysfunction secondary to the accumulation of ceroid-like material and resultant tissue damage. Variants in one of the ten currently known genes can result in this autosomal recessive disorder. Molecular analysis is useful in confirming the diagnosis and may offer some prognostic information that will aid in optimizing monitoring and surveillance for early detection of end-organ damage. Given the poor genotype-phenotype correlation, a sequential assessment of the most likely genes can be lengthy and expensive. A target gene panel analyzed by HTS can be considered and could be used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS. Our findings also expand the mutational spectrum of HPS, which may help in investigating phenotype-genotype relationships and assist genetic counselling for affected individuals.
Chronic interstitial lung diseases in children: diagnosis approaches
Published in Expert Review of Respiratory Medicine, 2018
Nadia Nathan, Laura Berdah, Keren Borensztajn, Annick Clement
Several metabolic disorders can be associated with ILD. Among them, Gaucher’s disease, an autosomal recessive disease is the most common lysosomal storage diseases. It is caused by a genetic deficiency of the gluco-cerebrosidase lysosomal enzyme that catalyzes the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. Niemann-Pick diseases (A, B, C) are rare genetic diseases primarily due to deficiency of sphingomyelinase resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte systems of multiple organs, mainly the brain, spleen, liver, lung, and bone marrow. Histology demonstrates lipid laden macrophages in the marrow, as well as ‘sea-blue histiocytes’ on pathology [48]. Hermansky-Pudlak syndrome is a heterogeneous group of autosomal recessive disorders associated with accumulation of a ceroid-like substance in lysosomes of a variety of tissues. It is characterized by albinism, bleeding tendency associated to poor platelet aggregation, and systemic complications associated to lysosomal dysfunction [49].