International Journal of Molecular Sciences Review Inherited Platelet Disorders: An Updated Overview Verónica Palma-Barqueros 1, Nuria Revilla 2, Ana Sánchez 1, Ana Zamora Cánovas 1, Agustín Rodriguez-Alén 3 , Ana Marín-Quílez 4, José Ramón González-Porras 4, Vicente Vicente 1 , María Luisa Lozano 1,† , José María Bastida 4,5,† and José Rivera 1,5,*,† 1 Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, 30008 Murcia, Spain; [email protected] (V.P.-B.); [email protected] (A.S.); [email protected] (A.Z.C.); [email protected] (V.V.); [email protected] (M.L.L.) 2 Servicio de Hematología, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; [email protected] 3 Servicio de Hematología, Hospital Virgen de la Salud, Complejo Hospitalario de Toledo, 45071 Toledo, Spain; [email protected] 4 Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain; [email protected] (A.M.-Q.); [email protected] (J.R.G.-P.); [email protected] (J.M.B.) 5 Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC), Sociedad Española de Trombosis y Hemostasia (SETH), 28006 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-(96)-834-1990; Fax: +34-(96)-826-1914 † These authors share senior authorship. Abstract: Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate Citation: Palma-Barqueros, V.; survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either Revilla, N.; Sánchez, A.; Zamora platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases Cánovas, A.; Rodriguez-Alén, A.; caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable Marín-Quílez, A.; González-Porras, according to the specific disease and even within the same type, ranging from almost negligible to J.R.; Vicente, V.; Lozano, M.L.; Bastida, life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), J.M.; et al. Inherited Platelet but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The Disorders: An Updated Overview. early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A Int. J. Mol. Sci. 2021, 22, 4521. genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to https://doi.org/10.3390/ijms22094521 proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these Academic Editor: Cristiano Fava diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients Received: 31 March 2021 should be informed and comprehend the potential implications of their genetic analysis. Unlike Accepted: 21 April 2021 the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Published: 26 April 2021 Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are Publisher’s Note: MDPI stays neutral therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized with regard to jurisdictional claims in hematology service with multidisciplinary support especially for syndromic IPDs is mandatory. published maps and institutional affil- iations. Keywords: congenital platelet disorders; inherited thrombocytopenias; platelet function disorders Copyright: © 2021 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. Inherited platelet disorders (IPD) comprise a heterogenous group of rare diseases This article is an open access article caused by molecular anomalies in genes that are relevant in platelet formation and/or distributed under the terms and function. The relevance of clinical complications in patients with these diseases is highly conditions of the Creative Commons variable, even within the same type, ranging from almost negligible to life-threatening. Attribution (CC BY) license (https:// Consequently, the early and accurate diagnosis of patients and their close medical follow- creativecommons.org/licenses/by/ up is long known to be of great importance [1]. At present, around 60 types of IPD due to 4.0/). Int. J. Mol. Sci. 2021, 22, 4521. https://doi.org/10.3390/ijms22094521 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4521 2 of 31 molecular defects in about 75 different genes have been recognised [2]. The true prevalence of each is unknown and, while it is estimated that they affect between 1:104 and 1:106 individual, more moderate disorders are certainly more common, since oftentimes patients go unnoticed for many years and even their entire lives. Noteworthy, a recent survey of the frequency in the general population of molecular variants in genes associated with platelet disorders, has revealed that about 3 in 1000 subjects have a clinically meaningful loss-of-function variant in genes involved in IPDs [3]. The two main groups of IPD are: i. Inherited thrombocytopenias, in which the most conspicuous defect is the low number of circulating normal-sized, large, or small platelets [4–6] (Figure1, Table1) ii. Inherited platelet function disorders, characterized by dysfunctional, typically hy- pofunctional, platelets resulting from defects of the membrane receptors, granules, elements involved in signal transduction, or other defects of the biochemical platelet machinery [7,8] (Figure1, Tables2–4) Thrombocytopenia and thrombocytopathy are typically associated. Figure 1. Inherited Platelet Disorders. The image shows the myriad of IPDs according to the protein and/or platelet function element which is affected by the genetic anomaly. Int. J. Mol. Sci. 2021, 22, 4521 3 of 31 Table 1. General features of inherited thrombocytopenias. Disease Type Inh. Gene Clinical & Laboratory Phenotype in Most Reported Cases Ref. (OMIM Code) Tcp/S/HM INHERITED THROMBOCYTOPENIAS WITH NORMAL PLATELET SIZE Very severe neonatal thrombocytopenia, amegakaryocytic; progression Congenital amegakaryocytic AR MPL S to aplastic anemia in childhood. [9,10] thrombocytopenia (CAMT) (604498) Severe bleeding tendency. Mono-allelic mutations are associated with mild thrombocytopenia. Bialellic mutations resemble CAMT. It does not respond to THPO-related thrombocytopenia AD/AR THPO S [11–13] allo-HSCTH but it responds to Romiplostim. Severe bleeding tendency. Severe neonatal thrombocytopenia; reduced/absent megakaryocytes. Radioulnar synostosis with Possible evolution to aplastic anemia in childhood. amegakaryocytic thrombocytopenia 1 AD HOXA11 S Radius and ulna synostosis with/without other skeletal alterations; [5,14] (RUSAT1, 605432) probable sensorineural hearing loss. Severe bleeding tendency. Severe neonatal thrombocytopenia. MECOM-related thrombocytopenia Reduced/absent megakaryocytes and/or hyporegenerative anemia. (including amegakaryocytic Radius and ulna synostosis with/without other skeletal alterations; AD MECOM S [15,16] thrombocytopenia 2 with Radioulnar B-cell deficiency. Possible renal or cardiac malformations and probable synostosis, (RUSAT2) (616738) sensorineural hearing loss. Severe bleeding tendency. Moderate-severe central neonatal thrombocytopenia that improves RBM8A (Microdeletion with age; bilateral absence of radius with or without other skeletal Thrombocytopenia with absent radii AR & rs139428292/ S abnormalities. Potential kidney, cardiac or central nervous [17] (TAR) (274000) rs201779890) system anomalies. Severe bleeding tendency. Mild-moderate neonatal thrombocytopenia. Platelet function defect “Aspirin-like”. Platelet granule deficiency. Familial platelet disorder with High risk (>40%) of acute myeloblastic leukemia or myelodysplastic propensity to acute myelogenous AD RUNX1 HM [18,19] syndrome at a young age; increases risk or lymphoblastic leukemia leukemia (FPD-AML) (601399) and solid tumor. Absent to moderate bleeding tendency. Mild-moderate neonatal thrombocytopenia. ANKRD26-related thrombocytopenia Some patients with high levels of hemoglobin and/or leukocytosis. AD ANKRD26 HM [18,20,21] (thrombocytopenia Type-2) (188000) Approximately 10% of patients acquire myeloid neoplasms. Absent to mild bleeding tendency. Int. J. Mol. Sci. 2021, 22, 4521 4 of 31 Table 1. Cont. Disease Type Inh. Gene Clinical & Laboratory Phenotype in Most Reported Cases Ref. (OMIM Code) Tcp/S/HM Red blood cells with high mean corpuscular volume. Platelets may show elongated α granules, impaired spreading and clot retraction. ETV6-related thrombocytopenia AD ETV6 HM High number of circulating CD34 + cells. Predisposition (30%) to [18,22,23] (thrombocytopenia Type-5) (616216) acquired lymphoid, myeloid, and myeloproliferative syndromes. Absent to mild bleeding tendency. Mild to moderate thrombocytopenia. Platelets with fewer α and IKZF5-related thrombocytopenia AD IKZF5 Tcp δ granules. [24] No bleeding tendency. Mild to moderate thrombocytopenia. May also present with CYCS-related thrombocytopenia AD CYCS Tcp