title: MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.
abstract: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pecci
authors.forename: Filomena
authors.initials: F
authors.lastname: Di Bari
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.forename: Maria
authors.initials: M
authors.lastname: Savino
authors.forename: Emanuele
authors.initials: E
authors.lastname: Panza
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nigro
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
authors.forename: Simone
authors.initials: S
authors.lastname: Gangarossa
authors.forename: Bianca
authors.initials: B
authors.lastname: Rocca
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
authors.forename: Nicola
authors.initials: N
authors.lastname: Bizzaro
authors.forename: Paola
authors.initials: P
authors.lastname: Malatesta
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Koivisto
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Roberto
authors.initials: R
authors.lastname: Musso
authors.forename: Carmine
authors.initials: C
authors.lastname: Pecoraro
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.forename: Umberto
authors.initials: U
authors.lastname: Magrini
authors.forename: Juan
authors.initials: J
authors.lastname: Rodriguez Soriano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002386:Cataract / Q000150:complications; D002648:Child; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000150:complications; D006417:Hematuria / Q000150:complications; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains / Q000235:genetics*; D009393:Nephritis / Q000150:complications; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D011507:Proteinuria / Q000150:complications; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000145:classification* / Q000150:complications / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains