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.
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.
Seri
Marco
M
Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy.
Pecci
Alessandro
A
Di Bari
Filomena
F
Cusano
Roberto
R
Savino
Maria
M
Panza
Emanuele
E
Nigro
Alessandra
A
Noris
Patrizia
P
Gangarossa
Simone
S
Rocca
Bianca
B
Gresele
Paolo
P
Bizzaro
Nicola
N
Malatesta
Paola
P
Koivisto
Pasi A
PA
Longo
Ilaria
I
Musso
Roberto
R
Pecoraro
Carmine
C
Iolascon
Achille
A
Magrini
Umberto
U
Rodriguez Soriano
Juan
J
Renieri
Alessandra
A
Ghiggeri
Gian Marco
GM
Ravazzolo
Roberto
R
Balduini
Carlo L
CL
Savoia
Anna
A
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
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains