title: Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.
abstract: BACKGROUND
  The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of two genes (POLR3A and POLR3B) responsible for the syndrome demonstrates that these three main characteristics can be variably combined among "Pol-III (polymerase III)-related leukodystrophies."
  
  
  METHODS
  We report on the clinical, neuroradiological and endocrinological follow-up of a male affected by 4H syndrome with confirmed POLR3B mutations (c.1568 T > A/p.V523E variant in exon 15 and the novel c.1988C > T/p.T663I mutation in exon 19). Spastic-ataxic gait with worsening of motor performance, progressive moderate intellectual disability and language difficulties were the main neurological findings observed. The first six years of substantial stability of the clinical and imaging features were followed by additional six years that showed a progressive worsening of motor, language and learning disabilities in relation to a progression of the cerebellar involvement. Hypogonadotropic hypogonadism and growth hormone deficiency followed by central hypocortisolism became part of the patient's phenotype. Thyroid function resulted unaffected during follow up.
  
  
  CONCLUSIONS
  A novel mutation in POLR3B in a patient with an analogue phenotype than those previously described but with more extensive endocrinological features, including hypogonadotropic hypogonadism, growth hormone deficiency and hypocortisolism, was described. These findings permit to better define the clinical spectrum of the disease, to direct specific genetic tests and to tailor clinical management.
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Viale del Tirreno 331, 56128, , Calambrone, Pisa, Italy. r.battini@fsm.unipi.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.affiliation: Department of Obstetrics, Gynecology, and Pediatrics, Pediatric Division, Santa Chiara University Hospital, Pisa, Italy. s.bertelloni@med.unipi.it.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bertelloni
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Viale del Tirreno 331, 56128, , Calambrone, Pisa, Italy. g.astrea@fsm.unipi.it.
authors.forename: Guja
authors.initials: G
authors.lastname: Astrea
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Viale del Tirreno 331, 56128, , Calambrone, Pisa, Italy. m.casarano@fsm.unipi.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Casarano
authors.affiliation: Laboratory of Molecular Medicine, Ospedale Bambino Gesù Research Chidren's Hospital, Rome, Italy. lorena.travaglini@opbg.net.
authors.forename: Lorena
authors.initials: L
authors.lastname: Travaglini
authors.affiliation: Department of Obstetrics, Gynecology, and Pediatrics, Pediatric Division, Santa Chiara University Hospital, Pisa, Italy. g.baroncelli@med.unipi.it.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Baroncelli
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Viale del Tirreno 331, 56128, , Calambrone, Pisa, Italy. robrain76@virgilio.it.
authors.forename: Rosa
authors.initials: R
authors.lastname: Pasquariello
authors.affiliation: Laboratory of Molecular Medicine, Ospedale Bambino Gesù Research Chidren's Hospital, Rome, Italy. enricosilvio.bertini@opbg.net.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Viale del Tirreno 331, 56128, , Calambrone, Pisa, Italy. g.cioni@fsm.unipi.it.|Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. g.cioni@fsm.unipi.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cioni
mesh_terms: D000848:Anodontia / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002648:Child; D005500:Follow-Up Studies; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D056784:Leukoencephalopathies / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D064926:Neurophysiological Monitoring; D010641:Phenotype