title: Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort.
abstract: OBJECTIVE
  Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations in these genes in a cohort of 144 unrelated Italian patients with CPHD and estimated the overall prevalence of mutations across different populations using a systematic literature review.
  
  
  METHODS
  A multicentre study of adult and paediatric patients with CPHD was performed. The PROP1, POU1F1, HESX1, LHX3 and LHX4 genes were analysed for the presence of mutations using direct sequencing. We systematically searched PubMed with no date restrictions for studies that reported genetic screening of CPHD cohorts. We only considered genetic screenings with at least 10 individuals. Data extraction was conducted in accordance with the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
  
  
  RESULTS
  Global mutation frequency in Italian patients with CPHD was 2·9% (4/136) in sporadic cases and 12·5% (1/8) in familial cases. The worldwide mutation frequency for the five genes calculated from 21 studies was 12·4%, which ranged from 11·2% in sporadic to 63% in familial cases. PROP1 was the most frequently mutated gene in sporadic (6·7%) and familial cases (48·5%).
  
  
  CONCLUSIONS
  The frequency of defects in genes encoding pituitary transcription factors is quite low in Italian patients with CPHD and other western European countries, especially in sporadic patients. The decision of which genes should be tested and in which order should be guided by hormonal and imaging phenotype, the presence of extrapituitary abnormalities and the frequency of mutation for each gene in the patient-referring population.
authors.affiliation: Unit of Paediatrics, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Rienzo
authors.affiliation: Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont and IRCAD, Novara, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Mellone
authors.affiliation: Unit of Paediatrics, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont and IRCAD, Novara, Italy.
authors.forename: Deepak
authors.initials: D
authors.lastname: Babu
authors.affiliation: Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont and IRCAD, Novara, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Fusco
authors.affiliation: Unit of Paediatrics, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Prodam
authors.affiliation: Unit of Paediatrics, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Petri
authors.affiliation: Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont and IRCAD, Novara, Italy.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Muniswamy
authors.affiliation: Department of Paediatrics, University of Messina, Messina, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Luca
authors.affiliation: Paediatric Section, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Mariacarolina
authors.initials: M
authors.lastname: Salerno
authors.affiliation: Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont and IRCAD, Novara, Italy.
authors.forename: Patricia
authors.initials: P
authors.lastname: Momigliano-Richardi
authors.affiliation: Unit of Paediatrics, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Bona
authors.affiliation: Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont and IRCAD, Novara, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Giordano
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D007558:Italy; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D008297:Male; D050817:Transcription Factor Pit-1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins; C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; C494187:POU1F1 protein, human; D050817:Transcription Factor Pit-1; D014157:Transcription Factors