title: A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome.
abstract: OBJECTIVE
  Multiple endocrine neoplasia type 4 (MEN4) is an autosomal dominant disorder that presents with a spectrum of clinical manifestations overlapping with those of MEN1 syndrome. It is caused by inactivating mutations of the CDKN1B gene, encoding for p27(kip1) cyclin-dependent kinase 2 inhibitor, implicated in cell cycle control. Eight mutations of CDKN1B in MEN4 patients have been published so far. The aim of this study was to characterize the molecular basis of a case of MEN1-like syndrome with a neuroendocrine tumor and persistent primary hyperparathyroidism (PHPT).
  
  
  METHODS
  Clinical, biochemical, and genetic evaluation were undertaken in the proband (a 53-year-old Caucasian woman) and in one 34-year-old son. The proband was operated for recurrent PHPT. Sequence analysis of the MEN1 and CDKN1B genes was performed on constitutional and parathyroid tissue DNA. Staining for p27 was carried out in parathyroid tissue.
  
  
  RESULTS
  Neither MEN1 mutations nor large deletions encompassing the MEN1 gene on chromosome 11q13.1 could be detected in the proband. A germline frameshift mutation of CDKN1B (371delCT) was revealed, predicted to generate a truncated p27 (CDKN1B) protein. This mutation was confirmed on somatic DNA from the pathological parathyroid tissue, with the retention of the WT allele.
  
  
  CONCLUSIONS
  We report a germline heterozygote frameshift mutation of the CDKN1B gene in a Caucasian woman with a long clinical history of MEN1-like multiple endocrine tumors, along with the finding of the mutation in her son. This is the first report of positive CDKN1B mutation analysis in a male subject and also the first description of recurrent hyperparathyroidism in MEN4.
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tonelli
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giudici
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giusti
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Cianferotti
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nesi
authors.affiliation: Surgical UnitBone Metabolic Diseases UnitDepartment of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy marialuisa.brandi@unifi.it.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
mesh_terms: D000328:Adult; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27