title: Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH?
abstract: BACKGROUND
  Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD).
  
  
  OBJECTIVE
  Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma.
  
  
  METHODS
  A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors.
  
  
  CONCLUSIONS
  We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USA.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Madson
authors.initials: M
authors.lastname: Almeida
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Maria
authors.initials: M
authors.lastname: de la Luz Sierra
authors.forename: Joey
authors.initials: J
authors.lastname: Matro
authors.forename: Evan
authors.initials: E
authors.lastname: Ball
authors.forename: Monalisa
authors.initials: M
authors.lastname: Azevedo
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lyssikatos
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Nicholas
authors.initials: N
authors.lastname: Patronas
authors.forename: Barbara
authors.initials: B
authors.lastname: Ferrando
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.forename: Aristides
authors.initials: A
authors.lastname: Lytras
authors.forename: George
authors.initials: G
authors.lastname: Tolis
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000172:Acromegaly / Q000235:genetics* / Q000378:metabolism; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D018389:Codon, Nonsense; D016368:Frameshift Mutation; D056426:Genetic Loci; D018095:Germ-Line Mutation; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; C491545:SDHD protein, human; D013006:Growth Hormone; D013385:Succinate Dehydrogenase