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Original article
Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies
  1. Mary R Richards1,
  2. Lacey Plummer1,
  3. Yee-Ming Chan1,2,
  4. Margaret F Lippincott1,
  5. Richard Quinton3,
  6. Philip Kumanov4,
  7. Stephanie B Seminara1
  1. 1Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
  3. 3Institute for Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK
  4. 4Clinical Center of Endocrinology and Gerontology, Medical University of Sofia, Sofia, Bulgaria
  1. Correspondence to Dr Stephanie B Seminara, Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit St., BHX 5, Boston, MA 02114, USA; sseminara{at}


Background A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.

Methods Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort.

Results Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance.

Conclusions These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.

  • POLR3B
  • Ataxia
  • Idiopathic Hypogonadotropic Hypogonadism
  • 4H Leukodystrophy
  • whole exome sequencing
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  • Contributors SBS was responsible for the concept and design of the study. MRR and SBS drafted the main manuscript. LP and SBS analysed and interpreted the data. RQ and PK contributed clinical data. Y-MC, MFL and LP revised the manuscript and made comments on the structure, details and grammar of the article.

  • Funding The research was supported by the National Institutes of Health Eunice Kennecy Shriver National Institute of Child Health and Human Development (P50HD028138).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Partners Human Research Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Additional phenotype or genotype information may be requested by contacting SBS.

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