title: Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome.
abstract: BACKGROUND
  A heterozygous de novo c.1228G>A mutation (E410K) in the TUBB3 gene encoding the neuronal-specific β-tubulin isotype 3 (TUBB3) causes the TUBB3 E410K syndrome characterized by congenital fibrosis of the extraocular muscles (CFEOM), facial weakness, intellectual and social disabilities, and Kallmann syndrome (anosmia with hypogonadotropic hypogonadism). All TUBB3 E410K subjects reported to date are sporadic cases.
  
  
  OBJECTIVE
  This study aimed to report the clinical, genetic, and molecular features of a familial presentation of the TUBB3 E410K syndrome.
  
  
  METHODS
  Case report of a mother and three affected children with clinical features of the TUBB3 E410K syndrome.
  
  
  METHODS
  Academic Medical Center.
  
  
  METHODS
  Genetic analysis of the TUBB3 gene and clinical evaluation of endocrine and nonendocrine phenotypes.
  
  
  RESULTS
  A de novo TUBB3 c.1228G>A mutation arose in a female proband who displayed CFEOM, facial weakness, intellectual and social disabilities, and anosmia. However, she underwent normal sexual development at puberty and had three spontaneous pregnancies with subsequent autosomal-dominant inheritance of the mutation by her three boys. All sons displayed nonendocrine features of the TUBB3 E410K syndrome similar to their mother but, in addition, had variable features suggestive of additional endocrine abnormalities.
  
  
  CONCLUSIONS
  This first report of an autosomal-dominant inheritance of the TUBB3 c.1228G>A mutation in a family provides new insights into the spectrum and variability of endocrine phenotypes associated with the TUBB3 E410K syndrome. These observations emphasize the need for appropriate clinical evaluation and complicate genetic counseling of patients and families with this syndrome.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center (R.B.), The Reproductive Endocrine Unit of the Department of Medicine (R.B.), Massachusetts General Hospital, Boston, Massachusetts 02114; Harvard Medical School (R.B., S.C., P.B.K., C.A., W.-M.C., E.C.E.), Boston, Massachusetts 02115; Department of Neurology (S.C., P.B.K., C.A., W.-M.C., E.C.E.), Kirby Neurobiology Center (S.C., C.A., W.-M.C., E.C.E.), and Department of Ophthalmology (S.E.M., E.C.E.), Boston Children's Hospital, Boston, Massachusetts 02115; and Howard Hughes Medical Institute (S.C., C.A., W.-M.C., E.C.E.), Chevy Chase, Maryland 20815.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Sheena
authors.initials: S
authors.lastname: Chew
authors.forename: Sarah E
authors.initials: SE
authors.lastname: MacKinnon
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics; D004700:Endocrine System Diseases / Q000235:genetics*; D015785:Eye Diseases, Hereditary / Q000235:genetics; D005260:Female; D005355:Fibrosis; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics; D008239:Lysine / Q000235:genetics; D008297:Male; D009886:Ophthalmoplegia; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D014404:Tubulin / Q000235:genetics*; D000093922:Congenital Cranial Dysinnervation Disorders
chemical_list: C498585:TUBB3 protein, human; D014404:Tubulin; D018698:Glutamic Acid; D008239:Lysine