Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome.

CONTEXT: 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.

DESIGN: Case report of a mother and three affected children with clinical features of the TUBB3 E410K syndrome.

SETTING: Academic Medical Center.

MAIN OUTCOME MEASURES: 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.