ESPE Abstracts

A teenage girl was referred to our paediatric endocrinology service at the age of 18years, with primary amenorrhoea. She was diagnosed with Moebius syndrome at the age of 2 years with bilateral facial weakness, ptosis and restricted eye movements following review with geneticists in 2002. She was also diagnosed with autistic spectrum disorder in early primary school age, associated with learning disability. She was born at term, at 3.03 kg (9^th centile). She had neonatal jaundice. She was hypotonic as a baby, and described to be late with her developmental milestones e.g. walking at the age of 2-3 years. She required dietetic support as a young child, with height and weight along the 0.4^th centile. She had breast development, up to Tanner stage B3-B4, which started at around 13-14 years of age, and axillary hair growth. Pubertal development then arrested, leading to her presentation to us. From an endocrine point of view, she has been found to have hypogonadotropic hypogonadism. She also has pituitary hypoplasia on MRI. She was reviewed in the joint genetics-endocrinology clinic in 2019 as pubertal arrest is not a typical feature of Moebius syndrome (MS). MS affects facial and orbital movements through absence of cranial nerves VI and VII. However, on further review of her MR imaging, her cranial nerves VI and VII were present. In addition, she had ptosis, and restricted movements in all directions of gaze, indicating ocular involvement well beyond movements controlled by cranial nerve VI, in keeping with a form of congenital fibrosis of extraocular muscles. Upon further history taking by our geneticist, she also had an impaired sense of smell. In 2013, this set of findings had been described in 8 other individuals around the world with a specific missense variant in the TUBB3 gene - E410K (TUBB c.1228G>A p.Glu410Lys). Targeted analysis of TUBB3 confirmed the same variant and she was diagnosed as the first known individual in the United Kingdom with TUBB3 E410K syndrome. TUBB3 E410K syndrome results from a mutation in the β-tubulin isotype III (TUBB3) gene, which mainly functions in nervous system development and axon generation and maintenance. Individuals with this syndrome has a range of described phenotypical features including Kallman syndrome, congenital fibrosis of the extraocular muscle, learning disability, and peripheral neuropathy. This case further amplifies the value of multidisciplinary re-evaluation of complex patients from time to time when the clinical diagnosis does not quite fit.