Endocrine Abstracts

We report a case of a girl with severe short stature (-3.5 SD) from the age of 2 years. She was born at term with a normal birth weight (-1.3 SD) to non-consanguineous Pakistani/British parents. She had global developmental delay, hypotonia and microcephaly (-2.0 SD). She also had juvenile xanthogranuloma, alternating esotropia, constipation and initial feeding difficulties. Her current height is -2.9 SD with a normal BMI, aged 11. Serum IGF1 at age 2 years was <25 (49-289 ng/ml), and was subsequently low or low-normal. Glucagon and primed insulin tolerance tests at age 6 and 11 years were normal (GH peaks 8.4 and 10.3 mcg/l). MRI brain and pituitary, karyotype, microarray and skeletal survey were normal. The Deciphering Developmental Disorders study reported a WAC (WW domain containing adapter with coil-coil) mutation on chromosome 10p12.1: (c.1298del heterozygote, p.(Ser433Leufs*8), resulting in a diagnosis of Desanto-Shinawi Syndrome (DESSH). This frameshift mutation has not been previously described. It is predicted to cause premature termination of the WAC protein and highly likely to be pathogenic. WAC pathogenic variants have been described throughout the gene. WAC is expressed in many tissues and expression in brain is highest in the caudate nucleus, substantia nigra and thalamus. WAC is involved in transcriptional regulation and meiosis, and increases mTOR activity. DESSH is a rare condition characterised by global developmental delay, behavioural problems, hypotonia, ocular and gastrointestinal abnormalities. Facial features of frontal bossing, flat nasal bridge and midfacial hypoplasia are common. Short stature is not usually reported as a main feature in DESSH; however, height was below -2 SD in approximately 30% of described cases and GHD has been reported in at least 2 patients. It is likely that the short stature in our case is related to the syndrome, and is associated with low IGF-1 concentration. In conclusion, we describe a new WAC variant leading to DESSH. We suggest that WAC variants may lead to short stature and that children with DESSH syndrome and short stature undergo endocrine evaluation. The role of WAC in growth and the GH-IGF1 axis deserves further research.