ESPE Abstracts

Background: SET domain-containing 5 (SETD5) is a member of the protein lysine-methyltransferase family that regulates gene expression. SETD5 gene mutations cause disorders of the epigenetic machinery which determinate phenotypic overlap characterized by several abnormalities. Recently, SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange syndromes. Pathogenic variants of SETD5 gene are primarily associated with intellectual delay and other several manifestations including severe short stature. Only a few reports are available on the use of recombinant growth hormone therapy (rhGH) in the aforementioned syndromes, none in the overlap syndrome.

Case Description: A 9-year-old female child was admitted to the pediatric endocrinology clinic for assessment of severe short stature. Her height was 103.3 cm (-5.46 SDS), weight 15.1 kg (-5.08 SDS), BMI 16.3 kg/m2 (-1.71 SDS). The target height for the proband was 151.65 cm (-1.80 SDS). Her bone age (BA) was 8 years. She had a prepuberal stage (Tanner stage 1). Physical examination revealed dysmorphic features, including a long triangular face, low-set and protruding ears, macrodontia of the central incisors and pointed palate. Biochemical examinations, including thyroid function and calcium homeostasis, were normal. The clonidine stimulation test revealed a normal GH peak (9,24 ng/ml). She had an intellectual disability with a total IQ of 68 (WISC-R). CHG-array detected a de novo SETD5 gene mutation (c.890_891delTT) classified as pathogenic variant. The SETD5 gene mutation is consistent with our patient's phenotype in the context of an overlap syndrome between the phenotype of KBG and Cornelia de Lange syndromes. Recombinant growth hormone therapy (rhGH) (at dose of 0,03 mg/kg/die) was started at the age of 12 years (pre-therapy data: height 114 cm, -5.22 SDS; growth velocity 3.9 cm/year, -3.6 DS; pubertal stage B1P1; bone age 10 years). After one year of treatment there was a significant increase in the growth velocity (7.2 cm/year, +3.2 DS), even though pubertal development has not yet begun.

Conclusion: To the best of our knowledge, this is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH. The initial response to rhGH therapy was satisfactory in terms of growth rate, although the effective response to therapy in terms of height outcome should be assessed during long-term follow-up.