Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature

Abstract

Background: SET domain-containing 5 (SETD5) is a member of the protein lysine-methyltransferase family. SETD5 gene mutations cause disorders of the epigenetic machinery which determinate phenotypic overlap characterized by several abnormalities. SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange (CdL) syndromes.

Case description: A female patient with severe short stature and intellectual disability had been followed since she was 9 years old. Several causes of short stature were ruled out. At the age of 12 years, her height was 114 cm (-5.22 SDS), weight 19 kg (-5.88 SDS), BMI 14.6 kg/m² (-2.26 SDS), and was Tanner stage 1. The target height for the proband was 151.65 cm (-1.80 SDS). The bone age (BA) was delayed by 3 years compared to chronological age. The growth rate was persistently deficient (<<2 SDS). Physical examination revealed dysmorphic features. Genetic analysis documented a de novo SETD5 gene mutation (c.890_891delTT), responsible for phenotypes in the context of an overlap syndrome between the phenotype of MDR23, CdL and KBG syndromes. Recombinant growth hormone therapy (rhGH) was started at the age of 12 years. After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased compared with the pre-therapy period.

Conclusion: This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH. The review of the scientific literature highlighted the clinical and molecular features of SETD5 gene mutation and the use of rhGH therapy in patients suffering from CdL and KBG syndromes.

Keywords: Cornelia de Lange syndrome; KBG syndrome; MDR23; SETD5 gene mutation; growth hormone therapy; overlap syndrome; short stature.

Figure 1

Images of the patient’s clinical dysmorphic features.

Figure 2

Auxological parameters and height velocity before and after the start of rhGH therapy. In the height velocity chart, the symbol ^ represents the 97th centile peak.