ESPE Abstracts

Introduction and Purpose: STAT3 gain-of-function (GOF) syndrome is a rare monogenic autosomal dominant disease, caused by activating mutations in the STAT3 gene encoding the STAT3 protein, which is involved in the signal transduction pathway. Disruption of STAT3 structure leads to an early-onset multi-organ disease, characterized by lymphoproliferation, autoimmune cytopenias and growth retardation. Treatment includes immunosuppression, immunotherapy and allogeneic hematopoietic stem cell transplantation. The purpose of this presentation is to describe a patient with STAT3 GOF syndrome and short stature.

Patients and Methods: Α 10-year-old girl presented to the clinic because of short stature. From patient’s history, normal birth weight, multiple hospitalizations since age 4.5 years and a diagnosis of STAT3 GOF syndrome at age 5.5 years, for which she underwent allogeneic hematopoietic stem cell transplantation at age 8.5 years, were reported. Clinical examination revealed normal weight, height below the 3^rd percentile and onset of puberty, confirmed by laboratory testing and an advanced bone age of 1 year. IGF-1 levels were normal (147ng/mL, normal range 104-431 ng/mL). The growth chart showed a decrease in the height growth rate since age 2.5 years (from the 50^th, down to the 3^rd percentile), a further decline (2.5cm/year) after symptoms onset and corticosteroid administration, an improvement after transplantation (5cm/year) and an acceleration due to the onset of puberty the last year (7.5cm/year). The GH test showed an increased GH response (39.4 ng/mL). Treatment with GnRH analogue was started, due to predicted final height (137 cm) below the target height (154cm). During the course, height stagnation and low IGF-1 levels (61.7 ng/mL, normal range 192-568 ng/mL) were observed. Initially attributed to administration of GnRH analogue, its discontinuation was decided. Due to repeated IGF-1 low values, GH tests were re-performed and ruled out GH deficiency. An IGF-1 generation test followed, the patient responded (tripling of IGF-1) and GH administration was started.

Results: After 3 months of treatment, an accelerated growth rate (2.5 cm) was observed. According to literature, STAT3 protein overactivity induces increased production of SOCS3, which blocks STAT5b, the dominant signal transducer in the GH pathway. Thus, IGF-1 production is inhibited.

Conclusion: STAT3 GOF syndrome is associated with short stature, due to IGF-1 deficiency and other clinical manifestations of the syndrome that affect growth rate. Further research is needed to establish the optimal therapeutic approach for managing short stature in these patients, although studies have shown that growth hormone administration is beneficial.