Metabolic effects of growth hormone.

Rationale:

Kabuki Syndrome (KS, OMIM 147920) is a multiple anomaly syndrome. Recently, an available genetic test strongly confirm the diagnosis KS with a mutation in MLL2 gene. Some of the clinical signs and symptoms in KS children are obesity, hypertension, hypotonia and short stature. Features resembling the metabolic syndrome (MS) and hypothalamic disturbance.

There seems to be an association between the disturbance of the growth hormone axis and several features of the metabolic syndrome (MS). The MS is characterized as a cluster of metabolic abnormalities that strongly increase the risk of cardiovascular disease and type II diabetes mellitus in adulthood. It is known that both GH and insulin-like growth factor-I (IGF-I) reduces these cardiovascular risk factors and has beneficial effects on body composition by reducing fat mass and increasing muscle mass.

The aim of this study is to evaluate the effect of GH treatment on changes in height velocity and obesity and the mechanisms involved in the regulation of these changes in body composition and TEE.



Objective:

The primary objective of this study is to assess the energy expenditure and body composition in KS children and its dependence of growth hormone. Secondly, we want to assess the effects of GH on metabolic risk parameters which are typical parameters for the metabolic syndrome in adults.
Study design: The subjects will be included in a prospective study. Total body water (TBW), TEE, basal metabolic rate (BMR) and physical activity level (PAL) measurements are performed over a 6-wk period. Markers of metabolic risk factors will be determined during routine blood controls. The children will be followed during one year of treatment to evaluate the change in height SD.



Study population:

Prepubertal, KS children who will start growth hormone treatment. A total of 20 subjects will be recruited at the Maastricht University Medical Centre, the Netherlands.



Intervention:

All subjects receive recombinant human (rh)GH in accordance with international guidelines for developmental syndromes.



Main study parameters/endpoints:

The short-term metabolic effects of GH treatment in KS children related with the long-term change in height SDS after one year.

The hypothesis is that rhGH treatment in children with KS results within 6 weeks in a change of metabolism recognizable as an increase of total energy expenditure (TEE). This change in metabolism can be used as a predictor of growth response in the first year of treatment and indicates a better body composition.

During the study, we will monitor the metabolic effects and efficacy of rhGH in KS subjects. A total of 20 KS subjects will be recruited at the Maastricht University Medical Centre, The Netherlands. All subjects will receive rhGH according to international consent. Total body water (TBW), total energy expenditure (TEE), basal metabolic rate (BMR) and physical activity level (PAL) measurements are performed over a 2-wk period using the doubly labeled water (DLW) method before and during GH treatment. Markers of metabolic risk factors will be determined during routine blood controls. Baseline characteristics of growth patterns, blood pressure, BMI and waist circumference are collected every three months during routine controls. Furthermore, the measurements will be linked with the anthropometric parameters of each individual assembling a prognostic growth profile, therefore the children will be followed during one year of treatment to evaluate the change in height standard deviation score (SDS).

Growth hormone treatment 1-1.4 mg/m2/day in 1 dd subcutaneous.