Prospective study on the metabolic and linear growth effects of growh hormone treatment in children with Kabuki Syndrome

Kabuki Syndrome (KS, OMIM 147920) is a multiple anomaly syndrome. The spectrum
of medical problems seen in Kabuki syndrome is diverse but all patients have
similar facial features. Recently, an available genetic test strongly confirm
the diagnosis KS with mutations in KDM6A or KMT2D (MLL2) gene. One of the
features in KS children is postnatal growth retardation, final stature is short
in KS children, mostly below -2 SDS. The cause of the growth retardation is
unknown, but growth hormone deficiency has been reported several times in
literature. Further clinical signs and symptoms in KS children are obesity,
hypertension, hypotonia and short stature. Features resembling the metabolic
syndrome (MS) and hypothalamic disturbance. Some of these features are also
seen in syndromes like Turner (TS) and Prader-Willi (PWS) patients. They do not
have a real growth hormone deficiency, but have proven benefit from growth
hormone therapy at supra-physiological doses obtaining a higher final height
than the expected one according to the natural history. Moreover, there is a
paucity of data regarding the cardiovascular and metabolic risk factors in
children with TS and PWS and the positive effect of GH treatment on these risk
factors. These children have an abnormal body composition, presence of
hypertension, dyslipidemia and hyperinsulemia and therefore fulfilment of the
criteria of the metabolic syndrome.

The primary objective of this study is to assess the relation between the short
term metabolic changes after start of rhGH therapy and the long term change in
height SDS after one and two years of treatment. Secondly, we want to assess
the effects of GH on metabolic risk parameters which are typical parameters for
the metabolic syndrome in adults. Furthermore, want to map the severity of
hypermobility and whether growth hormone therapy affects the degree of
hypermobility. We also want to look at the body proportions in children with
Kabuki syndrome and / or growth hormone treatment will affect this.

The study design is a prospective study monitoring the metabolic effects and
efficacy of rhGH in Kabuki syndrome subjects. 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, body proportions, laxity, 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 (Genotropin).

Growth hormone treatment is licensed for short stature in Turner syndrome (TS)
and Prader-Willi Syndrome (PWS) (EMEA), syndromes with the same characteristics
as KS. Studies on growth hormone treatment did not reveal any detrimental
effects of this therapy so far. Before the start of the study, subjects will be
screened for underlying growth pathology according to the Dutch Growth Research
Foundation guidelines , including growth hormone test. When enrolled in the
study, rhGH treatment will be started. All visits are linked with the routine
visit controls accordingly to the guidelines, except the visit before start of
GH treatment and the six week visit. Throughout these visits, routine blood
controls are used for determining metabolic risk markers, no extra blood
controls are used. The total amount of additional blood drawn would be maximum
20 ml. Risks of the doubly labeled water (DLW), Ventilated Hood (VH) method,
hyperlaxity evaluation and photometry are negligible. Making a X-rayed left
hand for bone age provides a minimal radiation.