• Developmental origins of adult diseases (prof. Dr A.C.S. Hokken-Koelega)
• Risk factors (genetic and environmental) for the development of diabetes mellitus type 2 (prof.dr A.C.S. Hokken-Koelega)
• Long-term effects during and after discontinuation of growth hormone treatment (prof.dr A.C.S. Hokken-Koelega) 
• Genetic research aimed at aetiology of growth- and metabolic disorders (prof.dr A.C.S. Hokken-Koelega)
• Gonadal function of patients with Turner syndrome and Prader Willi syndrome (prof.dr A.C.S. Hokken-Koelega)
• Growth prediction modeling (prof.dr A.C.S. Hokken-Koelega)
• Identification of biological and psychosocial factors related to psychosexual dysfunction in patients with disorders of sex development (DSD) (prof.dr. S.L.S. Drop) 
• Outcome of sexsteroid treatment of constitutional tall stature (prof.dr S.L.S. Drop)
• Molecular mechanisms regulating glucocorticoid sensitivity and its influence on inflammation and immune system (dr E.L.T. van der Akker)
• Diabetes mellitus type 1: early markers of macro-and micro-vascular complications in children and youth  (dr H.J. Aanstoot)
• Translational studies (Pompe Disease), neonatal registries of lysosomal storage diseases (prof.dr A. van de Ploeg)
• Pharmacokinetic studies regarding immunosuppressive therapy in pediatric patients following kidney transplantation (dr K Cransberg)

Developmental origins of adult diseases

In large groups of young adult subjects born term and preterm it was shown that size at birth did not associate with determinants of diabetes type 2 and cardiovascular disease in later life. These findings challenged the so-called Barker hypothesis that birth weight is associated with adult diseases. Also premature birth (which also result in a low birth weight) did not associate with most determinants.  Further investigation showed that the gain in weight for height in the first 3 months of life is associated with risk factors in early adulthood. This was a very important finding because based on these data it is likely that preventive strategies can be implemented to prevent rapid weight gain in early life.

Risk factors (genetic and environmental) for the development of DM type 2

As part of  the Generation R study it was shown that skin fold measures and fat mass percentage at the age of 6 months, measured by DXA scan, are associated with the gain in weight during the first 6 weeks after birth. Early weight gain tracks to DM T2 at later age. Breastfed children had lower fat percentage than bottle fed infants.

Long-term effects during and after discontinuation of growth hormone treatment

Based on our data FDA  and EMEA approved short stature after small for gestational birth (SGA) as an indication for GH treatment. We performed long term follow up studies 6 years after stop of GH. GH-treated persons had the same and for some parameters even better results than the untreated SGA subjects. A multicenter study in children with Prader Willi syndrome indicated these children have moderate to severe sleep apnea. In addition, central adrenal insufficiency during stress occurs in up to 60%. GH treatment was investigated in 2 randomized controlled trials showing no adverse effects on sleep apnea, adrenal function, scoliosis, and having positive effects on fat mass (lower) and muscle mass (more), bone density of body and spine, serum lipids as well as cognitive and motor functioning.

Genetic research aimed at aetiology of growth- and metabolic disorders

We started a European collaborative project (NESTEGG) to collect a very large group of children with various growth patterns to study mutation, deletions and genetic variants in relation to growth and development of weight for height.

In a large group of Dutch children with isolated GHD or multiple pituitary hormone deficiencies, almost none of the children had a gene abnormality.

Gonadal function of patients with Turner syndrome and Prader Willi syndrome

Gonadal function of girls with TS, from the age of 2 to adulthood was studied indicating that most girls do not have adequate gonadal function, but some have.

Girls with PWS have a quite normal pubertal development but the majority of the boys do not In addition, many girls have early adrenarche.

Growth prediction modelling

We developed and validated several prediction models for adult height. These models are now used in routine clinical care in many places in the world. In addition we developed more advanced models in order to further improve the prediction modelling.

Outcome of Disorders of Sex Development

A Dutch multicenter DSD study is focussing on the incidence of gender identity problems and problems in sexual functioning in relation to hormonal, genetic and psychosocial factors. A large database was developed. A similar collaborative study focusing also on cultural and socioeconomic aspects is conducted in Semarang (Indonesia).

Outcome of tall stature

In a large study regarding the outcome of sex-steroid treatment of tall adolescents it was established that high-dose oestrogen treated tall women experience more difficulties getting pregnant than untreated tall women and more often seek medical treatment for infertility. A high number of tall women are hypergonadotropic, however with relatively high AMH levels. In high-dose tall men gonadal function was not compromised.

Glucocorticoid sensitivity

In a cross-sectional study persons carrying the GR-9B haplotype were found to have a decreased GC transrepression with normal transactiviation. In another study children with sepsis or septic shock showed a transiet depression of GC receptors in neutrophils leading to increased resistance to cortisol.

Diabetes Mellitus type 1

An electronic patient data system has been developed storing clinical, laboratory and therapeutics data since 1998 of a large cohort  (n = 600) of pediatric patients with type 1 diabetes mellitus. In a large multinational multicenter study pPhysical activity was found to be strongly associated with psychological well-being but was weakly associated with metabolic control.

Lysosomal storage diseases

The natural course and the long term effects of enzyme treatment of children and adults with Pompe Disease was subject of several local and international multicenter studies  (EU 7^th frame work programme. A study of the muscle regeneration and recovery of patients with Pompe Disease was awarded by a research prize by the Princess Beatrx Fund.

Pediatric Kidney transplantation

The outcome of a large cohor of Dutch pediatric patients following kidney transplantation was studied; with emphasis on effects of various combinations of immunosuppressive therapy and co-morbidity, notably cardiovascular disease. A spectacular improvement in 1 year graft survival of first kidney transplant recipients was noted following introduction of a so-called shared initial immunosuppressive regimen  (corticosteroids, cyclosporine and MMF).   

Developmental origins of adult diseases

• Longitudinal growth and metabolic studies in normal baby cohort (well baby cohort)
• Cross-sectional and longitudinal metabolic studies in young adult cohorts at 18-24 years (Program/Premature studies) and 28-32 years (YAC study), compared to growth during early childhood
• Longitudinal study of growth and metabolic profile in offspring of mothers with chronic rheumatic disease
• Longitudinal study of growth and metabolic profile in offspring of mothers who underwent cardio surgery for congenital heart disease during childhood
• Cross-sectional study in very prematurely born children at the age of 6 months and 6 years

Risk factors (genetic and environmental) for the development of diabetes mellitus type 2

• Project in Generation R (at age 6, 24 months and 5 years)
• Long-term effects during and after discontinuation of growth hormone treatment
• Longitudinal study of safety in children born small for gestational age treated with GH
• Longitudinal study of efficacy and safety in children with Prader Willi syndrome treated with GH (randomized trial)
• Longitudinal study of efficacy and safety in young adults with Prader Willi syndrome treated with GH (randomized, double-blind, placebo/GH trial)
• European project (SAGHE) on long-term safety of adults who were treated with GH during childhood, in collaboration with 6 countries

Genetic research aimed at aetiology of growth and metabolic disorders

·    NESTEGG study: European project with 4 countries, study of gene variations in relation to fetal and postnatal growth disorders and metabolism

·    Hypopit study: national study of genes involved in the development of hypothalamus and pituitary and genetic variants in Dutch patients with GHD and panhypopituitarism

·     Functional studies to investigate the functional consequences of gene variants

Ovarian function of Turner patients

• Project financed by European Society of Pediatric Endocrinology, in collaboration with Germany and Switzerland

Growth prediction modelling

• Development and use of statistical models for growth prediction, including handling of incomplete datasets and prediction of adult height before start of GH treatment

Disorders of sex development (DSD)

·       Outcome study (multicenter) on clinical, hormonal, genetic and psychosocial aspects of DSD patients

·       Insight into pathophysiology and modulators of natural course of DSD employing a descriptive biochemical and molecular genomics approach to a large European patient cohort (EU 7^th frame work programme).

·       Natural course and implications of a stepwise multidisciplinary approach of DSD. A comparison of Semarang (Indonesia) and Rotterdam   (Erasmusgrant)

Constitutional Tall Stature

·       Long term effects of sex-steroid treatment in tall boys and girls

·       Genetic determinants of constitutional tall stature

Glucocorticoid sensitivity

·        Development of diagnostic tools for the measurement of individual glucocorticoid sensitivity in children

        ·        Early detection of Diabetes Damage in Youth and Search for early prevention

Lysosomal storage diseases

•  Translational studies, gene therapy, standardized clinical follow-up studies of patients with metabolic disorders  diagnosed following  neonatal screening.

        ·        Farmacokinetic studies regarding  inmmunosuppressive therapy in children following renal transplantation.

1.      Hokken-Koelega ACS, Stijnen T, De Ridder MAJ, et al. Growth hormone treatment in growth-retarded adolescents after renal transplant. Lancet 1994; 343: 1313-17.

2.      Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega AC. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age (SGA): Results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 2003; 88: 3584-90

3.      Den Brinker M, Joosten KF, Visser TJ, Hop WC, de Rijke YB, Hazelzet JA, Boonstra VH, Hokken-Koelega AC. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab 2005;90(9):5110-7

4.      Leunissen RWJ, Kerkhof GF, Stijnen T, Hokken-Koelega AC. Timing and tempo of First year catch-up growth influence cardiovascular and metabolic risk profile in early adulthood. JAMA 2009; 301(21):2234-42

5.      Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH.Germ cells tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr. Rev. 2006 Aug;27(5):468-84

6.      Van de Akker ELT, Koper JW, Boehmer ALM, Themmen APN, Verhoef-Post M, Timmerman MA, Otten BJ, Drop SLS, de Jong FH. Differential inhibition of 17a-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metab 2002;87(12):5714-21.

7.      Van den Akker EL, Russcher H, van Rossum EF, Brinkmann AO, de Jong FH, Hokken A, Pols HA, Koper JW, Lamberts SW. Glucocorticoid receptor polymorphism affects transrepression but not transactivation. J Clin Endocrinol Metab. 2006 Jul;91(7):2800-3.

8.      Aanstoot HJ, Anderson BJ, Daneman D, Danne T, Donaghue K, Kaufman F, Réa RR, Uchigata Y. The global burden of youth diabetes: perspectives and potential. Pediatr Diabetes. 2007 Oct;8 Suppl 8:1-44.

9.      van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. 2008 Oct11;372(9646):1342-53.

10.  Cransberg K, Bouts AH, Cornelissen EA, Lilien MR, Van Hoeck KJ, Hop WC, Nauta J. Recovery of graft function in pediatric kidney transplantation is not affected by delayed introduction of cyclosporine. Transplantation. 2008 Nov15;86 (9):1199-205.