Bases de données

Régistres

La Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED)  gère plusieurs bases de données.

BELGROW: collecte des données de (presque) tous les enfants qui étaient/sont traités par l’hormone de croissance en Belgique depuis que l’hormone de croissance est disponible en Belgique.

BELPUB: collectera à partir de 2017, des données des enfants atteints d’ une puberté précoce.

 

BELGROW, a nationwide registry for children treated with growth hormone

 

BELGROW is a Belgian registry that collects data of children and adolescents treated with growth hormone (GH) and followed by paediatric endocrinologists, members of the BESPEED (BElgian Society for PEdiatric Endocrinology and Diabetology). The registry was started in 1985 as the Registry of the Belgian Study Group for Pediatric Endocrinology (BSGPE) and was recently renamed BELGROW.

Objectives

The objectives of the registry are to study the epidemiological and demographic aspects of the children treated with GH and the short and long term efficacy (adult height) as well as the safety (adverse events) of the treatment. It allows also to assess the prediction of the response to GH using clinical, auxological, metabolic and genetic parameters. Furthermore it helps to identify and recruit patients for clinical studies. The final goal is to improve the care of patients with growth problems.

Data collection

The BESPEED members meet every month to present new candidates for GH treatment (peer review) and categorize them based on commonly agreed diagnostic criteria. Guidelines are used for the follow-up of the patients and for the parameters that are prospectively collected in the database.

The data of the patients are entered in a secured web based application by the clinicians, research physicians or research nurses after an informed consent is signed by the parents. The identity of the patients is not registered but replaced by a code. The study has been approved by the Ethics Committees of the participating centres. The coded data comply with privacy guidelines.

Thirteen centers are participating to the data collection in BELGROW: UZ Leuven (Leuven), UZ Gent (Gent), Cliniques Universitaires St-Luc (Bruxelles), UZ Antwerpen (Antwerpen), Hôpital Universitaire des Enfants Reine Fabiola (HUDERF) (Bruxelles), CHU Notre-Dame des Bruyères (Liège), UZ Brussel (Brussel), CHC Clinique de l’Espérance (Liège), UCL-CHU Mont-Godinne (Yvoir), Jessa ziekenhuis (Hasselt), ZNA Koningin Paola Kinderziekenhuis (Antwerpen), AZ Delta (Roeselaere), AZ Brugge (Brugge).

Patients

In Belgium, GH treatment is reimbursed for growth failure secondary to GH deficiency (since 1974), short stature as part of Turner syndrome (1990), Prader-Willi syndrome (2002) and short stature in children who were born small for gestational age (SGA) (2004) (figure 1). Some patients with a short stature for which a reimbursement is not (yet) available in Belgium can benefit from GH treatment in a Medical Need programme. Medical need programmes are or have been available for patients with idiopathic short stature (ISS), certain bone dysplasias and SHOX gene alterations and adolescents during the transition from paediatric to adult care.  The data of all those patients are collected in BELGROW. GH is also reimbursed in children with a growth retardation secondary to chronic renal insufficiency (CRI) but these patients are followed by nephrologists and are not included in BELGROW.

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Figure 1. Indications for GH treatment

 

 

 

 

 

Each year, about 200 children start a treatment with GH in Belgium. In 2014, about 1400 patients were actively treated with GH (figure 2); this is 3 times more than 25 years ago. Around 75% of these patients are treated for a short stature due to GH deficiency (GHD) or secondary to an intra-uterine growth retardation (about 500 patients in each of the indications). Approximately 140 patients are treated for short stature as part of a Turner syndrome, 50 patients for Prader-Willi syndrome and 30 patients for Noonan syndrome.

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Figure 2. Number of active patients treated with GH over the years

 

 

 

 

 

 

 

The cumulative number of patients treated with recombinant GH since 1985 and included in BELGROW is around 4000 patients (figure 3).

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Figure 3. Cumulative number of patients in BELGROW for the different indications

 Data analyses

The registry is regularly mined for scientific purposes. The short and long term (adult height) results on growth of patients included in BELGROW have been published for patients with idiopathic GHD (1), irradiated-induced GHD (2), Turner syndrome (3), and are in preparation for SGA and Noonan patients. These studies are described in more detail in the sections below.

In other studies, the psychosocial aspects and treatment acceptance of patients with Turner syndrome (4), GHD (5) and SGA patients have been assessed (6;7). The BESPEED members are involved in studies evaluating the quality of life in children with short stature and in children treated with GH.

Registries are useful to monitor the long term, real-world use of GH. The BESPEED was therefore invited to participate in a European consortium evaluating the long term effectiveness and safety of GH treatments in Europe (SAGhE).

The registry data are valuable to create and/or validate growth prediction models.

The BELGROW registry is also used in a project to search for genetic alterations in children born small for gestational age by whole exome sequencing (8).

 

In this section, we will review the indications of GH treatment and give a summary of different studies published using data of patients selected from BELGROW.

  1. Growth hormone deficiency

Growth hormone deficiency (GHD) in children is a relative uncommon cause of short stature. Based on data from the registry, the prevalence is estimated to be 1/4000-6000 children in Belgium (9). GHD is caused by an insufficient production of GH by the anterior pituitary gland. GHD can be congenital (20%) (genetic defects, anomalies of the brain) or acquired (35%) (tumour, irradiation, trauma..). But in 40% of the patients, the cause is unknown (idiopathic) (9). GHD can be isolated or associated with other pituitary deficiencies. The diagnosis is based on clinical and auxological criteria (growth velocity < 10th percentile), a low IGF-1 and a low peak concentration of GH after 2 GH stimulation tests. Depending on the aetiology, a MRI can show structural abnormalities of the pituitary-hypothalamic region, other brain anomalies or a brain tumor. The treatment consists in daily subcutaneously injections of GH at a dose of 25 µg/kg/day.

Adult height after GH treatment

 

Two retrospective studies have analysed the adult height of patients with GHD treated with GH included in BELGROW: one in patients with Idiopathic GHD (1) and the other in patients with GH deficiency after a brain tumour treated with cranial irradiation (2).

 

In the first study (1) , the efficacy of GH treatment on adult height was evaluated in 61 patients with idiopathic and congenital GHD. The patients were treated with subcutaneously GH injections at a dose of 25-33 µg/kg.day from a mean±SD age of 11.9±3.1 year and with a height at start of -2.7±0.8 SDS. After 5.1±2.1 years a mean adult height of -0.7±1.1 SDS was achieved, being 170.4±7.2 cm in boys and 158.0±6.4 cm in girls. 87% of the patients reached an adult height above the 3th centile and 92% a height within the genetically determined target height range.

Height SDS at start of rhGH treatment and adult height in patients with (a) spontaneous puberty and (b) induced puberty.

 

The second study (2) analysed adult height after GH therapy in 57 patients with irradiation-induced GH deficiency. Twenty-five children underwent a cranial irradiation (C-Irr) and 32 a cranio-spinal irradiation (CS-Irr) for a tumour outside the pituitary-hypothalamic-pituitary area. The CS-Irr group achieved an adult height (AH) of -1.8 (-4.2; 0.0) (median (range)) SDS which was significantly lower than is the C-Irr group (-0.8 (-2.5-1.4) SDS. In a quarter of the C-Irr group and 60% of the CS-Irr group, GH treatment failed to restore adult height to mid-parental height. Although GH failed to induce catch-up growth it prevented further height loss. The risk factors for being short at final height were young chronological age at end of tumour therapy, short stature at start of GH therapy and irradiation of the spine.

 

Evolution of height SDS before and during GH treatement in the C-Irr group (a) and in the CS-Irr group (b).

Development and evaluation of “response models”

In another paper (10), the first year response in 357 prepubertal Belgian children with idiopathic GH deficiency to GH treatment was analysed and a “growth response curve” was generated. This curve enables rapid identification of poor response to first-year GH treatment. The results also validate the published growth targets derived from the KIGS database.

A new analysis of final height data in idiopathic GH deficiency is ongoing.  In this study the usefulness of models that predict the final height outcome after the first year GH treatment is evaluated.

Retesting after GH treatment

It has been shown that a large proportion of children with idiopathic GH deficiency (GHD) have a normalized GH secretion when re-evaluated after GH treatment at adulthood. In a retrospective study (11) we re-assessed GH secretion in young adults treated with GH during infancy (10 patients with multiple pituitary hormone deficiencies (MPHD) and 33 patients with isolated GHD (IsGHD)) to determine which proportion had a normalised GH section. Furthermore we hypothesized that the normalisation could occur earlier during the course of GH treatment. For this reason we conducted also a prospective study to re-evaluate GH secretion after GH treatment given for 1 year in 18 children with Idiopathic GHD (2 with MPHD and 16 with isGHD).

In the retrospective study, taking the criteria used in adulthood to determine GHD (GH peak < 10 mU/L)), we found that all the 10 patients with multiple pituitary deficiencies were still GH deficient. In contrast only 15% of the patients with isolated GHD (36% of the patients with severe GHD and none of the patients with partial GHD) were still considered as GH deficient.

In the prospective study, the 2 patients with MPHD were still deficient at re-evaluation after 1 year. Among the 16 patients with IsGHD, 13 (81%) were still deficient (peak response <20 mU/L) after 1 year. Two of the 3 patients in whom GHD was not confirmed at retesting after 1 year GH showed again a deficient response at second retesting. We concluded that although many patients diagnosed with IsGHD during childhood have a normalized GH secretory capacity when retested during adulthood, early retesting after 1 year of treatment during childhood was not able to identify the patients with transient GH deficiency.

 

Quality of life

Divergent findings on the quality of life (QoL) and the psychosocial functioning of adults treated during childhood with growth hormone (GH) for GH deficiency (GHD) have been reported. In 2001, two psychologists working for the BESPEED evaluated the QoL and the perception of the effect of former GH treatment in 22 Belgian young adults with childhood GHD (5). They all were treated during childhood with GH for GHD (excluding those with acquired organic GHD cause).

This study showed that the psychosocial outcome of young adults with childhood GHD was more satisfying than in previous studies. This could be due to a more adequate GH treatment with better adult height results. Nevertheless, more difficulties with respect to psychosocial functioning were observed in patients with multiple pituitary hormone deficiencies compared to isolated GHD, in patients in whom GH treatment was started after 12 years of age and in patients with a height deficit < -3 SDS at the start of GH therapy, underlining the need for early diagnosis and treatment of childhood GHD, and of continuing medical follow-up and psychosocial counselling, particularly in these subgroups of patients.

 

  1. Turner syndrome

Turner syndrome occurs in about 1/2500 live-born girls. The diagnosis of Turner syndrome relies on genetic analysis showing a complete absence of a X chromosome (45,X) or a partial absence or an abnormality of a X chromosome.   Characteristic clinical features include an absence of pubertal development (gonadal dysgenesis) and a short stature or decreased height velocity.  Girls with Turner syndrome are treated with GH treatment at a dose of 50 µg/kg.day.

Adult height

A retrospective study on the adult heights of 186 Turner patients included in BELGROW treated with GH was published in 2003 (3). The influence of the age at onset of GH therapy and the age at onset of puberty on adult height were evaluated. Puberty was induced with ethinyloestradiol in 148 girls and started spontaneously in 38 patients.

GH therapy at a mean dose of 47 µg/kg.day resulted in a significant increase in adult height. The mean±SD adult height was 151.7±6.0 cm. This was 8.3 cm higher than the adult height of untreated women with Turner syndrome whose adult height was 143.4±5.6 cm. In this study, the age at start of GH treatment, a late or delayed puberty, spontaneous or induced puberty did not affect adult height.

Age at diagnosis

Although it is not clear whether early initiation of GH treatment will result in a taller final height, treatment at a young age in patients with Turner syndrome can normalize stature in childhood, allowing an age appropriate start of oestrogen therapy for puberty induction. Furthermore, early diagnosis has other advantages such as the prevention of comorbidities which may enhance the quality of life of girls with Tuner syndrome. A study aiming to evaluate the age at diagnosis in girls with Turner syndrome was published in 2005 (12) . It showed that the median age at diagnosis of Turner girls diagnosed between 1991 and 2002 in Belgium was 6.6 years which was significantly younger than those diagnosed a decade before (11.2 years). This favourable trend could be explained by an increased awareness for the diagnosis of Turner syndrome in short girls since the availability of growth promoting treatment and the advances in prenatal diagnostics and genetics. However 22% were still diagnosed after the age of 12, most of them with a serious height deficit. The recommendation was reconfirmed that a cytogenetic analysis is indicated in girls with unexplained short stature with a height more than 2 SD below the mean for age or below the parent specific lower limit of height.

 

Perception of Stature, acceptance of therapy and psychosocial functioning in children with Turner syndrome

A study evaluating the perception of stature, acceptance of therapy and psychosocial functioning was performed in 1998 in 31 girls with Turner syndrome during the 2 first years of GH therapy (4). They were divided in 3 age groups: 3-6, 7-12 and 13-16 years. This study showed that perception of stature, acceptance of therapy and psychosocial functioning appeared to be different according to age with only slight changes during 2 years GH therapy. The girls younger than 6 years – in contrary to the 2 older age groups- didn’t perceive height as a problem and they accepted the injections with difficulty because they don’t yet have a realistic representation of height and the rationale of treatment can’t be understood.  This study led to the proposal to wait until the age of 6 years before starting GH treatment in Turner girls.

Transition into adulthood

For patients with childhood-onset chronic disorders the transition from paediatric to adult-oriented health care is a difficult period for patients and for caretakers. Most of the patients with Turner syndrome are diagnosed during childhood and receive intensive medical follow-up . Little is known however about what happens to these patients after transition to adulthood. In order to gain insight into the actual medical care, health status, educational and occupational status and psychosocial functioning of young adult women with Turner syndrome, a survey was set up in 2002 (13). A questionnaire was sent to 160 patients treated with GH during childhood and followed in the BELGROW registry. 102 patients (64%) returned a filled out questionnaire. The mean age of the patients was 23.4±3.3 years. The study showed that 40.2% reported health problems. The most frequently reported were hypertension, hypothyroidism and back problems.  10.7% were obese but only 2 % reported overweight as a health problem.  An important number of women (14.5%) with induced puberty didn’t take oestrogen treatment anymore. Most of the women (60.7%) consulted only one physician (a general practitioner or a specialist) after transition to adulthood, 26.7 % consulted various specialists but 12.7% didn’t have any follow-up.   Compared with the Belgian population, more women with Turner syndrome attended university and more finished higher secondary education.  Fewer patients were married and more were still living with their parents. This study showed that, in Belgium, as in most other countries in the world, medical care for adult patients with Turner syndrome is suboptimal and that much more effort is needed to organize the transition from childhood to adult care. Since then, several members took the initiative to better structure the transition or set up dedicated Turner clinics.

Psychosocial functioning, self-concept and body-image in young adult women with Turner syndrome

In another study (14), the psychosocial functioning, self-concept and body image was evaluated in 30 young Turner women treated with GH and oestrogen and compared to 44 aged matched non-Turner female students. The authors found that the psychosocial adaptation of young adult women with Turner syndrome appeared to be quite satisfactory. The BMI and not height significantly influenced the appraisal score of the Body Attitude Scale. It was therefore emphasized that follow-up of adult women with Turner syndrome patients should not neglect the problem of overweight and the associated psychosocial consequences.

  1. Small for gestational age

Three to 5 % of the children are born with a weight and/or height at birth below -2 SD for a normal population.  Most of these children undergo a spontaneous catch-up growth and return to their genetic potential by the end of their second year of life. But 5-10% percent of the SGA patients do not catch-up and are at risk to have a short stature at adult age. Short (height <-2.5 SDS) children born SGA older than 4 years, with a height more than 1.0 SD below their target height, without catch-up growth (HV< 0.0 SDS) during the preceding year are eligible for a treatment with GH in Belgium. The dose of GH in this indication is 35 µg/kg.day.

Prediction of first year response to GH therapy

A prediction model for the 1st year height velocity (HV) during GH therapy, based on responses of the patients in a pharmacovigilance study (KIGS), has been published by Ranke et al. (15) to guide the therapeutic approach of short SGA patients. The validity of this model was tested on the data of 80 prepubertal Belgian SGA children included in BELGROW (16).  The KIGS model predicts the first year growth velocity within confidence limits of 2 cm, although with some overfitting and can be used to provide parents with realistic 1st year growth expectations.

Adult height

Many short SGA patients present at the clinic during puberty but currently there are very few data on final height in children that started treatment that late.  An ongoing retrospective study evaluates the near adult height and the pubertal height gain of GH treated short SGA children who started GH during puberty and compared to those who started before the onset of puberty.

Gene alterations examined by whole exome sequencing  in small for gestational age children with permanent growth failure

Another ongoing study explores the influence of gene alterations, studied by whole exome sequencing, as  a cause for intra uterine growth failure and as a predictor for response to GH therapy in very short children born SGA (8).

  1. SHOX

Haploinsufficiency (loss of function mutation of one allele) of the SHOX gene has been found in 2 to 15% of patients with idiopathic short stature and other disorders such as Leri-Weill syndrome. The most frequent SHOX mutations are gene deletions of the SHOX gene itself or a regulatory enhancer region located downstream of the coding region. The other gene defects are nonsense or missense mutations.

GH treatment is an approved yet not reimbursed treatment for patients with SHOX deficiency.  However, short patients can benefit from GH treatment in Belgium via a Medical Need Program. The molecular finding and the first year growth response to GH therapy was studied in 22 patients with SHOX deficiency (17). A deletion of the SHOX gene was found in 60% (n=13) of the patients, a deletion of the PAR 1 region in 22% (n=5) and a point mutation in 18% (n=4). The first year growth response to GH treatment was studied in the 17 prepubertal children starting at a mean age of 9.1±2.2 with a height of -3.1±0.5 SDS. After one year GH therapy at dose of 47.0±6.0 µg/kg.day, the height gain was 0.6±0.2 SDS. No side effects were reported. Long-term studies will determine whether the first year height gain will translate ultimately in a greater height without adverse events.

  1. Long term Safety of growth hormone treatment (SAGhE study)

SAGhE is a consortium of paediatric endocrinologists, epidemiologists and biostatisticians of 8 European countries (Belgium, France, Germany, Italy, the Netherlands, Sweden, Switzerland, UK) that was formed to address the questions of appropriateness and safety of GH treatment in Europe. (http://cordis.europa.eu/result/rcn/57069_fr.html)

More specifically, the objectives of the SAGhE study are:
– to constitute a large meta-cohort of young adults treated with recombinant growth hormone in childhood from representative EU countries;
– to evaluate the long term results of treatment on height and their determinants;
– to evaluate the correlates of height gains with quality of life in young adults;
– to evaluate the long term mortality and cancer morbidity and to compare it with the general population.

A meta-cohort of 25 000 adults treated with GH during childhood was constituted. Two preliminary papers on mortality have been published so far, one for the French cohort (18) and a second one including the Belgian, Swedish and the Dutch cohort (19).

In the French population-based register of children with idiopathic growth hormone deficiency, idiopathic short stature or born short for gestational age, all-cause and cause-specific mortality were analysed (18). The patients started recombinant growth hormone from 1985 to 1997. Follow-up data were available for 94.7 % of the 6928 children and provided 116 403 person-years of observation. The standardised mortality ratios (the ratio of observed deaths to the number of deaths in an age-matched and sex-matched French population) was the principal outcome measure. All-cause mortality was increased (SMR 1.33, 95% CI 1.08 – 1.64). In univariate analysis, shorter children at start of treatment and those who had received the highest doses of growth hormone had significantly increased mortality. The use of doses higher than 50 µg/kg/d was significant in multivariate analysis adjusted on height at start of treatment (Adjusted SMR 2.94, 95% CI 1.22 – 7.07). Mortality due to diseases of the circulatory system was increased (SMR 3.1, 95% CI 1.41 – 5.86), bone tumors (SMR 5.0, 95 %CI 1.01 – 14.76 and subarachnoid or intracerebral hemorrhage (SMR 6.7, 95 %CI 1.80 – 17.11) was increased.

After the release of data from the French part of the EU SAGHE study raising concerns on the long-term safety of GH treatment, preliminary data from Belgium, the Netherlands and Sweden were reported (19). The vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed in all patients diagnosed with isolated GH deficiency (isGHD), idiopathic short stature (ISS) or born small for gestational age (SGA) who started on recombinant GH during childhood from 1985 – 1997 and who had attained 18 years of age by the end of 2010.

Vital status was available for approximately 98 % of these 2543 patients, corresponding to 46 556 person-years of observation. Among 21 deaths identified, 12 were due to accidents, 4 were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect.
In conclusion, the majority of deaths (76 %) in these cohorts were caused by accidents or suicides, as expected in this age group.  Importantly, none of the patients died from cancer or from a cardiovascular disease.

Those results need to be further investigated on the entire SAGhE cohort including the data of 8 European countries.

 

 Conclusion

The BELGROW registry exists now for 30 years and has been proven to be a valuable scientific tool to study the demographics, the effectiveness and the safety of growth hormone treatment in different indications in the short and the long term.

When new studies are set up, BELGROW allows physicians to identify patients who can be recruited to participate not only to auxological studies but also to studies on quality of life, psychological functioning, genetic studies…

The results of these studies conducted with data of BELGROW help the physicians to adapt their treatment strategies and to provide better care for the children and adolescents with growth problems.

 

Reference list

(1)    Thomas M, Massa G, Bourguignon JP, Craen M, De Schepper J, de Zegher F, et al. Final height in children with idiopathic growth hormone deficiency treated with recombinant human growth hormone: the Belgian experience. Horm Res 2001;55(2):88-94.

(2)    Beckers D, Thomas M, Jamart J, Francois I, Maes M, Lebrethon MC, et al. Adult final height after GH therapy for irradiation-induced GH deficiency in childhood survivors of brain tumors: the Belgian experience. Eur J Endocrinol 2010 Mar;162(3):483-90.

(3)    Massa G, Heinrichs C, Verlinde S, Thomas M, Bourguignon JP, Craen M, et al. Late or delayed induced or spontaneous puberty in girls with Turner syndrome treated with growth hormone does not affect final height. J Clin Endocrinol Metab 2003 Sep;88(9):4168-74.

(4)    Lagrou K, Xhrouet-Heinrichs D, Heinrichs C, Craen M, Chanoine JP, Malvaux P, et al. Age-related perception of stature, acceptance of therapy, and psychosocial functioning in human growth hormone-treated girls with Turner’s syndrome. J Clin Endocrinol Metab 1998 May;83(5):1494-501.

(5)    Lagrou K, Xhrouet-Heinrichs D, Massa G, Vandeweghe M, Bourguignon JP, De Schepper Jean, et al. Quality of life and retrospective perception of the effect of growth hormone treatment in adult patients with childhood growth hormone deficiency. J Pediatr Endocrinol Metab 2001;14 Suppl 5:1249-60.

(6)    Lagrou K, Vanderfaeillie J, Froidecoeur C, Thomas M, Massa G, Tenoutasse S, et al. Effect of 2 years of high-dose growth hormone therapy on cognitive and psychosocial development in short children born small for gestational age. Eur J Endocrinol 2007 Feb;156(2):195-201.

(7)    Lagrou K, Froidecoeur C, Thomas M, Massa G, Beckers D, Craen M, et al. Concerns, expectations and perception regarding stature, physical appearance and psychosocial functioning before and during high-dose growth hormone treatment of short pre-pubertal children born small for gestational age. Horm Res 2008;69(6):334-42.

(8)    Rooman R. Protocol: Gene alterations examined by whole exome sequencing  in small for gestational age children with permanent growth failure treated with GH.  2014.

(9)    Thomas M, Massa G, Craen M, de ZF, Bourguignon JP, Heinrichs C, et al. Prevalence and demographic features of childhood growth hormone deficiency in Belgium during the period 1986-2001. Eur J Endocrinol 2004 Jul;151(1):67-72.

(10)    Straetemans S, Roelants M, Thomas M, Rooman R, De Schepper J. Reference curve for the first-year growth response to growth hormone treatment in prepubertal children with idiopathic growth hormone deficiency: validation of the KIGS first-year growth response curve using the Belgian Register for the Study of Growth and Puberty Problems. Horm Res Paediatr 2014;81(5):343-9.

(11)    Thomas M, Massa G, Maes M, Beckers D, Craen M, Francois I, et al. Growth hormone (GH) secretion in patients with childhood-onset GH deficiency: retesting after one year of therapy and at final height. Horm Res 2003;59(1):7-15.

(12)    Massa G, Verlinde F, De SJ, Thomas M, Bourguignon JP, Craen M, et al. Trends in age at diagnosis of Turner syndrome. Arch Dis Child 2005 Mar;90(3):267-8.

(13)    Verlinde F, Massa G, Lagrou K, Froidecoeur C, Bourguignon JP, Craen M, et al. Health and psychosocial status of patients with turner syndrome after transition to adulthood: the Belgian experience. Horm Res 2004;62(4):161-7.

(14)    Lagrou K, Froidecoeur C, Verlinde F, Craen M, De SJ, Francois I, et al. Psychosocial functioning, self-perception and body image and their auxologic correlates in growth hormone and oestrogen-treated young adult women with Turner syndrome. Horm Res 2006;66(6):277-84.

(15)    Ranke MB, Lindberg A, Cowell CT, Wikland KA, Reiter EO, Wilton P, et al. Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 2003 Jan;88(1):125-31.

(16)    Verlinde F, Thomas M, De Waele K, Gies I, Francois I, Beckers D, et al. First year growth response to Gh therapy in short prepubertal SGA patients: results from clinical practice in Belgium. Poster presented at 47th Annual meeting of the ESPE . 2008.

(17)    Thomas M, Tenoutasse S, Cools M, Maes M, De Schepper J, Heinrichs C, et al. First year growth response to growth hormone therapy in patients with short stature and SHOX deficiency. Poster presented at 50th Annual meeting of the ESPE . 2011.

(18)    Carel JC, Ecosse E, Landier F, Meguellati-Hakkas D, Kaguelidou F, Rey G, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab 2012 Feb;97(2):416-25.

(19)    Savendahl L, Maes M, Albertsson-Wikland K, Borgstrom B, Carel JC, Henrard S, et al. Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study. J Clin Endocrinol Metab 2012 Feb;97(2):E213-E217.