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Start small, think big: Growth monitoring, genetic analysis, treatment and quality
of life in children with growth disorders
Stalman, S.E.
Publication date
2016
Document Version
Final published version
Link to publication
Citation for published version (APA):
Stalman, S. E. (2016). Start small, think big: Growth monitoring, genetic analysis, treatment
and quality of life in children with growth disorders.
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chapter 8
Summary and
General Discussion
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The aim of this thesis is to focus on issues that arise when dealing with children with growth disorders – from growth monitoring and genetic analysis to treatment effects on growth and quality of life. This chapter summarizes and discusses the main out-comes of the various studies described in this thesis and presents implications and perspectives for future research.Growth Monitoring
The first part of this thesis focuses on guidelines for diagnostic workup of children with growth disorders, including either growth failure or overgrowth. Little is known about the optimal criteria for referral and diagnostic workup of children with growth disorders in order to uncover underlying pathology. Since the shape of a child’s growth curve is influenced by the etiology of the growth disorder (for example, congenital or acquired underlying disorders), genetic factors, pubertal development, environmental and in some cases even psychological factors, it has proven difficult to define cut-off criteria. Still, various studies have attempted to develop an efficient set of criteria and a number of consensus-based criteria as well as various evidence-based guidelines have been established [1-5]. However, evaluation and validation of such guidelines has sel-dom been performed and consensus on the most efficient criteria and their cut-offs has not been established. In Part 1 of this thesis we investigate the incidence of pathology in children with suspected growth disorders and evaluate existing guidelines for growth monitoring.
First, we retrospectively investigated the sensitivity and specificity of guidelines for diagnostic workup currently used in the Netherlands, Finland and the UK in a Dutch cohort of children aged 3 to 10 years with growth failure (Chapter 2). These children were referred for suspected disorders of growth to our general paediatric outpatient clinic. In 18% of these children a pathological condition was found explaining their
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Summary and General Discussion
growth failure. The Dutch [2] and Finnish guidelines [4], consisting of criteria for height standard deviation score (HSDS), distance to target height (i.e. the gender-adjusted mid-parental height) and a decreased growth rate were proven to be effective for use in growth monitoring, using similar cut-off values. Both guidelines showed a good sensitivity and specificity for detecting pathological causes of growth failure, with recent growth deflection as an important warning sign. The sensitivity of the UK guideline was considerably lower.
Second, in Chapter 3 we performed a similar study in adolescents, taking into account the influence of puberty on growth. In 7% of the adolescents a specific diagnosis could be established, so significant pathology at an adolescent age can still be found. Con-stitutional delay of growth and puberty was diagnosed in 10% of adolescents. A high sensitivity for detecting pathology was found when applying all Dutch criteria as used in children aged 3 to 10 years, whereas the sensitivity of the current Dutch recommenda-tion for adolescents (only a HSDS <-2.5) was considerably lower. This implicates that although establishment of auxological criteria in adolescents is complicated due to the influence of delayed pubertal onset on growth, all main growth criteria are important for growth monitoring in adolescents.
Third, we investigated the diagnostic workup and follow-up in children with tall stature (Chapter 4). We found a very low incidence of pathology (1.5%) in children referred for tall stature. Most children were classified as idiopathic tall or had constitutional ad-vancement of growth, and 50% of the patients referred for tall stature were not tall ac-cording to its definition (their HSDS was <+2.0). Furthermore, we observed that in only a few patients adult height reduction by epiphysiodesis was indicated and performed and that adult height prediction by Bayley and Pinneau (BP) results in overestimation of adult height. Based on our results and review of the literature we propose a new diagnostic flow chart, focussing on excluding pathology and giving suggestions for follow-up.
The similar sensitivities between the Dutch and the Finnish guidelines for growth failure can be explained by the comparable criteria and cut-off values for HSDS and distance to target height (TH). Regarding adolescents, not only height SDS should be used as an indication for pathological growth, but the other main growth criteria are equally important for the detection of pathology. Optimal criteria based on the Dutch and Finnish cut-off values could therefore be considered for future use, both in younger children and adolescents. Regarding the Finnish guideline, a complicating factor in its
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use is that calculation of certain criteria is complicated and can only be analysed by a computer.Since the Dutch referral criteria are relatively simple, and do not need computer-ized algorithms, they are now generally used in preventive child health care. When user-friendly software algorithms become available, we recommend to investigate the diagnostic yield of both sets of criteria in a prospective study, and explore possible improvements. One of the main limitations of the Dutch guideline is that an HSDS of less than -2.0 is an obligate criterion. This limits the sensitivity to detect pathology, because some forms of growth failure, particularly if acquired and if occurring in a child with tall parents, can be associated with a HSDS within the normal range, at least for several years. Hence, we investigated whether adding a recent growth deflection irrespective of HSDS as a criterion to the Dutch guideline would improve its sensitivity. Sensitivity indeed increased, but as expected specificity decreased below an acceptable level for population screening.
In general, when using criteria for growth monitoring some children with pathology will not be detected, emphasising the fact that at all times a detailed medical history and physical examination, followed by proper medical judgement, cannot be replaced by growth monitoring guidelines. We also advise every doctor evaluating a growth curve to always take the parental height into consideration in relation to the child’s height (irrespective of the actual HSDS) and pay attention to the course of the growth curve to detect any growth deflection.
In the future, we aim to collaborate with the Finnish group to investigate how frequently pathology was found in patients with a normal growth pattern according to their cri-teria. Furthermore, we aim to establish a modification of the current evidence-based guideline for children aged 3 to 10 years and develop a new guideline for 10 to 18 year olds. These novel guidelines will focus on the utility of performing additional investiga-tions in children referred because of a suspected growth disorder but without specific clues at medical examination. A prospective study in a large cohort will allow us to answer whether it is recommended to perform radiologic and laboratory investigations in such children in comparison to not performing additional investigations.
Although the incidence of pathology in children referred for tall stature is low and much lower than in short children, it remains important to uncover pathological causes of overgrowth given the sometimes serious underling conditions [1]. These include Marfan and Klinefelter syndrome, but also other genetic or endocrine disorders. In Marfan syndrome, serious cardiovascular anomalies such as aortic dilatation are seen
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Summary and General Discussion
[6] and thus early diagnosis and treatment of this disorder is important. Therefore, an adequate guideline for diagnostic workup in tall patients to uncover pathologies is necessary. In addition, as in children with growth failure, careful clinical assessment besides following guidelines is crucial, with special attention to developmental and behavioural problems that could be suggestive for a genetic disorder. Regarding the prediction of adult height, we and others [7] have observed an overestimation of adult height prediction by using the BP method and advise to use the De Waal method [8]. The incidence of pathological disorders in tall children is low, but current guidelines tend to focus on finding pathology, and give little attention to idiopathic forms of tall stature and recommendations for follow up [1, 3, 5]. We therefore developed a simple diagnostic algorithm. This algorithm focuses on excluding pathology and provides recommendations for follow-up. However, additional investigations are necessary in order to further develop an efficient guideline. Hence, our future aim is to perform a systematic literature study as well as a further analysis of tall children from our out-patient clinic and other clinics. Given the low incidence of pathology, large cohorts are needed to detect more patients with pathology. We hope that this would enable us to develop a more evidence-based guideline. In line with the intended research in children with growth failure, we will try to answer the question whether an additional diagnostic workup for Marfan and Klinefelter syndrome would be indicated in a large cohort of children with suspected overgrowth disorders without any clues for a specific diagnosis, compared to only assessing the child’s bone age, in addition to a proper medical history and physical examination.
Recently, a working group, consisting of paediatricians and paediatric endocrinolo-gists, researchers, public health care workers and representatives of patient associa-tions, has been composed, which submitted a grant proposal to carry out the above mentioned research in children with suspected growth disorders in the near future.
Genetic Analysis
In the second part of this thesis we performed genetic analyses in small for gestational age (SGA) newborns. In Chapter 5 we present our study investigating SGA newborns, using a combination of array-CGH, genome wide methylation array and whole exome sequencing (WES). In four patients we found a genetic abnormality that is likely to contribute to their restricted growth. These included three copy number variations
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(CNVs), a sequence variant in SOS1 (associated with Noonan syndrome [9]) and a widely disturbed methylation pattern in one patient. In most of the remaining patients, abnor-malities were found that could potentially influence fetal growth, including sequence variants and methylation disturbances, but its causality remains to be investigated further. Our results confirm that intrauterine growth is influenced by the function of a large number of genes and different genetic mechanisms [10, 11]. Furthermore, it shows the absence of a unifying theme explaining the dysregulation of fetal growth. We also show that there is no predominant type of genetic abnormality present in SGA newborns, since many patients show a combination of a CNV, sequence variant and methylation disturbances.Based on our findings, several implications for clinical practice arise. Our first obser-vation is that array-CGH uncovers a fairly high number of CNVs, all with a plausible causality in comparison to the more uncertain meaning of the methylation and exome results. For other indications, like intellectual disability, chromosomal microarrays are the first line diagnostic tool [12]. Therefore, we propose to initially perform array-CGH to uncover CNVs in the genetic diagnostic workup of SGA newborns, before performing more expensive forms of genome wide analyses. In the future, it is expected that genome sequencing will be able to uncover CNVs, and in combination with the expectation that it will become far less expensive, so that it may develop into a first line diagnostic tool. Furthermore, a thorough analysis of the patients’ family and their genetic variants and phenotypes as well as follow-up data could give more direction towards the possible underlying condition and could narrow down the diagnostic workup. Another, more complex issue is the implementation of epigenetic diagnostic strategies, for example with genome-wide methylation arrays. At this stage, our opinion is that its analysis and interpretation is too complex for clinical applications. Furthermore, we would need expression data to interpret the meaning of epigenetic alterations at gene expression level. It will remain a challenge in the future to functionally study all these genetic and epigenetic findings and to study their interactions. For now, diagnostic testing in a clinical setting for epigenetic disorders should be limited to known disorders with a characteristic phenotype, such as Silver-Russel syndrome.
Some limitations of our study form starting points for further research. First, we did not use a large appropriate for gestational age (AGA) cohort as a reference genome col-lection for the analysis of the whole exome data. Population allele frequency databases do not provide phenotypic data of individuals and thus limit the ability to determine whether a WES variant is causal, since some individuals could have been growth
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stricted at birth. Furthermore, we had no access to clinical follow-up data and were unable to evaluate the patients and their parents at a later age to confirm the phenotype. Therefore, for future purposes we aim to collect a well-defined large AGA cohort and perform exome sequencing in these individuals. In addition, we aim to repeat and confirm our results in a larger SGA cohort, potentially yielding similar variants and probably revealing many other variants as well as well as collecting follow-up data. One could consider performing whole genome sequencing instead of WES to uncover additional sequence variants in non-coding regions of the DNA. However, since our exome analyses already resulted in many potential variants explaining the patient’s low birthweight, we reason to first focus on WES. Based on our results and previous research, it is known that regulation of fetal growth is polygenic in most patients and can be explained by an interaction between the various genetic abnormalities. Such pathogenic mechanisms are extremely complex [13, 14] and separate studies in each patient to evaluate this in detail should be part future research. Additionally, functional analyses are required and will be conducted to prove the role of the observed variants in fetal growth.
Treatment
As pointed out in the introduction of this thesis, several growth disorders are approved indications for growth hormone treatment (GH-T) in children and adolescents [15]. Given the known positive effects of GH-T regarding growth, psychosocial and cognitive functioning, body composition and muscle strength, many children with other causes of short stature could benefit from treatment. However, many disorders in which short stature is part of the phenotype, have not been accepted as an indication for GH-T, usually because either the effects of treatment were considered insufficient, but also because the low incidence of the growth disorders did not allow proper evaluation. We investigated the effect of GH-T in patients with maternal uniparental disomy of chro-mosome 14 (matUPD(14)) in Chapter 6. MatUPD(14) resembles Prader-Willi syndrome (PWS); both syndromes are characterized by short stature, truncal obesity and hypoto-nia. In PWS, GH-T has shown to have a positive effect on growth and body composition [16, 17]. Our prospective observational study describes GH treatment in two girls with matUPD(14) during 2 years, and shows growth and weight parameters in another matUPD(14) girl in which pubertal and bone age development were too advanced to
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benefit from GH-T. In both treated girls, a considerable increase in height and IGF-1 levels was observed. In one patient in which treatment was started at an early age, also a decrease in weight and improved body composition was found. Furthermore, both treated girls experienced improved muscle strength, and no side-effects were reported. In the patient that could not be treated, growth remained far below average with an expected adult height of 135 cm, while weight continuously increased.Based on our results we conclude that GH-T in matUPD(14) cases can show beneficial effects on growth, body composition and muscle strength. We advise treating ma-tUPD(14) patients with GH-T and to start at a young age, preferably before the average onset of obesity in matUPD(14) at 3 years [17, 18]. Similar to GH-T in PWS, the dosage can initially be started at 0.3-0.5mg/m2 per day and adjusted towards 1.0 mg/m2 [18],
guided by the IGF-I levels, which should be kept below 2.0 SDS given the potentially increased risk of developing neoplasms under high IGF-1 levels [19]. Besides treatment with GH, it is important to (simultaneously) inhibit the precocious puberty which is typically seen in matUPD(14) patients, causing early maturation and closure of growth plates, and thus early cessation of growth.It is unclear how many children are known with matUPD(14), and probably patients are misdiagnosed with either PWS or are not being tested for a maternal disomy of chromosome 14. Therefore, we would rec-ommend always testing for matUPD(14) in patients with a PWS phenotype. In older children with a PWS-like phenotype and the presence of precocious puberty, we would recommend testing for matUPD(14) first.
Given that matUPD(14) is a rare disease, only a large international collaboration would allow to collect sufficient patients and children of different ages and pubertal stages. We would like to prospectively document the effects of growth hormone treatment in such larger cohort and evaluate treatment in patients that are currently treated or have been treated previously. By performing a larger, international study we will be able to determine detailed effectivity, the optimal age to start treatment, most appropriate dos-age and possible side-effects.
Quality of Life
Being short can cause psychosocial problems, and previous research has shown that these problems occur more frequently in medically referred short children [20]. Little is known about self-perceived psychosocial functioning of short children and few
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struments are available assessing perceptions of being short according to children and their parents [20]. Therefore, a valid tool to evaluate the quality of life (QoL) of short children, from both the child’s and parents’ perspectives is needed. The European Quality of Life in Short Stature Youth (QoLISSY) questionnaire was developed to evalu-ate the health-relevalu-ated QoL in short children [21], assessing QoL from the perspective of the child as well as the parents. It focuses of the following items: physical, emotional, coping, treatment, beliefs, future and the effects on the parents. In order to use the QoLISSY in Dutch patients, a translation process and psychometric testing of the original questionnaire was required as described in Chapter 7. The study describes the psychometric performance of the Dutch QoLISSY in children with idiopathic short stature and growth hormone deficiency and their parents. Our results show a good reliability based on its internal consistency, consistency between the initial test and re-test and the congruency between children and parents. Furthermore, a good validity of the QoLISSY based on the well-validated generic KIDSCREEN [22] and the original European sample was observed. Therefore, we conclude that the Dutch QoLISSY is a psychometrically reliable and valid short stature-specific QoL instrument in evaluat-ing the burden of beevaluat-ing short as well as treatment outcomes in clinical practice and research.
Previous studies regarding QoL in short stature recommended to use a disorder-specific questionnaire to measure QoL in short children treated with growth hormone [23, 24] instead of general QoL measures. For example, the TNO-AZL Children’s Quality of Life Short Stature module (TACQOL-S) was used to asses QoL [25]. To our knowledge, experience with this questionnaire is limited and the questionnaire was only translated into three languages, making cross-cultural comparisons difficult [26]. In addition, the Dutch QoLISSY showed a better internal consistency (α 0.80 – 0.95) compared to the TACQOL-S (α 0.57 - >0.70). Therefore, the QoLISSY seems a more reliable and valid tool for evaluating QoL in short stature and we reason that the questionnaire could be used for various purposes. First, it is an accessible tool for children and their parents to express thoughts and feelings regarding being short. Additionally, it will inform the doctor about how short children experience their height and possible as-sociated problems, enabling him or her to offer appropriate counselling. We would even urge to focus more on accepting or coping with being short, and the QoLISSY could well be used to evaluate such psychological interventions. The QoLISSY will soon be implemented in our outpatient growth clinic for this purpose. Second, the question-naire could measure the psychological benefits of GH-T. As mentioned earlier in this
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thesis, GH-T sometimes results in only a few centimetres height gain and therefore it is questionable whether GH-T in for example idiopathic short patients is worthwhile, with regard to the burden of daily injections. We believe assessing a child’s QoL should become part of care before, during and after GH-T.In line with this, the questionnaire could be used for future research in studies on GH-T in known or newly treated disorders characterized by short stature. Some studies have assessed QoL in patients treated with GH [23, 24, 27], showing improvement of health-related QoL in GH-treated children and adolescents, although a systematic review considered that the quality of all studies were suboptimal [28]. Furthermore, it is interesting that some children with short stature develop psychosocial problems while others don’t, possibly depending on factors like the severity of short stature and coping strategies [29]. For future research purposes, the QoLISSY questionnaire could be a valuable measure to gain more insights into the influence and relevance of those contributing factors. We would be interested in performing a QoL study in short children treated with growth hormone, compared to children receiving psychological interventions aimed at accepting and coping with their stature. As mentioned earlier, we also aim to perform future research on GH-T in matUPD(14), and assessment of the patients QoL could be measured using this tool. Due to the various translations of the QoLISSY, it is very useful in larger international studies.
General Conclusion
In this thesis we have discussed various aspects of human growth, including its aetiol-ogy, growth monitoring, diagnostic workup, treatment and quality of life. We have taken a step further in expanding the knowledge of growth disorders and treatment strategies and provide suggestions for future research.
Given the wide variation of shapes of growth curves and the many possible underlying conditions, pursuing an ideal combination of criteria for growth monitoring might just be infeasible. We acknowledge and underline the importance of growth monitoring in public and paediatric healthcare and would recommend to focus on each of the three main growth indicators (height, distance to target height and height velocity) using current evidence-based guidelines such as the Finnish and Dutch as a guide, in combi-nation with a proper medical history and physical examicombi-nation. The medical profession needs guidelines that are based on thorough and reliable research, but the clinician
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must never stop thinking for him- or herself: guidelines are made to guide, but the most valuable guide for an individual medical assessment is the child itself.
Future research should, according to us, therefore focus less on establishing optimal criteria and more on the utility of performing additional investigations in children referred because of a suspected growth disorder and without clues for a specific diagnosis. Given the generally limited knowledge of genetic disorders by primary health physicians and paediatricians, and the minor role of the clinical geneticist in this workup, we want to emphasize the importance of genetic diagnostics and its rapid developments. Maybe one day, the clinician may be able to offer every child with a dis-turbed growth pattern a whole genome sequence, as well as a genome-wide epigenetic assay. However, one should always have a keen eye for the ethical issues that always will go along with this.
To conclude, in this entire diagnostic process, one has to make sure that severe dis-orders and disdis-orders that require treatment are uncovered, but at the same time one should attempt to prevent medicalisation or stigmatisation of every short or tall child. What would our world look like if everybody had the same height, the same eye colour, or the same face shape? We believe that this variation, within certain limits, is what makes every human being unique and interesting. By accepting and valuing this and by passing this belief on to the next generation, quality of life of children with non-pathogenic short and tall stature could be increased without the interference of growth hormone treatment or height reduction surgery.
“It is an old saying, abundantly justified, that where sciences meet, there growth occurs” – Sir Frederick Gowland Hopkins
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