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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 1
General Introduction
and Thesis Outline
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1
General Introduction and Thesis Outline
A Short Girl
Zita1 is a 10-year old girl with growth failure. After an uncomplicated pregnancy, she was born at 38 weeks of gestation and weighed only 2340 grams, well below the aver-age. At one year she was still small, and her parents found the tone in her muscles low. Zita was not sitting yet and was also not babbling. So, her parents consulted their general practitioner (GP): Why is she smaller than other children? Why is she developing slowly? Could both be related and could Zita have an underlying disease? Their young GP did not yet have much experience with growth disorders and wondered: Should I refer her to a special-ist? Are there any criteria or guidelines available for this?
The GP first decided to wait a bit longer. At two years, Zita’s growth was still below all centiles on the growth chart, her development was also still slow, and the parents had noticed she looked a bit different compared to the family. So the GP referred her to a paediatrician. The paediatrician had a specific interest in children with growth disturbances, and knew about the guidelines that she could follow in her work-up. She thought that all signs and symptoms in Zita likely constituted a syndrome, and asked a clinical geneticist for help. The genetic evaluations showed Zita to have a known syndrome: she had received two chromosomes 14 from her mother instead of one from her mother and one from her dad. It explained her development, her growth pattern, and the way she looked. The parents were informed, and the paediatrician took over the further care.
At 7 years of age, Zita was 11 centimetres shorter than on average her peers were, while her parents were in fact quite tall. She had developed some overweight, something that was known to occur in this syndrome. Zita had difficulties with her short stature, it hindered her to participate in certain activities. She and her class mates would go to a theme park, and Zita wondered: Will I be tall enough to enter the attractions? Can the doctors make me taller?
Treatment with growth hormone to increase her height and improve her body composi-tion was considered by her paediatrician. She wondered: Is there any evidence available that in this syndrome growth hormone would increase Zita’s height and improve her body proportions? What could be the physical and psychological benefits of any treatment?
In this thesis, I aim to focus on each of these questions that arise when dealing with children with growth disorders like Zita – from referral, diagnostic workup and genetic analysis to diagnosis, treatment and quality of life.
1
Human Growth
The process of human growth starts at conception and ends when adult height has been reached. Every fetus has a genetically determined growth potential and its growth is further influenced by fetal, maternal and placental factors [1]. Fetal growth is defined as the increase in mass that occurs towards the end of the first trimester and birth [2]. From the third trimester of pregnancy, increase in body size is among other things achieved by linear growth, determined by the rate of growth plate chondrogenesis, and by increase of essential body stores, resulting in a nearly 20% increase in fat mass [2, 3]. Growth plate chondrogenesis plays an important role in height gain from the end of pregnancy to adolescence: decreased chondrogenesis causes short stature and increased chondrogenesis results in tall stature. Many factors, such as nutritional, genetic, paracrine and endocrine factors, regulate this process [3]. Furthermore, other disorders of the bone, like abnormal breakdown or remodelling of bone tissue, bone malformations and deformations can contribute to disturbed growth. For short stature, growth disorders include clinically defined syndromes, small for gestational age (SGA) with failure to catch-up growth, skeletal dysplasias, malnutrition, disorders in organ systems, growth hormone deficiency and other disorders of the growth hormone-IGF axis, endocrine- and metabolic disorders, psychosocial and iatrogenic causes and idiopathic short stature [4]. Regarding tall stature, disorders consist of dysmorphic syndromes, growth hormone overproduction, hyperinsulinism, familial glucocorticoid deficiency, hyperthyroidism, other endocrine disorders and idiopathic tall stature [4]. For some of these disorders, including certain dysmorphic syndromes and idiopathic short and tall stature, the mechanism for dysregulation of the growth plate remains unknown [3].
Growth Monitoring
Growth failure, which includes short stature, growth retardation or short stature in comparison to target height, is considered an early sign of various underlying pathologi-cal conditions and forms a common reason for referral to specialist paediatric care [5]. The incidence of pathological causes of growth failure in children aged below 10 years varies between 3 and 9.5% [6-9]. For adolescents with growth failure, the incidence of detectable disorders has been reported markedly lower, 1.3% [10]. Overgrowth or tall
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General Introduction and Thesis Outline
stature on the other hand is a less common reason for referral and underlying pathol-ogy is seen in this group of patients as well, but is very rare [11]. However, it remains important to rule out pathology in tall patients. The most common genetic causes of overgrowth, such as Fragile X syndrome, Marfan syndrome, Klinefelter syndrome and Sotos syndrome show incidences of <<0.1% [12-17].
In order to detect pathological causes of disturbed growth in children, an efficient sys-tem for growth monitoring and a diagnostic workup with a high sensitivity and speci-ficity is essential. Despite similarities in clinical presentation and etiology of growth disorders, national guidelines for screening and diagnostic workup in children and adolescents with growth failure or overgrowth vary widely [7, 18-23]. In Part 1 of the thesis we evaluate various national guidelines for growth monitoring and diagnostic workup in children and adolescents with growth failure and overgrowth. Chapter 2 describes a study evaluating the Dutch, Finnish and British screening guidelines in a cohort of children with growth failure. In Chapter 3 we present a study investigating the etiology, the role of puberty and the most useful criteria for diagnostic workup in a cohort of adolescents with growth failure. The study in Chapter 4 explores diagnostic workup and follow-up in children with tall stature and we present a simplified diagnos-tic algorithm for use in clinical pracdiagnos-tice.
Genetic Analysis
Part of the diagnostic workup in growth disorders includes genetic analysis. Genome-wide association studies (GWAS) have shown hundreds of genes involved in growth. Although over 400 loci showed to contribute to variation of normal stature, effect sizes per loci are small and these studies have provided limited insight into pathological causes of growth failure [24]. With respect to sequence variants, rare genetic variants with a large impact on growth cannot be found in GWAS.
The technical abilities to examine genetic disorders have increased dramatically in the past few years. Array-comparative genomic hybridization (array-CGH) and microarrays were introduced for the detection of copy number variants (CNVs) and the arrival of whole-exome sequencing (WES) enabled clinicians and researchers to detect muta-tions in virtually all exons of the genome, instead of testing each locus separately [25]. For children with growth disorders it has become clear that this genetic technology may greatly improve and accelerate the diagnostic process, at a lower cost. In the past
1
few years several genetic growth disorders have been discovered by WES, for example caused by CUL7, IGSF1, FGFR3, ACAN, PAPPA2 and XRCC2 mutations [26-31]. Further-more, epigenetic changes such as DNA methylation disturbances play a critical role in the development of disease. Genome-wide methylation arrays allowed assessment of methylation patterns across the entire genome [32].
Presumably, 30-50% of the variation in weight at birth can be explained by genetic causes, which includes chromosome imbalances, sequence variants and epigenetic disturbances. The London Dysmorphology Database contains over 400 entities associ-ated with prenatal growth failure [33] and GWAS have disclosed a number of variants associated with fetal growth [34]. Furthermore, numerous studies on epigenetic influences, especially methylation disturbances, have been performed [35-42]. Despite this, the (dys)regulation of prenatal growth is still only understood to a limited extent. The study in Chapter 5 shows a unique combination of genetic studies in a cohort of small for gestational age (SGA) newborns, using array-CGH, WES and a genome-wide methylation array.
Treatment
Several growth disorders, such as Turner syndrome, SHOX gene haploinsufficiency, Noonan syndrome, growth hormone deficiency (GHD) and Prader-Willi syndrome, are approved indications for growth hormone treatment (GH-T) in children and ado-lescents [43]. Besides increasing growth and final height, treatment can be beneficial for psychosocial and cognitive functioning, body composition and muscle strength. In addition to these disorders, other disorders in which GH-T has not been investigated yet, could benefit from this treatment. Chapter 6 describes a therapeutic study in pa-tients with maternal Uniparental Disomy 14 (matUPD(14)), a syndrome that resembles Prader-Willi syndrome (PWS) and is characterized by short stature, truncal obesity and precocious puberty. Treatment with GH has not been reported in detail for this syndrome before. Therefore, we observed the effect of GH-T in matUPD(14) patients on growth and body composition during a 2-year follow-up period.
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General Introduction and Thesis Outline
Quality of life
Literature suggests that a child develops a certain attitude towards short and tall stature from an early age. Tall stature is considered a positive phenomenon in contrast to short stature, even in very young children [44]. Negative stereotypes regarding short stature constitute a potential source of psychosocial stress for the affected child. Therefore, an important aim of growth hormone therapy besides increasing height, is psychological improvement of short individuals [45]. Regarding growth hormone therapy, on average 10-14 cm height gain can be expected after treatment in children with in growth hor-mone deficiency (GHD) [46], 5-8 cm in Turner syndrome [47] and 3-6 cm in idiopathic short stature (ISS) [48, 49]. Nevertheless, it is questionable whether GH-T, in the form of subcutaneous injections for many years, actually improves the child’s quality of life when only a few centimetres in height can be gained, especially in otherwise ‘healthy’ ISS children.
To subjectively investigate in what way children experience the burden of being small as well as the quality of life outcome of GH-T, the European Quality of Life in Short Stature Youth was developed and psychometrically tested [50]. In the study presented in Chapter 7, the original European QoLISSY questionnaire, as developed for young patients with GHD and ISS, was translated to Dutch and psychometrically tested in GHD and ISS patients and their parents in the Netherlands.
1
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