UvA-DARE (Digital Academic Repository)
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 2
Application of the Dutch,
Finnish and British Screening
Guidelines in a Cohort of
Children with Growth Failure
Susanne E. Stalman, Ilse Hellinga, Paula van Dommelen, Raoul C.M. Hennekam, Antti Saari, Ulla Sankilampi, Leo Dunkel,
Jan M. Wit, Gerdine A. Kamp, Frans B. Plötz
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Abstract
Aims
To evaluate three guidelines for selecting short children for diagnostic workup in a general pediatric clinic.
Methods
All patients (n = 131) aged 3.00-9.99 years who were referred for growth failure to a gen-eral pediatric clinic were evaluated for their medical history and growth and examined. All of them underwent the same standardized diagnostic workup. Retrospectively, the criteria for the diagnostic workup from three guidelines (proposed in the Netherlands, Finland and the UK) were applied, and their sensitivity was assessed. A Dutch reference sample (n = 958) was used for calculating population specificity.
Results
In 23 patients (17.6%), a pathological cause of their growth failure was found. The sen-sitivity of the original Dutch, Finnish and British guidelines was 73.9, 78.3 and 56.5% and their specificity 98.5, 83.7 and 95.8%, respectively. When adding recent growth deflection to the Dutch guideline, sensitivity increased to 87%, but specificity decreased markedly (to 87%).
Conclusion
The proposed cutoff values for height standard deviation score and distance to target height/mid-parental height, as used in the Netherlands and Finland, are effective for population growth monitoring, and superior to the monitoring algorithm in the UK. Growth deflection irrespective of height is an important sign of acquired growth disor-ders, but its specificity is too low for population screening.
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Introduction
Short stature or growth retardation is considered a relatively early sign of underlying pathology in children. In several countries, a system of growth monitoring is estab-lished in primary health care, with referral to secondary and/or tertiary care of patients suspected for a pathological cause [1]. Criteria for growth monitoring and diagnostic workup should ideally have a high sensitivity and specificity.
Despite similarities in the clinical presentation and etiology of growth failure in various parts of the world, national guidelines for the screening and diagnostic approach vary considerably [2,3]. Indeed, even in countries using a similar set of growth indicators [i.e. height standard deviation score (HSDS), distance to target height and growth rate], such as the Netherlands, Finland and England, different cutoff limits are used. The Dutch guideline is based on a set of 4 criteria which show a high sensitivity (76-86%) for detecting pathological causes of growth failure in children aged 3.00-9.99 years [4]. It has subsequently been suggested to add 2 additional criteria in primary health care [5]. A similar set of auxological criteria was reported by a Finnish group, showing a sensitivity of 97% in screening for Turner syndrome [6]. In the UK, height and weight are measured at the age of 4-5 and 10-11 years [7,8], and recommendations are provided for criteria for further assessment based on growth rate and distance to mid-parental height [9-11].
The aim of our study was to analyze the sensitivity and specificity of these three guide-lines in a pediatric clinic examining children that were referred for growth failure.
Methods
Study Population
All children between 3.00 and 9.99 years of Dutch, North African or Southeastern Eu-ropean ethnicity referred to our pediatric endocrine outpatient growth clinic for growth failure (Growth Clinic, Tergooi Hospitals, Hilversum, The Netherlands) between Janu-ary 2010 and June 2013 were included. Excluded were (1) adopted children, (2) children of other ethnicities and (3) children with missing medical records.
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Diagnostic Workup
At our growth clinic, all referred patients underwent a standardized diagnostic workup which includes an evaluation of the medical and family history, detailed auxological measurements, bone age assessment and a physical examination with special atten-tion to dysmorphisms and body disproporatten-tions. A pediatrician with special training in endocrinology and growth disorders decided whether a further diagnostic workup was indicated, which included (if indicated) further referral to a pediatric endocrinologist or clinical geneticist. If insufficient indications for disturbed growth were found, pa-tients were discharged from further follow-up, or the pediatrician decided on watchful waiting. On patients with indications for disturbed growth, further investigations were carried out. If an immediate indication for a specific diagnosis was present, targeted further investigations of this disease were conducted. If no specific clues were found, full laboratory assessments of blood and urine were performed. In case of abnormal IGF-1 levels (<-1.0 SDS), a growth hormone provocation test was performed with cloni-dine; if necessary, a second test was performed using arginine, after priming with tes-tosterone esters in boys and ethinyl estradiol in girls. In case of abnormal IGF-1 (<-1.0 SDS), a peak growth hormone value of >6.7 ng/ml was considered a normal response; in case of an IGF-1 level <-2.0 SDS, a peak growth hormone value of >10 ng/ml was con-sidered a normal response. In addition, in case of disproportion, defined as a sitting height/height ratio >+2.0 SDS [12] and/or a low arm span for height (<96.5%) [13], a radiographic evaluation of the skeleton was performed. Screening for a short stature homeobox (SHOX)-containing gene defect was planned in case of a Rappold score >4 [13]. In case a girl showed an HSDS >2.0 below the target height SDS (THSDS), genetic testing for Turner syndrome was performed, except if additional clinical or laboratory findings made such a diagnosis unlikely (e.g. low follicle-stimulating hormone levels and no dysmorphisms). In case of an abnormal phenotype, the patient was referred to a clinical geneticist for evaluation, and, if indicated, genetic testing was performed.
Diagnoses and Definitions
Growth failure in our population included short stature and/or abnormally low height velocity [14] and/or large distance to target height. Short stature was defined as an HSDS below -2.0 according to the ESPE Classification [14]. Patients with pathological causes of short stature were classified as having primary or secondary growth disorders. The remaining children with an HSDS <-2.0 were classified as having idiopathic short
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stature [14]. The children were further subclassified into either familial or nonfamilial cases [15,16]. Children with an HSDS ≥-2.0 were classified as ‘non-short’.Criteria according to the Dutch, Finnish and British Guidelines
The three guidelines for growth monitoring contain various criteria which were as-sessed both separately and as a set to allow for calculating the sensitivity and specificity of both the individual criteria and the full guidelines. These guidelines were tested on the children referred for growth failure to establish if the sensitivity of the guidelines for detecting pathological causes of growth failure was sufficient. We also tested them on a Dutch reference sample (n = 958) for calculating population specificity.
According to the Dutch guideline for children aged 3.00-9.99 years with short stature [4], an additional workup would be indicated if any of the following criteria applied: (1) HSDS <-2.5; (2) HSDS <-2.0 and dysmorphic features or disproportion; (3) HSDS <-2.0 and HSDS >1.6 SD below THSDS (the original cutoff of 2.0 SD below the THSDS was changed when a new formula of target height was used [16] and the secular change in height had stopped [17]), or (4) HSDS <-2.0 and height deflection (>1.0 SD). Two addi-tional consensus-based criteria have been suggested for primary health care: (5) HSDS >2.5 SD below THSDS and (6) growth deflection irrespective of HSDS [5]. We evaluated the suitability of the set of 4 criteria and the set of 6 criteria separately. In the absence of a definition of a recent ‘growth deflection’, we used the following cutoff values: >0.5 SD/1 year, >0.7 SD/2 years or >1.0 SD/undefined time, irrespective of height, in contrast to criterion 4.
Screening parameters according to the Finnish guideline include HSDS, distance between HSDS and THSDS (THSDSDEV) and HSDS change over time (ΔHSDS), and
optimal cutoff points were defined at maximum sensitivity and specificity values [6]. Regarding THSDSDEV, the cutoff limit is variable: the cutoff value is multiplied by an
age- and gender-specific reference value (SD) for target height [6]. This results in the following criteria: (1) HSDS ≤-2.2414; (2) THSDSDEV ≤-2.2414 × SD, and (3) ΔHSDS
≤-2.2414. In order to apply the Finnish criteria to our population, Dutch reference data for calculating HSDS and THSDS were used [4].
In the UK, an HSDS below the 0.4th centile (<-2.67 SD) at the age of 4-5 years is used as a referral cutoff [8,10,11]; also at 10-11 years, height and weight are measured. Ad-ditional rules are specified in the current UK growth charts: a height centile more than 3 centile spaces (>2.0 SD) below the mid-parental height centile and a drop in height
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of more than 2 centile spaces (>1.33 SD) [10,11]. Also for the evaluation of the British criteria, Dutch reference data were used for calculating SDS [4].
Statistical Analysis
All data were collected from case records and analyzed in SPSS version 21. Descriptive statistics were used to quantify the incidence of pathological causes of growth failure and to determine whether the various criteria according to the three guidelines were met. The formulas used for the Finnish criteria for THSDSDEV and ΔHSDS differ from
the Dutch and British, since they can only be determined by computerized calculation instead of interpreting the growth data directly.
For ΔHSDS, the following formula is used: (HSDS2 - HSDS1)/SD, where SD = sqrt(2 ×
(1 - r)), where r = (exp(2 × z) - 1)/(exp (2 × z) + 1), where z is calculated according to age- and gender-specific formulas using the age distance (age2 - age1) and the mean age (age2 + age1)/2 between two height measurements, where age2 is the age at the visit at our clinic, and age1 the age at which the patient’s growth rate changed. For the calculation of height- for-age SDS deviation from the THSDS, age-specific SD for THSDSDEV were used. Sensitivity, specificity and likelihood ratios were calculated for
all criteria, using MedCalc for Windows version 12.7.8 (MedCalc Software, Belgium).
Ethics Approval
Approval for the study was obtained by the Scientific Review Committee of Tergooi Hospitals (reference No. kv/15.04).
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Results
Study Population
A total of 131 patients between 3.00 and 9.99 years referred for growth failure were even-tually included for analysis (fig. 1), and all underwent the same standardized diagnostic workup followed by additional investigations based on the pediatrician’s judgement. Pa-thology was found in 23 patients with growth failure (17.6%): a primary growth disorder in 8 children and a secondary growth disorder in 15 (Table 1; Fig. 1). Five of the 23 patients presented with an HSDS ≥-2.0. Among the 69 patients with an HSDS <-2.0, no specific diagnosis could be made in 51 patients (73.9%), and they were thus classified as having idiopathic short stature. The majority had nonfamilial short stature (n = 35) (Fig. 1).
Criteria according to the Dutch, Finnish and British Guidelines
The auxological characteristics of the children with pathological diagnoses according to the criteria of the Dutch, Finnish and British guidelines are shown in Table 1.
Excluded n = 14
Adopted children (n = 3), children with another ethnicity than Dutch, North African or Southeastern European (n = 4) and children with
missing data (n = 7)
Patients referred for short stature 3.00–9.99 years
n = 145
Patients included for analyses
n = 131
Boys
n = 76 n = 55Girls
Non-short
n = 37 Idiopathicn = 29 Primaryn = 4 Secondaryn = 6 Non-shortn = 20 Idiopathicn = 22 Primaryn = 4 Secondaryn = 9
Familial
n = 9 Non-familialn = 20 Familialn = 7 Non-familialn = 15
Figure 1. Overview of the study population. The majority of the children referred for growth failure showed an HSDS ≥-2.0 or were diagnosed with idiopathic short stature. A few children with an HSDS ≥-2.0 at pre-sentation had a previous HSDS <-2.0, and in a number of children, the HSDS was >1.6 SD below the THSDS. Among the children with idiopathic short stature, the majority had nonfamilial short stature and was prepu-bertal. Ten boys and 13 girls were diagnosed with a pathological cause of their growth failure, further classi-fied into primary and secondary growth disorders.
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Growth characteristics of the children with pathology (n = 23) Pathologic diagnosis
a Age, years; M/F Dutch guideline b Finnish guideline b British guideline b
Indication for diagnostic workup
1) 2) 3) 4) 5) 6) 1) 2) 3) 1) 2) 3) Dutch – 4 criteria Dutch – 6 criteria Finnish British SGA 4.6, M + -+ -+ + -+ -+ + + + SGA 4.4, M + -+ -+ + -+ + -+ + + + SGA 5,7, M + -+ + + -+ + -+ + -+ + + + SGA 7.7, M -+ -+ -+ + + -+ -+ + + + SGA 6.6, F -+ -+
-Known cardiac disorder
8.8, M -+ -+ -+ -+ + + + Psychosocial 7.0, M -+ -+ -+ -+ + + + Methylphenidate 9.3, M -Methylphenidate 9.8, M + -+ -+ -+ + + -Turner syndrome 6.1, F -+ -+ -+ + -+ -+ + + + SHO X deficiency 6.4, F + + + -+ + -+ -+ + + + SHO X deficiency 9.6, F -+ + -+ -+ + -+ + + -Mucopolysaccharidosis 3.3, M -+ -* -+ -+ -+ Mucopolysaccharidosis 3.3, M -+ -* -+ -Celiac disease 5.1, M -+ -+ -Celiac disease 5.2, F + -+ -+ -+ + -+ + -+ + + + Celiac disease 5.7, F + -+ + -+ + + -Celiac disease 5.8, F + -+ -+ + -+ -+ + + + Gitelman syndrome 8.4, F -+ -+ -+ + + -Partial GH deficiency 3.5, F + -+ -+ -+ + -* + -+ + + +
Acquired GH deficiency due to meningitis
4.8, F + + + -+ + + + + + + -+ + + + IGF-I resist ance 3.5, F + + + -+ + + -* -+ + + -Hypothyroidism 9.2, F
-Number fulfilling criterion
11 4 16 1 7 5 17 14 2 7 9 1 17 20 18 13
ational age; GH=growth hormone; IGF-I=insulin like growth factor I. * Age below 4 years.
b for criteria and numbering, see t
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Sensitivity, Specificity and Likelihood Ratios
The sensitivity, as well as the estimated population specificity and positive likelihood ratios for the various elements of the three guidelines, are shown in Table 2. For the Dutch guideline, the population specificity could not be calculated for HSDS <-2.0 + dysmorphisms/disproportions, since dysmorphisms and disproportions were not recorded for the reference population [4]. The addition of 1 of the 2 consensus-based criteria (recent growth deflection irrespective of the HSDS) to the Dutch guideline led to the detection of 3 more patients, increasing the sensitivity to 87%, but at the expense of a lower specificity (87%). No additional patients were detected with criterion 3 (ΔHSDS ≤-2.2414) of the Finnish guideline, but the specificity of this guideline decreased to Table 2. Sensitivity, specificity and likelihood ratios
Sensitivity – pathology (n = 23) Specificity – Dutch reference sample (n = 958) Positive likelihood ratio Dutch guidelines (1) HSDS <–2.5 48 (27–69) 99.1 (98.2–99.6) 50.91 (2) HSDS <–2.0 + dysmorphisms/disproportions 17 (5–39) – – (3) HSDS <–2.0 + HSDS >1.6 below THSDS 70 (47–87) 99.1 (98.2–99.6) 74.05 (4) HSDS <–2.0 + height deflection >1.0 SD 4 (0–22) 99.9 (99.4–100) 41.61
Any of the 4 growth criteria positivea 74 (52–90) 98.5 (97.6–99.2) 50.58
(5) HSDS >2.5 below THSDS 30 (13–53) 99.8 (99.3–100) 145.78
(6) Recent growth deflectionb
22 (7–44) 87.6 (85.2–89.7) 1.75
Any of the 6 growth criteria positivec 87 (66–97) 87.0 (84.7–89.0) 6.66
Finnish guidelines
(1) HSDS ≤–2.2414 74 (52–90) 98.4 (97.4–99.1) 47.21
(2) THSDSDEV ≤–2.2414 × SD 61 (39–80) 94.4 (92.7–95.7) 10.80
(3) ΔHSDS/SD ≤–2.2414 9 (1–28) 88.0 (85.7–90.1) 0.73
Any of the 3 criteria positive 78 (56–93) 83.7 (81.2–86.0) 4.81
British guidelines
(1) HSDS <–2.67 at 4–5 years 30 (13–53) 99.4 (98.7–99.8) 52.41
(2) HSDS >2.0 below MPHSDS 39 (20–61) 99.0 (98.1–99.5) 37.49
(3) Height deflection >1.33 SD 4 (0–22) 97.1 (95.8–98.1) 1.49
Any of the 3 criteria positive 57 (34–77) 95.8 (94.4–97.0) 13.54
Values are percentages (95% confidence intervals) or ratios. MPHSDS = Mid-parental HSDS.
a For the specificity of the Dutch reference sample: any of criteria (1), (3) and (4). b Defined as >0.5 SD/1 year,
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83.7% when applying this rule. The criterion for height deflection according to the British guideline led to the detection of 1 more patient, and also reduced the specificity.
Discussion
We investigated the sensitivity of the criteria for diagnostic workup presently used in three countries in a cohort of children referred for growth failure to a general pediatric clinic. With the Dutch [4] and the Finnish guidelines [6], a sensitivity of 74 and 78% was reached at a specificity of 98.5 and 83.7%, respectively. The sensitivity of the UK criteria was considerably lower (57%). Growth deflection (irrespective of the HSDS), as included in the Finnish and British guidelines and added to the original Dutch guide-line, led to a decrease in specificity of all guidelines below an acceptable level (>98%) for population screening.
The present sensitivity of the Dutch guideline (74%) is in line with the sensitivity (76-86%) in the original studies [4]. The sensitivity of the Finnish guideline (78%) is lower than reported for screening in Turner syndrome (97%) [6], but still within the same range as that reported for the original Dutch guideline. The similar sensitivities of these two guidelines can be explained by their use of the combination of HSDS and distance to target height, with comparable cutoff values varying for these screening criteria. Cases that did not conform to any of the proposed Dutch or Finnish criteria included 1 with SGA (Table 1, case 5), 1 with methylphenidate use (case 8), 2 with mucopolysac-charidosis (cases 13 and 14), 1 with celiac disease (case 15) and 1 with hypothyroidism (case 23). The main reason for this was that 5 of those patients (cases 8, 13-15 and 23) were in fact not short (HSDS ≥-2.0). This emphasizes the limitation of the Dutch guide-line in particular, in which the first 4 criteria are based on an HSDS of at least <-2.0. Furthermore, this study also shows that despite carefully designed referral criteria, their diligent application would still not identify 25% of children with a pathological cause of their growth failure. This underlines that a detailed medical history and physical examination, followed by proper medical judgement, cannot be replaced by just strictly following growth-related guidelines. The present study also demonstrates that growth failure-related disorders may occur in children who are not (yet) short but show other parameters of disturbed growth; the diagnoses of the present cases that did not con-form to the Dutch or Finnish criteria were made based on the medical history (cases 5 and 8), observation of dysmorphisms (cases 13 and 14), growth deflection (case 15) and
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clinical suspicion of hypothyroidism (case 23). For the British guideline, several cases with diagnoses requiring medical attention, which would only be found by abnormal growth, would have been missed (cases 12, 14, 15, 17, 19 and 22). The lower sensitivity of the UK guideline is due to the stricter cutoff values used for HSDS and height deflec-tion. The sensitivity of all guidelines can be improved by adding the parameter of recent growth deflection (>0.5 SD/1 year, >0.7 SD/2 years, >1.0 SD/undefined time), but the low specificity does not allow this parameter to be added routinely. Growth deflection can occur relatively commonly during the prepubertal period, and during this prepu-bertal growth dip, the response of growth hormone secretion to the stimulation tests mimics that of growth hormone deficiency. Still, recent growth deflection should be considered a red flag in primary health care, and any abnormal symptom or sign should lead to referral to a specialist clinic.Our cohort may be considered a representative sample for various causes of pathology among children with growth failure in a general population. First, the prevalence of pathological causes among all the children of this cohort is comparable to most previ-ous observations in children with growth failure, reporting an incidence between 1.3 and 19.8% [3, 18,19,20,21,22,23]. In none of these studies was a complete detailed rou-tine diagnostic workup performed. In a recent North American study, a lower incidence (1.3%) of pathology in short children was reported [23]. This may be explained by the exclusion of children with low height velocity and/or abnormal symptoms, a higher average age compared to our population and a high percentage of missing medical growth records. Second, we identified patients with pathology even though they did not conform to any of the criteria of the guidelines, again emphasizing the importance of clinical judgement besides strictly following standardized criteria.
We acknowledge that there are also several limitations. First, this is a cohort originat-ing from a soriginat-ingle general pediatric center. It may well be that the diagnostic yield may be different from an academic center. Second, the number of participants is still small; thus, our analyses are limited to descriptive statistics, and the 95% confidence intervals have a wide range. Third, use in the past of existing Dutch guidelines by the pediatri-cians as well as referring doctors from primary care may have led to a biased approach, resulting in the relatively high sensitivity of the criteria used in the Dutch guideline. In conclusion, this study demonstrates that the proposed cutoff values for HSDS and distance to target height/mid-parental height, as used in the Netherlands and Finland, can be effectively used for growth monitoring. Both the Dutch and the Finnish
guide-2
lines show a good sensitivity for detecting pathological causes of growth failure, with recent growth deflection as an important warning sign.
Acknowledgements
We are grateful to Dr. Charlotte Wright for providing information about the British guideline. We wish to thank Liselotte de Kloet for her contributions and Bea Jansen van ‘t Land, Desirée Paap, Lidi Schilperoort, Irene Bergsma and Ingrid van de Woude for taking good care of the patients at the growth clinic and for performing accurate auxo-logical measurements. Funding for data collection was provided by Tergooi Hospitals, Blaricum, The Netherlands. The sponsor had no involvement in the study.
Disclosure Statement
The authors indicate that they have no financial relationships relevant to this paper or potential conflicts of interest to disclose.
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