Towards a Rational and Efficient Diagnostic Approach in Children Referred for Tall Stature and/or Accelerated Growth to the General Paediatrician

The primary goal of the systematic diagnostic approach of children with tall stature and/or accelerated growth (TS/AG) is to diagnose or exclude secondary growth disorders as well as primary (syndromic) growth disorders, most notably Klinefelter syndrome (KS) and Marfan syndrome (MFS). Another goal is to adequately predict adult height based on the growth pattern, pubertal development and skeletal age, and if indicated discuss possibilities regarding eventual adult height reduction therapy.

There is little information about the frequency of pathologic causes of TS/AG detected in a paediatric clinic; in the three available retrospective studies, the frequency varied from 1.5 to 12% [1‒3]. We assume that the frequency not only depends on the type of clinic (secondary vs. tertiary care) but also on the quality of the clinical assessment, different diagnostic strategies and limitations regarding genetic testing. In this context, it is noteworthy that at least two clinically important diagnoses associated with TS (KS and MFS) are rarely diagnosed before puberty [4, 5]. We speculate that with increased attention to diagnostic clues as well as easier accessible tools for genetic testing (such as array analysis and specific growth-related whole exome sequencing (WES)-based gene panels), the diagnostic yield will increase.

In contrast to prior reviews on TS/AG [2, 6‒9], which mainly discussed the differential diagnosis of TS/AG, we aim at offering a problem-oriented guide to the evaluation of TS/AG by focusing on the question “what is the most rational and efficient diagnostic approach for children referred for TS/AG?,” further subdivided into three sub-questions: (1) What are important diagnostic clues in medical history and physical examination? (2) What is the role of the shape of the growth curve as a diagnostic clue? (3) What is the role of additional laboratory and genetic testing? As a result of an extensive literature search, we propose a new systematic approach to evaluate children referred for TS/AG.

As a starting point, we collected data on incidence, prevalence and clinical features of the medical conditions accompanying TS/AG, based on the list presented in the International Classification of Paediatric Endocrine ­Diagnoses” (ICPED) [10, 11] (online suppl. Table; for all online suppl. material, see www.karger.com/doi/10.1159/000500810). Most conditions are considered very rare, and for all of these there is only scarce information about incidence, prevalence, distribution of height standard deviation score (SDS) and occurrence of TS without additional clinical features. A timely diagnosis of the most frequent medical condition associated with TS (KS), with an estimated incidence of 1.0–1.5 per 1,000 births [12, 13], is hampered by the fact that height in many patients is within the population range (<+2 SDS), while clinical features are generally mild. This is probably the main reason why only 10% of patients are diagnosed before puberty [4]. The diagnosis of the medical condition with the most severe clinical consequences (MFS) is hampered by its rather low incidence (estimated at 23 per 100,000 births [14]) and variable clinical presentation. Furthermore, because of the dominant inheritance, height of children with MFS is usually within the target height (TH) range, so that the distinction between MFS and the familial subcategory of idiopathic TS (ITS) can be difficult. We believe that one of the key aims of the diagnostic approach of TS/AG should be to diagnose KS and MFS at an earlier age.

The central feature of this mini review is a diagnostic flowchart for TS/AG, supplemented by tables containing the most important diagnostic clues for growth disorders, including relevant issues from the medical history and physical signs (including dysmorphic features) indicative for pathology. We also propose indications for additional laboratory and genetic testing.

This paper is an adaptation of a formal evidence-based guideline for children from 0 to 18 years in the Dutch language, authorised by the Paediatric Association of the Netherlands and other medical societies, intended for use by the general paediatrician [15]. We expect that it will also assist primary care physicians, youth health care physicians, general practitioners, clinical geneticists and paediatric endocrinologists in detecting pathologic causes of TS/AG at an early age.

Mirroring the criteria for children with short stature and/or growth deceleration, we propose to define TS/AG in childhood or adolescence if linear growth complies with one or more of the following criteria: (1) tall for the ethnic population; (2) tall in comparison to parental heights; or (3) growth acceleration, defined as a positive change of height SDS (HSDS). Cut-off points for each of these criteria are arbitrary, but the conventional approach is to use statistical limits that label approximately 2–3% of children in the population as “abnormally tall.” Tall for the ethnic population is usually defined as an HSDS >+2.0, based on suitable reference charts for height for age, sex and ethnicity. About the second criterion (tall for familial genetic origin), there is more discussion, caused by the use of different equations for calculating TH and by uncertainty whether secular trends should be incorporated. We favour the use of the conditional THSDS, defined as the mid-parental height adjusted for assortative mating and regression bias, using the parent-parent correlation and the parent-offspring correlation [16]. This conditional THSDS is 0.72 times the average of parental HSDS (independent of sex), and a child’s HSDS is expected to be situated within ±1.6 SDS of the conditional THSDS [16]. The third criterion (AG) is a longitudinal parameter and stands for a positive change in HSDS over time, away from the THSDS. There are no reliable data of what should be considered “abnormal AG,” and any cut-off limit should be adjusted for the duration of the interval. In analogy to short stature, in which a negative change of >1 SDS over an undetermined time interval was considered abnormal (in the age range of 3–10 years) [17], we suggest to label AG as a positive change of HSDS >1 SDS over an undetermined time interval before the onset of puberty. During puberty, this cut-off is expected to have a low specificity, due to considerable variation in pubertal timing.

It is generally assumed that in the large majority of children with TS/AG attending the paediatric clinic, no pathologic cause can be found [1‒3]. In accordance with the ICPED classification [11], we label children with an HSDS >+2 of unknown origin as ITS, which can be subdivided into familial or non-familial TS (FTS or NFTS), depending on the child’s height residing within or above the TH range. It is believed that FTS has a polygenic origin in most children, implying the accumulation of multiple “tall gene variants” in a family [18]. If a child is both tall for the ethnic population and familial genetic origin (NFTS), but also if HSDS is >+1.6 SDS above TH but still within the population range, one would expect an increased a priori likelihood of a pathologic cause, and a higher diagnostic yield of laboratory testing. Growth acceleration (ΔHSDS >+1) can be associated with a height within or above the population range. It has been described in “constitutional advancement of growth” (CAG), the assumed mirror image of constitutional delay of growth and puberty [19], but is also an important sign of a secondary growth disorder.

Fundamental in the diagnostic approach of TS/AG is the flowchart (Fig. 1). The starting point is the child that is referred under suspicion of a condition associated with TS/AG, or a child visiting the paediatrician for a different reason but with sudden (unexpected) accelerating growth. In our opinion, it is crucial to set this starting point, irrespective of whether the growth pattern is “abnormal” in the statistical sense, since several syndromes associated with TS/AG often present with a height within the population range. To accomplish an effective screening for growth disorders, we formulated diagnostic clues for primary and secondary growth disorders. The most relevant clues are shown in Figure 1, but in fact there are several more, as shown in Tables 1-3. They concern the medical history, family history, physical evaluation and growth pattern. Based on the presence or absence of diagnostic clues for primary or secondary growth disorders, the clinician may decide to perform laboratory investigations or third-line consultations.

The three diagnostic categories are: primary growth disorders, secondary growth disorders and ITS. Primary growth disorders are thought to be intrinsic to the epiphyseal growth plate [20], for example most genetic syndromes, such as KS and MFS. Secondary growth disorders are assumed to have a systemic effect on the growth plates, for example central or peripheral precocious puberty, hyperthyroidism and pituitary gigantism. As mentioned earlier, the term ITS just indicates that the aetiology is unknown.

In order to assist the physician to construct a rational differential diagnosis, we extended the list of conditions associated with TS/AG included in the ICPED [11] by adding epidemiological and clinical data (online suppl. Table). The table is subdivided into the three diagnostic categories.

One of the relevant issues to inquire about is foetal growth. A history of excessive foetal growth is strongly suggestive of a primary growth disorder. While information about birthweight can usually be reported by the parents, this is less often the case for birth length. In the absence of numerical information on birth length, the clinician should try to acquire the first length measurement after birth, calculate length SDS (adjusted for gestational age) and use this as a proxy for birth length SDS.

Another diagnostic clue for primary growth disorders is any form of developmental delay, such as slow motor development, cognitive delay (learning problems) or delay in development of speech and language. Also behavioural problems, such as problems in social contacts (autism spectrum disorder) are parts of some genetic syndromes associated with TS/AG, such as KS. Notably, such symptoms are usually not part of the phenotype of MFS. When reviewing the systems, the physician should inquire about cardiac or eye conditions (as clues for MFS). Furthermore, information about the onset and presentation of pubertal signs (as clues for (pseudo)precocious puberty) should be collected, as well as information about symptoms of other secondary growth disorders (Table 1 and 2; Fig. 1). In the family history, information should be collected about a possible dominant pattern of TS and cardiac or eye conditions, as an indicator of MFS. Pubertal timing of the parents and other relatives may provide clues for a genetic form of early or delayed puberty.

Besides height, weight and head circumference, also body proportions should be assessed. We recommend to measure sitting height and calculate the sitting height/height ratio, and convert this to an SDS based on reference data from a country with a similar average height compared with the ethnicity of the patient. Reference data are available for the UK [21], the Netherlands [22], China [23], Spain [24] and Turkey [25].

Furthermore, arm span can be measured and compared with height (as a difference: arm span minus height [26], or as a ratio: arm span divided by height [27]). An arm span/height ratio above 1.05 is considered indicative for MFS [27], although its value as a diagnostic clue in children is dubious [28]. It is furthermore noteworthy that skeletal manifestations of MFS such as a positive arm span/height ratio or scoliosis are less common in Asian MFS patients [29, 30]. Also adult KS patients typically show a positive arm span/height ratio, with arm span exceeding height with at least 2 cm [31], but there is no evidence regarding this in childhood. Arm span furthermore seems to vary depending on the origin of the supernumerary X-chromosome [32].

During the full physical evaluation, the physician should pay special attention to dysmorphic features that are associated with growth disorders (Table 3). Tanner stage should be determined and comparison with reference data (or its expression as SDS for age and sex) can provide information about a possible disorder of pubertal timing [33‒35]. Observations obtained at physical examination can be compared with a list of clinical features of KS (Table 4) [4] and MFS (see Revised Ghent criteria [27] and for the systemic score see Table 5). Although a systemic score ≥7 points indicates systemic involvement in adults, cardiac sonography and/or genetic testing for MFS should be considered with a lower threshold (e.g. when the systemic score is ≥3–4 points) in children [36].

Expert consensus and/or overview articles are available for many other syndromes associated with TS, ­including Sotos syndrome (including a clinical score, Table 6) [37, 38], Fragile X syndrome [39], Beckwith-Wiedemann syndrome [40], Simpson-Golabi-Behmel [41], Ehlers-Danlos syndrome, kyphoscoliotic type [42], Loeys-Dietz syndrome [43], homocystinuria [44], Lujan-Fryns syndrome [45], congenital contractural arachnodactyly [46], MEN type IIB [47], Weaver syndrome [48], PTEN hamartoma tumour syndrome [49], Malan syndrome [50] and Shprintzen-Goldberg syndrome [51].

Analysis of the linear growth curve essentially includes three elements: (1) HSDS at presentation; (2) the difference between HSDS and THSDS [52]; and (3) the shape of the linear growth curve against the background of population reference chart, objectified by longitudinal data on height, its SDS and the change over time. Besides linear growth, also data on weight or (preferably) body mass index (BMI) over time have to be analysed, as well as head circumference.

In Figure 2, growthcurves of boys with KS are shown [53]. While in most boys HSDS stays within the population range, growth accelerates from 3 years onward, which is particularly clear between 5 and 8 years, predominantly due to an increase in leg length growth [4, 12, 53, 54]. Before the onset of puberty, height usually remains stable. Reports about the pubertal growth spurt vary from normal [12] to diminished [32, 53, 54]. Most boys have an HSDS in the upper half of the reference range [55]. Average adult height is approximately 4–10 cm above the mean for the population [12, 55, 56].

Figures 3a and 3b show the growth curves of Korean male and female MFS patients [30], compared with their Korean contemporaries. The mean HSDS in this cohort is consistently above +2 SDS from age 2 onwards. It is noteworthy that not all patients are tall compared with the reference charts.

Figure 4 showsan example of accelerating growth in a prepubertal girl due to growth hormone excess caused by a pituitary adenoma [57]. It shows accelerating growth over time, with the HSDS increase eventually surpassing +2.5 SDS. At 7 years and 8 months, the adenoma was surgically removed followed by decelerated growth. At the age of 13, puberty was medically induced and growth hormone was started.

In line with common practice, we advise to assess bone age in each child referred for TS/AG. The purpose is threefold. First, it serves as a diagnostic tool, influencing the likelihood of several causes. For example, advanced bone age is part of the presentation of certain primary growth disorders (e.g. Sotos syndrome, Weaver syndrome), but also of (pseudo)precocious puberty, hyperthyroidism and CAG [19, 58, 59]. Second, the radiograph can suggest certain diagnoses, such as long slender phalanges in MFS. Third, bone age serves as the basis of adult height prediction in children above approximately 10 years. In fact, adult height prediction is a frequent reason for referring a tall child.

Bone age is usually assessed using the Greulich and Pyle method [60], and predicted adult height (PAH) is usually calculated with the Bayley and Pinneau (B&P) method [61]. Obviously, the reliability of PAH increases with age and bone age, and one should realise that for boys there is an average overprediction of 2.5 cm (with an SD of 4.3 cm), while in girls PAH is on average similar to the attained adult height (with an SD of 4.6 cm) [62]. At the present time, a computerised system is available which assesses bone age and PAH (BoneXpert) [63], with a mean difference of 0.2–0.3 years below G&P. The resulting PAH is based on the B&P method and validated in several populations [64‒66], but not specifically for tall children. There is an underprediction of 0.8 cm with an SD of 3.1 cm in girls and 2.8 cm in boys [66].

If PAH is >+2.3 SDS (>200 cm for boys, >185 cm for girls in The Netherlands), we advise to repeat a bone age and PAH estimation when height has reached 185 cm in boys or 170 cm in girls. If puberty starts late or shows a slow progression, one should be aware of the possibility that attained height may be substantially higher than predicted, so that more frequent bone age assessments may be indicated.

After a careful medical history, physical examination, growth analysis and bone age determination, the clinician makes an estimate of the likelihood of a pathogenic growth disorder (primary or secondary), based on the collected diagnostic clues (Fig. 1). This will indicate the direction of further diagnostic steps. If there are clues for both categories, both routes can be taken.

In case of at least one clue for a primary growth disorder, the clinician should decide if there are sufficient indications to test for KS, MFS or other syndromes, given the important therapeutic implications of early diagnosis and management.

Early detection of KS allows for timely recognition of psychosocial problems enabling syndrome-specific guidance. It can also lead to adequate management of gynaecomastia and hypogonadism (for a list of other clinical features of KS, see Table 4). If pubertal development is delayed or slow, androgen treatment can be administered, and timely discussions can be started about testicular sperm extraction [12].

It is difficult to diagnose KS in childhood and adolescence. Most individuals are diagnosed antenatally or in adulthood, for example in men who are investigated for azoospermia. The most important clinical features include a characteristic growth pattern (as detailed in a previous paragraph), small testicular volume, elevated luteinising hormone and follicle-stimulating hormone levels in contrast with normal serum testosterone levels, and various psychosocial issues [55, 67]. For example, in a Danish cohort all patients had a smaller testicular volume in adulthood, gynaecomastia in 44%; cryptorchidism was reported in 14%, and 36% required speech therapy or educational support [55]. The abnormal biochemical parameters became evident after onset of puberty and correlated with histological findings of a gradual deterioration of seminiferous tubules and massive Leydig cell hyperplasia in adults [55].

The psychosocial issues vary with age [68]. Between 0–4 years, motor development is slow, and boys can present clumsy. Approximately 50% have speech delay. Between 4 and 11 years, boys still encounter problems with speech and language, and 75% have reading problems (dyslexia) [69, 70]. Diminished short-term memory has also been described. Boys with KS can show withdrawn behaviour and may find it difficult to attain social contacts. In adolescence, low self-esteem and learning problems can occur [71].

The growth data show that if testing for KS would be performed in all boys with TS, the diagnostic yield would be very low. Instead, the combination of AG (with a height in childhood above the TH) with developmental problems (particularly regarding speech and language development) should lead the clinician to perform genetic testing for KS.

With respect to the method of genetic testing, the conventional approach has been to perform a karyotype. We believe that an array analysis (SNP array or CGH array) is currently a more efficient technique, since it also allows for detection of copy number variants (microdeletions and microduplications), and if SNP array is used most forms of uniparental disomy (UPD) [72]. An example of a syndrome associated with TS caused by a microduplication is triple SHOX gene copy syndrome (caused by SHOX duplications), associated with relatively long legs [73]. An example of a TS syndrome caused by UPD is Beckwith-Wiedemann syndrome [74]. If the array analysis is positive for KS (or negative in a child with high clinical suspicion of KS), we advise to refer the patient to a centre of expertise. A false negative result of the array analysis or karyotyping can occur in low-grade mosaicism (<10–20%) [75]. When mosaicism is suspected, fluorescence in situ hybridization on ≥200 cells may be used, and additional samples (e.g. epithelial cells from buccal mucosa) can be studied as analysis of cells derived from different germ layers may improve the detection rate [76].

Early detection of MFS enables follow-up of cardiovascular, ocular and other health problems and may also detect MFS in family members upon screening. An early diagnosis is particularly important to prevent life-threatening aortic dissection seen in MFS; prophylactic aortic surgery is usually performed in early adulthood but can also be necessary in childhood [5]. Unfortunately, MFS is often diagnosed at an adult age (especially in case of a de novo mutation). In a Danish cohort, the diagnosis only became apparent because of a major cardiac event in 12.9% of patients [5]. A late diagnosis hampers adequate cardiovascular monitoring, medical intervention to reduce stress on the aortic wall and eventual surgery [77].

The most important systemic features of MFS (Table 5) [27] are included in Tables 1-3. In childhood, height can either be within or above the population range. As approximately 75% of patients with MFS have inherited the FBN1 mutation from one of their parents, their TS may be falsely interpreted as familial ITS. Therefore, a detailed family history and close inspection of MFS signs in the parents is important in any child referred for TS/AG.

In case of suspicion of MFS, we advise to refer the patient to a (paediatric) cardiologist and clinical geneticist, and especially in children aged ≤5 years also to an ophthalmologist. The cardiologist will perform an ultrasound of the heart, paying special attention to mitral valve insufficiency and the Z score of the aortic root diameter. The ophthalmologist will pay special attention to the clinical assessment of ectopia lentis (which most often arises in early childhood, but infrequently also thereafter [78]) and myopia. A clinical geneticist (preferably affiliated to a Marfan expert clinic) may differentiate between MFS and several Marfan-like syndromes (online suppl. Table) and may perform genetic testing of FBN1 and/or a panel of genes including FBN1. In case of a diagnosis, genetic counselling will be offered to the patient and family. Please note that referral to a clinical geneticist is also justified in case of multiple MFS features (systemic score ≥3–4) without aortic root dilatation, ectopia lentis and/or myopia, as these features may not or not yet be present in a child with MFS [36]. If MFS is diagnosed, follow-up should ideally be offered by a multidisciplinary Marfan expert clinic.

The terms “neonatal MFS” or “severe early onset MFS” should be preserved for children with a de novo variant in exon 24–32 in FBN1 which results in a strong dominant-negative effect. These children have a severe form of MFS and usually die within childhood due to cardiopulmonary insufficiency [79].

Suggestions for additional biochemical and genetic testing are given in Table 7. When there are no signs for KS or MFS, or if these syndromes have been ruled out, the physician should consider discussing the further diagnostic workup with a clinical geneticist or paediatric endocrinologist. At that level, the clinical features (online suppl. Table) may be sufficiently clear and specific to warrant a candidate gene approach. For example, a large head circumference and specific dysmorphic features could lead to targeted testing of genes associated with Fragile X syndrome, Sotos syndrome, Malan syndrome, Weaver syndrome or PTEN hamartoma tumour syndrome [80] (genetic testing for FMR1repeat length, NSD1, NFIX, EZH2 and PTEN, respectively). For Sotos syndrome, clinical scores have been developed to guide the physician in deciding whether genetic testing is indicated (Table 6) [37, 38]. Beckwith-Wiedemann syndrome was recently redefined as a spectrum and the provided scoring system has a low threshold for genetic testing [40].

In case of global developmental delay/intellectual disability and TS/AG without any other specific clues that may lead to a diagnosis, we suggest that local clinical guidelines should be followed, which may typically include metabolic screening, FMR1repeat lengths study, array analysis, a trio WES-based panel (WES in patient and parents) for genes associated with intellectual disability, and untargeted trio WES or, if already available, whole genome sequencing (WGS).

In case no diagnostic clues are present, a hypothesis-free approach can be chosen, such as an array analysis and a WES/WGS approach, first using a gene panel for TS/AG.

If one or more diagnostic clues are indicative of a secondary growth disorder, further diagnostic procedures depend on the specific clinical features (online suppl. Table, Tables 1-3, Fig. 1). Our suggestions for additional laboratory testing are presented in Table 7. The four principal secondary growth disorders are (pseudo)precocious puberty, hyperthyroidism, GH overproduction and obesity. Obese children display an AG and an advanced bone age [81], which sometimes presents as HSDS >+2. However, pubertal and skeletal development are usually advanced, and consequently adult height is within the normal range [82]. The remainder of secondary growth disorders are extremely rare and when these diagnoses are expected, or when height is extreme (>+3 SDS, or >+2.5 SDS taller than TH), we suggest to refer the patient to a paediatric endocrinologist, clinical geneticist or centre of expertise.

In the absence of clues indicative of a primary or secondary growth disorder, or after excluding any suspected primary or secondary growth disorders, the next step is to decide if the growth pattern can be considered statistically normal, abnormal or very abnormal. If HSDS >+2, the diagnostic label can be ITS, which can further be subdivided into familial and non-familial. If HSDS <+2, but 1.6 SD taller than TH, the child is unusually tall for his/her parental height. If height accelerates more than expected (ΔHSDS >+1) without signs of puberty, one can consider the diagnosis CAG. If this seems unlikely, further follow-up may be a watchful approach.

If height is extremely tall for the population, we recommend referring the child to a paediatric endocrinologist, clinical geneticist or centre of expertise. We acknowledge that there is no scientific evidence for any cut-off points for these growth measures; we arbitrarily chose >+3 SDS for the population or >2.5 SDS taller than TH. In such patients, further genetic tests, for example a specific WES-based gene panel or a “trio WES” can be considered.

Most children referred for TS/AG end up with the “non-diagnosis” ITS. Some of these (and some patients with primary TS syndromes as well) may wish to limit their adult height. Our present approach is that if the PAH is above +2.3 SDS, the therapeutic options (percutaneous epiphysiodesis or no treatment) are discussed with the patient and parents, taking their perspectives and coping abilities into consideration. Although in the Netherlands epiphysiodesis is only carried out if PAH is >205 cm for males and >185 cm for females, a slightly lower cut-off point for discussing this topic was chosen because of the inaccuracy of PAH (in the order of magnitude of ±5 cm). In this discussion, the physician explains the current status of percutaneous epiphysiodesis of the growth plates around the knee in terms of efficacy and safety [83]. Percutaneous epiphysiodesis can result in a diminution of one-third of the expected residual growth and is associated with few adverse effects [83‒85]. The previously used treatment with supraphysiologic sex hormone treatment in adolescence is currently regarded as obsolete, because of the potential risk of decreased fertility in women and the low benefit to risk ratio in men [86‒89].

In comparison to previous reviews on the diagnostic approach in children with TS/AG [2, 6‒9], our approach starts with the child that is referred because of suspicion of TS/AG, instead of starting with the tall child. The main potential advantage of our approach is that this may lead to a higher percentage of boys with KS already diagnosed before puberty, because prepubertal boys with KS usually have a height within the normal range but are crossing SDS lines between 5 and 8 years. Primary child health professionals should be aware of the spectrum of clinical (e.g. speech problems) and growth characteristics of KS and refer boys suspected for KS to the paediatrician. Similarly, the clinical features of MFS should be well known to primary and secondary child health care professionals, so that the mean age of diagnosing MFS may be decreased.

Our approach is also different because it offers a stepwise approach based on diagnostic clues from medical history, physical examination and growth assessment (Fig. 1). Other novel elements are the advice to use array analysis instead of karyotyping to diagnose or rule out KS, which may also lead to other diagnoses (copy number variants and uniparental isodisomy). We emphasise that most diagnoses associated with TS/AG are rare and usually associated with specific clinical features. This implies that a thorough medical history, physical examination and growth analysis are crucial in the diagnostic process.

The authors are grateful for the fruitful discussions with and input from all members of the Working Group on Triage and Diagnosis of Growth Disorders in Children and Adolescents, initiated by the Paediatric Association of the Netherlands (NVK), in collaboration with Dutch Youth Health Care Physicians (AJN) and the Dutch Society for Clinical Genetics (VKGN) and supported by Dr. Irina M. Mostovaya and Dr. Anouk M.M. Vaes (advisors from the Knowledge Institute of the Dutch Association of Medical Specialists). The resulting national guideline has been authorised by the NVK, AJN, VKGN and accepted by the Netherlands Association of Internal Medicine (NIV), Dutch Society for Clinical Chemistry and Laboratory Medicine (NVKC), Dutch Klinefelter Patients Association (NKV) and the Contact Group Marfan Netherlands (CMN), after integrating their comments on the draft guideline. We are grateful for the constructive comments by Dr. Sabine Hannema (paediatric endocrinologist LUMC and medical advisor of the Dutch Klinefelter association). We furthermore thank the Korean Academy of Medical Sciences for granting permission of the use of Figures 3a and 3b and Prof. Jan Lebl (Prague, Czech Republic) for providing clinical, anthropometric and genetic information on the child of Figure 4.

The authors have no ethical conflicts to disclose.

J.M.W. is member of advisory boards of OPKO, Merck, Ammonett, Aeterna Zentaris, Agios and Biomarin and received speaker’s fees from Pfizer, Versartis, Sandoz, Lilly, Novo Nordisk, JCR, Merck and Ipsen. The other authors have no conflicts of interest to declare.

The authors are grateful for the grant from the “Stichting Kwaliteitsgelden Medisch Specialisten” for realising the guideline. The authors received no funding for writing this paper.

P.L. took the lead in writing the manuscript. J.M.W., W.O. and G.A.K. were involved in planning and supervised subsequent versions of the manuscript, and L.A.M. provided critical feedback of the draft guideline and revised subsequent drafts of this manuscript. All authors consented to the submitted version. Other members of the Working Group (B.B., S.G.K., R.J.O. and J.A.d.W.) approved the submitted version.

Boudewijn Bakker (Department of Paediatrics, University Medical Center Utrecht, Utrecht, the Netherlands), Sarina G. Kant (Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands), Roelof J. Odink (Department of Paediatrics, Catharina Hospital, Eindhoven, and Department of Paediatrics, Máxima Medical Center, Eindhoven, The Netherlands) and Jeroen A. de Wilde (Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands).

Jan M. Wit and Wilma Oostdijk contributed equally to this work. Other members of the Dutch Working Group on Triage and Diagnosis of Growth Disorders in Children are listed in the Appendix.