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Tall stature and/or accelerated growth (TS/AG) in a child can be the result of a primary or secondary growth disorder, but more frequently no cause can be found (idiopathic TS). The conditions with the most important therapeutic implications are Klinefelter syndrome, Marfan syndrome and secondary growth disorders such as precocious puberty, hyperth...
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... 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]. ...Citations
... Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype. KEYWORDS isolated tall stature, growth plate, NAV2, all-trans retinoic acid, oligogenic inheritance, IFT140, Xenopus Introduction Tall stature, by definition, comprises the upper 2.3 percent of a population (1). Pathological causes of tall stature are rare and include endocrine diseases (such as GH producing tumours) and various genetic conditions, such as chromosomal abnormalities (e.g., Klinefelter syndrome), monogenic conditions (Marfan (MIM #154700), Sotos (MIM #117550) or Weaver (MIM #277590) syndromes) or imprinting disorders (Beckwith-Wiedemann syndrome) (1,2). ...
... KEYWORDS isolated tall stature, growth plate, NAV2, all-trans retinoic acid, oligogenic inheritance, IFT140, Xenopus Introduction Tall stature, by definition, comprises the upper 2.3 percent of a population (1). Pathological causes of tall stature are rare and include endocrine diseases (such as GH producing tumours) and various genetic conditions, such as chromosomal abnormalities (e.g., Klinefelter syndrome), monogenic conditions (Marfan (MIM #154700), Sotos (MIM #117550) or Weaver (MIM #277590) syndromes) or imprinting disorders (Beckwith-Wiedemann syndrome) (1,2). In most cases, isolated (nondysmorphic) tall stature runs in the family and gets the diagnostic label of familial or constitutional tall stature. ...
... In most cases, isolated (nondysmorphic) tall stature runs in the family and gets the diagnostic label of familial or constitutional tall stature. Since no cause can be established in such cases, we suggested to use the term "idiopathic tall stature", with two subgroups (familial and non-familial) (1). ...
Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two ( Ift140, Nav2 ) of the six genes were well-expressed in the growth plate. Nav2 ( p -value 1.91E-62) as well as Ift140 ( p -value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140 , NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2 , in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.
... These overgrowth syndromes typically affect childhood from the prenatal to the postnatal phases, involving the development of the patients, in particular Beckwith-Wiedemann and Sotos syndromes that may be associated with hormone imbalance and increased susceptibility to malignancy [17]. The presence of cardiovascular abnormalities, skin anomalies, skeletal malformations, facial dysmorphisms, abnormalities of the genitalia, and neurodevelopmental delay, may also suggest an underlying syndromic cause [18]. ...
Tall stature is defined as height greater than the threshold of more than 2 standard deviations above the average population height for age, sex, and ethnicity. Many studies have described the main aspects of this condition during puberty, but an analysis of the characteristics that the physician should consider in the differential diagnosis of gigantism—tall stature secondary to a pituitary tumour—during the transition age (15–25 years) is still lacking.
A comprehensive search of English-language original articles was conducted in the MEDLINE database (December 2021-March 2022). We selected all studies regarding epidemiology, genetic aspects, and the diagnosis of tall stature and gigantism during the transition age.
Generally, referrals for tall stature are not as frequent as expected because most cases are familial and are usually unreported by parents and patients to endocrinologists. For this reason, lacking such experience of tall stature, familiarity with many rarer overgrowth syndromes is essential. In the transition age, it is important but challenging to distinguish adolescents with high constitutional stature from those with gigantism. Pituitary gigantism is a rare disease in the transition age, but its systemic complications are very relevant for future health. Endocrine evaluation is crucial for identifying conditions that require hormonal treatment so that they can be treated early to improve the quality of life and prevent comorbidities of individual patient in this age range.
The aim of our review is to provide a practical clinical approach to recognise adolescents, potentially affected by gigantism, as early as possible.
... Notably, individuals with MFS in taller populations attain a relatively shorter final height compared to the reference population than in shorter populations (Figure 4). Growth charts based on population reference studies are valuable tools for assessing growth in children in preventive and curative child health care, and identifying short or tall stature (or faltering or accelerating growth) which should lead to further diagnostic work-up (Lauffer et al., 2019;Wit et al., 2019). Moreover, assessment of the individual growth curve plotted on height-for-age charts in combination with bone age analysis permits prediction of adult height and thereby facilitates decision-making concerning epiphysiodesis in the case of extremely tall predicted stature (Goedegebuure et al., 2018;Rozendaal et al., 2005). ...
... As an example of unexpected findings, exon skipping of exon 52 in 50% of the fibrillin-1 mRNA resulted in complete loss of fibrillin-1 fiber formation in the extracellular matrix, while fibers reappeared when >80% of exon skipping was achieved, revealing that a mismatch in size of the fibrillin-1 protein may hamper fibrillin-1 fiber formation (Cale et al., 2021 This study presents some limitations. First, selection bias is a potential concern since MFS is possibly an underdiagnosed condition in childhood, due to the apparent mildness of the MFS phenotype in some individuals (Lauffer et al., 2019). Furthermore, by omitting data of individuals recorded after epiphysiodesis or hormone therapy, we may have missed the tallest measurements of children in the datasets. ...
To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS‐related height increase across populations. Height and weight data of individuals with MFS aged 0–21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype–phenotype relationships, FBN1 variant type was included as an independent variable in height‐for‐age and BMI‐for‐age models. MFS‐related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height‐for‐age, BMI‐for‐age, and weight‐for‐height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1‐HI variants were associated with taller height in both sexes, and decreased BMI in females (p‐values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS.
... Tall stature is a common reason for paediatric endocrinologist or clinical geneticist consultation that aims at early detection and treatment of possible underlying primary or secondary pathological causes [1]. Several guidelines on the diagnostic approach to tall stature and accelerated growth have been published [1][2][3][4][5][6]. ...
... Tall stature is a common reason for paediatric endocrinologist or clinical geneticist consultation that aims at early detection and treatment of possible underlying primary or secondary pathological causes [1]. Several guidelines on the diagnostic approach to tall stature and accelerated growth have been published [1][2][3][4][5][6]. The guidelines suggest that children over three years with either height SDS (HSDS) +2.5 [1,2,7] or height deviation from target height (HSDS-THSDS) +2 SDS [3,5,6], should be evaluated in specialized healthcare. ...
... Several guidelines on the diagnostic approach to tall stature and accelerated growth have been published [1][2][3][4][5][6]. The guidelines suggest that children over three years with either height SDS (HSDS) +2.5 [1,2,7] or height deviation from target height (HSDS-THSDS) +2 SDS [3,5,6], should be evaluated in specialized healthcare. Additionally, the most comprehensive guideline on tall stature, the Dutch national guideline [1], recommends that molecular genetic studies including whole-exome sequencing (WES) could be considered as a part of the comprehensive diagnostic evaluation in extremely tall children, defined as HSDS +3 from the age and sex specific population mean (i.e. ...
Background
Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall children subject to population-wide growth monitoring and screening rules.
Methods
Subjects with HSDS ≥+3 after three years of age born between 1990 and 2010 were identified from the Helsinki University Hospital district growth database. We comprehensively reviewed their medical records up to December 2020 and recorded underlying diagnoses, auxological data, and clinical features.
Findings
We identified 424 subjects (214 girls and 210 boys) who fulfilled the inclusion criteria. Underlying growth disorder was diagnosed in 61 (14%) patients, in 36 (17%) girls and 25 (12%) boys, respectively (P=0•15). Secondary causes were diagnosed in 42 (10%) patients and the two most frequent secondary diagnoses, premature adrenarche, and central precocious puberty were more frequent in girls. Primary disorder, mainly Marfan or Sotos syndrome, was diagnosed in 19 (4%) patients. Molecular genetic studies were used as a part of diagnostic work-up in 120 subjects. However, array CGH or next-generation sequencing studies were seldom used. Idiopathic tall stature (ITS) was diagnosed in 363 (86%) subjects, and it was considered familial in two-thirds. Dysmorphic features or a neurodevelopmental disorder were recorded in 104 (29%) children with ITS. The probability of a monogenic primary growth disorder increased with the degree of tall stature and deviation from target height.
Interpretation
A considerable proportion of extremely tall children have an underlying primary or secondary growth disorder, and their risk is associated with auxological parameters. Clinical features related to syndromic tall stature were surprisingly frequent in subjects with ITS, supporting the view that syndromic growth disorders with mild phenotypes may be underdiagnosed in extremely tall children. Our results lend support to comprehensive diagnostic work-up of extremely tall children.
Funding
Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, and Helsinki University Hospital research grants.
... Groeistoornissen kunnen worden onderverdeeld in twee groepen. De eerste groep wordt veroorzaakt door afwijkingen van de groeischijf zelf en wordt aange-duid als 'primaire groeistoornissen' [2,3]. Voorbeelden van primaire groeistoornissen die gepaard gaan met een kleine lengte zijn een groot aantal dysmorfe syndromen, zoals het Turner-syndroom, het Noonansyndroom, het Prader-Willi-syndroom en skeletdysplasieën. ...
... In deze leeftijdsgroep was de sensitiviteit voor het opsporen van groeistoornissen goed. De specificiteit van beide richtlijnen was echter laag, vermoedelijk door het verstorende effect van een vertraagde puberteitsgroeispurt. Voor de verwijzing van kinderen en adolescenten met een grote lengte zijn verschillende expert opinion reviews gepubliceerd [3,[11][12][13][14]. Deze zijn echter in de eerste plaats bestemd voor kinderartsen en kinderarts-endocrinologen. JGZ-professionals hebben aangegeven behoefte te hebben aan een richtlijn die gericht is op de vroegsignalering van aandoeningen die samenhangen met een grote lengte en om adolescenten te identificeren met wie een gesprek over het verminderen van de eindlengte kan worden overwogen [3]. ...
... De specificiteit van beide richtlijnen was echter laag, vermoedelijk door het verstorende effect van een vertraagde puberteitsgroeispurt. Voor de verwijzing van kinderen en adolescenten met een grote lengte zijn verschillende expert opinion reviews gepubliceerd [3,[11][12][13][14]. Deze zijn echter in de eerste plaats bestemd voor kinderartsen en kinderarts-endocrinologen. JGZ-professionals hebben aangegeven behoefte te hebben aan een richtlijn die gericht is op de vroegsignalering van aandoeningen die samenhangen met een grote lengte en om adolescenten te identificeren met wie een gesprek over het verminderen van de eindlengte kan worden overwogen [3]. ...
Inleiding: Het doel van dit onderzoek was het ontwikkelen van een richtlijn voor Jeugdgezondheidszorg (JGZ)-professionals om aandoeningen die samenhangen met een kleine lengte (en/of trage groei) of een grote lengte (en/of snelle groei) vroegtijdig op te sporen. Methode: Op basis van literatuur en advies van een expertcommissie werd de vorige JGZ-richtlijn Signalering van en verwijscriteria bij kleine lichaamslengte voor kinderen van 0 tot 10 jaar geactualiseerd en uitgebreid naar adolescenten (10 tot 18 jaar). Verder werden verwijscriteria voor grote lengte toegevoegd. De specificiteit van nieuwe verwijscriteria werd berekend in een cohort van gezonde Nederlandse kinderen van 0 tot 10 jaar (n = 970). Daarnaast werd de invloed van een late puberteit op de standaarddeviatiescore (SDS) voor lengte op basis van de Nederlandse groeidiagrammen onderzocht. Resultaten: Groeiparameters van de richtlijn zijn: (1) lengte, (2) de afstand tussen lengte en de streeflengte (target height) en (3) een groeiafbuiging of -toename in SDS. Andere parameters zijn aanwijzingen uit de anamnese en het lichamelijk onderzoek, bijvoorbeeld gedragsproblemen, vroege of vertraagde puberteit, lichaamsdisproportie en dysmorfe kenmerken. Conclusie: JGZ-professionals hebben nu een geactualiseerde richtlijn voor het verwijzen van kinderen met een kleine of grote lengte naar specialistische zorg. Verder onderzoek naar de diagnostische opbrengst na verwijzing en de specificiteit in de dagelijkse praktijk is wenselijk.
... 8 Growth in height accelerates from the age of 3 years onward, and, on average, adult men with KS are taller than the general population. 9 Learning difficulties, delayed speech development, or problems in relationships with their peers and siblings during childhood are more frequent than in boys with normal karyotype. 10 Among boys with KS, gynaecomastia is common at pubertal age, but it is transient in most cases. ...
Objective
Klinefelter syndrome (KS) (47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre.
Design and Patients
Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms.
Measurements and Results
One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (−2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started.
Conclusions
Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.
... 10 In this age group, the sensitivity to detect pathological growth disorders was good, but the specificity of both guidelines was low, presumably due to the interfering effect of a delayed pubertal growth spurt. Regarding guidelines for children and adolescent with tall stature, several expert opinion reviews have been published 3,[11][12][13][14] ; however, these are primarily aimed at paediatricians and paediatric endocrinologists. PCHC professionals have indicated that they feel a need for a guideline aimed at the screening for pathology associated with tall stature and to identify adolescents with whom a discussion about potential adult height reduction can be considered. ...
... PCHC professionals have indicated that they feel a need for a guideline aimed at the screening for pathology associated with tall stature and to identify adolescents with whom a discussion about potential adult height reduction can be considered. 3 The aim of our study was to update the Dutch PCHC guideline for short stature aged 0-9 years, extend this guideline to adolescents (10-17 years) and create a new guideline for tall stature aged 0-17 years. Height standard deviation score (HSDS) was calculated based on the Fourth nationwide growth study. ...
... Various expert-based algorithms for the diagnostic approach of a child or adolescent with tall stature by the paediatrician or paediatric endocrinologist have been reported. 3,[11][12][13][14] In the few studies on the diagnostic yield of pathological causes of tall stature, the prevalence appeared to be low. 3 ...
Aim
To develop a guideline for preventive child healthcare professionals in order to improve early detection of pathological disorders associated with short stature (or growth faltering) or tall stature (or accelerated growth).
Methods
We updated the previous Dutch guideline for short stature in children aged 0‐9 years and extended it to adolescents (10‐17 years), and added a guideline for tall stature, based on literature and input from an expert committee. Specificities were calculated in a cohort of healthy Dutch children aged 0‐9 years (n = 970). We investigated the impact of a late onset of puberty on height standard deviation score based on the Dutch growth charts.
Results
Growth parameters of the guideline include height, the distance between height and target height and change of height over time. Other parameters include diagnostic clues from medical history and physical examination, for example behavioural problems, precocious or delayed puberty, body disproportion and dysmorphic features.
Conclusion
Preventive child healthcare professionals now have an updated guideline for referring short or tall children to specialist care. Further research is needed on the diagnostic yield after referral and specificity at field level.
... Syndromic patients show a combination of relevant alterations, such as neurodevelopmental delay, macrocephaly, major cardiac abnormalities, facial dysmorphic features and skeletal alterations, and these characteristics usually cluster in unique, classical phenotypes that lead to the identification of the underlying genetic etiology. However, many of these conditions, such as Sotos (OMIM 117550), Weaver (OMIM 277590) and Malan (OMIM 614753) syndromes, have overlapping phenotypes, making it very difficult to clinically distinguish these conditions, especially later in life (2,3,4,5). Besides, most genes already associated with generalized overgrowth are large and do not have hotspots, which makes an approach by candidate gene a time and labor-consuming option to attempt diagnosis confirmation (3,6). ...
... Arm span and head circumference were obtained using a measuring tape. Abnormal body proportion was defined by sitting height/ height ratio SDS <−2 or arm span/height ratio >1.05 (2,14). Measures were also obtained from all available relatives and mid-parental height was calculated using the formula ((father's height + mother's height ± 13 cm)/2) and then expressed in SDS. ...
... Based on our results, we suggest that multigene analysis should be included in the systematic investigation of all syndromic patients with tall stature, regardless of whether they have a clinical suspicion or not. This approach has been recently advised in a systematic review, and our results endorse this rationale (2). The benefit of a genetic investigation of non-syndromic patients remains uncertain and perhaps an assessment of a larger number of these patients could be enlightening, especially in a polygenic context. ...
Context:
Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach.
Objective:
To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder.
Design:
Screening by karyotype (n=42), chromosome microarray analyses (CMA) (n=16), MS-MLPA (n=2) targeted panel (n=12) and whole exome sequencing (n=31).
Patients and methods:
We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n=30) and non-syndromic (n=12) subgroups.
Main outcome measures:
Frequencies of pathogenic findings.
Results:
We identified 2 patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith-Wiedemann syndrome by targeted MS-MLPA analysis and 9 cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1=3, NSD1=2, NFIX=1, SUZ12=1, CHD8=1, MC4R=1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients.
Conclusion:
A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.
Context
Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype.
Objective
To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail.
Methods
Children with FTS (the life-maximum height in both the child and his/her taller parent > 2 SD for age and sex) referred to the Endocrinology center of Motol University Hospital were enrolled into the study. Their DNA was examined cytogenetically and via a next-generation sequencing panel of 786 genes associated with growth. The genetic results were evaluated by the American College of Molecular Genetics and Genomics guidelines. All of the participants underwent standard endocrinological examination followed by specialized anthropometric evaluation.
Results
In total, 34 children (19 girls) with FTS were enrolled in the study. Their median height and their taller parent's height were 3.1 SD and 2.5 SD, respectively. The genetic cause of FTS was elucidated in 11/34 (32.4%) children (47,XXX and 47,XYY karyotypes, SHOX duplication, and causative variants in NSD1 [in 2], SUZ12 [in 2], FGFR3, CHD8, GPC3, and PPP2R5D genes). Ten children had absent syndromic signs and 24 had dysmorphic features.
Conclusion
Monogenic (and cytogenetic) etiology of FTS can be found among children with FTS. Genetic examination should be considered in all children with FTS regardless of the presence of dysmorphic features.
The implementation of high-throughput and deep sequencing methods in routine genetic diagnostics has significantly improved the diagnostic yield in patient cohorts with growth disturbances and becomes increasingly important as the prerequisite of personalised medicine. They provide considerable chances to identify even rare and unexpected situations, nevertheless we must be aware of their limitations. A simple genetic test in the beginning of a testing cascade might also help to identify the genetic cause of specific growth disorders. However, the clinical picture of genetically caused growth disturbance phenotypes can vary widely, and there is a broad clinical overlap between different growth disturbance disorders. As a consequence, the clinical diagnosis and therewith connected the decision on the appropriate genetic test is often a challenge. In fact, the clinician asking for genetic testing has to weigh different aspects in this decision process, including appropriateness (single gene test, stepwise procedure, comprehensive testing), turn-around-time as the basis for a rapid intervention, and economic considerations. Therefore, a frequent question in that context is “what to test when”. In this review we aim to review genetic testing strategies and their strengthens and limitations, and to raise awareness for the future implementation of an interdisciplinary genome medicine in diagnoses, treatment and counselling of growth disturbances.
