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Nature Reviews. Endocrinology Dec 2015In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore,... (Review)
Review
In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH-IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain.
Topics: Animals; Body Height; Gene Dosage; Growth Disorders; Growth Plate; Human Growth Hormone; Humans; Insulin-Like Growth Factor I
PubMed: 26437621
DOI: 10.1038/nrendo.2015.165 -
Gene Oct 2016FBN1 encodes the gene for fibrillin-1, a structural macromolecule that polymerizes into microfibrils. Fibrillin microfibrils are morphologically distinctive fibrils,... (Review)
Review
FBN1 encodes the gene for fibrillin-1, a structural macromolecule that polymerizes into microfibrils. Fibrillin microfibrils are morphologically distinctive fibrils, present in all connective tissues and assembled into tissue-specific architectural frameworks. FBN1 is the causative gene for Marfan syndrome, an inherited disorder of connective tissue whose major features include tall stature and arachnodactyly, ectopia lentis, and thoracic aortic aneurysm and dissection. More than one thousand individual mutations in FBN1 are associated with Marfan syndrome, making genotype-phenotype correlations difficult. Moreover, mutations in specific regions of FBN1 can result in the opposite features of short stature and brachydactyly characteristic of Weill-Marchesani syndrome and other acromelic dysplasias. How can mutations in one molecule result in disparate clinical syndromes? Current concepts of the fibrillinopathies require an appreciation of tissue-specific fibrillin microfibril microenvironments and the collaborative relationship between the structures of fibrillin microfibril networks and biological functions such as regulation of growth factor signaling.
Topics: Animals; Disease Models, Animal; Fibrillin-1; Genetic Predisposition to Disease; Humans; Marfan Syndrome; Mutation
PubMed: 27437668
DOI: 10.1016/j.gene.2016.07.033 -
The Journal of Pediatrics Oct 2013To describe auxologic, physical, and behavioral features in a large cohort of males with 47,XYY (XYY), ages newborn to young adult.
OBJECTIVE
To describe auxologic, physical, and behavioral features in a large cohort of males with 47,XYY (XYY), ages newborn to young adult.
STUDY DESIGN
This is a cross-sectional descriptive study of male subjects with XYY who were evaluated at 1 of 2 specialized academic sites. Subjects underwent a history, physical examination, laboratory testing, and cognitive/behavioral evaluation.
RESULTS
In 90 males with XYY (mean age 9.6 ± 5.3 years [range 0.5-36.5]), mean height SD was above average (1.0 ± 1.2 SD). Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%). There was testicular enlargement for age (>2 SD) in 41/82 (50%), but no increase in genital anomalies. No physical phenotypic differences were seen in boys diagnosed prenatally vs postnatally. Testosterone, luteinizing hormone, and follicle stimulating hormone levels were in the normal range in most boys. There was an increased incidence of asthma, seizures, tremor, and autistic spectrum disorder (ASD) compared with the general population rates. Prenatally diagnosed boys scored significantly better on cognitive testing and were less likely to be diagnosed with ASD (P < .01).
CONCLUSIONS
The XYY phenotype commonly includes tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor. Physical phenotypic features were similar in boys diagnosed prenatally vs postnatally. Prenatal diagnosis was associated with higher cognitive function and less likelihood of an ASD diagnosis.
Topics: Adolescent; Adult; Child; Child Behavior; Child, Preschool; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Hand Deformities; Humans; Infant; Male; Megalencephaly; Muscle Hypotonia; Neuropsychological Tests; Phenotype; Sex Chromosome Disorders; Social Class; Surveys and Questionnaires; XYY Karyotype; Young Adult
PubMed: 23810129
DOI: 10.1016/j.jpeds.2013.05.037 -
Hormone Research in Paediatrics 2016Tall stature is a common reason for consultation of a paediatric endocrinologist. It is important to always consider underlying pathology. We propose a diagnostic... (Review)
Review
Tall stature is a common reason for consultation of a paediatric endocrinologist. It is important to always consider underlying pathology. We propose a diagnostic flowchart based on five questions. (1) Does the child have tall stature? (2) Is there evidence of a syndrome? (3) Has there been growth acceleration? (4) Are there signs of puberty? (5) Does the child grow within the target height range? Diagnostic tests can then be ordered targeted to the suspected disorder. The Bayley-Pinneau and Tanner-Whitehouse methods are reasonably accurate in predicting adult height based on bone age in girls, but neither method performs well in boys. Tall stature is not a pathological condition and generally does not need treatment. However, adolescents with a strong treatment wish and their parents should be counselled on the effectivity and safety of available treatments including surgery and high-dose sex steroids. Surgical epiphysiodesis has the advantage that a reasonable height reduction can be achieved at a more advanced bone age, allowing a more accurate adult height prediction to base any treatment decision on. We feel that high-dose oestrogen treatment should no longer be used because of its association with reduced fecundity and imminent ovarian failure.
Topics: Adolescent; Body Height; Child; Child, Preschool; Female; Gonadal Steroid Hormones; Growth Disorders; Humans; Infant; Male; Pregnancy; Puberty
PubMed: 26845047
DOI: 10.1159/000443685 -
The Journal of Clinical Endocrinology... Jan 2024Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature,... (Review)
Review
Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.
Topics: Humans; Autism Spectrum Disorder; Abnormalities, Multiple; Syndrome; Histone Methyltransferases; Intellectual Disability; Epigenesis, Genetic
PubMed: 37450557
DOI: 10.1210/clinem/dgad420 -
Lancet (London, England) Nov 2020Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height...
Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants.
BACKGROUND
Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents.
METHODS
For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5-19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence.
FINDINGS
We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9-10 kg/m. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes-gaining too little height, too much weight for their height compared with children in other countries, or both-occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls.
INTERPRETATION
The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks.
FUNDING
Wellcome Trust, AstraZeneca Young Health Programme, EU.
Topics: Adolescent; Adolescent Development; Bayes Theorem; Body Height; Body Mass Index; Child; Child Development; Child, Preschool; Female; Health Status Indicators; Humans; Internationality; Male; Meta-Analysis as Topic; Population Health; Young Adult
PubMed: 33160572
DOI: 10.1016/S0140-6736(20)31859-6