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Advances in Pediatrics Aug 2022Growth hormone (GH) is an injectable medication originally used to replace the deficiency of the hormone, but has expanded to treating conditions that may reduce growth... (Review)
Review
Growth hormone (GH) is an injectable medication originally used to replace the deficiency of the hormone, but has expanded to treating conditions that may reduce growth and adult height even when the body maintains endogenous GH production. In the United States, there are 8 Food and Drug Administration (FDA)-approved indications for pediatric GH therapy: GH deficiency, Prader-Willi Syndrome, small for gestational age (SGA) without catch-up growth, idiopathic short stature, Turner syndrome, SHOX gene haploinsufficiency, Noonan Syndrome, and chronic renal insufficiency. We characterize the growth patterns and effects of GH treatment in each of these indications. We also review patterns of growth that warrant referral to a pediatric endocrinologist, as well as safety updates. This review is intended to guide practitioners on the initial evaluation and management of patients with short stature, and the indications for GH therapy.
Topics: Adult; Child; Dwarfism; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Prader-Willi Syndrome; Turner Syndrome; United States
PubMed: 35985710
DOI: 10.1016/j.yapd.2022.03.005 -
Orphanet Journal of Rare Diseases Jan 2019Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been... (Review)
Review
Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been described for more than 50 years, there is still a great deal to be learned about the medical issues that arise secondary to this diagnosis, the manner in which these are best diagnosed and addressed, and whether preventive strategies can ameliorate the problems that can compromise the health and well being of affected individuals. This review provides both an updated discussion of the care needs of those with achondroplasia and an exploration of the limits of evidence that is available regarding care recommendations, controversies that are currently present, and the many areas of ignorance that remain.
Topics: Achondroplasia; Bone Diseases, Developmental; Humans; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 30606190
DOI: 10.1186/s13023-018-0972-6 -
Current Opinion in Pediatrics Aug 2021Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening... (Review)
Review
PURPOSE OF REVIEW
Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening approach. The purpose of this review is to describe the optimal genetic approach for evaluating short stature, challenges of genetic testing, and recent advances in genetic testing for short stature.
RECENT FINDINGS
Genetic testing, such as karyotype, chromosomal microarray, targeted gene sequencing, or exome sequencing, has served to identify the underlying genetic causes of short stature. When determining which short stature patient would benefit from genetic evaluation, it is important to consider whether the patient would have a single identifiable genetic cause. Specific diagnoses permit clinicians to predict responses to growth hormone treatment, to understand the phenotypic spectrum, and to understand any associated co-morbidities.
SUMMARY
The continued progress in the field of genetics and enhanced capabilities provided by genetic testing methods expands the ability of physicians to evaluate children with short stature for underlying genetic defects. Continued effort is needed to elaborate new genetic causes of linear growth disorders, therefore, we expand the list of known genes for short stature, which will subsequently increase the rate of genetic diagnosis for children with short stature.
Topics: Body Height; Child; Dwarfism; Genetic Testing; Growth Disorders; Humans; Exome Sequencing
PubMed: 34101704
DOI: 10.1097/MOP.0000000000001033 -
Current Opinion in Pediatrics Aug 2018Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability... (Review)
Review
PURPOSE OF REVIEW
Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature.
RECENT FINDINGS
In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, ACAN, NPPC, NPR2, PTPN11 (and other rasopathies), FBN1, IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings. In addition, novel genetic causes of syndromic short stature have been discovered, including pathogenic variants in BRCA1, DONSON, AMMECR1, NFIX, SLC25A24, and FN1.
SUMMARY
Isolated growth disorders are often monogenic. Specific genetic causes typically have specific biochemical and/or phenotype characteristics which are diagnostically helpful. Identification of additional subjects with a specific genetic cause of short stature often leads to a broadening of the known clinical spectrum for that condition. The identification of novel genetic causes of short stature has provided important insights into the underlying molecular mechanisms of growth failure.
Topics: Child; Dwarfism; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Growth Disorders; Humans; Exome Sequencing; Whole Genome Sequencing
PubMed: 29787394
DOI: 10.1097/MOP.0000000000000653 -
International Journal of Molecular... May 2021Achondroplasia (ACH) is a disease caused by a missense mutation in the (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in... (Review)
Review
Achondroplasia (ACH) is a disease caused by a missense mutation in the (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in humans. The treatment of ACH is necessary and urgent because untreated achondroplasia has many complications, both orthopedic and neurological, which ultimately lead to disability. This review presents the current and potential pharmacological treatments for achondroplasia, highlighting the advantages and disadvantages of all the drugs that have been demonstrated in human and animal studies in different stages of clinical trials. The article includes the potential impacts of drugs on achondroplasia symptoms other than short stature, including their effects on spinal canal stenosis, the narrowing of the foramen magnum and the proportionality of body structure. Addressing these effects could significantly improve the quality of life of patients, possibly reducing the frequency and necessity of hospitalization and painful surgical procedures, which are currently the only therapeutic options used. The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.
Topics: Achondroplasia; Animals; Human Growth Hormone; Humans; Mutation, Missense; Natriuretic Peptide, C-Type; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 34070375
DOI: 10.3390/ijms22115573 -
Frontiers in Endocrinology 2022The evaluation of children with short stature includes monitoring over a prolonged period to establish a growth pattern as well as the exclusion of chronic medical... (Review)
Review
The evaluation of children with short stature includes monitoring over a prolonged period to establish a growth pattern as well as the exclusion of chronic medical conditions that affect growth. After a period of monitoring, evaluation, and screening, growth hormone stimulation testing is considered when the diagnosis of growth hormone deficiency (GHD) is entertained. Though flawed, growth hormone stimulation tests remain part of the comprehensive evaluation of growth and are essential for the diagnosis of growth hormone (GH) deficiency. Variables including testing length, growth hormone assay and diagnostic cut off affect results. Beyond the intrinsic issues of testing, results of GH stimulation testing can be influenced by patient characteristics. Various factors including age, gender, puberty, nutritional status and body weight modulate the secretion of GH.
Topics: Child; Dwarfism, Pituitary; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Puberty
PubMed: 35757429
DOI: 10.3389/fendo.2022.902364 -
Endocrine Reviews Apr 2019The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice... (Review)
Review
The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.
Topics: Aging; Animals; Dwarfism, Pituitary; Growth Hormone; Humans; Laron Syndrome; Longevity
PubMed: 30576428
DOI: 10.1210/er.2018-00216 -
Frontiers in Endocrinology 2022Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the...
CONTEXT
Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy.
OBJECTIVE
This is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response.
PATIENTS AND METHODS
One hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including , and . The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized.
RESULTS
Twenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include , , , , and in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years.
CONCLUSIONS
A proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required.
Topics: Cohort Studies; Collagen; Dwarfism; Human Growth Hormone; Humans; Musculoskeletal Abnormalities; Mutation; Recombinant Proteins
PubMed: 35250876
DOI: 10.3389/fendo.2022.820001 -
Advances in Therapy Sep 2023Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment... (Review)
Review
BACKGROUND
Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research.
METHODS
Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines.
RESULTS
Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments.
CONCLUSIONS
This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies.
Topics: Humans; Quality of Life; Achondroplasia; Human Growth Hormone; Cost-Benefit Analysis
PubMed: 37382866
DOI: 10.1007/s12325-023-02549-3 -
Acta Bio-medica : Atenei Parmensis Mar 2020To assess the long-term effect of growth hormone (GH) therapy in a large cohort of short children with different etiologies.
Effect of growth hormone treatment on children with idiopathic short stature (ISS), idiopathic growth hormone deficiency (IGHD), small for gestational age (SGA) and Turner syndrome (TS) in a tertiary care center.
OBJECTIVES
To assess the long-term effect of growth hormone (GH) therapy in a large cohort of short children with different etiologies.
PATIENTS AND METHODS
We evaluated retrospectively the anthropometric data of 252 short children [height SDS <-2: 154 children with growth hormone deficiency (GHD), 63 with idiopathic short stature (ISS), 26 with SGA, and 9 with Turner syndrome (TS)] who were treated, in our center, with GH between 1-2007 and 1-2018. Before and during recombinamt growth-hormone (recGH) treatment, auxological parameters including height (Ht), weight (Wt), Ht - Z score (HtSDS), body mass index (BMI) and BMISDS were recorded every 6 months; bone age (BA) was assessed every 12 months.
RESULTS
At the end of first year of rhGH therapy and after an average of 3 years treatment all groups of short children had significant increase in HtSDS, which was higher in GHD compared to other groups. Children with GHD, SGA, ISS and TS increased their HtSDS by an average of 2.2, 1.46, 0.6 and 0.99 SD, respectively at the end of follow up period (for all groups, p: <0.001). The bone age/chronological age (BA/CA) ratio did not differ significantly among ISS, GHD and SGA groups after GH therapy. The HtSDS gain was higher in children with GHD compared to other ISS, SGA and TS groups (p:< 0.01; p: 0.015 and p: 0.029, respectively). HtSDS improvement occurred during the first 3 years of rhGH therapy. The BMISDS increased significantly in children with GHD, after 3 years of rhGH therapy (p: < 0.001). After rhGH treatment, the BMISDS decreased significantly in children with ISS and SGA (p: < 0.01 and < 0.001, respectively) but did not change in children with TS (p: 0.199).
CONCLUSIONS
Children with GHD, SGA, ISS and TS exhibited significant increases in HtSDS when treated with rhGH for 3 years. The HtSDS gain was higher in children with GHD compared to other groups.
Topics: Body Height; Body Mass Index; Child; Child, Preschool; Cohort Studies; Dwarfism; Female; Follow-Up Studies; Hormone Replacement Therapy; Human Growth Hormone; Humans; Male; Recombinant Proteins; Retrospective Studies; Tertiary Care Centers; Turner Syndrome; Weight Gain
PubMed: 32191651
DOI: 10.23750/abm.v91i1.9182