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Indian Pediatrics Dec 2007A 12-year-old male child presented with bilateral visual loss and short stature. He had dysmorphic faces, barrel shaped chest and short limbs with enlarged peripheral...
A 12-year-old male child presented with bilateral visual loss and short stature. He had dysmorphic faces, barrel shaped chest and short limbs with enlarged peripheral joints. In addition he had bilateral retinal detachment with secondary cataract formation. Skeletal survey revealed irregular platyspondyly, hypoplastic femoral head and enlarged epiphysis of long bones with cloud like calcification. Radiological features were diagnostic of Kniest syndrome. The child underwent pars plana lensectomy and a vitreo-retinal surgery with silicon oil infusion in the right eye for retinal detachment.
Topics: Child; Diagnosis, Differential; Dwarfism; Fetal Diseases; Humans; Male; Retinal Detachment; Syndrome; Ultrasonography, Prenatal; Vision Disorders
PubMed: 18175850
DOI: No ID Found -
International Journal of Molecular... May 2018Growth hormone (GH) promotes body growth by binding with two GH receptors (GHRs) at the cell surface. GHRs interact with Janus kinase, signal transducers, and... (Review)
Review
Growth hormone (GH) promotes body growth by binding with two GH receptors (GHRs) at the cell surface. GHRs interact with Janus kinase, signal transducers, and transcription activators to stimulate metabolic effects and insulin-like growth factor (IGF) synthesis. However, process dysfunctions in the GH⁻GHR⁻IGF-1 axis cause animal dwarfism. If, during the GH process, GHR is not successfully recognized and/or bound, or GHR fails to transmit the GH signal to IGF-1, the GH dysfunction occurs. The goal of this review was to focus on the GHR mutations that lead to failures in the GH⁻GHR⁻IGF-1 signal transaction process in the dwarf phenotype. Until now, more than 90 GHR mutations relevant to human short stature (Laron syndrome and idiopathic short stature), including deletions, missense, nonsense, frameshift, and splice site mutations, and four GHR defects associated with chicken dwarfism, have been described. Among the 93 identified mutations of human GHR, 68 occur extracellularly, 13 occur in GHR introns, 10 occur intracellularly, and two occur in the transmembrane. These mutations interfere with the interaction between GH and GHRs, GHR dimerization, downstream signaling, and the expression of GHR. These mutations cause aberrant functioning in the GH-GHR-IGF-1 axis, resulting in defects in the number and diameter of muscle fibers as well as bone development.
Topics: Animals; Dwarfism; Gene Expression Regulation; Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mutation; Receptors, Somatotropin; Signal Transduction
PubMed: 29748515
DOI: 10.3390/ijms19051433 -
Journal of Clinical Research in... 2014Short stature is one of the major components of many dysmorphic syndromes. Growth failure may be due to a wide variety of mechanisms, either related to the growth... (Review)
Review
Short stature is one of the major components of many dysmorphic syndromes. Growth failure may be due to a wide variety of mechanisms, either related to the growth hormone (GH)/insulin-like growth factor axis or to underlying unknown pathologies. In this review, the relatively more frequently seen syndromes with short stature (Noonan syndrome, Prader-Willi syndrome, Silver-Russell syndrome and Aarskog-Scott syndrome) were discussed. These disorders are associated with a number of endocrinopathies, as well as with developmental, systemic and behavioral issues. At present, GH therapy is used in most syndromic disorders, although long-term studies evaluating this treatment are insufficient and some controversies exist with regard to GH dose, optimal age to begin therapy and adverse effects. Before starting GH treatment, patients with syndromic disorders should be evaluated extensively.
Topics: Dwarfism; Growth Disorders; Human Growth Hormone; Humans; Syndrome
PubMed: 24637303
DOI: 10.4274/Jcrpe.1149 -
Orphanet Journal of Rare Diseases Oct 2023Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score... (Review)
Review
BACKGROUND
Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care.
OBJECTIVE
To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally.
METHODS
An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD.
RESULTS
As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing.
CONCLUSIONS
To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.
Topics: Humans; Insulin-Like Growth Factor I; Quality of Life; Laron Syndrome; Dwarfism; Growth Disorders
PubMed: 37805563
DOI: 10.1186/s13023-023-02928-7 -
Contrast Media & Molecular Imaging 2022Currently, the prevalence of dwarfism in children in China is about 3%, which is a very large percentage compared with the large population base. With the increase of...
Currently, the prevalence of dwarfism in children in China is about 3%, which is a very large percentage compared with the large population base. With the increase of influencing factors, the prevalence of dwarfism is on the increase. However, there is a lack of awareness of dwarfism among parents and a lack of in-depth analysis of the causes of dwarfism and a low level of treatment among doctors. Early expert system knowledge base relies on manual editing, which is a traditional, semi-intelligent auxiliary diagnostic system, and is unable to perform disease diagnosis and clinical treatment monitoring well. Many studies have turned to the combination of IoT for bone age determination and its role in the diagnosis and monitoring of clinical treatment of dwarfism. In this study, 15 children with short stature who underwent health checkups at a hospital were enrolled in the study, and a G-P spectrum method was used to determine the bone age of all the enrolled subjects, and the results obtained in the process of bone age determination were systematically analyzed. The results showed that the bone age measurement technique has sufficient reference value for evaluating the quality and diagnosing diseases, and the research and development of this technique is of great significance for the development of modern clinical medicine.
Topics: Child; Humans; Dwarfism; Bone and Bones; Reference Values
PubMed: 36262996
DOI: 10.1155/2022/7247932 -
Journal of Postgraduate Medicine 2024We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling....
We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.
Topics: Male; Infant, Newborn; Humans; Child, Preschool; Epilepsy; Dementia; Amelogenesis Imperfecta; Abnormalities, Multiple; Osteochondrodysplasias; Dwarfism; Symporters; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 37706418
DOI: 10.4103/jpgm.jpgm_1001_22 -
The Journals of Gerontology. Series A,... Jun 2020The gut microbiome (GM) represents a large and very complex ecosystem of different microorganisms. There is an extensive interest in the potential role of the GM in...
The gut microbiome (GM) represents a large and very complex ecosystem of different microorganisms. There is an extensive interest in the potential role of the GM in different diseases including cancer, diabetes, cardiovascular diseases, and aging. The GM changes over the lifespan and is strongly associated with various age-related diseases. Ames dwarf (df/df) mice are characterized by an extended life- and healthspan, and although these mice are protected from many age-related diseases, their microbiome has not been studied. To determine the role of microbiota on longevity animal models, we investigated the changes in the GM of df/df and normal control (N) mice, by comparing parents before mating and littermate mice at three distinct time points during early life. Furthermore, we studied the effects of a 6-month calorie restriction (CR), the most powerful intervention extending the lifespan. Our data revealed significant changes of the GM composition during early life development, and we detected differences in the abundance of some bacteria between df/df and N mice, already in early life. Overall, the variability of the microbiota by genotype, time-point, and breeding pair showed significant differences. In addition, CR caused significant changes in microbiome according to gastrointestinal (GI) location (distal colon, ileum, and cecum), genotype, and diet. However, the overall impact of the genotype was more prominent than that of the CR. In conclusion, our findings suggest that the gut microbiota plays an important role during postnatal development in long-living df/df mice and CR dietary regimen can significantly modulate the GM.
Topics: Animals; Caloric Restriction; Dwarfism; Female; Gastrointestinal Microbiome; Growth Hormone; Longevity; Male; Mice; Mice, Mutant Strains; Models, Animal
PubMed: 31665244
DOI: 10.1093/gerona/glz236 -
Hormone Research in Paediatrics 2018Assessing cost-effectiveness of human growth hormone (hGH) treatment to augment height is complicated by uncertainty about how best to measure its therapeutic effect.... (Review)
Review
Assessing cost-effectiveness of human growth hormone (hGH) treatment to augment height is complicated by uncertainty about how best to measure its therapeutic effect. Cost-conscious growth promotion practice, however, is possible and likely an emerging practical requisite as health care payers increasingly deny the medical necessity of and restrict support for short stature treatment. The increase in denials is not surprising given the expansion and continued high cost of hGH treatment, debate about the value of such treatment, and universal need to restrain burgeoning health care costs. Renunciation of sweeping payer rejection of hGH-for-height treatment is strengthened by cost-conscious practices that (1) recommend no treatment for most short children and restrict treatment to severe, likely disabling short stature; (2) initiate hGH treatment only after evidence-based informed assent; (3) utilize alternative less costly and less invasive options when possible; (4) minimize hGH treatment duration and dosage; and (5) resist enhancement of normal adult stature. A new era of cost-conscious hGH prescribing that prompts thoughtful restraint in hGH use could help preserve hGH approval for children most in need of treatment.
Topics: Child; Cost-Benefit Analysis; Drug Costs; Dwarfism; Growth Disorders; Human Growth Hormone; Humans; Insurance, Health, Reimbursement
PubMed: 30269127
DOI: 10.1159/000493397 -
Frontiers in Endocrinology 2022This study analyzed eight Chinese short stature children with aggrecan deficiency, and aimed to investigate potential genotype-phenotype correlations, differences in... (Review)
Review
Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: Novel heterozygous variants in eight Chinese children and a review of the literature.
OBJECTIVE
This study analyzed eight Chinese short stature children with aggrecan deficiency, and aimed to investigate potential genotype-phenotype correlations, differences in clinical characteristics between the Chinese and the Western populations, and effectiveness of recombinant human growth hormone therapy in patients with variants through a review of the literature.
METHODS
Pediatric short stature patients with heterozygous variants were identified using whole-exome sequencing. Subsequently, a literature review was carried out to summarize the clinical features, genetic findings, and efficacy of growth-promoting therapy in patients with variants.
RESULTS
We identified seven novel mutations and one recurrent variant. Patients in our center manifested with short stature (average height SDS: -3.30 ± 0.85) with slight dysmorphic characteristics. The prevalence of dysmorphic features in the Chinese populations is significantly lower than that in the Western populations. Meanwhile, only 24.24% of aggrecan-deficient Chinese children showed significantly advanced bone age (BA). Promising therapeutic benefits were seen in the patients who received growth-promoting treatment, with an increase in growth velocity from 4.52 ± 1.00 cm/year to 8.03 ± 1.16 cm/year.
CONCLUSION
This study further expanded the variation spectrum of the gene and demonstrated that Chinese children with short stature who carried heterozygous variants exhibited early growth cessation, which may remain unnoticed by clinicians as most of these children had very mild dysmorphic characteristics and showed BA that was consistent with the chronological age. Genetic testing may help in the diagnosis.
Topics: Humans; Child; Aggrecans; Heterozygote; Dwarfism; Asian People; China
PubMed: 36387899
DOI: 10.3389/fendo.2022.1015954 -
Journal of Bone and Mineral Research :... Mar 2019NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.3 deletion involving the Nell-1 gene was...
NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.3 deletion involving the Nell-1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell-1 in endochondral ossification by investigating Nell-1-specific inactivation in Col2α1-expressing cell lineages. Nell-1 ; Col2α1-Cre (Nell-1 KO) mice were generated for comprehensive analysis. Nell-1 KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell-1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell-1 KO femurs and tibias exhibited significantly reduced length, bone mineral density (BMD), bone volume per tissue volume (BV/TV), trabecular number/thickness, cortical volume/thickness/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro-CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col-2, Col-10, and fewer BrdU-positive chondrocytes were observed in thinner Nell-1 KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched-1, PTHrP, and PTHrP receptor. Primary Nell-1 KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh-PTHrP signaling molecules can be partially rescued by exogenous Nell-1 protein. Moreover, intranuclear Gli-1 protein and gene expression of the Gli-1 downstream target genes, Hip-1 and N-Myc, were also significantly decreased with Nell-1 inactivation. Notably, the rescue effects were diminished/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell-1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte-specific Nell-1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh-PTHrP feedback loop. © 2018 American Society for Bone and Mineral Research.
Topics: Animals; Calcium-Binding Proteins; Chondrocytes; Dwarfism; Hedgehog Proteins; Mice; Mice, Knockout; Osteogenesis; Osteoporosis; Parathyroid Hormone-Related Protein; X-Ray Microtomography
PubMed: 30352124
DOI: 10.1002/jbmr.3615