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European Journal of Paediatric Dentistry Sep 2023Aarskog-Scott syndrome (AAS) is a rare developmental disorder characterised by facial dysmorphism, genital and limb anomalies as well as disproportionate acromelic short...
BACKGROUND
Aarskog-Scott syndrome (AAS) is a rare developmental disorder characterised by facial dysmorphism, genital and limb anomalies as well as disproportionate acromelic short stature. Clinical diagnosis is based on physical examination and the presence of the most characteristic clinical signs. The diagnosis can be finally confirmed by molecular tests, which identify mutations in the FGD1 gene.
CASE REPORT
The report outlines the orthodontic treatment of a 6-year-old male patient, who was diagnosed with AAS syndrome. He presents all facial and oral clinical signs of this syndrome. The extent of maxillary hypoplasia and early dental crowding are so significant that immediate expansion therapy is required.
CONCLUSION
Dental management of patients with AAS syndrome represents a challenge for paediatric dentists. The key to improving a patient's aesthetic, functional and psychological condition is making the correct orthodontic decision.
Topics: Male; Child; Humans; Guanine Nucleotide Exchange Factors; Mutation; Dwarfism; Genitalia, Male
PubMed: 37337880
DOI: 10.23804/ejpd.2023.1953 -
Veterinary and Comparative Orthopaedics... Sep 2021The aim of this study was to characterize the radiographic alignment of thoracic and pelvic limbs and evaluate for intervertebral disc disease in cats with feline...
OBJECTIVE
The aim of this study was to characterize the radiographic alignment of thoracic and pelvic limbs and evaluate for intervertebral disc disease in cats with feline disproportionate dwarfism (FDD).
STUDY DESIGN
Observational cross-sectional study. Radiographic joint orientation angles were measured in 10 thoracic and pelvic limbs from 5 FDD cats and compared with those angles measured in 24 thoracic limbs and 100 pelvic limbs from skeletally normal cats. Magnetic resonance imaging of the spine was performed in 2 FDD cats for the evaluation of pathology of the intervertebral discs or vertebrae.
RESULTS
All limbs from FDD cats possessed deformities. FDD humeri demonstrated procurvatum proximally, and recurvatum distally in the sagittal plane, but showed no difference in the frontal plane. FDD radii possessed excessive recurvatum proximally, and procurvatum distally in the sagittal plane, and varus proximally and valgus distally in the frontal plane. Whereas no torsion was discernible in the humeri, all radii had external torsion. In the frontal plane, FDD femurs exhibited varus both proximally and distally whereas the tibia possessed proximal valgus and distal varus. No torsion in the pelvic limbs was observed. No spinal pathology was detected in the FDD cats included in the original study.
CONCLUSION
Feline disproportionate dwarfism results in significant appendicular deformity in all limbs. The incidence of intervertebral disc degeneration in FDD cats is inconclusive.
Topics: Animals; Cat Diseases; Cats; Cross-Sectional Studies; Dwarfism; Magnetic Resonance Imaging; Radiography; Tibia
PubMed: 34082456
DOI: 10.1055/s-0041-1730355 -
Orphanet Journal of Rare Diseases Jul 2023Heterozygous loss-of-function variants in the NPR2 gene cause short stature with nonspecific skeletal abnormalities and account for about 2 ~ 6% of idiopathic short...
OBJECTIVE
Heterozygous loss-of-function variants in the NPR2 gene cause short stature with nonspecific skeletal abnormalities and account for about 2 ~ 6% of idiopathic short stature. This study aimed to analyze and identify pathogenic variants in the NPR2 gene and explore the therapeutic response to recombinant growth hormone (rhGH).
METHODS
NPR2 was sequenced in three Chinese Han patients with short stature via exome sequencing. In vitro functional experiments, homology modeling and molecular docking analysis of variants were performed to examine putative protein changes and the pathogenicity of the variants.
RESULT
Three patients received rhGH therapy for two years, and two NPR2 heterozygous variants were identified in three unrelated cases: c.1579 C > T,p.Leu527Phe in patient 1 and c.2842dupC,p.His948Profs*5 in patient 2. Subsequently, a small gene model was constructed, and transcriptional analysis of the synonymous variant (c.2643G > A) was performed in patient 3, which revealed the deletion of exon 17 and the premature formation of a stop codon (p.His840Gln*). Functional studies showed that both NPR2 variants, His948Profs*5 and His840Gln*, failed to produce cGMP in the homozygous state. Furthermore, the Leu527Phe variant of NPR2 was almost unresponsive to the stimulatory effect of ATP on CNP-dependent guanylyl cyclase activity. This loss of response to ATP has not been previously reported. The average age of patients at the start of treatment was 6.5 ± 1.8 years old, and their height increased by 1.59 ± 0.1 standard deviation score after 2 years of treatment.
CONCLUSION
In this report, two novel variants in NPR2 gene were described. Our findings broaden the genotypic spectrum of NPR2 variants in individuals with short stature and provid insights into the efficacy of rhGH in these patients.
Topics: Child; Child, Preschool; Humans; Adenosine Triphosphate; Body Height; Dwarfism; Growth Hormone; Molecular Docking Simulation; Mutation; Receptors, Atrial Natriuretic Factor
PubMed: 37501190
DOI: 10.1186/s13023-023-02757-8 -
Genes Jun 2022Heterozygous variants in the gene, which encodes the B-type natriuretic peptide receptor (NPR-B), a regulator of skeletal growth, were reported in 2-6% cases of...
Heterozygous variants in the gene, which encodes the B-type natriuretic peptide receptor (NPR-B), a regulator of skeletal growth, were reported in 2-6% cases of idiopathic short stature (ISS). Using next-generation sequencing (NGS), we aimed to assess the frequency of variants in our study cohort consisting of 150 children and adolescents with ISS, describe the phenotypic spectrum with a growth pattern including birth data, and study the response to growth hormone (GH) treatment. A total of ten heterozygous pathogenic/likely pathogenic variants and two heterozygous variants of uncertain significance were detected in twelve participants (frequency of causal variants: 10/150, 6.7%). During follow-up, the individuals presented with a growth pattern varying from low-normal to significant short stature. A clinically relevant increase in BMI (a mean gain in the BMI SDS of +1.41), a characteristic previously not reported in individuals, was observed. In total, 8.8% participants born small for their gestational age (SGA) carried the causal variant. The response to GH treatment was variable (SDS height gain ranging from -0.01 to +0.74). According to the results, variants present a frequent cause of ISS and familial short stature. Phenotyping variability in growth patterns and variable responses to GH treatment should be considered.
Topics: Adolescent; Body Height; Child; Dwarfism; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Infant, Small for Gestational Age; Receptors, Atrial Natriuretic Factor
PubMed: 35741827
DOI: 10.3390/genes13061065 -
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 -
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 -
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 -
Hormone Research in Paediatrics 20113-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8.... (Review)
Review
3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth.
Topics: Adolescent; Adolescent Development; Animals; Body Height; Carrier Proteins; Child; Child Development; Cullin Proteins; Cytoskeletal Proteins; Dwarfism; Humans; Intellectual Disability; Muscle Hypotonia; Mutant Proteins; Silver-Russell Syndrome; Spine
PubMed: 22156540
DOI: 10.1159/000334392 -
Italian Journal of Pediatrics Mar 2021To verify the prevalence of novel definitions of familial short stature on a cross-sectional cohort of children referred for short stature when their height and that of...
OBJECTIVE
To verify the prevalence of novel definitions of familial short stature on a cross-sectional cohort of children referred for short stature when their height and that of both parents were measured.
METHODS
We consecutively enrolled 65 individuals referred for short stature when both parents were present. We defined "target height-related short stature" (TH-SS) when child's height is ≤ - 2 SDS and included in the range of target height; suspected "autosomal dominant short stature" (AD-SS) when child height and at least one parent height are ≤ - 2 SDS; "constitutional familial short stature" (C-FSS) when a child with TH-SS does not have any parents with height ≤ - 2 SDS.
RESULTS
Of 65 children referred for SS, 48 individuals had a height ≤ - 2 SDS. Based on the parents' measured heights, 24 children had TH-SS, 16 subjects AD-SS, and 12 individuals C-FSS. If we had considered only the parents' reported height, 3 of 24 children with TH-SS, 9 of 16 with AD-SS, and 10 of 12 with C-FSS would have been lost.
CONCLUSION
We suggest novel definitions to adequately detect and approach the cases of FSS since C-FSS (25%) might not need any specific investigation, while on the contrary, AD-SS (33%) should undergo genetic evaluation. Moreover, this study underlines that adequate measurement and consideration of children's and parents' heights (individually and together) are crucial in the clinical evaluation of every child with short stature.
Topics: Adolescent; Body Height; Child; Child, Preschool; Cohort Studies; Cross-Sectional Studies; Dwarfism; Female; Growth Disorders; Humans; Male; Parents
PubMed: 33750447
DOI: 10.1186/s13052-021-01018-3 -
Oncotarget Sep 2015
Topics: Animals; Centrosome; Dwarfism; Genetic Predisposition to Disease; Humans; Microcephaly; NIMA-Related Kinases; Phenotype; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 26309075
DOI: 10.18632/oncotarget.5139