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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 973-976, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625935

RESUMO

OBJECTIVE: Two brothes with Seckel's syndrome 1(SCKL1) were reported and a literature review was carried to provide clinical and genetic information of this rare disease. METHODS: Clinical data of the two children were collected, and the peripheral blood was extracted for whole exome sequencing. Literature of the disease were reviewed. RESULTS: The two patients were 11 years and 9.5 years old when examined for short stature. They presented with intrauterine growth retardation, intellectual disability, microcephaly, birdhead-like face and coffee au lait spots. The bone age was more than 2 years behind the chronical age and the growth hormone levels were normal. Whole exome sequencing revealed novel compound heterozygous variants c.1A>G (p.M1?) and c.4853-18A>G of ART gene in both children. CONCLUSION: Children with prenatal onset short stature, developmental delay, microcephaly and special facial featuresshould be considered for the possibility of Seckel's syndrome, whole exome sequencing could help to confirm the clinical diagnosis.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Nanismo , Deficiência Intelectual , Microcefalia , Criança , Nanismo/genética , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Irmãos , Sequenciamento Completo do Exoma
2.
Eur J Endocrinol ; 185(5): 691-705, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34516402

RESUMO

Objective: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.


Assuntos
Estatura/genética , Osso e Ossos/anormalidades , Nanismo/genética , Osteocondrodisplasias/genética , Adolescente , Antropometria , Criança , Pré-Escolar , Feminino , Variação Genética , Lâmina de Crescimento/anormalidades , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Linhagem , Prevalência
3.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502207

RESUMO

The complexity of skeletal pathologies makes use of in vivo models essential to elucidate the pathogenesis of the diseases; nevertheless, chondrocyte and osteoblast cell lines provide relevant information on the underlying disease mechanisms. Due to the limitations of primary chondrocytes, immortalized cells represent a unique tool to overcome this problem since they grow very easily for several passages. However, in the immortalization procedure the cells might lose the original phenotype; thus, these cell lines should be deeply characterized before their use. We immortalized primary chondrocytes from a Cant1 knock-out mouse, an animal model of Desbuquois dysplasia type 1, with a plasmid expressing the SV40 large and small T antigen. This cell line, based on morphological and biochemical parameters, showed preservation of the chondrocyte phenotype. In addition reduced proteoglycan synthesis and oversulfation of glycosaminoglycan chains were demonstrated, as already observed in primary chondrocytes from the Cant1 knock-out mouse. In conclusion, immortalized Cant1 knock-out chondrocytes maintained the disease phenotype observed in primary cells validating the in vitro model and providing an additional tool to further study the proteoglycan biosynthesis defect. The same approach might be extended to other cartilage disorders.


Assuntos
Hidrolases Anidrido Ácido/fisiologia , Condrócitos/patologia , Anormalidades Craniofaciais/patologia , Nanismo/patologia , Glicosaminoglicanos/metabolismo , Instabilidade Articular/patologia , Ossificação Heterotópica/patologia , Fenótipo , Polidactilia/patologia , Animais , Linhagem Celular Transformada , Condrócitos/metabolismo , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/metabolismo , Nanismo/etiologia , Nanismo/metabolismo , Instabilidade Articular/etiologia , Instabilidade Articular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ossificação Heterotópica/etiologia , Ossificação Heterotópica/metabolismo , Polidactilia/etiologia , Polidactilia/metabolismo
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 757-760, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365618

RESUMO

OBJECTIVE: To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome. METHODS: Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis. RESULTS: The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4). CONCLUSION: The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.


Assuntos
Nanismo , Doenças Genéticas Ligadas ao Cromossomo X , Deformidades Congênitas da Mão , Criança , Face/anormalidades , Genitália Masculina/anormalidades , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas , Humanos , Masculino , Mutação
5.
Orphanet J Rare Dis ; 16(1): 297, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217350

RESUMO

BACKGROUND: Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). METHODS: Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018-2020 and evaluated by TES. RESULTS: For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were - 3.27 ± 1.25, - 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu-Cheney syndrome, Sheldon-Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). CONCLUSIONS: A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.


Assuntos
Nanismo , Osteocondrodisplasias , Nanismo/genética , Exoma/genética , Humanos , Mutação/genética , República da Coreia , Sequenciamento Completo do Exoma
6.
Arch Virol ; 166(9): 2495-2504, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34232400

RESUMO

Short beak and dwarfism syndrome (SBDS) emerged in Cherry Valley duck flocks in China in 2015, and novel goose parvovirus (NGPV) was shown to be the etiological agent of SBDS. To date, it is not known whether SBDS-related NGPV isolates possess common molecular characteristics. In this study, three new NGPV strains (namely, SDHT16, SDJN19, and SDLC19) were isolated from diseased ducks showing typical signs of SBDS and successfully passaged in embryonated goose or Cherry Valley duck eggs. The complete genome sequences of these NGPV strains were 98.9%-99.7% identical to each other but showed slightly less similarity (95.2%-96.1% identity) to classical GPV strains. A total of 16 common amino acid substitutions were present in the VP1 proteins of six NGPV strains (SDHT16, SDJN19, SDLC19, QH, JS1, and SDLC01) compared with the classical Chinese GPV strains, nine of which were identical to those found in European GPV strain B. The non-structural protein Rep1 of the six NGPV strains had 12 common amino acid substitutions compared with the classical GPV strains. Phylogenetic analysis indicated that the Chinese NGPV strains clustered with the European SBDS-related NGPV strains, forming a separate branch that was distinct from the group formed by the classical GPV strains. The present study shows the common molecular characteristics of NGPV isolates and suggests that the Chinese NGPV isolates probably share a common ancestor with European SBDS-related NGPV strains.


Assuntos
Nanismo/veterinária , Nanismo/virologia , Parvovirinae/classificação , Parvovirinae/genética , Filogenia , Doenças das Aves Domésticas/virologia , Animais , China , Patos/virologia , Gansos/virologia , Genoma Viral , Infecções por Parvoviridae/virologia , Parvovirus/genética , Alinhamento de Sequência , Sequenciamento Completo do Genoma
7.
J Equine Vet Sci ; 103: 103643, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34281639

RESUMO

Dwarfism is a skeletal disorder that causes abnormal growth. In Miniature horses, dwarfism can occur as chondrodysplastic dwarfism, an autosomal recessive disorder associated with five mutations (D1, D2, D3*, D4 and c.6465A > T variant) in the aggrecan (ACAN) gene. The aim of this study was to evaluate the expression of aggrecan (at the gene and protein level) and specific cytokines (IL-1ß, IL-6, and TNF-α) in the articular cartilage of Miniature horses with chondrodysplastic dwarfism (D4/c.6465A > T genotype). Metatarsal bone samples from eight dwarf Miniature horses were collected for histopathological analysis, and articular cartilage was collected to detect and quantify aggrecan levels through Western blotting and determine the relative expression levels of ACAN, IL-1ß, IL-6, and TNF-α through qPCR. All affected animals presented chondrodysplasia-like lesions with disorganization of the chondrocyte layers and reduced the amount of an extracellular matrix. No significant difference in aggrecan expression levels in uncleaved samples from the dwarf and control groups (composed of phenotypically normal animals of similar age and breed (P = .7143)) was found using Western blotting. qPCR revealed that ACAN gene expression was higher in the affected animals than in normal animals (P = .0119). No significant difference in cytokine levels was detected between the groups. Mutant aggrecan may interfere with normal cellular function, leading to chondrodysplasia and the observed phenotypic findings.


Assuntos
Cartilagem Articular , Nanismo , Doenças dos Cavalos , Agrecanas/genética , Animais , Nanismo/genética , Nanismo/veterinária , Doenças dos Cavalos/genética , Cavalos , Interleucina-6/genética , Fator de Necrose Tumoral alfa/genética
8.
BMC Pediatr ; 21(1): 293, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193099

RESUMO

BACKGROUND: The spondylodysplastic Ehlers-Danlos subtype (OMIM #130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter. PRESENTATION OF CASES: We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans. CONCLUSIONS: This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.


Assuntos
Nanismo , Síndrome de Ehlers-Danlos , Instabilidade Articular , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Humanos , Instabilidade Articular/genética , Masculino , Fenótipo , Irmãos
9.
Nat Commun ; 12(1): 4067, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210973

RESUMO

Ataxia Telangiectasia and Rad3-related (ATR) protein, as a key DNA damage response (DDR) regulator, plays an essential function in response to replication stress and controls cell viability. Hypomorphic mutations of ATR cause the human ATR-Seckel syndrome, characterized by microcephaly and intellectual disability, which however suggests a yet unknown role for ATR in non-dividing cells. Here we show that ATR deletion in postmitotic neurons does not compromise brain development and formation; rather it enhances intrinsic neuronal activity resulting in aberrant firing and an increased epileptiform activity, which increases the susceptibility of ataxia and epilepsy in mice. ATR deleted neurons exhibit hyper-excitability, associated with changes in action potential conformation and presynaptic vesicle accumulation, independent of DDR signaling. Mechanistically, ATR interacts with synaptotagmin 2 (SYT2) and, without ATR, SYT2 is highly upregulated and aberrantly translocated to excitatory neurons in the hippocampus, thereby conferring a hyper-excitability. This study identifies a physiological function of ATR, beyond its DDR role, in regulating neuronal activity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neurônios/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Nanismo , Fármacos Atuantes sobre Aminoácidos Excitatórios , Facies , Hipocampo , Camundongos , Microcefalia , Mutação , Células de Purkinje , Transdução de Sinais , Sinaptotagmina II/metabolismo
10.
Genes (Basel) ; 12(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064542

RESUMO

Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics.


Assuntos
Nanismo/patologia , Fenótipo , Transportadores de Sulfato/genética , Adolescente , Criança , Nanismo/epidemiologia , Nanismo/genética , Feminino , Finlândia , Efeito Fundador , Genes Recessivos , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação , Adulto Jovem
12.
Ann Glob Health ; 87(1): 48, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34164261

RESUMO

Background: Blood transfusion is a traditional treatment for ß-thalassemia (ß-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in parenchymal tissue organs and endocrine glands that cause their dysfunctions as the iron regulatory system can't excrete excess iron from the bloodstream. Objective: To evaluate the prevalence of iron-related complications (short stature, growth retardation, and growth hormone deficiency) in ß-thalassemia major (ßTM) patients. Methods: We performed an electronic search in PubMed, Scopus, and Web of Sciences to evaluate the prevalence of growth hormone impairment in ß-thalassemia major (ßTM) patients worldwide. Qualities of eligible studies were assessed by the Joanna Briggs Institute checklist for the prevalence study. We used Comprehensive Meta-Analysis (Version 2) to calculate the event rate with 95% CIs, using a random-effects model for all analyses. Findings: Seventy-four studies were included from five continents between 1978 and 2019; 70.27% (Asia), 16.21% (Europe), 6.75% (Africa), 2.70% (America), 1.35% (Oceania), and 2.70% (Multicenter). The overall mean age of the participants was about 14 years. The pooled prevalence of short stature (ST) was 48.9% (95% CI 35.3-62.6) and in male was higher than female (61.9%, 95% CI 53.4-69.7 vs. 50.9%, CI 41.8-59.9). The pooled prevalence of growth retardation (GR) was 41.1% and in male was higher than in female (51.6%, 95% CI 17.8-84 vs. 33.1%, CI 9.4-70.2). The pooled prevalence of growth hormone deficiency (GHD) was 26.6% (95% CI 16-40.8). Conclusion: Our study revealed that near half of thalassemia patients suffer from growth impairments. However, regular evaluation of serum ferritin levels, close monitoring in a proper institute, suitable and acceptable treatment methods besides regular chelation therapy could significantly reduce the patients' complications.


Assuntos
Nanismo , Doenças do Sistema Endócrino , Sobrecarga de Ferro/complicações , Talassemia beta , Adolescente , Transfusão de Sangue , Estatura , Feminino , Humanos , Masculino , Talassemia beta/complicações , Talassemia beta/epidemiologia , Talassemia beta/terapia
13.
RNA ; 27(9): 1046-1067, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34162742

RESUMO

RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene EXOSC2 cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (short stature, hearing loss, retinitis pigmentosa, and distinctive facies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic EXOSC2 missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous S. cerevisiae gene RRP4 The resulting rrp4 mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in rrp4-G226D cells that model EXOSC2 p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in EXOSC2 impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.


Assuntos
Exorribonucleases/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Mutação de Sentido Incorreto , RNA Fúngico/genética , Proteínas de Ligação a RNA/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Nanismo/enzimologia , Nanismo/genética , Nanismo/patologia , Exorribonucleases/química , Exorribonucleases/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/química , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Facies , Expressão Gênica , Glicina/química , Glicina/metabolismo , Perda Auditiva/enzimologia , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Modelos Biológicos , Modelos Moleculares , Conformação Proteica , RNA Fúngico/química , RNA Fúngico/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Retinite Pigmentosa/enzimologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , Síndrome
14.
Twin Res Hum Genet ; 24(3): 187-190, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34137366

RESUMO

Selective termination is the term used for the elimination of an abnormal fetus. In contrast, multifetal pregnancy reduction refers to the termination of one or more members of a twin or higher-order multiple birth set, respectively, to reduce the high risks associated with these pregnancies. The procedure can also be used when a serious physical condition is detected prenatally in a member of a multiple birth set. In a minority of cases, selective termination has reduced two healthy fetuses to one when parents wanted just one additional child in the family. In the present article, the perspectives of a surviving twin whose family wished to terminate both healthy fetuses are examined. Next, past and present twin studies of primordial dwarfism, public service motivation, an analytical model, the global twinning rate and germline differences are summarized. The article concludes with a synopsis of twin-related news that covers twins and Dyngus Day, triplets born in an Austrian displaced persons' camp, the film Superior - about estranged identical twin sisters, a couple adopting their own twins after surrogacy and a new case of twins and primordial dwarfism, a condition introduced in the research reviews.


Assuntos
Nanismo , Refugiados , Áustria , Criança , Feminino , Células Germinativas , Humanos , Motivação , Gravidez , Gêmeos Monozigóticos
15.
Curr Opin Pediatr ; 33(4): 458-463, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34101704

RESUMO

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.


Assuntos
Nanismo , Estatura/genética , Criança , Nanismo/diagnóstico , Nanismo/genética , Testes Genéticos , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Humanos , Sequenciamento Completo do Exoma
17.
Eur J Endocrinol ; 185(2): 323-332, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34125705

RESUMO

Context: Short stature in children is a common reason for referral to pediatric endocrinologists. The underlying cause of short stature remains unclear in many cases and patients often receive unsatisfactory, descriptive diagnoses. While textbooks underline the rarity of genetic causes of growth hormone (GH) insensitivity and the severity of its associated growth failure, increased genetic testing in patients with short stature of unclear origin has revealed gene defects in the GH/insulin-like growth factor (IGF-I) axis associated with milder phenotypes. As such, heterozygous IGF1 gene defects have been reported as a cause of mild and severe short stature. Here, we aimed to describe the clinical and hormonal profile of children with IGF1 haploinsufficiency and their short-term response to growth hormone treatment (GHT). Case descriptions: We describe five patients presenting with short stature, microcephaly, and in four out of five born small for gestational age diagnosed with IGF1 haploinsufficiency. The phenotype of these patients resembles that of previously described cases with similar gene defects. In our series, segregation of the short stature with the IGF1 deletion is evident from the pedigrees and our data suggests a modest response to GHT. Conclusions: This study is the first case series of complete heterozygous IGF1 deletions in children. The specific genetic defects provide a clear image of the phenotype of IGF1 haploinsufficiency - unbiased by heterozygous mutations with possible dominant negative effects on IGF-I function. We increase the evidence for IGF1 haploinsufficiency as a cause of short stature, microcephaly, and SGA.


Assuntos
Nanismo/diagnóstico , Nanismo/genética , Haploinsuficiência/genética , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Fator de Crescimento Insulin-Like I/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem
18.
Int J Paleopathol ; 33: 158-169, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957552

RESUMO

OBJECTIVE: This research evaluates the occurrence of generalised microdontia and proportionate osteodysplasia in human remains from a Chalcolithic cemetery with early evidence of metalworking in Cyprus (Souskiou-Laona; 3500-2800 BCE). MATERIALS: Skeletal and dental remains from Tomb 236 Individual A, in comparison with other human remains from Souskiou-Laona (MNI: 203). METHODS: Macroscopic, microscopic, and metric observation of osteodysplasia and microdontia. RESULTS: Smaller than usual permanent teeth and adult long bones were discovered, with epiphyseal fusion complete. The cranium, and the zygomatic bones were smaller than other adult remains. CONCLUSIONS: Differential diagnosis includes pituitary dwarfism and Majewski/Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPDII), which are two types of proportionate dwarfism with presentation of microdontia. This individual appears to display skeletal changes consistent with Majewski/Microcephalic Osteodysplastic Primordial Dwarfism Type II. SIGNIFICANCE: This is the first case of MOPDII in the archaeological record worldwide, and it is the oldest case of proportionate dwarfism known to date. The presence of an adult probable female with primordial dwarfism at Chalcolithic cemetery of Souskiou-Laona indicates that mutations of the pericentrin (PCNT) gene were present in this early period. LIMITATIONS: The remains of the individual were incomplete and poorly preserved. SUGGESTIONS FOR FURTHER RESEARCH: Histology may lead to more detailed information on the individual's age and life story (osteobiography).


Assuntos
Nanismo , Microcefalia , Osteocondrodisplasias , Adulto , Feminino , Retardo do Crescimento Fetal , Humanos , Osteocondrodisplasias/genética
19.
Int J Paleopathol ; 33: 234-244, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34023583

RESUMO

OBJECTIVE: This paper discusses the possible etiologies for the proportionate short stature of a female individual and provides data to allow the diagnosis of future cases of Turner Syndrome (TS) in paleopathology. MATERIALS: Skeleton of a 26-years-old maid, from the Coimbra Identified Skeletal Collection, who died of measles in 1920. METHODS: Macroscopic examination, imaging techniques, and metric analysis. RESULTS: Her estimated height is 138.91-144.3 cm, approximately three standard deviations below the average female stature for early 20th century Portugal. The crural, brachial, humero-femoral, and intermembral indexes show a proportionate body, uncommon in dwarfism. Small skull with prominent frontal, maxillary prognathism, enamel hypoplasia, cribra orbitalia, porotic hyperostosis, proliferative reaction in the petrous portion of the temporal, obliterated sagittal suture, oval foramen magnum, and small mandible with masculine features. The sternal ends of the ribs are wider and vertebrae present developmental defects (e.g. atlas with both left transverse foramina and posterior tubercle open, absence of the right transverse foramen in the axis, sacrum with six vertebrae). CONCLUSIONS: The differential diagnosis point to a possible case of Turner Syndrome. SIGNIFICANCE: This study describes the features of Turner Syndrome and provide detail metric analysis of this individual, which will be useful for future paleopathological diagnoses. LIMITATIONS: The confirmation of the diagnosis will only be possible through genetic analysis. SUGGESTIONS FOR FURTHER RESEARCH: Reanalysis of skeletal individuals with short stature to detect possible cases of Turner Syndrome.


Assuntos
Nanismo , Síndrome de Turner , Adulto , Estatura , Feminino , Humanos , Paleopatologia , Coluna Vertebral
20.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33955509

RESUMO

Short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome is a rare autosomal recessive disease caused by POC1 centriolar protein A (POC1A) pathogenic variants. However, knowledge of genotypic and phenotypic features of SOFT syndrome remain limited as few families have been examined; therefore, the clinical identification of SOFT syndrome remains a challenge. The aim of the present case report was to investigate the genetic cause of this syndrome in a patient with a short stature, unusual facial appearance, skeletal dysplasia and sparse body hair. Giemsa banding and exome sequencing were performed to investigate the genetic background of the family. Spiral computed tomography and magnetic resonance imaging were used for investigating further phenotypic features of the patient. Exome sequencing identified that POC1A had two compound heterozygous variants, namely c.850_851insG and c.593_605delGTGGGACGTGCAT, which, to the best of our knowledge, have not been reported elsewhere. Novel phenotypes were also identified as follows: i) Metaphyseal dysplasia was alleviated (and/or even disappeared) with age; ii) the density of the femoral neck was uneven and the hyperintensity signal of the metaphysis was stripe­like. Thus, the present case report expands the knowledge regarding phenotypic and genotypic features of SOFT syndrome.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Anormalidades Craniofaciais/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Cabelo/anormalidades , Atrofia Muscular/genética , Unhas Malformadas/genética , Osteocondrodisplasias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Criança , Anormalidades Craniofaciais/diagnóstico por imagem , Feminino , Humanos , Atrofia Muscular/diagnóstico por imagem , Unhas Malformadas/congênito , Osteocondrodisplasias/diagnóstico por imagem , Fenótipo , Sequenciamento Completo do Exoma
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