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1.
Horm Res Paediatr ; : 1-9, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31715605

RESUMO

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by dysmorphic facial features, short stature, and expressive language delay. OBJECTIVE: The aim of this study was to describe a cohort of patients with FHS and review the literature about the response to recombinant human growth hormone (rhGH) therapy. METHODS: Anthropometric and laboratory data from 7 patients with FHS were described. The molecular diagnosis was established by multigene analysis. Moreover, we reviewed the literature concerning patients with FHS treated with rhGH. RESULTS: All 7 patients were born small for gestational age. At first evaluation, 6 patients had a height standard deviation score (SDS) ≤-2 and 1 had short stature in relation to their target height. Bone age was usually delayed, which rapidly advanced during puberty. Nonspecific skeletal abnormalities were frequently noticed, and normal to elevated plasma IGF-I levels were observed in all except 1 patient with growth hormone deficiency. Information about 20 patients with FHS treated with rhGH was analyzed (4 from our cohort and 16 from the literature). The median height changes during the treatment period (approx. 2.9 years) were 1.1 SDS (range from -0.4 to 3.1). Nontreated patients had an adult height SDS of -4.1 ± 1.2 (n = 10) versus -2.6 ± 0.8 SDS (n = 7, p 0.012) for treated patients. CONCLUSION: We observed a laboratory profile compatible with IGF-1 insensitivity in some patients with FHS. Nevertheless, our study suggests that children with FHS may be considered as candidates for rhGH therapy. Further studies are necessary to establish the real benefit and safety of rhGH therapy in these patients.

3.
Clin Genet ; 96(3): 261-265, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31219618

RESUMO

Short stature homeobox (SHOX) haploinsufficiency is a frequent cause of short stature. Despite advances in sequencing technologies, the identification of SHOX mutations continues to be performed using standard methods, including multiplex ligation-dependent probe amplification (MLPA) followed by Sanger sequencing. We designed a targeted panel of genes associated with growth impairment, including SHOX genomic and enhancer regions, to improve the resolution of next-generation sequencing for SHOX analysis. We used two software packages, CONTRA and Nexus Copy Number, in addition to visual analysis to investigate the presence of copy number variants (CNVs). We evaluated 15 patients with previously known SHOX defects, including point mutations, deletions and a duplication, and 77 patients with idiopathic short stature (ISS). The panel was able to confirm all known defects in the validation analysis. During the prospective evaluation, we identified two new partial SHOX deletions (one detected only by visual analysis), including an intragenic deletion not detected by MLPA. Additionally, we were able to determine the breakpoints in four cases. Our results show that the designed panel can be used for the molecular investigation of patients with ISS, and it may even detect CNVs in SHOX and its enhancers, which may be present in a significant fraction of patients.

4.
Horm Res Paediatr ; 91(4): 252-261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31132774

RESUMO

OBJECTIVES: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). MATERIALS AND METHODS: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). RESULTS: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were -3.1 ± 0.7 and -0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11- patients. GV SDS increased from -1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from -1.9 ± 2.6 to -0.1 ± 2.6 in PTPN11- patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11- (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were -2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. CONCLUSIONS: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11- patients showed a poor response to rhGH. However, this PTPN11- group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.

5.
J Clin Endocrinol Metab ; 104(7): 2827-2841, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30830215

RESUMO

CONTEXT: Primary ovarian insufficiency (POI) is a cause of female infertility. However, the genetic etiology of this disorder remains unknown in most patients with POI. OBJECTIVE: To investigate the genetic etiology of idiopathic POI. PATIENTS AND METHODS: We performed whole-exome sequencing of 11 families with idiopathic POI. To gain insights into the potential mechanisms associated with this mutation, we generated two mouse lines via clustered regularly interspaced short palindromic repeats/Cas9 technology. RESULTS: A pathogenic homozygous missense mutation (c.149A>G; p.Asp50Gly) in the POLR3H gene in two unrelated families was identified. Pathogenic mutations in this subunit have not been associated with human disorders. Loss-of-function Polr3h mutation in mice caused early embryonic lethality. Mice with homozygous point mutation (Polr3hD50G) were viable but showed delayed pubertal development, characterized by late first estrus or preputial separation. The Polr3hD50G female and male mice showed decreased fertility later in life, associated with small litter size and increased time to pregnancy or to impregnate a female. Polr3hD50G mice displayed decreased expression of ovarian Foxo3a and lower numbers of primary follicles. CONCLUSION: Our manuscript provides a case of POI caused by missense mutation in POLR3H, expanding the knowledge of molecular pathways of the ovarian function and human infertility. Screening of the POLR3H gene may elucidate POI cases without previously identified genetic causes, supporting approaches of genetic counseling.

6.
J Clin Endocrinol Metab ; 104(6): 2023-2030, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30602027

RESUMO

CONTEXT: Patients born small for gestational age (SGA) who present with persistent short stature could have an underlying genetic etiology that will account for prenatal and postnatal growth impairment. We applied a unique massive parallel sequencing approach in cohort of patients with exclusively nonsyndromic SGA to simultaneously interrogate for clinically substantial genetic variants. OBJECTIVE: To perform a genetic investigation of children with isolated short stature born SGA. DESIGN: Screening by exome (n = 16) or targeted gene panel (n = 39) sequencing. SETTING: Tertiary referral center for growth disorders. PATIENTS AND METHODS: We selected 55 patients born SGA with persistent short stature without an identified cause of short stature. MAIN OUTCOME MEASURES: Frequency of pathogenic findings. RESULTS: We identified heterozygous pathogenic or likely pathogenic genetic variants in 8 of 55 patients, all in genes already associated with growth disorders. Four of the genes are associated with growth plate development, IHH (n = 2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1), and two are involved in the RAS/MAPK pathway, PTPN11 (n = 1) and NF1 (n = 1). None of these patients had clinical findings that allowed for a clinical diagnosis. Seven patients were SGA only for length and one was SGA for both length and weight. CONCLUSION: These genomic approaches identified pathogenic or likely pathogenic genetic variants in 8 of 55 patients (15%). Six of the eight patients carried variants in genes associated with growth plate development, indicating that mild forms of skeletal dysplasia could be a cause of growth disorders in this group of patients.

7.
Brain ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985992

RESUMO

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

8.
Eur J Med Genet ; 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30006057

RESUMO

BACKGROUND/AIM: Primary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient. PATIENT AND METHODS: An adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelectXT DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing. RESULTS: Two rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants. CONCLUSION: Our results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.

9.
Eur J Med Genet ; 61(3): 130-133, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29133208

RESUMO

BACKGROUND: Fanconi Anemia (FA) is a rare and heterogeneous genetic syndrome. It is associated with short stature, bone marrow failure, high predisposition to cancer, microcephaly and congenital malformation. Many genes have been associated with FA. Previously, two adult patients with biallelic pathogenic variant in Breast Cancer 1 gene (BRCA1) had been identified in Fanconi Anemia-like condition. CLINICAL REPORT: The proband was a 2.5 year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features. Her parents were third degree cousins. Routine screening tests for short stature was normal. METHODS: We conducted whole exome sequencing (WES) of the proband and used an analysis pipeline to identify rare nonsynonymous genetic variants that cause short stature. RESULTS: We identified a homozygous loss-of-function BRCA1 mutation (c.2709T > A; p. Cys903*), which promotes the loss of critical domains of the protein. Cytogenetic study with DEB showed an increased chromosomal breakage. We screened heterozygous parents of the index case for cancer and we detected, in her mother, a metastatic adenocarcinoma in an axillar lymph node with probable primary site in the breast. CONCLUSION: It is possible to consolidate the FA-like phenotype associated with biallelic loss-of-function BRCA1, characterized by microcephaly, short stature, developmental delay, dysmorphic face features and cancer predisposition. In our case, the WES allowed to establish the genetic cause of short stature in the context of a chromosome instability syndrome. An identification of BRCA1 mutations in our patient allowed precise genetic counseling and also triggered cancer screening for the patient and her family members.


Assuntos
Proteína BRCA1/genética , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Predisposição Genética para Doença , Homozigoto , Mutação , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo
10.
J Clin Endocrinol Metab ; 103(2): 604-614, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155992

RESUMO

Context: Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders. Objective: To investigate the cause of short stature and to determine the phenotype of patients with IHH mutations, including the response to recombinant human growth hormone (rhGH) therapy. Patients and Methods: We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders. Molecular analyses were performed to evaluate the potential impact of N-terminal IHH variants. Results: We identified 10 pathogenic or possibly pathogenic variants in IHH, an important regulator of endochondral ossification. Molecular analyses revealed a smaller potential energy of mutated IHH molecules. The allele frequency of rare, predicted to be deleterious IHH variants found in short-stature samples (1.6%) was higher than that observed in two control cohorts (0.017% and 0.08%; P < 0.001). Identified IHH variants segregate with short stature in a dominant inheritance pattern. Affected individuals typically manifest mild disproportional short stature with a frequent finding of shortening of the middle phalanx of the fifth finger. None of them have classic features of brachydactyly type A1, which was previously associated with IHH mutations. Five patients heterozygous for IHH variants had a good response to rhGH therapy. The mean change in height standard deviation score in 1 year was 0.6. Conclusion: Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH.


Assuntos
Nanismo/genética , Proteínas Hedgehog/genética , Hormônio do Crescimento Humano/uso terapêutico , Anormalidades Musculoesqueléticas/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Nanismo/complicações , Família , Feminino , Frequência do Gene , Terapia de Reposição Hormonal , Humanos , Lactente , Masculino , Anormalidades Musculoesqueléticas/complicações , Linhagem , Resultado do Tratamento , Adulto Jovem
11.
Genet Med ; 20(1): 91-97, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28661490

RESUMO

PurposeC-type natriuretic peptide (CNP) and its principal receptor, natriuretic peptide receptor B (NPR-B), have been shown to be important in skeletal development. CNP and NPR-B are encoded by natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor 2 (NPR2) genes, respectively. While NPR2 mutations have been described in patients with skeletal dysplasias and idiopathic short stature (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, no mutations in NPPC have been described in patients to date.MethodsNPPC was screened in 668 patients (357 with disproportionate short stature and 311 with autosomal dominant ISS) and 29 additional ISS families in an ongoing whole-exome sequencing study.ResultsTwo heterozygous NPPC mutations, located in the highly conserved CNP ring, were identified. Both showed significant reductions in cyclic guanosine monophosphate synthesis, confirming their pathogenicity. Interestingly, one has been previously linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant.ConclusionsOur results demonstrate, for the first time, that NPPC mutations cause autosomal dominant short stature in humans. The NPPC mutations cosegregated with a short stature and small hands phenotype. A CNP analog, which is currently in clinical trials for the treatment of achondroplasia, seems a promising therapeutic approach, since it directly replaces the defective protein.


Assuntos
Nanismo/diagnóstico , Nanismo/genética , Genes Dominantes , Mutação , Peptídeo Natriurético Tipo C/genética , Adolescente , Sequência de Aminoácidos , Criança , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Gráficos de Crescimento , Heterozigoto , Humanos , Masculino , Peptídeo Natriurético Tipo C/química , Fenótipo , Sequenciamento Completo do Exoma
12.
Endocrine ; 58(3): 442-447, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29067606

RESUMO

PURPOSE: Primary ovarian failure (POF) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women leading to infertility under the age of 40 years. POF is a heterogeneous disease with different causes, and several genes have been associated with the POF phenotype. Thus, Whole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by POF. METHODS: All exons of both sisters were massively sequenced by WES, and the segregation was confirmed by Sanger sequencing. RESULTS: The novel homozygous c.1489delT variant in the NOBOX gene was identified in the two sisters with POF. Their parents were heterozygous carriers of this variant and, therefore, consistent with an autosomal recessive mode of inheritance. The c.1489delT NOBOX variant has not been previously reported in any public available databases (1000Genomes, 6500ESP/EVS, ExAC, and gnomAD). Furthermore, this variant was neither present in 387 Brazilian exomes control individuals nor in 200 fertile Brazilian women screened by Sanger sequencing. CONCLUSION: We report the first familial case of a novel homozygous NOBOX variant with an autosomal recessive mode of inheritance, thus allowing for a genetic diagnosis of primary ovarian failure.


Assuntos
Proteínas de Homeodomínio/genética , Insuficiência Ovariana Primária/genética , Fatores de Transcrição/genética , Adolescente , DNA/genética , Feminino , Deleção de Genes , Genes Recessivos , Testes Genéticos , Genoma , Gonadotropinas/sangue , Homozigoto , Hormônios/sangue , Humanos , Linhagem , Análise de Sequência de DNA , Irmãos , Adulto Jovem
13.
Sex Dev ; 11(3): 137-142, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28591755

RESUMO

Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46,XX girl and a 46,XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c.1298C>A;p.Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/EVS) and Brazilian exome controls. Moreover, it is highly conserved and predicted as deleterious in all prediction sites analyzed. In conclusion, the novel homozygous FSHR variant observed in 2 siblings with HH can expand the spectrum of FSHR mutations in humans.


Assuntos
Hipogonadismo/genética , Mutação de Sentido Incorreto/genética , Receptores do FSH/genética , Irmãos , Adolescente , Adulto , Sequência de Bases , Brasil , Família , Feminino , Homozigoto , Humanos , Masculino , Linhagem , Sequenciamento Completo do Exoma
14.
Genet Mol Biol ; 40(2): 436-441, 2017 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28590503

RESUMO

Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

15.
Genet. mol. biol ; 40(2): 436-441, Apr.-June 2017. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-892403

RESUMO

ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

16.
J Pediatr Endocrinol Metab ; 30(1): 111-116, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27941173

RESUMO

BACKGROUND: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. CASE PRESENTATION: The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8. RESULTS: We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p.Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. CONCLUSIONS: This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.


Assuntos
Estatura/genética , Nanismo/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Mutação/genética , Receptores do Fator Natriurético Atrial/genética , Pré-Escolar , Nanismo/genética , Feminino , Genótipo , Transtornos do Crescimento/etiologia , Heterozigoto , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Linhagem , Fenótipo , Prognóstico
17.
J Clin Endocrinol Metab ; 102(2): 460-469, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27870580

RESUMO

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

18.
Horm Res Paediatr ; 86(5): 342-348, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27245183

RESUMO

BACKGROUND: Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene (FBN1). METHODS: Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx. -4 SDS). They were otherwise asymptomatic and only had mild facial dysmorphisms. Extensive endocrine work-up did not reveal an underlying etiology. Exome sequencing was performed in each family. RESULTS: Exome sequencing identified the presence of the same heterozygous missense variant c.C5183T (p.Ala1728Val) in the FBN1 gene in both P1 and P2. This variant was previously reported in a patient with GD2 and associated cardiac valvulopathy and hepatomegaly. Detailed clinical re-examination, cardiac and skeletal imaging did not reveal any abnormalities in P1 or P2 other than mild hip dysplasia. CONCLUSION: This report broadens the phenotypic spectrum of growth disorders associated with FBN1 mutations. Identical mutations give rise to a wide phenotypic spectrum, ranging from isolated short stature to a more classic picture of GD2 with cardiac involvement, distinct facial dysmorphisms and various skeletal anomalies.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Exoma , Fibrilina-1/genética , Transtornos do Crescimento/genética , Deformidades Congênitas dos Membros/genética , Mutação de Sentido Incorreto , Adulto , Substituição de Aminoácidos , Doenças do Desenvolvimento Ósseo/patologia , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/patologia , Humanos , Lactente , Deformidades Congênitas dos Membros/patologia , Masculino
19.
Horm Res Paediatr ; 80(6): 449-56, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24296787

RESUMO

AIMS: To determine the presence of abnormal body proportion, assessed by sitting height/height ratio for age and sex (SH/H SDS) in healthy and short individuals, and to estimate its role in selecting short children for SHOX analysis. METHODS: Height, sitting height and weight were evaluated in 1,771 healthy children, 128 children with idiopathic short stature (ISS), 58 individuals with SHOX defects (SHOX-D) and 193 females with Turner syndrome (TS). RESULTS: The frequency of abnormal body proportion, defined as SH/H SDS >2, in ISS children was 16.4% (95% CI 10-22%), which was higher than in controls (1.4%, 95% CI 0.8-1.9%, p < 0.001). The SHOX gene was evaluated in all disproportionate ISS children and defects in this gene were observed in 19%. Among patients with SHOX-D, 88% of children (95% CI 75-100%) and 96% of adults had body disproportion. In contrast, SH/H SDS >2 were less common in children (48%, 95% CI 37-59%) and in adults (28%, 95% CI 20-36%) with TS. CONCLUSION: Abnormal body proportions were observed in almost all individuals with SHOX-D, 50% of females with TS and 16% of children considered ISS. Defects in SHOX gene were identified in 19% of ISS children with SH/H SDS >2, suggesting that SH/H SDS is a useful tool to select children for undergoing SHOX molecular studies.


Assuntos
Estatura , Análise Mutacional de DNA , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/genética , Postura , Adolescente , Adulto , Fatores Etários , Criança , Desenvolvimento Infantil , Estudos Transversais , Feminino , Humanos , Masculino , Seleção de Pacientes , Fenótipo , Proteína de Homoeobox de Baixa Estatura , Síndrome de Turner/genética
20.
J Clin Endocrinol Metab ; 98(10): E1636-44, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24001744

RESUMO

CONTEXT: Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for mutations in natriuretic peptide receptor B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some children with idiopathic short stature (ISS). OBJECTIVE: The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS. PATIENTS AND METHODS: The NPR2 coding region was directly sequenced in 47 independent patients with ISS. The functional consequences of NPR2 nonsynonymous variations were established using in vitro cell-based assays. RESULTS: Three novel heterozygous NPR2 mutations were identified: c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), and c.2455C>T (p.Arg819Cys). These allelic variants were not found in our controls or in the 1000 Genomes database. In silico analysis suggested that the three missense mutations are probably damaging. All of them were selected for in vitro functional evaluation. Cells transfected with the three mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide. Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect. These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7). One of these patients and two relatives have disproportionate short stature, whereas in another patient a nonspecific skeletal abnormality was observed. All three of these patients were treated with recombinant human GH (33-50 µg/kg · d) without significant height SD score change during therapy. CONCLUSIONS: We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature.


Assuntos
Estatura/genética , Nanismo/genética , Receptores do Fator Natriurético Atrial/genética , Criança , Feminino , Heterozigoto , Humanos , Masculino , Mutação
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