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1.
Ital J Pediatr ; 45(1): 72, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196119

RESUMO

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. There is currently no treatment for BBS, but some morbidities can be managed. Accurate molecular diagnosis is often crucial for the definition of appropriate patient management and for the development of a potential personalized therapy. METHODS: We developed a next-generation-sequencing (NGS) protocol for the screening of the 18 most frequently mutated genes to define the genotype and clarify the mutation spectrum of a cohort of 20 BBS Italian patients. RESULTS: We defined the causative variants in 60% of patients; four of those are novel. 33% of patients also harboured variants in additional gene/s, suggesting possible oligogenic inheritance. To explore the function of different genes, we looked for correlations between genotype and phenotype in our cohort. Hypogonadism was more frequently detected in patients with variants in BBSome proteins, while renal abnormalities in patients with variations in BBSome chaperonin genes. CONCLUSIONS: NGS is a powerful tool that can help understanding BBS patients' phenotype through the identification of mutations that could explain differences in phenotype severity and could provide insights for the development of targeted therapy. Furthermore, our results support the existence of additional BBS loci yet to be identified.

2.
J Clin Immunol ; 39(5): 470-475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129864

RESUMO

PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.

3.
J Pediatr Endocrinol Metab ; 32(2): 159-165, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30703060

RESUMO

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT - high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H - low/normal TSH and low fT4), subclinical hypothyroidism (SH - high TSH and normal fT4), and hyperthyroidism (HyperT - low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.


Assuntos
Biomarcadores/sangue , Hipotireoidismo/diagnóstico , Síndrome de Prader-Willi/complicações , Hormônios Tireóideos/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/etiologia , Lactente , Masculino , Pessoa de Meia-Idade , Síndrome de Prader-Willi/fisiopatologia , Prognóstico , Testes de Função Tireóidea , Adulto Jovem
4.
Minerva Endocrinol ; 42(4): 325-330, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27304071

RESUMO

BACKGROUND: Patients with childhood-onset GH deficiency (GHD) are usually retested after achievement of near final height, to verify whether they need to continue GH treatment. We investigated if GH stimulation test is necessary to confirm a persistent status of GHD or if other parameters could be a reliable predictor of GHD persistence. METHODS: One-hundred and sixty-four children with idiopathic GHD (55 females and 109 males) were retested when they reached near final height using GH releasing hormone (GHRH)+arginine test or arginine alone. RESULTS: At diagnosis, 23.8% of patients showed severe GHD (GH peak at diagnosis <5 ng/mL) and 76.2% showed partial GHD (GH peak <10 ng/mL). At time of retesting, 82.1% of severe GHD and 82.4% of partial GHD patients showed transient GHD. IGF-I levels were not different between persistent (0.18±1.18 SDS) and transient GHD subjects (0.17±0.82 SDS). Furthermore, among persistent severe GHD patients only two showed very reduced levels of IGF-I (<-2.0 SDS). CONCLUSIONS: The majority of patients idiopathic GHD proved to be transient. IGF-I levels alone do not discriminate subjects with persistent from those with transient GHD. Therefore, after the end of GH substitutive treatment, a re-evaluation of GH secretion is mandatory to verify the persistence of GHD in adulthood.


Assuntos
Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Adolescente , Estatura , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/tratamento farmacológico , Feminino , Hormônio do Crescimento/uso terapêutico , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/tratamento farmacológico , Fator de Crescimento Insulin-Like I/análise , Masculino , Valor Preditivo dos Testes , Prognóstico
5.
Minerva Pediatr ; 68(1): 11-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26864719

RESUMO

BACKGROUND: Idiopathic central precocious (PP) and early puberty (EP) are frequently associated with psychopathological problems. The aim of this study was to evaluate the quality of body experiences and psychological aspects in girls with PP and EP, as well as the impact of these conditions on their families and the subjects' vulnerability. METHODS: Subjects with PP or EP, aged 7-15 years, were evaluated through the administration of a self-report questionnaire (Children's Depression Inventory, CDI), along with a projective test (Human Figure Drawing Test, HFDT). Their parents filled in a questionnaire about their child's behavior (Child Behavior Checklist 4-18, CBCL). RESULTS: Twenty-nine girls with PP or EP were compared to 55 age-matched healthy girls. The 13.8% of subjects with EP or PP presented depressive traits, and the 48.3% reported suicidal thoughts at the CDI (vs. CONTROLS: P<0.05). At the HFDT, a lower psychological maturity and a more negative self-image, that determine a vulnerability to psychopathology and mental suffering, were observed in those subjects with a past EP or PP, who entered in adolescence. CONCLUSION: EP and PP are complex conditions, which combine somatic symptoms with negative psychological sequelae, including an increased risk for depression and a distorted body perception. The use of projective tests for the assessment of body perception might help the clinician come to a deeper understanding of the therapeutic needs of girls with PP or EP.


Assuntos
Depressão/epidemiologia , Puberdade Precoce/psicologia , Autoimagem , Ideação Suicida , Adolescente , Estudos de Casos e Controles , Criança , Comportamento Infantil , Feminino , Humanos , Escalas de Graduação Psiquiátrica , Inquéritos e Questionários
6.
Ital J Pediatr ; 41: 71, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26444854

RESUMO

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant disorder characterized by specific features including short stature, distinctive facial dysmorphic features, congenital heart defects, hypertrophic cardiomyopathy, skeletal anomalies and webbing of the neck. Molecular screening has shown that the majority of individuals with NS have a mutation in the PTPN11 gene. Noonan syndrome children may show an impaired growth hormone (GH)/insulin-like growth factor axis. Moreover, recombinant human GH (rhGH) has been shown to improve growth rate in patients with NS, although data are still limited. METHODS: In the present study, we assessed growth response following GH therapy (0.25 mg/Kg/week) in 5 (2 M and 3 F) GH-deficient NS patients (NSGHD, mean age 8.5 years) and in 5 (2 M and 3 F) idiopathic GH deficient (IGHD, mean age 8.6 years) patients. We also evaluated the safety of rhGH therapy in NS patients with GHD. RESULTS: At the beginning of GH treatment, height and growth rate were statistically lower in NSGHD children than in IGHD ones. During the first three years of rhGH therapy, NSGHD patients showed a slight improvement in height (from -2.71 SDS to -2.44 SDS) and growth rate (from -2.42 SDS to -0.23 SDS), although the values were always significantly lower than in IGHD children. After five years of rhGH treatment, height gain was higher in IGHD children (mean 28.3 cm) than in NSGHD patients (mean 23.6 cm). During the first five years of rhGH therapy, regular cardiological and haematological check-ups were performed, leading to the conclusion that rhGH therapy was safe. CONCLUSIONS: In conclusion, pre-pubertal NS children with GHD slightly increased their height and growth rate during the first years of GH therapy, although the response to rhGH treatment was significantly lower than IGHD children. Furthermore, the therapy appeared to be safe since no severe adverse effects were reported, at least during the first five years. However, a close follow-up of these patients is mandatory, especially to monitor cardiac function.


Assuntos
Estatura/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Síndrome de Noonan/tratamento farmacológico , Criança , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Masculino , Resultado do Tratamento
7.
BMC Med Genet ; 16: 47, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26149167

RESUMO

BACKGROUND: In about one third of healthy subjects, the microscopic analysis of chromosomes reveals heteromorphisms with no clinical implications: for example changes in size of the short arm of acrocentric chromosomes. In patients with a pathological phenotype, however, a large acrocentric short arm can mask a genomic imbalance and should be investigated in more detail. We report the first case of a chromosome 22 with a large acrocentric short arm masking a partial trisomy of the distal long arm, characterized by SNP array. We suggest a possible molecular mechanism underlying the rearrangement. CASE PRESENTATION: We report the case of a 15-year-old dysmorphic girl with low grade psychomotor retardation characterized by a karyotype with a large acrocentric short arm of one chromosome 22. Cytogenetic analysis revealed a normal karyotype with a very intense Q-fluorescent and large satellite on the chromosome 22 short arm. Fluorescence in situ hybridisation analysis showed a de novo partial trisomy of the 22q13.2-qter chromosome region attached to the short arm of chromosome 22. SNP-array analysis showed that the duplication was 8.5 Mb long and originated from the paternal chromosome. Haplotype analysis revealed that the two paternal copies of the distal part of chromosome 22 have the same haplotype and, therefore, both originated from the same paternal chromosome 22. A possible molecular mechanism that could explain this scenario is a break-induced replication (BIR) which is involved in non-reciprocal translocation events. CONCLUSION: The combined use of FISH and SNP arrays was crucial for a better understanding of the molecular mechanism underlying this rearrangement. This strategy could be applied for a better understanding of the molecular mechanisms underlying cryptic chromosomal rearrangements.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Técnicas Genéticas , Transtornos Psicomotores/patologia , Trissomia/genética , Adolescente , Cromossomos Humanos Par 22/genética , Biologia Computacional , Feminino , Haplótipos/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicomotores/genética , Trissomia/patologia
8.
Ital J Pediatr ; 40: 80, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25391451

RESUMO

Severe Congenital Neutropenia type 4 (SCN4, OMIM 612541) is a rare autosomal recessive disease due to mutations in the G6PC3 gene. The phenotype comprises neutropenia of variable severity and other anomalies including congenital heart defects, prominent superficial veins, uro-genital anomalies, facial dysmorphism, growth and developmental delay and intermittent thrombocytopenia. In some patients, SCN represents the only manifestation of the disease. Variable findings have been reported at bone marrow examination ranging from a maturation arrest at the myelocyte/promyelocyte stage (either in a hypocellular or hypercellular context) to myelokathexis. Here we report two patients harbouring two novel mutations in the G6PC3 gene, including the first Italian patient even described. Both the patients share profound neutropenia with severe infections early in life; in one case non-hematopoietic stigmata of the syndrome, including evident facial dysmorphism and vascular anomalies, appeared gradually over time, prominently in the second decade. Therefore, G6PC3 defects should be considered in any case of congenital, unexplained neutropenia regardless of the clinical phenotype. Both patients are on G-CSF treatment with no evidence of malignant evolution. Even if G6PC3 deficiency seems not to have a propensity towards malignancy, a careful evaluation is warranted.


Assuntos
DNA/genética , Glucose-6-Fosfatase/genética , Mutação , Neutropenia/congênito , Pré-Escolar , Análise Mutacional de DNA , Feminino , Glucose-6-Fosfatase/metabolismo , Humanos , Recém-Nascido , Masculino , Neutropenia/genética , Neutropenia/metabolismo , Linhagem , Fenótipo , Fatores de Tempo , Adulto Jovem
10.
Mol Cytogenet ; 7: 25, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24735523

RESUMO

We report on a nine years old girl born after 41 weeks of normal gestation with psychomotor retardation, speech delay and minimal dysmorphic signs: antimongolic cut eyes, small mouth, short philtrum and hypertelorism. The use of the high-resolution Affymetrix Human Mapping GeneChip 250 K NspI array allowed the characterization of a de novo 1Mb deletion on the short arm (p22) of a chromosome 8. Molecular cytogenetic-FISH with BAC probes (RP11) confirmed the deletion. The deleted region includes part of the sarcoglycan zeta (SGCZ) gene, involved in the sarcoglycan complex formation, and the microRNA 383. The deletion described in our patient falls 319 Kb upstream of the Tumor Suppressor Candidate 3 (TUSC3) gene. In this chromosomal region, a limited number of cases of overlapping deletions, of variable extensions and characterized by heterogeneous clinical phenotype, have been reported. The deleted region described in our patient is the smallest among those so far described in this region.

11.
Hum Mutat ; 35(7): 841-50, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24633898

RESUMO

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients' lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Doenças Hematológicas/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/tratamento farmacológico , Linhagem Celular , Códon sem Sentido/efeitos dos fármacos , Estudos de Coortes , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Estudos de Associação Genética , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Haploinsuficiência , Doenças Hematológicas/tratamento farmacológico , Histona Desmetilases/genética , Proteínas de Homeodomínio/genética , Humanos , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Proteínas Nucleares/genética , Sítios de Splice de RNA , Análise de Sequência de DNA , Transcrição Genética , Doenças Vestibulares/tratamento farmacológico
12.
Am J Med Genet A ; 161A(10): 2614-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23950054

RESUMO

Wave-shaped ribs were detected at prenatal ultrasound in a 20(+1) week female fetus. At birth, skeletal radiographs showed marked hypomineralization and suggested hypophosphatasia. However, elevated blood calcium and alkaline phosphatase excluded hypophosphatasia and raised the possibility of Jansen metaphyseal dysplasia. Molecular analysis of the PTH/PTHrP receptor gene (PTH1R) showed heterozygosity for a previously undescribed transversion variant (c.1373T>A), which predicts p.Ile458Lys. In vitro evaluation of wild type and mutant PTH/PTHrP receptors supported the pathogenic role of the p.Ile458Lys substitution, and confirmed the diagnosis of Jansen metaphyseal dysplasia. This disorder may present prenatally with wavy ribs and in the newborn with hypomineralization, and may therefore be confused with hypophosphatasia. The mottled metaphyseal lesions typically associated with this disease appear only in childhood.


Assuntos
Mutação de Sentido Incorreto , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Adulto , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Feminino , Humanos , Recém-Nascido , Gravidez , Radiografia , Ultrassonografia Pré-Natal
13.
J Clin Endocrinol Metab ; 98(9): E1516-23, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23894156

RESUMO

CONTEXT: Adenotonsillar tissue hypertrophy and obstructive sleep apnea have been reported during short-term GH treatment in children with Prader-Willi syndrome (PWS). OBJECTIVE: We conducted an observational study to evaluate the effects of long-term GH therapy on sleep-disordered breathing and adenotonsillar hypertrophy in children with PWS. DESIGN: This was a longitudinal observational study. PATIENTS AND METHODS: We evaluated 75 children with genetically confirmed PWS, of whom 50 fulfilled the criteria and were admitted to our study. The patients were evaluated before treatment (t0), after 6 weeks (t1), after 6 months (t2), after 12 months (t3), and yearly (t4-t6) thereafter, for up to 4 years of GH therapy. The central apnea index, obstructive apnea hypopnea index (OAHI), respiratory disturbance index, and minimal blood oxygen saturation were evaluated overnight using polysomnography. We evaluated the adenotonsillar size using a flexible fiberoptic endoscope. RESULTS: The percentage of patients with an OAHI of >1 increased from 3 to 22, 36, and 38 at t1, t4, and t6, respectively (χ(2) = 12.2; P < .05). We observed a decrease in the respiratory disturbance index from 1.4 (t0) to 0.8 (t3) (P < .05) and the central apnea index from 1.2 (t0) to 0.1 (t4) (P < .0001). We had to temporarily suspend treatment for 3 patients at t1, t4, and t5 because of severe obstructive sleep apnea. The percentage of patients with severe adenotonsillar hypertrophy was significantly higher at t4 and t5 than at t0. The OAHI directly correlated with the adenoid size (adjusted for age) (P < .01) but not with the tonsil size and IGF-1 levels. CONCLUSION: Long-term GH treatment in patients with PWS is safe; however, we recommend annual polysomnography and adenotonsillar evaluation.


Assuntos
Tonsila Faríngea/patologia , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Tonsila Palatina/patologia , Síndrome de Prader-Willi/tratamento farmacológico , Apneia Obstrutiva do Sono/etiologia , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipertrofia/induzido quimicamente , Lactente , Masculino , Polissonografia , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/patologia , Apneia Obstrutiva do Sono/patologia
14.
J Cyst Fibros ; 12(2): 165-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22981294

RESUMO

OBJECTIVE: Growth delay in cystic fibrosis is frequent and is usually the result of several interacting causes. It most often derives from severe respiratory impairment and severe malabsorption. There are however patients whose clinical condition is not severe enough to be held accountable for this phenomenon. We aimed at describing patients who showed growth delay, who were not affected by severe pulmonary disease or malabsorption and who, when tested, showed a reduced GH secretion after stimulation with conventional agents. We noticed a disproportionately large prevalence of growth hormone (GH) release deficit (GHRD) in pediatric cystic fibrosis (CF) patients. PATIENTS AND METHODS: We examined all patients under our care in the period 2006-11, who were older than 5 and younger than 16 years old. We focussed on those who fell below the 3rd height percentile, or whose growth during the previous 18 months faltered by >2SD, and who did not present clinical conditions that could reasonably explain their failure to thrive. These patients were subjected to standard GH provocative tests. RESULTS: Out of 285 who matched the age criterion, 33 patients also matched the height percentile criterion. While 15/33 suffered clinical conditions that could reasonably explain their failure to thrive, 18/33 underwent GH release provocative tests and 12/18 showed a release deficit. CONCLUSIONS: We conclude that impaired GH secretion is more frequent among CF patients compared to the prevalence of GH deficiency in the general population and that GH release impairment may be an independent cause of growth delay in CF. Our findings are in agreement with recent studies that have described low GH levels in CF piglets and in neonates with CF [1].


Assuntos
Fibrose Cística/complicações , Transtornos do Crescimento/etiologia , Hormônio do Crescimento Humano/deficiência , Adolescente , Criança , Feminino , Humanos , Israel , Itália , Masculino
15.
J Pediatr Endocrinol Metab ; 24(7-8): 477-81, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21932585

RESUMO

The aetiology of impaired growth hormone (GH) secretion in Prader-Willi syndrome (PWS) remains controversial due to the common occurrence of obesity. To further clarify whether suboptimal GH secretion in PWS is an artefact of excess weight, we evaluated both GH immunological activity and GH bioactivity after arginine administration in 23 non-obese PWS patients [seven females, aged 6.9 +/- 0.9 years, body mass index (BMI) SDS 0.63 +/- 0.26], in comparison with a control group of 32 healthy subjects, matched for age, gender and BMI (10 females, aged 7.9 +/- 0.3 years, BMI SDS 0.21 +/- 0.20). Serum GH concentration was measured with a time-resolved immunofluorometric assay (IFMA), while GH bioactivity was evaluated by the Nb2 cell bioassay. Serum IGF-I concentrations were measured by double-antibody RIA. GH mean peak after pharmacological stimulation was significantly lower in PWS individuals compared with controls when measured either by IFMA (6.05 +/- 1.23 microg/L vs. 23.7 +/- 1.06 microg/L, p < 0.0001) or by Nb2 (6.87 +/- 0.55 microg/L vs. 12.88 +/- 0.19 microg/L, p < 0.0001). Analysis of integrated GH secretion (AUC) confirmed that the PWS group differed significantly from the control subjects (387.9 +/- 76.1 microg/L/h vs. 1498.1 +/- 56.2 microg/L/h, p < 0.0001); the same result was obtained when the GH rise after arginine administration was expressed as nAUC (278.2 +/- 53.3 microg/L/h vs. 1443.6 +/- 52.5 microg/L/h, p < 0.0001). PWS patients had an IGF-I SDS significantly lower than those found in control subjects (p < 0.0001). Subnormal IGF-I values were present in 19 PWS individuals (82.6%) and two healthy controls (6.2%). These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurs in PWS.


Assuntos
Hormônio do Crescimento Humano/metabolismo , Síndrome de Prader-Willi/metabolismo , Adolescente , Arginina/farmacologia , Índice de Massa Corporal , Linhagem Celular Tumoral , Proliferação de Células , Criança , Pré-Escolar , Feminino , Fluorimunoensaio , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Linfoma/metabolismo , Masculino , Obesidade/etiologia , Síndrome de Prader-Willi/sangue , Síndrome de Prader-Willi/fisiopatologia , Prolactina/antagonistas & inibidores , Reprodutibilidade dos Testes , Taxa Secretória/efeitos dos fármacos
16.
Hum Mutat ; 32(7): 760-72, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21387466

RESUMO

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.


Assuntos
Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Proteína SOS1/genética , Adolescente , Adulto , Criança , Éxons , Feminino , Estudos de Associação Genética , Comunicação Interatrial/genética , Comunicação Interventricular/genética , Humanos , Mutação INDEL/genética , Íntrons , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Mutação de Sentido Incorreto/genética , Conformação Proteica , Estenose da Valva Pulmonar/genética , Proteína SOS1/química
17.
Eur J Med Genet ; 54(3): 361-4, 2011 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21211576

RESUMO

To date, more than 100 cases with a deletion of chromosome 2q have been identified, although studies reporting small interstitial deletions involving the 2q24.2-q24.3 region are still rare. Here, we have described the genotype and the phenotype of a boy with a 5.3 Mb de novo deletion in this region, identified by SNP array analysis. The selected region included 20 genes, of which 4 are prominently expressed in the brain. Their combined haplo-insufficiency could explain the main clinical features of this patient which included mental retardation, severe hypotonia, joint laxity and mild dysmorphic traits.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 2/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/patologia , Anormalidades Múltiplas/patologia , Pré-Escolar , Transtornos Cromossômicos/patologia , Face/anormalidades , Humanos , Cariotipagem , Masculino , Análise em Microsséries/métodos , Polimorfismo de Nucleotídeo Único
18.
Eur J Hum Genet ; 18(7): 768-75, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20125191

RESUMO

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterised by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): four de novo and three inherited rearrangements not reported among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clinical RSTS phenotype is difficult to assess.


Assuntos
Proteína de Ligação a CREB/genética , Dosagem de Genes/genética , Síndrome de Rubinstein-Taybi/genética , Adolescente , Adulto , Desequilíbrio Alélico/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Facies , Feminino , Deformidades Congênitas do Pé/complicações , Deformidades Congênitas do Pé/genética , Genoma Humano/genética , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/genética , Humanos , Lactente , Recém-Nascido , Padrões de Herança/genética , Masculino , Síndrome de Rubinstein-Taybi/complicações , Adulto Jovem
20.
Am J Med Genet A ; 146A(7): 861-72, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18203198

RESUMO

Twenty-five medical centers and the Prader-Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4-46.7). Two hundred thirty-eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death.


Assuntos
Síndrome de Prader-Willi/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Cromossomos Humanos Par 15 , Feminino , Hormônio do Crescimento/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Lactente , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/fisiopatologia
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