Noonan syndrome: from phenotype to growth hormone therapy

A síndrome de Noonan (SN) é uma síndrome genética comum que constitui importante diagnóstico diferencial em pacientes com baixa estatura, atraso puberal ou criptorquidia. A SN apresenta grande variabilidade fenotípica e é caracterizada principalmente por dismorfismo facial, cardiopatia congênita e baixa estatura. A herança é autossômica dominante com penetrância completa. O diagnóstico é clínico, com base em critérios propostos por van der Burgt, em 1994. Recentemente, diversos genes envolvidos na via de sinalização RAS-MAPK foram identificados como causadores da SN: PTPN11, KRAS, SOS1, RAF1 e MEK1. O tratamento com hormônio de crescimento (hrGH) é proposto para corrigir a baixa estatura observada nestes pacientes. Estudos recentes apontam que pacientes com SN por mutações no gene PTPN11 apresentam pior resposta ao tratamento com hrGH quando comparado com pacientes sem mutações no PTPN11. Este artigo revisará os aspectos clínicos, moleculares e do tratamento da baixa estatura de crianças com SN com hrGH.Noonan Syndrome (NS) is one of the most common genetic syndromes and it is an important differential diagnosis in children with short stature, delayed puberty and cryptorchidism. NS is characterized by dysmorphic facial features, congenital heart defects and short stature, but there is a great variability in phenotype. NS may occur in a pattern consistent with autosomal dominant inheritance with almost complete penetrance. The diagnosis is based on a clinical score system proposed by van der Burgt e cols. in 1994. In recent years, germline mutations in the components of RAS-MAPK (mitogen activated protein kinase) pathway have been shown to be involved in the pathogenesis of NS. Mutations in PTPN11, KRAS, SOS1, RAF1 e MEK1 can explain 60-70% of NS molecular cause. Growth hormone therapy is proposed to correct the short stature observed in these patients. Recent studies suggest that the presence of PTPN11 mutations in patients with NS indicates a reduced growth response to short-term hrGH treatment. In this article, it is reviewed clinical and molecular aspects of NS and hrGH treatment for short stature.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Coocorrência de mutações nos genes PTPN11 e SOS1 na síndrome de Noonan: este achado prediz um fenótipo mais grave?

Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.A síndrome de Noonan (SN) é uma doença gênica autossômica dominante, com expressão clínica variável, caracterizada por baixa estatura, dismorfismos faciais e cardiopatia. Diferentes genes da via de sinalização RAS/MAPK são responsáveis pela síndrome, sendo as mais frequentes: PTPN11, SOS1, RAF1 e KRAS. O objetivo deste estudo foi relatar um paciente com SN que apresenta mutações em dois genes da via RAS/MAPK a fim de estabelecer se essas mutações levam a uma expressão mais grave do fenótipo. Utilizou-se sequenciamento direto dos genes PTPN11, SOS1, RAF1 e KRAS. Foram identificadas duas mutações em heterozigose previamente descritas: p.N308D e p.R552G nos genes PTPN11 e SOS1, respectivamente. A paciente apresenta quadro clínico típico semelhante ao dos pacientes com SN e mutação em um único gene, mesmo naqueles com a mesma mutação identificada na paciente. Não foi observado um fenótipo mais grave ou atípico na paciente, sugerindo que as mutações não apresentam um efeito aditivo

Tegumentary manifestations of Noonan and Noonan-related syndromes

OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11)

Hiperglicemia incidental em crianças: duas famílias com MODY 2 identificadas em brasileiros

Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative beta-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); beta-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative beta-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24O diabetes do tipo MODY (maturity-onset diabetes of the young) caracteriza-se por herança autossômica dominante, início precoce da hiperglicemia e defeitos na secreção de insulina. Os subtipos de MODY apresentam diferenças genéticas, metabólicas e clínicas. O MODY 2 é caracterizado por hiperglicemia leve assintomática e raramente requer tratamento farmacológico. O diagnóstico preciso de MODY é importante para se determinar o tratamento e o prognóstico. Relatamos duas mutações no gene GCK em heterozigose identificadas durante investigação de baixa estatura. Caso 1: paciente do sexo masculino, com 14 anos, pré-púbere, avaliado por atraso constitucional do crescimento e da puberdade. Durante o acompanhamento, apresentou glicemia de jejum alterada (113 mg/dL), aumento de HbA1c (6,6%) e anticorpos anticélulas β negativos. Seu pai e dois irmãos também apresentavam glicemia levemente elevada. A mãe tinha glicemia normal. Foi identificada no gene GCK uma mutação missense em heterozigose, p.Arg191Trp. Dezoito membros da família foram rastreados e 11 apresentavam essa mutação. Caso 2: paciente do sexo masculino, com 4 anos, em avaliação por baixa estatura. Não apresentou alterações laboratoriais, exceto por glicemia elevada (118 mg/dL). Anticorpos anticélulas β foram negativos. Seu pai, uma tia paterna e a avó paterna também apresentavam glicemia discretamente elevada, e a mãe, glicemia normal. A mutação missense em heterozigose, p.Glu221Lys, foi identificada no paciente-índice e em 4 membros da família. Todos os pacientes afetados apresentavam hiperglicemia leve. Essas mutações não foram identificadas nos indivíduos com glicemia normal. O rastreamento de mutações no gene GCK deve ser considerado em pacientes com hiperglicemia crônica leve e de início precoce, história familiar de glicemia elevada e anticorpos anticélulas β negativos. Arq Bras Endocrinol Metab. 2012;56(8):519-24Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [301477/2009-4]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Universidade de Sao Paulo (Programa de Apoio aos Novos Docentes)Universidade de Sao Paulo (Programa de Apoio aos Novos Docentes) [2010.1.37155.1.8

Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects Hiperglicemia incidental em crianças: duas famílias com MODY 2 identificadas em brasileiros

SUMMARY Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative β-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); β-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative β-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24 SUMÁRIO O diabetes do tipo MODY (maturity-onset diabetes of the young) caracteriza-se por herança autossômica dominante, início precoce da hiperglicemia e defeitos na secreção de insulina. Os subtipos de MODY apresentam diferenças genéticas, metabólicas e clínicas. O MODY 2 é caracterizado por hiperglicemia leve assintomática e raramente requer tratamento farmacológico. O diagnóstico preciso de MODY é importante para se determinar o tratamento e o prognóstico. Relatamos duas mutações no gene GCK em heterozigose identificadas durante investigação de baixa estatura. Caso 1: paciente do sexo masculino, com 14 anos, pré-púbere, avaliado por atraso constitucional do crescimento e da puberdade. Durante o acompanhamento, apresentou glicemia de jejum alterada (113 mg/dL), aumento de HbA1c (6,6%) e anticorpos anticélulas β negativos. Seu pai e dois irmãos também apresentavam glicemia levemente elevada. A mãe tinha glicemia normal. Foi identificada no gene GCK uma mutação missense em heterozigose, p.Arg191Trp. Dezoito membros da família foram rastreados e 11 apresentavam essa mutação. Caso 2: paciente do sexo masculino, com 4 anos, em avaliação por baixa estatura. Não apresentou alterações laboratoriais, exceto por glicemia elevada (118 mg/dL). Anticorpos anticélulas β foram negativos. Seu pai, uma tia paterna e a avó paterna também apresentavam glicemia discretamente elevada, e a mãe, glicemia normal. A mutação missense em heterozigose, p.Glu221Lys, foi identificada no paciente-índice e em 4 membros da família. Todos os pacientes afetados apresentavam hiperglicemia leve. Essas mutações não foram identificadas nos indivíduos com glicemia normal. O rastreamento de mutações no gene GCK deve ser considerado em pacientes com hiperglicemia crônica leve e de início precoce, história familiar de glicemia elevada e anticorpos anticélulas β negativos. Arq Bras Endocrinol Metab. 2012;56(8):519-2

The Interactive Effect of GHR-Exon 3 and -202 A/C IGFBP3 Polymorphisms on rhGH Responsiveness and Treatment Outcomes in Patients with Turner Syndrome

Context: There is great interindividual variability in the response to recombinant human (rh) GH therapy in patients with Turner syndrome (TS). Ascertaining genetic factors can improve the accuracy of growth response predictions. Objective: The objective of the study was to assess the individual and combined influence of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on the short-and long-term outcomes of rhGH therapy in patients with TS. Design and Patients: GHR-exon 3 and -202 A/C IGFBP3 genotyping (rs2854744) was correlated with height data of 112 patients with TS who remained prepubertal during the first year of rhGH therapy and 65 patients who reached adult height after 5 +/- 2.5 yr of rhGH treatment. Main Outcome Measures: First-year growth velocity and adult height were measured. Results: Patients carrying at least one GHR-d3 or -202 A-IGFBP3 allele presented higher mean first-year growth velocity and achieved taller adult heights than those homozygous for GHR-fl or -202 C-IGFBP3 alleles, respectively. The combined analysis of GHR-exon 3 and -202 A/C IGFBP3 genotypes showed a clear nonadditive epistatic influence on adult height of patients with TS treated with rhGH (GHR-exon 3 alone, R-2 = 0.27; -202 A/C IGFBP3, R-2 = 0.24; the combined genotypes, R-2 = 0.37 at multiple linear regression). Together with clinical factors, these genotypes accounted for 61% of the variability in adult height of patients with TS after rhGH therapy. Conclusion: Homozygosity for the GHR-exon3 full-length allele and/or the -202C-IGFBP3 allele are associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with TS. (J Clin Endocrinol Metab 97: E671-E677, 2012)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [05/04726-0, 05/50144-2]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [301339/2008-9, 300938/06-3, 475870/2009-3, 301477/2009-4

Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway

Noonan syndrome (NS) and Noonan-like syndromes (NLS) are autosomal dominant disorders caused by heterozygous mutations in genes of the RAS/MAPK pathway. The aim of the study was to construct specific growth charts for patients with NS and NLS. Anthropometric measurements (mean of 4.3 measurements per patient) were obtained in a mixed cross-sectional and longitudinal mode from 127 NS and 10 NLS patients with mutations identified in PTPN11 (n?=?90), SOS1 (n?=?14), RAF1 (n?=?10), KRAS (n?=?8), BRAF (n?=?11), and SHOC2 (n?=?4) genes. Height, weight, and body mass index (BMI) references were constructed using the lambda, mu, sigma (LMS) method. Patients had birth weight and length within normal ranges for gestational age although a higher preterm frequency (16%) was observed. Mean final heights were 157.4?cm [-2.4 standard deviation score (SDS)] and 148.4?cm (-2.2?SDS) for adult males and females, respectively. BMI SDS was lower when compared to Brazilian standards (BMI SDS of -0.9 and -0.5 SDS for males and females, respectively). Patients harboring mutations in RAF1 and SHOC2 gene were shorter than other genotypes, whereas patients with SOS1 and BRAF mutations had more preserved postnatal growth. In addition, patients with RAF1 and BRAF had the highest BMI whereas patients with SHOC2 and KRAS mutations had the lowest BMI. The present study established the first height, weight, and BMI reference curves for NS and NLS patients, based only on patients with a proven molecular cause. These charts can be useful for the clinical follow-up of patients with NS and NLS. (c) 2012 Wiley Periodicals, Inc.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP [08/50184-2, 07/59555-0]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq [301339/2008-9, 300982/2009-7, 301477/2009-4]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: Report of another family with metopic craniosynostosis

Noonan syndrome (NS) and Noonan-related disorders [cardio-facio-cutaneous (CFC), Costello, Noonan syndrome with multiple lentigines (NS-ML), and neurofibromatosis-Noonan syndromes (NFNS)] are a group of developmental disorders caused by mutations in genes of the RAS/MAPK pathway. Mutations in the KRAS gene account for only a small proportion of affected Noonan and CFC syndrome patients that present an intermediate phenotype between these two syndromes, with more frequent and severe intellectual disability in NS and less ectodermal involvement in CFC syndrome, as well as atypical clinical findings such as craniosynostosis. Recently, the first familial case with a novel KRAS mutation was described. We report on a second vertical transmission (a mother and two siblings) with a novel mutation (p.M72L), in which the proband has trigonocephaly and the affected mother and sister, prominent ectodermal involvement. Metopic suture involvement has not been described before, expanding the main different cranial sutures which can be affected in NS and KRAS gene mutations. The gene alteration found in the studied family is in close proximity to the one reported in the other familial case (close to the switch II region of the G-domain), suggesting that this specific region of the gene could have less severe effects on intellectual ability than the other KRAS gene mutations found in NS patients and be less likely to hamper reproductive fitness. (c) 2012 Wiley Periodicals, Inc.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [08/50184-2

Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients

Background Mutations in the PTPN11 gene are the main cause of Noonan syndrome (NS). The presence of some NS features is a frequent finding in children with idiopathic short stature (ISS). These children can represent the milder end of the NS clinical spectrum and PTPN11 is a good candidate for involvement in the pathogenesis of ISS. Objective To evaluate the presence of mutations in PTPN11 in ISS children who presented NS-related signs and in well-characterized NS patients. Patients and methods We studied 50 ISS children who presented at least two NS-associated signs but did not fulfil the criteria for NS diagnosis. Forty-nine NS patients diagnosed by the criteria of van der Burgt et al. were used to assess the adequacy of these criteria to select patients for PTPN11 mutation screening. The coding region of PTPN11 was amplified by polymerase chain reaction (PCR), followed by direct sequencing. Results No mutations or polymorphisms were found in the coding region of the PTPN11 gene in ISS children. Nineteen of the 49 NS patients (39%) presented mutations in PTPN11. No single characteristic enabled us to distinguish between NS patients with or without PTPN11 mutations. Conclusion Considering that no mutations were found in the present cohort with NS-related signs, it is unlikely that mutations would be found in unselected ISS children. The van der Burgt et al. criteria are adequate in attaining NS diagnosis and selecting patients for molecular studies. Mutations in the PTPN11 gene are commonly involved in the pathogenesis of NS but are not a common cause of ISS.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[05/04726-0]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[05/501444-2 to L.R.M]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)[301246/95-5 to B.B.M.]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)[300938/06-3 to I.J.P.A.]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)[307951/06-5 to A.A.L.J.

Can the Insulin Sensitivity Index (ISI) in Association with Insulin-like Growth Factor Binding Protein-1 Identify Insulin Resistance Early in Overweight Children?

Association between insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) has been reported. This prompted us to evaluate the power of the insulin sensitivity index (ISI) in association with IGFBP-1 to identify IR early in obese children/adolescents. OGTT was performed in 34 obese/overweight children/adolescents. Glucose, insulin and IGFBP-1 were measured in serum samples and ISI was calculated. Considering the presence of three or more risk factors for IR as a criterion for IR, ISI 4.6 showed very low IGFBP-1 levels. Conclusion: ISI <4.6 is a good indicator of early peripheral IR and, associated with IGFBP-1, can identify increased risk of hepatic IR. Low IGFBP-1 levels among non-IR children may indicate increased portal insulin levels.Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pediat, BR-14049900 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Med Ribeirao Preto, Dept Med, BR-14049900 Ribeirao Preto, SP, BrazilWeb of Scienc