SEARCH

SEARCH BY CITATION

Keywords:

  • Noonan syndrome;
  • Noonan-like syndrome;
  • short stature;
  • body mass index;
  • growth charts

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

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. © 2012 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Noonan syndrome (NS; OMIM 163950) is a frequent autosomal dominant disorder characterized by facial dysmorphism, short stature, and congenital heart defects. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11; OMIM 176876) gene was the first causative gene identified in this condition and encodes a tyrosine phosphatase protein (SHP2) which participates in the RAS/MAPK signaling pathway [Tartaglia et al., 2001]. In the past decade, other genes which also encode proteins in the RAS/MAPK signaling pathway have been uncovered as NS causative genes accounting for approximately 75% of affected individuals. To date, mutations in PTPN11, KRAS, NRAS, SOS1, RAF1, BRAF, SHOC2, MEK1, and CBL genes have been related to NS or closely related conditions, comprising Noonan syndrome with multiple lentigines (NS/ML, also termed LEOPARD syndrome; OMIM 151100), Noonan-like syndrome (NLS) with loose anagen hair (NS/LAH; OMIN 607721) and the recently documented “CBL-mutation associated” syndrome (reviewed in [Tartaglia et al., 2011]). NLS comprising Costello syndrome (CS; OMIM 218040), cardiofaciocutaneous syndrome (CFC; OMIM 115150), neurofibromatosis type 1 (OMIM 162200), and Legius syndrome (OMIM 611431) are disorders clinically related to NS and also harbor mutations in genes encoding for signal transducers implicating in the same pathway like HRAS, KRAS, NF1, BRAF, SPRED1, MEK1, and MEK2. Because of the similar molecular mechanisms disturbing the RAS/MAPK signaling pathway and clinical overlap, NS and these NLS are now grouped into a neurocardiofacialcutaneous syndrome family [Bentires-Alj et al., 2006] or the RAS-opathies [Tidyman and Rauen, 2009].

One of the cardinal signs of NS and NLS is proportional postnatal short stature [Jorge et al., 2009], although the physiopathological mechanism of growth impairment remains unclear. The two standardized growth curves of patients with NS were developed before the identification of the molecular mechanisms involved in these syndromes [Ranke et al., 1988; Witt et al., 1986]. Growth curves for height have been constructed for other syndromes characterized by short stature, such as achondroplasia [Horton et al., 1978] and Turner syndrome [Ranke et al., 1983]. These curves allow identifying individuals with severe growth deficit that need additional medical attention. The purpose of this study was to establish data on growth patterns, including BMI evaluation, for patients with NS and NLS in whom mutations in causative genes had been identified, allowing for an adequate representation of the broad phenotypic spectrum of these syndromes.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Study Protocol

This is part of an ongoing study of a molecular analysis of a cohort of patients with NS and NLS, approved by the local Ethics Committee. Informed parental consent and/or patient assent were obtained before initiating the studies. One hundred thirty-seven patients with NS and the related conditions (80 males and 57 females), harboring mutation in RAS/MAPK-related genes, had anthropometric evaluation from the neonatal period to adulthood. The diagnosis of NS (n = 119), NS/ML (n = 4), NS/LAH (n = 4), and CFC (n = 10) was established by the clinical geneticist (D.R.B.) based on clinical features. None of these patients were treated with growth hormone.

Each child contributed with only one single measurement for each age group. Height and weight were collected in a mixed longitudinal and cross-sectional mode and the minimal interval between two anthropometric evaluations was 6 months. Evaluations were performed at the same period of the day and included assessment of weight (measured with a digital scale) and standing height (measured with a stadiometer). Length of infants under the age of 2 years was measured in the supine position fully extended. Patients were considered to be at final height once they had grown less than 0.5 cm/year over a period of at least 12 months and/or had adult bone age. Weight and length at birth were expressed as standard deviation scores (SDS) for gestational age and sex [Usher and McLean, 1969]. Height and body mass index (BMI) were expressed as SDS for age and sex for constructed NS-specific standards.

The patients were part of a cohort of 182 patients with NS and NLS that were, in a sequence, screened for PTPN11, SOS1, RAF1, KRAS, BRAF, and SHOC2 mutations. Part of this cohort has been previously reported [Ferreira et al., 2008; Brasil et al., 2010b]. Eighty-six out of 119 NS patients had mutations in PTPN11, 14 in SOS1, 10 in RAF1, seven in KRAS, and two in BRAF gene. Four patients with NS/LAH had mutation in SHOC2 gene. Nine CFC patients had BRAF mutations and one had KRAS mutation. Four NS with multiple lentigines patients had PTPN11 mutation. All observed mutations were previously described and associated with NS and/or NLS. Patients were evaluated following standard protocol and no children had signs of malnutrition.

Molecular Analysis

PCR and sequence analysis were performed for all coding exons of PTPN11, SOS1, KRAS, and BRAF. Evaluation of PTPN11, SOS1, and KRAS genes were conducted according to previous published protocols [Ferreira et al., 2005; Brasil et al., 2010a, b]. For the RAF1 gene, PCR and sequence analysis focused on exons 7, 14, and 17, described as hotspot regions [Pandit et al., 2007; Ko et al., 2008]. Sequence analysis of SHOC2 gene focused on exon 2 where a substitution of a glycine for serine at position 2 (p.Ser2Gly) has been described [Cordeddu et al., 2009].

Statistical Analysis

Sex-specific centile curves for height, weight, and BMI were constructed using the lambda, mu, and sigma (LMS) method by the Growth Analyser software Version 3.5 (Ed. Dutch Growth Foundation, Rotterdam, Netherlands). This method is based on the principle that anthropometric data can be converted to a standard normal distribution by a Box-Cox transformation for any given age [Cole and Green, 1992]. To achieve this transformation, three smoothed age-related curves are used, namely the median curve (M curve), the coefficient of variation of the measurement as it changes with age (S curve), and the Box-Cox power needed at each age to convert the data to a Gaussian distribution (L curve). A table of corresponding smoothed L, M, and S values is accessible and these values can be used to calculate any required centile or SDS curve using a simple formula that involves the L, M, and S values at any given age [Cole and Green, 1992].

All data were recorded on a computer database and analyzed using SigmaStat version 3.5 (Systat Software Inc. Chicago, IL). Genotype-group comparisons were made by one-way ANOVA followed by post hoc Tukey test for multiple comparisons, as appropriate. A P-value <0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Length and Weight at Birth

Information on gestational age, weight and length at birth was available in 119, 114, and 83 patients, respectively. One hundred (84%) children were born between 37th and 42nd weeks of gestational age, whereas 19 children (16%) were born preterm for unknown reasons. NS and NLS patients had normal birth weight (3,144 ± 597 g, corresponding to 0.2 ± 1.6 SDS), although the birth length was slightly compromised (48.0 ± 3.0 cm, corresponding to −1.1 ± 1.4 SDS).

NS/NLS Specific Growth Chart Construction

One hundred twenty-five out of 137 patients were evaluated during their growth period, resulting in 536 observations (mean of 4.3 measurements per patient). Patients carrying PTPN11 mutations contribute for 63 ± 10% of all measurements in each age. The other genotypes contributed in each age group similarly. Selected centile values for height, weight, and BMI by age and sex (3rd, 10th, 25th, 50th, 75th, 90th, 97th) are presented in the Supporting Information online (see eTables S1–S3) and the related charts are depicted in Figures 1 and 2. The height equivalent degrees of freedom (edf) parameters were: L1.8M8S2.6 and L1M6S2 for boys and girls, respectively. The mean final height of males was 157.4 ± 8.0 cm and females was 148.4 ± 5.6 cm, resulting in a difference of 9.0 cm between the genders. These adult heights correspond to height SDS of −2.4 and −2.2 for Brazilian healthy adult men and women, respectively [Silva et al., 2010]. The weight edf parameters were: L2M7S3 for boys and girls. The mean adult weight of males was 47.6 ± 8.7 kg and of females was 48.2 ± 11 kg, corresponding to weight SDS −1.6 and −1.0 for Brazilian healthy adult men and women, respectively [Silva et al., 2010]. The BMI edf parameters were: L2M7S2.5 and L1.6M4.5S2 for boys and girls, respectively. The mean adult BMI of males was 18.8 ± 2.2 kg/m2 and females was 19.9 ± 3.5 kg/m2. Regarding BMI of patients with NS and NLS, the mean observed values correspond to −0.9 and −0.5 SDS for Brazilian healthy men and women, respectively [Silva et al., 2010]. The comparison between NS/NLS and standard growth charts for height and BMI are depicted in Figure 3.

thumbnail image

Figure 1. Height (A), weight (B), and BMI (C) for age in boys with Noonan and Noonan-like syndrome with mutation in the RAS/MAPK pathway (with individual data point).

Download figure to PowerPoint

thumbnail image

Figure 2. Height (A), weight (B), and BMI (C) for age in girls with Noonan and Noonan-like syndrome with mutation in the RAS/MAPK pathway (with individual data point).

Download figure to PowerPoint

thumbnail image

Figure 3. Comparison of the constructed growth chart for NS/NLS (blue for boys and pink for girls) with CDC Chart 2000 (green). The subparts (A,B) for height for age and (C,D) for BMI for age in male (A,C) and female (B,D).

Download figure to PowerPoint

Genotype Influence on Growth

Gestational age, birth length and weight did not differ among genotype groups. Concerning postnatal growth, patients with SHOC2 mutations were shorter than other genotypes (mean height SDS for NS/NLS-standard of −1.3 ± 0.7, P < 0.001). In addition, patients with RAF1 mutations were shorter (−0.5 ± 0.9) than patients with SOS1 mutation (0.4 ± 0.8, P < 0.001), BRAF mutations (0.4 ± 0.8, P < 0.001), and PTPN11 mutations (0.0 ± 1.1, P = 0.008; Fig. 4A). The lowest BMI values were observed in patients with SHOC2 mutation (mean BMI SDS for NS/NLS-standard of −2.0 ± 1.2, P < 0.001), followed by patients with KRAS mutations (−0.9 ± 0.8, P < 0.001) in comparison with other genotypes. In contrast, patients with RAF1 mutations (0.8 ± 0.7, P < 0.001) and BRAF mutations (0.8 ± 1.0, P < 0.001) had the highest BMI of the whole cohort (Fig. 4B).

thumbnail image

Figure 4. Height SDS (A) and BMI SDS (B) for NS/NLS-standard in Noonan syndrome patients regarding the affected genes (PTPN11, SOS1, RAF1, BRAF, KRAS, and SHOC2). A: Comparison of height among genotypes: (a) SHOC2 patients versus other genotypes, P < 0.001; (b) RAF1 patients versus SOS1 and BRAF, P < 0.001; (c) RAF1 patients versus PTPN11 patients, P = 0.008. B: Comparison of BMI among genotypes: (d) SHOC2 patients versus other genotypes, P < 0.001; (e) KRAS patients versus other genotypes, P < 0.001; (f) RAF1 and BRAF patients versus other genotypes, P < 0.001.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Several genes related to the RAS/MAPK pathway are associated with NS and NLS, allowing the etiological identification of these syndromes in the majority of patients [Romano et al., 2010; Tartaglia et al., 2010]. In the present study, height, weight, and BMI for age and sex charts were constructed using a large sample of NS and NLS patients with confirmed mutations in causative genes.

Growth charts are used to compare individual's height, weight, and other parameters to an applicable reference population. Specific growth charts for genetic disorders are important to understand the natural course of growth in affected patients and help management [Horton et al., 1978; Ranke et al., 1983]. In this context, the first standardized growth curves of NS patients were constructed in 1986 and consist of a cross-sectional study that reported retrospective growth data on 112 patients (64 males and 48 females) ranging in age from birth to 60 years [Witt et al., 1986]. The resulting 173 measurements reproduced 1.5 observations for each patient (only a single measurement was available for 97 patients). Final height was obtained at age 18 years and the mean height was 161 cm for males and 150.5 cm for females (mean adult height SDS of −2.4 for male and −2.2 for female) [Witt et al., 1986]. The second study recorded 392 measurements in 89 males and 355 measurements in 55 female patients and allowed a more detailed description of the natural growth of NS. Mean height in both sexes followed along the 3rd centile until about 12 years (males) and 10 years (females). Thereafter, height fell below the normal range and mean height in patients over age 19 years approached 162.5 cm in men and 152.7 cm in women (a mean adult height SDS of −2.5 for men and −2.2 for women) [Ranke et al., 1988]. In both studies, the diagnosis was based on clinical judgment in view of the typical abnormal findings observed in patients with NS [Witt et al., 1986; Ranke et al., 1988]. However, establishing the clinical diagnosis of NS can be very difficult, particularly in patients with mild forms [Mendez and Opitz, 1985]. Additionally, a marked change of phenotype with age has been well documented, resulting in a subtle phenotype in adult patients. These difficulties, in a pregenomic era, might have led the authors to include only typical and more affected NS patients in these cohorts. In the present study, only patients with confirmed molecular diagnosis were included, independently of the severity of clinical manifestation. The confirmation of the diagnosis by molecular analyses rendered false diagnosis very unlikely and allowed the inclusion of some individuals with subtle phenotype.

Regarding prenatal growth, our results were in line with previous reports [Mendez and Opitz, 1985; Allanson, 1987], showing that patients with NS and NLS had birth weight and length within the normal ranges. We observed our preterm frequency (16%) higher than average for Brazilian standards (7%) for unknown reasons [Ministerio da Saude, 2010]. Polyhydramnios is frequent in the NS [Baldassarre et al., 2011], which could be the cause of prematurity in our series; however, the information regarding the conditions of birth were not available in most cases to confirm this hypothesis.

Despite normal intrauterine growth pattern, height drops off within the first year of life. During the prepubertal period the mean height for NS/NLS patients follows below the 3rd centile on standard growth curve (Fig. 3A,B). The height falls more than 2.5 SD below the mean height for age after the age of 11 in females and after the age of 12 in males, probably due to the delayed puberty observed in these patients. In our data, height centile lines in males do not show a final plateau, suggesting thus that growth may continue beyond the age of 20.

The present study was the first that evaluated BMI in patients with NS and NLS. BMI in these patients were lower when compared to standards from age 7 to 17 years (Fig. 3C,D). These results raise the intriguing possibility that mutations associated with NS and NLS could have an influence on metabolism and control of energy storage. Insulin and leptin, two important hormones involved in satiety signals, act also through the RAS/MAPK pathway [Schwartz and Seeley, 1997]. It will be of great interest to characterize the metabolism of NS and NLS patients in view of these findings.

Several studies concerning genotype–phenotype correlations have shown different growth patterns according to the mutated gene [Shaw et al., 2007; Tartaglia et al., 2007; Zenker et al., 2007; Ko et al., 2008; Kobayashi et al., 2010]. Our longitudinal growth evaluation disclosed that patients harboring mutations in RAF1 and SHOC2 gene have more severe growth impairment, whereas patients with SOS1 and BRAF mutations have more preserved postnatal growth pattern (Fig. 4A). In addition, RAF1 and BRAF patients had the highest BMI in comparison with other genotypes, whereas patients with SHOC2 and KRAS mutations had the lowest ones (Fig. 4B). The causes for these differences among genotypes remain unanswered despite current progress obtained in molecular knowledge in NS.

The Brazilian population consists of a broad ethnic heterogeneity [Pena et al., 2011]. However, the values of height and weight of both sexes in normal young Brazilians reached the standard for each age group of the reference values of WHO and CDC [Kuczmarski et al., 2000; WHO, 2006; Silva et al., 2010]. This knowledge prompted us to consider that present growth charts for NS and NLS were not only useful for growth assessment in Brazil but also in other countries with similar background. In conclusion, the present study generates new height, weight, and BMI references curves for NS and NLS based on patients with proven mutations in the RAS/MAPK pathway.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo—FAPESP (08/50184-2 and 07/59555-0 to A.C.M.) and from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico—CNPq (301339/2008-9 to B.B.M., 300982/2009-7 to I.J.P.A., and 301477/2009-4 to A.A.L.J.). We would like to thank Adriana Farrant Braz and Renata Cunha Scalco for being present at Endocrinology office and for attending NS and NLS patients.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information
  • Allanson JE. 1987. Noonan syndrome. J Med Genet 24: 913.
  • Baldassarre G, Mussa A, Dotta A, Banaudi E, Forzano S, Marinosci A, Rossi C, Tartaglia M, Silengo M, Ferrero GB. 2011. Prenatal features of Noonan syndrome: Prevalence and prognostic value. Prenat Diagn 31: 949954.
  • Bentires-Alj M, Kontaridis MI, Neel BG. 2006. Stops along the RAS pathway in human genetic disease. Nat Med 12: 283285.
  • Brasil AS, Malaquias AC, Wanderley LT, Kim CA, Krieger JE, Jorge AA, Pereira AC, Bertola DR. 2010a. Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: Does this predict a more severe phenotype? Arq Bras Endocrinol Metabol 54: 717722.
  • Brasil AS, Pereira AC, Wanderley LT, Kim CA, Malaquias AC, Jorge AA, Krieger JE, Bertola DR. 2010b. PTPN11 and KRAS gene analysis in patients with Noonan and Noonan-like syndromes. Genet Test Mol Biomarkers 14: 425432.
  • Cole TJ, Green PJ. 1992. Smoothing reference centile curves: The LMS method and penalized likelihood. Stat Med 11: 13051319.
  • Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, Cecchetti S, Cardinale A, Martin J, Schackwitz W, Lipzen A, Zampino G, Mazzanti L, Digilio MC, Martinelli S, Flex E, Lepri F, Bartholdi D, Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossi C, Tenconi R, Zenker M, Merlo D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD, Tartaglia M. 2009. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet 41: 10221026.
  • Ferreira LV, Souza SA, Arnhold IJ, Mendonca BB, Jorge AA. 2005. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metab 90: 51565160.
  • Ferreira LV, Souza SC, Montenegro LR, Malaquias AC, Arnhold IJ, Mendonca BB, Jorge AA. 2008. Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients. Clin Endocrinol (Oxf) 69: 426431.
  • Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. 1978. Standard growth curves for achondroplasia. J Pediatr 93: 435438.
  • Jorge AA, Malaquias AC, Arnhold IJ, Mendonca BB. 2009. Noonan syndrome and related disorders: A review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res 71: 185193.
  • Ko JM, Kim JM, Kim GH, Yoo HW. 2008. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet 53: 9991006.
  • Kobayashi T, Aoki Y, Niihori T, Cave H, Verloes A, Okamoto N, Kawame H, Fujiwara I, Takada F, Ohata T, Sakazume S, Ando T, Nakagawa N, Lapunzina P, Meneses AG, Gillessen-Kaesbach G, Wieczorek D, Kurosawa K, Mizuno S, Ohashi H, David A, Philip N, Guliyeva A, Narumi Y, Kure S, Tsuchiya S, Matsubara Y. 2010. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: Dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat 31: 284294.
  • Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL. 2000. CDC growth charts: United States. Adv Data 127. PMID: 11183293.
  • Mendez HM, Opitz JM. 1985. Noonan syndrome: A review. Am J Med Genet 21: 493506.
  • Ministerio da Saude. 2010. Health Brazil 2010: Health analysis and selected evidences on impact of health surveillance actions. Brasilia: Ministerio da Saude. 372 p.
  • Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. 2007. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39: 10071012.
  • Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy Fde S, Kohlrausch F, Magno LA, Montenegro RC, Moraes MO, de Moraes ME, de Moraes MR, Ojopi EB, Perini JA, Racciopi C, Ribeiro-Dos-Santos AK, Rios-Santos F, Romano-Silva MA, Sortica VA, Suarez-Kurtz G. 2011. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE 6: e17063.
  • Ranke MB, Pfluger H, Rosendahl W, Stubbe P, Enders H, Bierich JR, Majewski F. 1983. Turner syndrome: Spontaneous growth in 150 cases and review of the literature. Eur J Pediatr 141: 8188.
  • Ranke MB, Heidemann P, Knupfer C, Enders H, Schmaltz AA, Bierich JR. 1988. Noonan syndrome: Growth and clinical manifestations in 144 cases. Eur J Pediatr 148: 220227.
  • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. 2010. Noonan syndrome: Clinical features, diagnosis, and management guidelines. Pediatrics 126: 746759.
  • Schwartz MW, Seeley RJ. 1997. Seminars in medicine of the Beth Israel Deaconess Medical Center. Neuroendocrine responses to starvation and weight loss. N Engl J Med 336: 18021811.
  • Shaw AC, Kalidas K, Crosby AH, Jeffery S, Patton MA. 2007. The natural history of Noonan syndrome: A long-term follow-up study. Arch Dis Child 92: 128132.
  • Silva DA, Pelegrini A, Petroski EL, Gaya AC. 2010. Comparison between the growth of Brazilian children and adolescents and the reference growth charts: Data from a Brazilian project. J Pediatr (RioJ) 86: 115120.
  • Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. 2001. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29: 465468.
  • Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD. 2007. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 39: 7579.
  • Tartaglia M, Zampino G, Gelb BD. 2010. Noonan syndrome: Clinical aspects and molecular pathogenesis. Mol Syndromol 1: 226.
  • Tartaglia M, Gelb BD, Zenker M. 2011. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 25: 161179.
  • Tidyman WE, Rauen KA. 2009. The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19: 230236.
  • Usher R, McLean F. 1969. Intrauterine growth of live-born Caucasian infants at sea level: Standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 74: 901910.
  • WHO. 2006. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl 450: 7685.
  • Witt DR, Keena BA, Hall JG, Allanson JE. 1986. Growth curves for height in Noonan syndrome. Clin Genet 30: 150153.
  • Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, Doerr HG, Gaspar H, Hofbeck M, Gillessen-Kaesbach G, Koch A, Meinecke P, Mundlos S, Nowka A, Rauch A, Reif S, von Schnakenburg C, Seidel H, Wehner LE, Zweier C, Bauhuber S, Matejas V, Kratz CP, Thomas C, Kutsche K. 2007. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet 44: 651656.

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Additional supporting information may be found in the online version of this article.

FilenameFormatSizeDescription
ajmg_35519_sm_SuppTabS1.doc90KTable S1: Selected centile values for height by age and sex (3rd, 10th, 25th, 50th, 75th, 90th, 97th) of Noonan syndrome patients harboring mutations in causative genes.
ajmg_35519_sm_SuppTabS2.doc90KTable S2: Selected centile values for weight by age and sex (3rd, 10th, 25th, 50th, 75th, 90th, 97th) of Noonan syndrome patients harboring mutations in causative genes.
ajmg_35519_sm_SuppTabS3.doc90KTable S3: Selected centile values for BMI by age and sex (3rd, 10th, 25th, 50th, 75th, 90th, 97th) of Noonan syndrome patients harboring mutations in causative genes.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.