Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11

Abstract

RESUMOIntrodução: Aproximadamente 50% dos pacientes com síndrome de Noonan (SN) apresentam mutações em heterozigose no gene PTPN11. Objetivo: Avaliar a freqüência de mutações no PTPN11 em pacientes com SN e analisar a correlação fenótipo-genótipo. Pacientes: 33 pacientes com SN. Método: Extração de DNA de leucócitos periféricos e seqüenciamento dos 15 exons do P T P N 1 1. R e s u l t a d o s : Nove diferentes mutações m i s s e n s e n o P T P N 1 1, incluindo a mutação P491H, ainda não descrita, foram encontradas em 16 dos 33 pacientes. As características clínicas mais freqüentes dos pacientes com SN foram: pavilhão auricular com rotação incompleta e espessamento da helix (85%), baixa estatura (79%), prega cervical (77%) e criptorquidismo nos meninos (60%). O Z da altura foi de -2,7 ± 1,2 e o do IMC foi de -1 ± 1,4. Os pacientes com mutação no P T P N 1 1 apresentaram maior freqüência de estenose pulmonar do que os pacientes sem mutação (38% vs. 6%, p< 0,05). Pacientes com ou sem mutação no PTPN11 não diferiram em relação à média do Z da altura, Z do IMC, freqüência de alterações torácicas, características faciais, criptorquidia, retardo mental, dificuldade de aprendizado, pico de GH ao teste de estímulo e Z de IGF-1 ou IGFBP-3. Conclusão: Identificamos mutações no PTPN11 em 48,5% dos pacientes com SN, os quais apresentaram maior freqüência de estenose pulmonar. Introduction: Around 50% of Noonan syndrome (NS) patients present heterozygous mutations in the PTPN11 gene. Aim: To evaluate the frequency of mutations in the PTPN11 in patients with NS, and perform phenotype-genotype correlation. Patients: 33 NS patients (23 males). Methods: DNA was extracted from peripheral blood leukocytes, and all 15 PTPN11 exons were directly sequenced. Results: Nine different missense mutations, including the novel P491H, were found in 16 of 33 NS patients. The most frequently observed features in NS patients were posteriorly rotated ears with thick helix (85%), short stature (79%), webbed neck (77%) and cryptorchidism (60%) in boys. The mean height SDS was -2.7 ± 1.2 and BMI SDS was -1 ± 1.4. Patients with PTPN11 mutations presented a higher incidence of pulmonary stenosis than patients without mutations (38% vs. 6%, p< 0.05). Patients with and without mutations did not present differences regarding height SDS, BMI SDS, frequency of thorax deformity, facial characteristics, cryptorchidism, mental retardation, learning disabilities, GH peak at stimulation test and IGF-1 or IGFBP-3 SDS. Conclusion: We identified missense mutations in 48.5% of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients. (Arq Bras Endocrinol Metab 2007;51/3:450-456)

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

“…During the clonidine test to evaluate GH secretion, the patient had a GH peak of 8.5 µg/L, ruling out GH deficiency. These hormonal findings were similar to the ones observed in other NS patients in our group (30).…”

Noonan Syndrome and Related Disorders: A Review of Clinical Features and Mutations in Genes of the RAS/MAPK Pathway

“…Several further studies confirmed PTPN11 as the most affected gene in NS patients and demonstrated a mutation frequency of 38–100 and 37–52% in individuals with familial and sporadic NS, respectively [7, 19, 27, 28]. …”

Noonan syndrome-causing genes

“…On the other hand, to determine the exact frequency of Noonan syndrome mutations, we excluded all data obtained from the screening of cohorts initially presenting with a particular condition (i.e., the mutational screening of Noonan syndrome patients with cardiac hypertrophy). The data gathered from the 82 included studies are summarized in Table 1 [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108].…”