A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency.

BACKGROUND: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. RESULTS: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. CONCLUSION: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.

[Phenotype variability in Noonan syndrome patients with and without PTPN11 mutation]. / Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11.

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.

Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11 / Phenotype variability in Noonan syndrome patients with and without PTPN11 mutation

INTRODUÇÃO: Aproximadamente 50 por cento 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 PTPN11. RESULTADOS: Nove diferentes mutações missense no PTPN11, 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 por cento), baixa estatura (79 por cento), prega cervical (77 por cento) e criptorquidismo nos meninos (60 por cento). O Z da altura foi de -2,7 ± 1,2 e o do IMC foi de -1 ± 1,4. Os pacientes com mutação no PTPN11 apresentaram maior freqüência de estenose pulmonar do que os pacientes sem mutação (38 por cento vs. 6 por cento, 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 por cento dos pacientes com SN, os quais apresentaram maior freqüência de estenose pulmonar.

INTRODUCTION: Around 50 percent 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 percent), short stature (79 percent), webbed neck (77 percent) and cryptorchidism (60 percent) 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 percent vs. 6 percent, 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 percent of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients.