OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Neurofibromatosis-Noonan syndrome (NFNS). METHODS: A child with NFNS who was treated at the Department of Endocrinology of Hangzhou Children's Hospital in January 2024 was selected as the study subject. Clinical data of the child was collected by retrospective analysis. Peripheral venous blood samples (2 mL each) were collected from the child and his parents. Genomic DNA was extracted, and trio-whole exome sequencing (Trio-WES) of the family was carried out. Sanger sequencing was used to perform family verification on the candidate variants. The identified variants were classified for pathogenicity according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the "ACMG guidelines"). This study has been approved by the Medical Ethics Committee of Hangzhou Children's Hospital (Ethics No. 2021-06). RESULTS: The child was a 7-year and 4-month-old male. He has short stature, numerous café-au-lait spots on the neck and trunk, and special facial features such as a full forehead, wide interpupillary distance, a low nasal bridge, and low-set ears. The results of Trio-WES showed that the he had harbored the NF1 gene c.3773G>T (p.W1258L) mutation, which was verified by Sanger sequencing to be de novo in origin. The NF1 gene was associated with NFNS, which has an autosomal dominant inheritance. According to the ACMG guidelines, this variant was judged to be a likely pathogenic variant (PS2+PM2+PP3+PP2). No pathogenic variant in genes associated with Noonan syndrome, such as PTPN11, SOS1, RAF1, RIT1, and KRAS, was found. CONCLUSION The child with NFNS has clinical features such as short stature, special facial features, and café-au-lait spots. The c.3773G>T (p.W1258L) variation in the NF1 gene may be the genetic etiology of the NFNS child in this study. The results of this study has enriched the variation spectrum of the NF1 gene.
Child ; Humans ; Male ; Exome Sequencing ; Mutation ; Neurofibromatosis 1/genetics* ; Neurofibromin 1/genetics* ; Noonan Syndrome/genetics*

Child ; Chromosomes, Human, Y ; genetics ; Female ; Humans ; Lower Extremity ; pathology ; Lymphedema ; diagnosis ; genetics ; Noonan Syndrome ; diagnosis ; genetics

OBJECTIVETo investigate the mutations in protein tyrosine phosphatase, nonreceptor-type 11 (PTPN11) gene in patients with Noonan syndrome (NS).

METHODSThree sporadic patients with NS were studied. Genomic DNAs were extracted from peripheral blood leukocytes. All 15 coding exons and their flanking intronic boundaries of the PTPN11 gene were amplified by polymerase chain reaction and followed by direct sequencing. DNAs from parents were sequenced in the corresponding region when the mutation was detected in their affected child. The identified mutation was screened in 100 healthy individuals for exclusion of polymorphism by restriction endonuclease digestion of the PCR products. Protein conservation analysis was performed among 10 species using an online ClustalW tool.

RESULTSDirect DNA sequence analysis identified a heterozygous 181G to A change in exon 3 of the PTPN11 gene in one patient, which resulted in the substitution of an aspartic acid residue by an asparagine at codon 61. The mutation was absent in his parents and 100 controls, and is located in a highly conserved amino acid site. No mutation in the coding region of PTPN11 gene was observed in the other two patients.

CONCLUSIONThe p.D61N mutation was reported previously in Caucasians and is a de-novo mutation in this patient. Our study further confirmed that the p.D61N is a pathogenic mutation for NS and consistent with the clinical diagnosis. Additional genes may be involved in the other two patients with NS, indicating high genetic heterogeneity of this disease.

Amino Acid Sequence ; Base Sequence ; Case-Control Studies ; Child ; Exons ; Female ; Humans ; Male ; Molecular Sequence Data ; Mutation, Missense ; Noonan Syndrome ; enzymology ; genetics ; Point Mutation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; chemistry ; genetics ; metabolism ; Sequence Alignment ; Young Adult

Base Sequence ; Child ; Female ; Heart Septal Defects, Atrial ; complications ; diagnosis ; Humans ; Molecular Sequence Data ; Noonan Syndrome ; complications ; diagnosis ; genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; genetics