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Co-Occurring SHOC2 and PTPN11 Mutations in a Patient With Severe/Complex Noonan Syndrome-Like Phenotype
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
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2011 (English)In: American Journal of Medical Genetics Part A, ISSN 1552-4825, Vol. 155, no 6, 1217-1224 p.Article in journal (Refereed) Published
Abstract [en]

Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A> G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c. 1226G>C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, cafe-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p. Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.

Place, publisher, year, edition, pages
2011. Vol. 155, no 6, 1217-1224 p.
Keyword [en]
Noonan syndrome, SHOC2, PTPN11, RAS-MAPK pathway, mutation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-156160DOI: 10.1002/ajmg.a.33987ISI: 000291944200003OAI: oai:DiVA.org:uu-156160DiVA: diva2:430863
Available from: 2011-07-13 Created: 2011-07-12 Last updated: 2013-01-23Bibliographically approved
In thesis
1. Genetic and Clinical Investigation of Noonan Spectrum Disorders
Open this publication in new window or tab >>Genetic and Clinical Investigation of Noonan Spectrum Disorders
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Noonan spectrum disorders belong to the RASopathies, a group of clinically related developmental disorders caused by dysregulation of the RAS-MAPK pathway. This thesis describes genetic and clinical investigations of six families with Noonan spectrum disorders.

In the first family, the index patient presented with severe Noonan syndrome (NS) and multiple café-au-lait (CAL) spots, while four additional family members displayed multiple CAL spots only. Genetic analysis of four RAS-MAPK genes revealed a de novo PTPN11 mutation and a paternally inherited NF1 mutation, which could explain the atypically severe NS, but not the CAL spots trait in the family. The co-occurrence of two mutations was also present in another patient with a severe/complex NS-like phenotype. Genetic analysis of nine RASopathy-associated genes identified a de novo SHOC2 mutation and a maternally inherited PTPN11 mutation. The latter was also identified in her brother. Both the mother and the brother displayed mild phenotypes of NS. The results from these studies suggest that an additive effect of co-occurring mutations contributes to severe/complex NS phenotypes.

The inherent difficulty in diagnosing Noonan spectrum disorders is evident in families with neurofibromatosis-Noonan syndrome (NFNS). An analysis of nine RASopathy-associated genes in a five-generation family with NFNS revealed a novel NF1 mutation in all affected family members. Notably, this family was initially diagnosed with NS and CAL spots. The clinical overlap between NS and NFNS was further demonstrated in three additional NFNS families. An analysis of twelve RASopathy-associated genes revealed three different NF1 mutations, all segregating with the disorder in each family. These mutations have been reported in patients with NF1, but have, to our knowledge, not been associated with NFNS previously. Together, these findings support the notion that NFNS is a variant of NF1. Due to the clinical overlap between NS and NFNS, we propose screening for NF1 mutations in NS patients negative for mutations in NS-associated genes, preferentially when CAL spots are present.

In conclusion, this thesis suggests that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway contributes to the clinical variability observed within Noonan spectrum disorders and further demonstrates the importance of accurate genetic diagnosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 830
Keyword
RASopathies, Noonan syndrome, neurofibromatosis type 1, neurofibromatosis-Noonan syndrome, RAS-MAPK pathway, mutation
National Category
Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-183325 (URN)978-91-554-8511-5 (ISBN)
Public defence
2012-12-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-16 Created: 2012-10-24 Last updated: 2013-01-23Bibliographically approved

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