A PTPN11 Gene Mutation (Y63C) Causing Noonan Syndrome is Not Associated with Short Stature in General Population

Background: Noonan syndrome (NS), a dominant autosomal genetic disorder that prevents normal development, and exhibits cardiac defects, which is estimated to appear in 50% to 90% of patients. Son of sevenless homolog 1 (SOS1) gene mutation has been identified as a major gene causing NS and attributes to the development of cardiomyopathy and congenital heart defects. SOS1 is a guanine nucleotide exchange factor for RAS and is known to interact with growth factor receptor-bound protein 2 (GRB2). Recently, we have generated induced pluripotent stem cells (iPSCs)-derived cardiomyocytes (iCMCs) from cardiac fibroblasts obtained from a NS patient carrying SOS1 gene variant 1654A>G. Hypothesis: Since NS is known to have aberrant RAS-MAPK signaling, we hypothesize that iCMCs derived from NS patient (NS-iCMCs) may have atypical RAS signaling leading to the development of cardiomyopathy. Methods and Results: We have compared the normal skin fibroblast-derived iPSCs (N-iPSCs) and N-iCMCs with NS patient-derived induced NS-iPSCs and NS-iCMCs. Our qRT-PCR results showed that the mRNA expressions of signaling molecules HRAS, GRB2 and SOS1 were significantly decreased in NS-iCMCs compared with N-iCMCs (Figure A), and further confirmed through the protein expression by Western immunoblotting (Figure B). These results were in association with a significantly decreased mRNA and protein expressions of cardiac transcription factor GATA4, and structural proteins alpha sarcomeric actinin-2 (ACTN2), cardiac troponin T (TNNT2) and tropomyosin alpha-1 (TPM1) in NS-iCMCs compared with N-iCMCs. Further studies are underway to explore the difference in the guanine nucleotide exchange factor (GEF) activity and ERK activation between NS-iCMCs and N-iCMCs. Conclusion: Our current findings clearly indicate that the SOS1-associated signaling molecules HRAS and GRB2 were disrupted in NS-iCMCs, which may result in the development of cardiomyopathy in NS patients.

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IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene

HORMONES ◽

10.1007/bf03401289 ◽

2013 ◽

Vol 12 (1) ◽

pp. 86-92 ◽

Cited By ~ 9

Author(s):

Silvano Bertelloni ◽

Giampiero I. Baroncelli ◽

Eleonora Dati ◽

Silvia Ghione ◽

Fulvia Baldinotti ◽

...

Keyword(s):

Noonan Syndrome ◽

Ptpn11 Gene ◽

Prepubertal Children ◽

Igf I ◽

Generation Test

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Central giant cell lesions with an unusual behavior in patient with Noonan syndrome: A case report with 8-year follow-up

Research Society and Development ◽

10.33448/rsd-v10i1.11563 ◽

2021 ◽

Vol 10 (1) ◽

pp. e13510111563

Author(s):

Gleysson Matias de Assis ◽

Marcelo Leite Machado da Silveira ◽

José Wittor de Macêdo Santos ◽

Humberto Pereira Chaves Neto ◽

Lucas Melo da Costa ◽

...

Keyword(s):

Giant Cell ◽

Noonan Syndrome ◽

Pulmonary Stenosis ◽

Clinical Information ◽

Patient Discharge ◽

Blood Analysis ◽

Unusual Behavior ◽

Ptpn11 Gene ◽

Mandibular Injuries

This study describes a patient with Noonan syndrome affected by multiple Central Giant Cell Lesions (CGCL) in jaws. The lesions presented an unusual behavior since there was no regression size after puberty. The syndrome was diagnosed by collecting clinical information, represented by ocular hypertelorism, low insertion of ears, pulmonary stenosis, cryptorchidism, cardiac abnormalities, short stature, multiple CGCL in the jaws, and blood analysis that found a mutation of the PTPN11 gene. The treatment consisted of systemic calcitonin for a period of 14 months and three surgical procedures at distinct moments. The patient is currently with 20 years and in the eighth-year of follow-up. Although he presented an improvement in deformity, radiological findings showed remodeling without resolution of mandibular injuries, making it clear that injuries will did not always regress after puberty and not confirm previously publications in the literature. We therefore advocate a larger time of follow-up before patient discharge in these cases.

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Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.33713 ◽

2010 ◽

Vol 152A (11) ◽

pp. 2768-2774 ◽

Cited By ~ 12

Author(s):

Murat Derbent ◽

Yekta Oncel ◽

Kürşad Tokel ◽

Birgül Varan ◽

Ayşegül Haberal ◽

...

Keyword(s):

Noonan Syndrome ◽

Gene Mutations ◽

Ptpn11 Gene

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Prolonged thrombocytopenia in a neonate with Noonan syndrome: a case report

Journal of International Medical Research ◽

10.1177/0300060520936445 ◽

2020 ◽

Vol 48 (8) ◽

pp. 030006052093644

Author(s):

Meng Li ◽

Jinghui Zhang ◽

Nianzheng Sun

Keyword(s):

Platelet Count ◽

Case Report ◽

Noonan Syndrome ◽

Immune Thrombocytopenia ◽

Perinatal Asphyxia ◽

Juvenile Myelomonocytic Leukemia ◽

Normal Range ◽

Ptpn11 Gene ◽

Alloimmune Thrombocytopenia ◽

Myelomonocytic Leukemia

We report a case of a Chinese neonate who was diagnosed with Noonan syndrome and had persistent, self-limited thrombocytopenia. The neonate was admitted to the Neonatology Department 20 minutes after birth because of respiratory distress. From birth until 2 months of age, platelet values fluctuated between approximately 6 and 30 × 109/L. There was no intracranial hemorrhage. However, the child had a transient hypocalcemic seizure and fever. We excluded thrombocytopenia caused by perinatal asphyxia, immune thrombocytopenia, fetomaternal alloimmune thrombocytopenia, juvenile myelomonocytic leukemia, and chromosome 13, 18, and 21 trisomy syndromes. Despite treatment with anti-infective agents and transfusion of platelets and immunoglobulin, the platelet count did not return to the normal range. Genetic testing confirmed a PTPN11 gene mutation, which led to the diagnosis of Noonan syndrome. At 3 months of age, the platelet count gradually increased without intervention and returned to the normal range by 6 months. We speculate that the thrombocytopenia in this case was closely related to Noonan syndrome.

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Noonan syndrome: a clinical and genetic study of 31 patients

Revista do Hospital das Clínicas ◽

10.1590/s0041-87811999000500003 ◽

1999 ◽

Vol 54 (5) ◽

pp. 147-150 ◽

Cited By ~ 16

Author(s):

Débora Romeo Bertola ◽

Sofia M. M. Sugayama ◽

Lilian Maria José Albano ◽

Ae Kim Chong ◽

Claudette Hajaj Gonzalez

Keyword(s):

Congenital Anomaly ◽

Short Stature ◽

Family Member ◽

Genetic Study ◽

Noonan Syndrome ◽

Autosomal Dominant ◽

Clinical Findings ◽

Multiple Congenital Anomaly ◽

Genetic Characteristics ◽

Cardiac Anomalies

Noonan syndrome is a multiple congenital anomaly syndrome, inherited in an autosomal dominant pattern. We studied 31 patients (18 males and 13 females) affected by this disorder regarding their clinical and genetic characteristics. The most frequent clinical findings were short stature (71%); craniofacial dysmorphisms, especially hypertelorism, ptosis, downslanting of the palpebral fissures; short or webbed neck (87%); cardiac anomalies (65%), and fetal pads in fingers and toes (70%). After studying the probands' first-degree relatives, we made the diagnosis of Noonan syndrome in more than one family member in three families. Therefore, the majority of our cases were sporadic.

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