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Molecular Medicine Reports Nov 2016Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of... (Review)
Review
Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of genetic disorders presenting with CALM have mutations that are involved in human skin pigmentation regulation signaling pathways, including KIT ligand/KIT proto‑oncogene receptor tyrosine kinase and Ras/mitogen‑activated protein kinase. These disorders, which include Legius syndrome, Noonan syndrome with multiple lentigines or LEOPARD syndrome, and familial progressive hyperpigmentation) are difficult to distinguish from NF1 at early stages, using skin appearance alone. Furthermore, certain syndromes are clinically overlapping and molecular testing is a vital diagnostic method. The present review aims to provide an overview of these 'NF1‑like' inherited diseases and recommend a cost‑effective strategy for making a clear diagnosis among these diseases with an ambiguous borderline.
Topics: Cafe-au-Lait Spots; Diagnosis, Differential; Humans; LEOPARD Syndrome; Mutation; Neurofibromatosis 1; Noonan Syndrome; Pathology, Molecular; Signal Transduction; Skin Pigmentation
PubMed: 27666661
DOI: 10.3892/mmr.2016.5760 -
Archives of Medical Science : AMS Feb 2017Noonan syndrome (NS) is an autosomal dominant disorder with vast heterogeneity in clinical and genetic features. Various symptoms have been reported for this abnormality...
Noonan syndrome (NS) is an autosomal dominant disorder with vast heterogeneity in clinical and genetic features. Various symptoms have been reported for this abnormality such as short stature, unusual facial characteristics, congenital heart abnormalities, developmental complications, and an elevated tumor incidence rate. Noonan syndrome shares clinical features with other rare conditions, including LEOPARD syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. Germline mutations in the RAS-MAPK (mitogen-activated protein kinase) signal transduction pathway are responsible for NS and other related disorders. Noonan syndrome diagnosis is primarily based on clinical features, but molecular testing should be performed to confirm it in patients. Due to the high number of genes associated with NS and other RASopathy disorders, next-generation sequencing is the best choice for diagnostic testing. Patients with NS also have higher risk for leukemia and specific solid tumors. Age-specific guidelines for the management of NS are available.
PubMed: 28144274
DOI: 10.5114/aoms.2017.64720 -
Development (Cambridge, England) May 2014Germline mutations in PTPN11, encoding Shp2, cause Noonan syndrome (NS) and LEOPARD syndrome (LS), two developmental disorders that are characterized by multiple...
Germline mutations in PTPN11, encoding Shp2, cause Noonan syndrome (NS) and LEOPARD syndrome (LS), two developmental disorders that are characterized by multiple overlapping symptoms. Interestingly, Shp2 catalytic activity is enhanced by NS mutations and reduced by LS mutations. Defective cardiac development is a prominent symptom of both NS and LS, but how the Shp2 variants affect cardiac development is unclear. Here, we have expressed the most common NS and LS Shp2-variants in zebrafish embryos to investigate their role in cardiac development in vivo. Heart function was impaired in embryos expressing NS and LS variants of Shp2. The cardiac anomalies first occurred during elongation of the heart tube and consisted of reduced cardiomyocyte migration, coupled with impaired leftward heart displacement. Expression of specific laterality markers was randomized in embryos expressing NS and LS variants of Shp2. Ciliogenesis and cilia function in Kupffer's vesicle was impaired, likely accounting for the left/right asymmetry defects. Mitogen-activated protein kinase (MAPK) signaling was activated to a similar extent in embryos expressing NS and LS Shp2 variants. Interestingly, inhibition of MAPK signaling prior to gastrulation rescued cilia length and heart laterality defects. These results suggest that NS and LS Shp2 variant-mediated hyperactivation of MAPK signaling leads to impaired cilia function in Kupffer's vesicle, causing left-right asymmetry defects and defective early cardiac development.
Topics: Animals; Benzamides; Body Patterning; Cell Movement; Cilia; Embryo, Nonmammalian; Heart Defects, Congenital; Heart Function Tests; Humans; LEOPARD Syndrome; Mitogen-Activated Protein Kinase Kinases; Mutation; Myocytes, Cardiac; Noonan Syndrome; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Zebrafish; Zebrafish Proteins
PubMed: 24718990
DOI: 10.1242/dev.106310 -
Hormone Research 2009Noonan syndrome (NS) is one of the most common syndromes transmitted by a mendelian mode. In recent years, germline mutations that affect components of the RAS-MAPK... (Review)
Review
Noonan syndrome (NS) is one of the most common syndromes transmitted by a mendelian mode. In recent years, germline mutations that affect components of the RAS-MAPK (mitogen-activated protein kinase) pathway were shown to be involved in the pathogenesis of NS and four rare syndromes with clinical features overlapping with NS: Leopard syndrome, cardio-facio-cutaneous syndrome, Costello syndrome and neurofibromatosis type 1. Several hormones act through receptors that stimulate the RAS-MAPK pathway, and therefore, NS and related disorders represent a remarkable opportunity to study the implication of the RAS-MAPK pathway in different endocrine systems. Additionally, children with NS frequently are referred to the endocrinologist because of short stature, delayed puberty and/or undescended testes in males. In this paper, we review the diagnostic, clinical and molecular aspects of NS and NS-related disorders.
Topics: Diagnosis, Differential; Female; Genes, ras; Germ-Line Mutation; Human Growth Hormone; Humans; MAP Kinase Signaling System; Male; Neoplasms; Noonan Syndrome; ras Proteins
PubMed: 19258709
DOI: 10.1159/000201106 -
Journal of Pharmacological Sciences Nov 2020SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene in human. Clinically, SHP2 has been identified as a causal factor of several diseases,... (Review)
Review
SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene in human. Clinically, SHP2 has been identified as a causal factor of several diseases, such as Noonan syndrome, LEOPARD syndrome as well as myeloid malignancies. Interestingly, both loss-of-function and gain-of-function mutations occur in the PTPN11 gene. Analyses by biochemical and cell biological means as well as probing with small molecule compounds have demonstrated that SHP2 has both phosphatase-dependent and independent functions. In comparison with its phosphatase activity, the non-phosphatase-like function of SHP2 has not been well introduced or summarized. This review mainly focuses on the phosphatase-independent functions and its regulation by small molecule compounds as well as their use for disease therapy.
Topics: Cerebrosides; Depsipeptides; Gain of Function Mutation; Humans; LEOPARD Syndrome; Loss of Function Mutation; Molecular Targeted Therapy; Noonan Syndrome; Phosphoric Monoester Hydrolases; Piperidines; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; Signal Transduction
PubMed: 32921395
DOI: 10.1016/j.jphs.2020.06.002 -
Hereditas Sep 2021LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple...
LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple lentigines and cafe´-au-lait spots, electrocardiographic conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Phenotype overlap complicates clinical discrimination within RASopathies, making the diagnosis of LEOPARD more confusing and challenging. Besides, LEOPARD patients do not usually present with all these typical clinical features, increasing the possibility of underdiagnosis or misdiagnosis.Herein, we report a case of LEOPARD syndrome in a patient who only presented with pigmented skin spots and was initially diagnosed with multiple acquired melanocytic nevi. Subsequent pathological examination confirmed the diagnosis of multiple lentigines rather than melanocytic nevi. A genetic study showed a germline PTPN11 (Tyr279Cys) mutation and raised the suspicion of LEOPARD syndrome. A subsequent ECG examination detected potential cardiac defects and confirmed the diagnosis of LEOPARD. We considered that the potential damage of other systems underlying the skin multiple lentigines should not be ignored. The diagnosis of LEOPARD syndrome in an early stage before cardiac damage has reached a serious and irreversible stage can be meaningful for patients to fully understand the potential risks, complications and prognosis of the disease and to take appropriate precautions to prevent the potential risk of cardiac damage.
Topics: Humans; LEOPARD Syndrome; Mutation; Phenotype; Skin; Skin Neoplasms
PubMed: 34488904
DOI: 10.1186/s41065-021-00199-5 -
Dermatology Practical & Conceptual Jan 2018LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan...
LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis.
PubMed: 29445579
DOI: 10.5826/dpc.0801a14 -
Trends in Cardiovascular Medicine May 2011In this review, we focus on elucidating the cardiac function of germline mutations in the PTPN11 gene, encoding the Src homology-2 (SH2) domain-containing protein... (Review)
Review
In this review, we focus on elucidating the cardiac function of germline mutations in the PTPN11 gene, encoding the Src homology-2 (SH2) domain-containing protein tyrosine phosphatase SHP2. PTPN11 mutations cause LEOPARD syndrome (LS) and Noonan syndrome (NS), two disorders that are part of a newly classified family of autosomal dominant syndromes termed "RASopathies," which are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase pathway. LS and NS mutants have opposing biochemical properties, and yet, in patients, these mutations produce similar cardiac abnormalities. Precisely how LS and NS mutations lead to such similar disease etiology remains largely unknown. Recent complementary in vitro, ex vivo, and in vivo analyses reveal new insights into the functions of SHP2 in normal and pathological cardiac development. These findings also reveal the need for individualized therapeutic approaches in the treatment of patients with LS and NS and, more broadly, patients with the other "RASopathy" gene mutations as well.
Topics: Animals; Cardiomegaly; Disease Models, Animal; Genes, ras; Germ-Line Mutation; Heart Defects, Congenital; Humans; LEOPARD Syndrome; MAP Kinase Signaling System; Noonan Syndrome; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 22681964
DOI: 10.1016/j.tcm.2012.03.006 -
Frontiers in Endocrinology 2022Endocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the...
BACKGROUND AND OBJECTIVES
Endocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in a consecutive unselected cohort of patients with RASopathies.
STUDY DESIGN
72 patients with a genetically confirmed RASopathy (Noonan syndrome [NS], N=53; 29 LEOPARD syndrome [LS], N=2; cardiofaciocutaneous syndrome [CFCS], N=14; subjects showing co-occurring pathogenic variants in and , N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism.
RESULTS
Short stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (p<0.05) when considering the entire case load and both NS and CFCS groups. Vitamin D and Calcitonin levels were significantly lower (p< 0.01), Parathormone levels significantly higher (p<0.05) in patients compared to the control group (p<0.05). Patients with lower BMD showed reduced physical activity and joint pain. Finally, anti-TPO antibody levels were significantly higher in patients than in controls when considering the entire case load and both NS and CFCS groups.
CONCLUSIONS
The collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.
Topics: Humans; Research; Endocrine System
PubMed: 36483002
DOI: 10.3389/fendo.2022.1030398 -
International Journal of Fertility &... Jan 2014Female genital tuberculosis (TB) remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of... (Review)
Review
Female genital tuberculosis (TB) remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquired immunodeficiency syndrome (AIDS). Genital TB is commonly asymptomatic, and it is diagnosed during infertility investigations. Despite of recent advances in imaging tools, such as computerized tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpingography is still the standard screening test for evaluation of tubal infertility and a valuable tool for diagnosis of female genital tuberculosis. Tuberculosis gives rise to various appearances on hysterosalpingography (HSG) from non-specific changes to specific findings. The present pictorial review illustrates and describes specific and non-specific radiographic features of female genital tuberculosis in two parts. Part I presents specific findings of tuberculosis related to tubes such as "beaded tube", "golf club tube", "pipestem tube", "cobble stone tube" and "leopard skin tube". Part II describes adverse effects of tuberculosis on structure of endometrium and radiological specific findings such as "dwarfed" uterus with lymphatic intravasation and occluded tubes, "T-shaped" tuberculosis uterus, "pseudounicornuate" uterus and "Collar-stud abscess", which have not been encountered in the majority of non-tuberculosis cases.
PubMed: 24520493
DOI: No ID Found