Noonan syndrome associated with systemic lupus erythematosus

Lisbona, MP; Moreno, Mireia; Orellana, C.; Gratacós, Jordi; Larrosa, M.

doi:10.1177/0961203308094996

Cited by 16 publications

(7 citation statements)

References 16 publications

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“…They also showed partially similar presentations (e.g., age and the presence of serositis). A retrospective review of patients with SLE and a RASopathy phenotype revealed at least six patients with no accompanying genetic information (Alanay, Balc, & Ozen, ; Amoroso et al, ; Cerpa‐Cruz et al, ; Lisbona, Moreno, Orellana, Gratacos, & Larrosa, ; Lopez‐Rangel et al, ; Martin, Gencyuz, & Petty, ). It would be helpful to re‐evaluate these previous patients to determine whether they indeed have pathogenic variants in RASopathy genes, including SHOC2 .…”

Section: Discussionmentioning

confidence: 99%

Systemic lupus erythematosus in a patient with Noonan syndrome‐like disorder with loose anagen hair 1: More than a chance association

Uehara

Hosogaya

Matsuo

et al. 2018

American J of Med Genetics Pt A

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Systemic lupus erythematosus (SLE) has been reported among patients with RASopathy. Five patients have been reported: three with SHOC2 variants, one with a PTPN11 variant, and one with a KRAS variant. SHOC2 variant might represent a relatively common predisposing factor for SLE among the RASopathy genes. However, the clinical details were only reported for two patients, while information on the remaining patient appeared only in a tabular format with minimal clinical description. Here, we report a patient with a SHOC2 variant and SLE. The proband was a 28-year-old male patient with intellectual disabilities, a short stature, dysmorphic facial features, and thin hair. He developed hypertrophic cardiomyopathy and afebrile generalized seizures at the ages of 7 and 18 years, respectively. At the age of 24 years, he presented with a 3-day history of intermittent fever accompanied by right chest pain and a malar butterfly rash. He fulfilled both the American College of Rheumatology (ACR) criteria and the Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE and was successfully treated with prednisolone. Medical exome sequencing identified a de novo SHOC2 variant (c.4A > G, p.S2G). The present report of a second patient who fulfills both the ACR criteria and the SLICC criteria of SLE. We suggest that the association between SHOC2 variant and SLE represents more than a chance association. In the event of fever of unknown origin in patients with constitutional SHOC2 pathogenic variant, SLE should be suspected.

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Section: Discussionmentioning

confidence: 99%

Systemic lupus erythematosus in a patient with Noonan syndrome‐like disorder with loose anagen hair 1: More than a chance association

Uehara

Hosogaya

Matsuo

et al. 2018

American J of Med Genetics Pt A

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“…Shared cardinal characteristics of the RASopathies include short stature, craniofacial malformations, webbed neck, cardiac malformation, variable cognitive delay and an increased risk of cancer development [80,81]. Twelve patients with NS/Noonan-related syndrome phenotype and SLE characteristics have been described to date [80][81][82][83][84][85][86][87][88][89][90][91]. Of these 12 patients, four had SHOC2 mutations, two had KRAS and one had a PTPN11 mutation [80,81,[84][85][86]90,91].…”

Section: Rasopathiesmentioning

confidence: 99%

“…Of these 12 patients, four had SHOC2 mutations, two had KRAS and one had a PTPN11 mutation [80,81,[84][85][86]90,91]. The remaining five patients with RASopathy and SLE are molecularly undiagnosed [82,83,[87][88][89]. Overall, the most frequently reported manifestation associated with SLE was arthritis (n = 8/11), followed by pericarditis/pleuritis (n = 7/11), autoimmune cytopenia (6/11), and skin involvement (n = 2/8).…”

Section: Rasopathiesmentioning

confidence: 99%

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

100

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Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

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“…SHP2 is a ubiquitously expressed protein tyrosine phosphatase that modulates nearly all cytokine, integrin, and tyrosine receptor signaling pathways. It also appears to have a causal genetic link to SLE and other autoimmune-like disorders; indeed, more than 50 patients with NS, an autosomal dominant disorder principally caused by GOF SHP2 mutations, have been subsequently diagnosed with SLE (30)(31)(32)(33)(34)(35). Additionally, NS mice (SHP2 D61G/+ ) develop splenomegaly, have increased neutrophils and leukocytes, and develop an autoimmune-like disease (26).…”

Section: Figure 5 Shp2 Activity Specifically Modulates Dn T Cell Promentioning

confidence: 99%

“…Nearly all NS mutations of SHP2 are catalytically hyperactivated, i.e., they have increased PTP activity (23,24) and behave as gain-of-function (GOF) alleles (23)(24)(25)(26)(27)(28)(29). Importantly, to date, over 50 cases of NS have been linked to the development of SLE, as demonstrated by the onset of polyarthritis, pericarditis, and production of antinuclear and anti-DNA antibodies in these patients (30)(31)(32)(33)(34)(35). Taken together, these data suggest that a functional and/or genetic association between SLE and SHP2 activity likely exists.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus

Wang

Mizui

Zeng

et al. 2016

Journal of Clinical Investigation

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Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain-containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.

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Noonan syndrome associated with systemic lupus erythematosus

Cited by 16 publications

References 16 publications

Systemic lupus erythematosus in a patient with Noonan syndrome‐like disorder with loose anagen hair 1: More than a chance association

Systemic lupus erythematosus in a patient with Noonan syndrome‐like disorder with loose anagen hair 1: More than a chance association

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus

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