Hashimoto thyroiditis with an unusual presentation of cardiac tamponade in Noonan syndrome

Lee, Mi Ji; Kim, Byung Young; Sook, Jae; Choi, Young Joo; Kim, Young Ok; Cho, Hwa Jin; Kim, Chan Jong

doi:10.3345/kjp.2016.59.11.s112

Cited by 10 publications

(10 citation statements)

References 12 publications

(17 reference statements)

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“…A wide phenotypic variability and genetic heterogeneity have also been described in individuals with Noonan syndrome in relation to rare variants in PTPN11 [18]. Here, we show that even in the general population, common and rare variants in PTPN11 are independently associated with phenotypes such as hypothyroidism, small birth weight and low percent of body fat observed in some Noonan syndromes cases [19][20][21]. In GTex [12], numerous variants in PTPN11, such as rs11066309, rs3741983 and rs11066322 were significantly associated with a decreased expression in atrial appendage, adipose tissue, thyroid and skin and esophagus.…”

Section: Noonan Syndrome Is Caused By Mutations In Ptpn11 and Part Ofsupporting

confidence: 55%

A phenome-wide association study of four syndromic genes reveals pleiotropic effects of common and rare variants in the general population

Tcheandjieu

Aguirre²,

Gustafsson

et al. 2019

Preprint

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The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a few phenotypes of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore pleiotropy of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, TBX1, FBN1, PTPN11, NOTCH2, and MAP2K1) and performed a gene burden testing. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

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Section: Noonan Syndrome Is Caused By Mutations In Ptpn11 and Part Ofsupporting

confidence: 55%

A phenome-wide association study of four syndromic genes reveals pleiotropic effects of common and rare variants in the general population

Tcheandjieu

Aguirre²,

Gustafsson

et al. 2019

Preprint

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“…A wide phenotypic variability and genetic heterogeneity have also been described in individuals with Noonan syndrome in relation to rare variants in PTPN11 [ 22 ]. Here, we show that even in the general population, common and rare variants in PTPN11 are independently associated with phenotypes such as hypothyroidism, small birth weight and low percent of body fat observed in some cases of Noonan syndrome [ 21 – 23 ]. In GTEx [ 15 ], numerous variants in PTPN11 , such as rs11066309, rs3741983 and rs11066322 were significantly associated with a decreased expression in atrial appendage, adipose tissue, thyroid and skin and esophagus.…”

Section: Discussionmentioning

confidence: 99%

A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population

et al. 2020

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The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

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“…In these children, the pericardial effusion is not recognized or is identified accidentally during radiological tests performed for different clinical reasons. Most cases of pericardial effusion accompanying HT are diagnosed in children with syndromes, such as Down syndrome, that are frequently associated with heart disease and/or with thyroid malfunction and that routinely undergo laboratory and radiological tests to exclude these problems [ 8 , 9 , 10 ]. However, when it is not promptly identified and treated, the fluid accumulation can lead to unexpected heart problems, including tamponade [ 8 , 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…In these patients, particularly when pericardial effusion is the only relevant sign of disease, the HT diagnosis remains very difficult. The effusion can increase uncontrolled for months and lead to more severe complications such as cardiac tamponade [ 9 , 10 ]. This means that attention should be paid to pericardial effusion with a poorly defined origin; moreover, in the presence of this clinical manifestation, HT should be excluded, and adequate hormonal therapy should be prescribed to avoid risks of a negative outcome.…”

Section: Introductionmentioning

confidence: 99%

Pericardial Effusion as a Presenting Symptom of Hashimoto Thyroiditis: A Case Report

Leonardi

Penta

Cofini

et al. 2017

IJERPH

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Background: Hashimoto thyroiditis (HT) is the most frequent cause of acquired hypothyroidism in paediatrics. HT is usually diagnosed in older children and adolescents, mainly in females and is rare in infants and toddlers with cardiac involvement, including pericardial effusion, that can be found in 10% to 30% of adult HT cases. In this paper, a child with HT and pericardial effusion as the most important sign of HT is described. Case presentation: A four-year-old male child suffering for a few months from recurrent abdominal pain sometimes associated with vomiting underwent an abdominal ultrasound scan outside the hospital. This led to the identification of a significant pericardial effusion. At admission, his family history revealed that both his mother and maternal grandmother suffered from HT and that both were treated with l-thyroxine (LT4). The clinical examination did not reveal any pathological signs other than a palpable thyroid. His weight was 21 kg (78th percentile), his height was 101.8 cm (12th percentile) and his body max index (BMI) was 20.26 (96th percentile). On a chest radiograph, his heart had a globular appearance and the lung fields were normal. An echocardiography confirmed and determined the effusion amount (max, 23 mm; 600 mL) with light impairment of the heart kinetics. The ECG showed sinus bradycardia with a normal ST tract. Based on the blood test results, an infectious cause of the pericardial fluid excess was considered unlikely. Thyroid function testing revealed very high thyrotropin (TSH, 487 μIU/mL; normal range, 0.340–5.600 μIU/mL) and low serum-free thyroxine (fT4, 0.04 ng/dL; normal range, 0.54–1.24 ng/dL) levels. High thyroid peroxidase antibody titres in the blood were evidenced (>1500 UI/L; normal values, 0.0–9.0 UI/L). The thyroid ultrasound was consistent with thyroiditis. HT was diagnosed, and LT4 replacement therapy with levothyroxine sodium 1.78 µg/kg/die was initiated, with a gradual increase of the administered dose. The treatment was successful because a complete regression of the effusion after one month was evidenced, with a substantial modification towards normality of the thyroid function tests. One year later, the substitutive therapy led to complete normalization of the thyroid function indexes. A slight reduction of weight (BMI, 17.60 for age) and an increase of the velocity of height growth were evidenced. Conclusions: When fluid is identified in the pericardial space and pericarditis of unknown origin is diagnosed, the thyroid function should be immediately evaluated to prescribe substitutive hormonal therapy if necessary and thereby avoid overt hypothyroidism development and the risk of cardiac tamponade.

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Hashimoto thyroiditis with an unusual presentation of cardiac tamponade in Noonan syndrome

Cited by 10 publications

References 12 publications

A phenome-wide association study of four syndromic genes reveals pleiotropic effects of common and rare variants in the general population

A phenome-wide association study of four syndromic genes reveals pleiotropic effects of common and rare variants in the general population

A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population

Pericardial Effusion as a Presenting Symptom of Hashimoto Thyroiditis: A Case Report

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