Further Evidence That Defects in Main Thyroid Dysgenesis-Related Genes Are an Uncommon Etiology for Primary Congenital Hypothyroidism in Mexican Patients: Report of Rare Variants in FOXE1, NKX2-5 and TSHR

Alcántara-Ortigoza, Miguel Ángel; Sánchez-Verdiguel, Iraís; Fernández-Hernández, Liliana; Enríquez-Flores, Sergio; González-Núñez, Aidy; Hernández‐Martínez, Nancy Leticia; Sánchez, Carmen; Ángel, Ariadna González-del

doi:10.3390/children8060457

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…The thymus hypoplasia and CH might be coincidental findings, given that we discarded a microdeletion in 22q11 as the cause of the thymus hypoplasia, and CH due to thyroid dysgenesis is a common entity in Mexico. Pathogenic variants in PAX8 and FOXE1 have been documented in a very low proportion of Mexican patients with CH (2.5%) [19], but we discarded this possibility by complete Sanger sequencing of the loci. It remains possible that other single-gene variations may synergistically contribute to the clinical manifestations in our patient, as recently exemplified by the association of TIMP3 risk variants with bicuspid aortic valve development in patients with Turner syndrome [20].…”

Section: Discussionmentioning

confidence: 99%

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis

González-del Angel,

Alcántara-Ortigoza,

Ramos

et al. 2023

IJMS

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Trisomy X is the most frequent sex chromosome anomaly in women, but it is often underdiagnosed postnatally because most patients do not show any clinical manifestation. It is estimated that only 10% of patients with trisomy X are diagnosed by clinical findings. Thus, it has been proposed that the clinical spectrum is not yet fully delimited, and additional uncommon or atypical clinical manifestations could be related to this entity. The present report describes a female carrying trisomy X but presenting atypical manifestations, including severe intellectual disability, short stature, thymus hypoplasia, and congenital hypothyroidism (CH). These clinical findings were initially attributed to trisomy X. However, chromosome microarray analysis (CMA) subsequently revealed that the patient also bears a heterozygous 304-kb deletion at 16p11.2. This pathogenic copy-number variant (CNV) encompasses 13 genes, including TUFM. Some authors recommend that when a phenotype differs from that described for an identified microdeletion, the presence of pathogenic variants in the non-deleted allele should be considered to assess for an autosomal recessive disorder; thus, we used a panel of 697 genes to rule out a pathogenic variant in the non-deleted TUFM allele. We discuss the possible phenotypic modifications that might be related to an additional CNV in individuals with sex chromosome aneuploidy (SCA), as seen in our patient. The presence of karyotype-demonstrated trisomy X and CMA-identified 16p11.2 deletion highlights the importance of always correlating a patient’s clinical phenotype with the results of genetic studies. When the phenotype includes unusual manifestations and/or exhibits discrepancies with that described in the literature, as exemplified by our patient, a more extensive analysis should be undertaken to enable a correct diagnosis that will support proper management, genetic counseling, and medical follow-up.

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Section: Discussionmentioning

confidence: 99%

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis

González-del Angel,

Alcántara-Ortigoza,

Ramos

et al. 2023

IJMS

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“…The identified p.Arg25Cys variant is a common variant often identified in patients with conotruncal heart anomalies (15,16), but to the best of our knowledge, it has never been described in young patients with ventricular arrhythmias (Table S1) (7,8,15,16,(19)(20)(21)(22)(23)(24)(25). Moreover, this variant was also reported in patients with thyroid ectopy, athyreosis and thyroid hypoplasia, but without cardiac malformations (7,8).…”

Section: Discussionmentioning

confidence: 81%

A young boy with ventricular arrhythmias and thyroid dysgenesis: two genes are not enough?

Franceschi¹,

Maines²,

Bellizzi³

et al. 2022

Archives of Endocrinology and Metabolism

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Congenital hypothyroidism (CH) may be caused by biallelic variants in the TSHR gene. CH due to thyroid dysgenesis has also been linked to pathogenic variants of the nucleotide kinase 2, homeobox 5 (NKX2-5) gene, which can also cause sudden cardiac death from ventricular arrhythmia. In particular, the NKX2-5 p.Arg25Cys missense variant has been repeatedly reported in patients with congenital heart defects and, more rarely, with hypogonadism. We report the case of a 7 year old boy with ventricular arrhythmias, thyroid dysgenesis and intellectual disability, born from consanguineous Tunisian parents. Exome sequencing and segregation analysis revealed two potentially relevant variants: the NKX2-5 p.Arg25Cys variant (maternally inherited), as well as a single heterozygous TSHR p.Gln90Pro variant (paternally inherited). Of note, a male sibling of the proband, presenting with intellectual disability only, carried the same two variants. No other TSHR variants, or other potentially relevant variants were identified. In this proband, despite the identification of variants in two genes potentially correlated to the phenotype, a definite genetic diagnosis could not be reached. This case report highlights the complexity of exome data interpretation, especially when dealing with families presenting complex phenotypes and variable expression of clinical traits.

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Congenital Hypothyroidism Patients With Thyroid Hormone Receptor Variants Are Not Rare: A Systematic Review

Wang

et al. 2021

INQUIRY

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Background Primary congenital hypothyroidism (CH) is a common endocrine and metabolic disease. Various genetic factors, including the thyroid hormone receptor (TSHR), play an important role in CH. Aim To explore the occurrence of pathogenic TSHR variants in CH. Methods We searched published articles in PubMed, Web of Science, and Cochrane Library databases, from the establishment of the database to September 26, 2021. Studies with sequencing partial or full exons of TSHR in CH patients were included. Gene polymorphism was excluded. Results A total of 66 articles (44 case-control studies and 22 case reports) were selected from the database. Though case-control studies, we found the incidence of pathogenic TSHR variants were not rare (range from 0% to 30.6%) and varied greatly in different countries and race. The pathogenic genotypes varied in different regions. All the variants were “loss-of-function” mutations, in which the p.(Arg450His) variant was the most common variant. In addition, we analyzed the case reports and found that CH patients with a family genetic background expressed homozygous genotypes. Homozygotes had more obvious symptoms of hypothyroidism and higher risk of comorbidities than heterozygotes. Conclusion Pathogenic TSHR variants are not uncommon cause of the CH, especially in the Arabs. The role of TSHR gene detection in the treatment of children with CH needs to be further studied.

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Further Evidence That Defects in Main Thyroid Dysgenesis-Related Genes Are an Uncommon Etiology for Primary Congenital Hypothyroidism in Mexican Patients: Report of Rare Variants in FOXE1, NKX2-5 and TSHR

Cited by 3 publications

References 52 publications

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis

A young boy with ventricular arrhythmias and thyroid dysgenesis: two genes are not enough?

Congenital Hypothyroidism Patients With Thyroid Hormone Receptor Variants Are Not Rare: A Systematic Review

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