Thyroid Involvement in Two Patients with Bannayan-Riley-Ruvalcaba Syndrome

Peiretti, Valentina; Mussa, Alessandro; Feyles, Francesca; Tuli, Gerdi; Santanera, Arianna; Méndez-Vidal, Cristina; Ferrero, Giovanni Battista; Corrias, Andrea

doi:10.4274/jcrpe.984

Cited by 17 publications

(3 citation statements)

References 19 publications

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“…Multinodular goiter due to multiple follicular adenomas appears in 43–75% of patients, sometimes including oncocytic or clear cells or a hyalinizing trabecular tumor-like pattern [ 123 , 187 , 192 , 193 ]. The most common types of malignant tumors are PTC (60%), including the follicular variant of PTC, FTC (14–45%), poorly differentiated and anaplastic thyroid carcinoma (ATC) (6%) [ 123 , 185 , 187 , 192 ].…”

Section: Syndromic Familial Non-medullary Thyroid Carcinoma (Sfnmtc)mentioning

confidence: 99%

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

et al. 2021

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Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be “sporadic” is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.

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Section: Syndromic Familial Non-medullary Thyroid Carcinoma (Sfnmtc)mentioning

confidence: 99%

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

et al. 2021

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“… 25 Interestingly, neuromuscular phenotypes, such as joint hyperextensibility, muscle hypotonia, lipid storage myopathy, and delayed psychomotor development, have been observed in BRRS patients. 1 , 2 , 4 Muscle weakness and hypotonia cause affected BRRS infants to appear “floppy” and with delayed development of motor skills. None of our BRRS patients had a reported personal or family history of heart disease, and we speculate that the type and spectrum of the variants observed and their existence in particular protein domains may contribute to the observed clinical phenotypes in these distinct disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical features manifest neonatally and are often variable amongst individuals. 2 In addition to the cardinal clinical features, other reported phenotypes include high birth weight, developmental delay, mild-to-severe mental retardation, delayed psychomotor development, muscle hypotonia, lipid storage myopathy, joint hyperextensibility, pectus excavatum, and scoliosis. 1 , 3 – 5 Clinically, the differential diagnosis includes other genetic disorders with overlapping phenotypes of macrocephaly, gastrointestinal polyposis, and benign tumors, such as Cowden syndrome (CS; MIM 158350), juvenile polyposis syndrome (JPS; MIM 174900), Peutz–Jeghers syndrome (PJS; MIM 175200), and neurofibromatosis type 1 (NF1; MIM 162200).…”

Section: Introductionmentioning

confidence: 99%

Germline TTN variants are enriched in PTEN-wildtype Bannayan–Riley–Ruvalcaba syndrome

Yehia

Eng

2017

npj Genomic Med

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Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare congenital disorder classically characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis. Germline PTEN mutations have been reported in up to 60% of BRRS patients. The remaining cases are of unknown genetic etiology. We exome-sequenced 35 unrelated PTEN-wildtype patients with classic presentation of BRRS and identified TTN germline missense variants in 12/35 (34%) patients. TTN encodes TITIN, a key structural and functional muscle protein. Exome and TTN-targeted sequencing in an additional unrelated series of 231 BRRS-like patients revealed 37 (16%) additional patients with germline TTN variants. All variants were predicted to be deleterious and equally distributed between the A-band and I-band protein domains. Rare TTN variants (MAF ≤ 0.0001) are enriched in classic BRRS patients compared to BRRS-like (OR = 2.7, 95% CI 1.21-5.94, p = 1.6 × 10-2) and multiple population controls (OR = 2.2, 95% CI 1.01-4.20, p = 4.7 × 10-2). Germline TTN mutations of different genotypes, inheritance patterns, and protein domain enrichment have been identified in multiple cardiac and/or skeletal muscular disorders. Functional interrogation of I-band variant p.Cys5096Arg identified in one of our classic BRRS patients, using CRISPR-Cas9 genome-edited cell lines, reveals an increased growth and lack of contact inhibition phenotype associated with increased levels of or phosphorylation of focal adhesion kinase (FAK) in mutant cells. These findings suggest that TITIN could play a role in overgrowth-relevant pathways and phenotypes. In summary, our observations suggest TTN as a candidate predisposing gene in classic PTEN-wildtype BRRS patients, perhaps suggesting this syndrome join the growing list of Titinopathies.

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Looking for the hidden mutation: Bannayan–Riley–Ruvalcaba syndrome caused by constitutional and mosaic 10q23 microdeletions involving PTEN and BMPR1A

Golas

Auber

Ripperger

et al. 2019

American J of Med Genetics Pt A

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The PTEN hamartoma tumor syndrome (PHTS) is caused by heterozygous germline variants in PTEN. Here, we report two unrelated patients with juvenile polyposis, macrocephaly, intellectual disability, and hyperpigmented skin macules. Both patients were clinically suspected for the Bannayan–Riley–Ruvalcaba syndrome (BRRS), a PHTS subentity. By array‐CGH analysis, we identified an interstitial 10q23.1q23.3 deletion in a buccal mucosa sample of Patient 1 that encompassed PTEN, BMPR1A, and KLLN, among others. In contrast, neither sequencing nor array‐CGH analysis identified a pathogenic variant in PTEN or BMPR1A in a blood sample of Patient 2. However, in a surgical specimen of the thyroid gland high‐level mosaicism for a 10q23.2q23.3 deletion was observed. Additionally, the pathogenic PTEN variant c.956_959delCTTT p.(Thr319LysfsTer24) was detected in his thyroid tissue. The frame shift variant was neither detected in the patient's blood nor in his buccal mucosa sample. Low‐level mosaicism for the microdeletion was identified in a buccal swap sample, and reanalysis of the blood sample suggested marginal‐level mosaicism for deletion. The 10q23.2q23.3 deletion mosaicism was also identified in a subsequently resected colonic polyp. Thus, in both cases, the diagnosis of a 10q23 deletion syndrome, which clinically presented as BRRS, was established. Overall, the study expands the BRRS spectrum and highlights the relevance of considering mosaicism in PHTS. We conclude that in all patients with a clear clinical suspicion of PHTS, in which genetic analyses of DNA from blood and buccal swap samples fail to identify causative genetic variants, genetic analyses of additional tissues are recommended.

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Thyroid Involvement in Two Patients with Bannayan-Riley-Ruvalcaba Syndrome

Cited by 17 publications

References 19 publications

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

Germline TTN variants are enriched in PTEN-wildtype Bannayan–Riley–Ruvalcaba syndrome

Looking for the hidden mutation: Bannayan–Riley–Ruvalcaba syndrome caused by constitutional and mosaic 10q23 microdeletions involving PTEN and BMPR1A

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