case_images: PMC11257912_01
case_images: Pedigree, clinical characteristics of the family. The present age of the individuals is shown below the symbols, followed by the age at menarche, other phenotypic features, and genotype interpretation. ID, intellectual disability; NT, not tested; PTC, papillary thyroid carcinoma; genotypes are expressed by normal allele (wt) and mutated allele (mt). An arrow indicates the index case. The index case had anosmia, pubertal delay, intellectual disability, and strabismus. Also, PTC was diagnosed at the age of 16 years. Her mother had hyposmia, and the age of menarche was 16 years.
case_images: fendo-15-1426916-g001.jpg
case_images: PMC11257912_01_fendo-15-1426916-g001.jpg
case_images: f1
case_images: Her mother had regular menstrual periods since the age of 17 years (shown in  Figure 1 ).
case_images: Pathology specimens, radiographs of the vertebrae, and magnetic resonance imaging of brain. Bilateral and multifocal papillary thyroid carcinoma; the largest tumor is 1.2 cm in diameter, encapsulated, and has irregular borders and infiltrative features within the gland. (A) A focal papillary area (black arrow), and normal thyroid tissue next to it (red arrow). (B) Nuclear overlapping (black arrow), intranuclear inclusions (red arrow), and nuclear grooves (blue arrow) in the tumor cells. (C) CK 19 immunostaining is positive in tumor cell cytoplasm. (D) Galectin 3 immunostaining is positive in tumor cell cytoplasm. Direct radiographies of vertebra at the time of diagnosis (E) and one-year after sex steroid replacement (F). Mild height loss of the vertebral bodies was improved after one year of sex steroid replacement therapy. (G, H) sagittal and transverse sections of magnetic resonance imaging of brain display a normal skull shape.
case_images: fendo-15-1426916-g002.jpg
case_images: PMC11257912_01_fendo-15-1426916-g002.jpg
case_images: f2
case_images: Mild height loss was present in vertebral bodies on direct graphs (shown in  Figure 2 ), and at the age of 16.5 years, estradiol was commenced at a dose of 0.5 mg/day peroral. Pathological evaluation revealed multifocal papillary thyroid carcinoma (shown in  Figure 2 ) (the largest tumor is 1.2 cm in diameter, encapsulated, and has irregular borders and infiltrative features within the gland).
case_images: Genomic analysis of the patient. (A) The image showing the intragenic CNV of the TCF12 in the BAM file of the WES data which is visualized by the Integrative Genomics Viewer (Broad Institute, MA) tool. Note that the peak volumes of the reads of the exon 7 and 8 on the NM_207037 transcript and the first exon on the NM_207040 transcript of the patient were as half as the controls studied in the same sequencing run. However, the peak volumes of the reads of exon 9-12 were similar to the controls. Deleted exon 6 could not be shown in the figure because of the distance of it to the other exons. (B) The image shows the intragenic CNV of the TCF12 in the SNP microarray data.
case_images: fendo-15-1426916-g003.jpg
case_images: PMC11257912_01_fendo-15-1426916-g003.jpg
case_images: f3
case_images: On the other hand, WES analysis revealed a CNV involving exon 1 and exon 6-8 in TCF12 associated with HH and/or craniosynostosis (shown in  Figure 3A ), and a heterozygous missense variant, c.214C>A (p.Leu72Met) rs696217, in GHRL gene (NM_016362) associated with susceptibility to obesity (not shown). TCF12 included the exon 6-8 of the canonical transcript, NM_207037, and the first exon of the NM_207040 transcript (shown in  Figure 3A ). Thereupon, the SNP microarray data was reviewed and it was noticed that the CNV in TCF12 was missed in the first analysis (shown in  Figure 3B ).