case_images: PMC11646312_01
case_images: Case I parathyroid localization studies. (A) Thyroid US showed a heterogenous hypoechoic lesion posterior to the left thyroid lobe measuring 0.9 cm deep x 0.9 cm wide x 1.5 cm long (arrow, sagittal view). (B) Internal vascularity within the lesion was evident using doppler imaging (arrow, sagittal view). (C) On technetium-99m sestamibi scintigraphy physiologic uptake or the radiotracer was seen in the thyroid gland on the immediate images (arrow). (D) One hour delayed sestamibi images showed poor washout of radiotracer (arrow) but no areas of focal radiotracer retention. (E, F) No focal areas of uptake were observed on SPECT/CT images in the region correlating with the lesion identified on US (arrows).
case_images: ziae149f1.jpg
case_images: PMC11646312_01_ziae149f1.jpg
case_images: f1
case_images: PHPT was made, DXA showed Z-scores of -1.9 at the hip, and -2.2 at the spine and 1/3 forearm. Parathyroid localization with neck ultrasound (US) revealed a 1.5 cm solid, heterogenous, hypoechoic nodule posterior to the left thyroid lobe (Figure 1A and B). However, technetium-99m sestamibi scintigraphy and single photon emission computed tomography/CT (SPECT/CT) did not show any areas of focal uptake (Figure 1C-F). Measurement of evolutionary conservation using the UCSC Genome Browser indicates that the nucleotide at the -3 position is conserved (phyloP 2.3967), substantially more so than bases immediately upstream (Figure S1).
case_images: Sashimi plots drawn from RNA-sequencing data. (A) A sample of the proband's peripheral blood demonstrated the native splice site (arrow, ~80% use) and introduction of a cryptic splice site (~20% use). Read densities at splice junction sites are shown; junction reads are plotted as arcs. (B) A zoomed-in image of the splice junction site reveals the insertion of two intronic nucleotides (dashed box) in the affected family members but not in an unaffected control patient (proband, (top); sister, (middle); control, (bottom)).
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case_images: PMC11646312_02_ziae149f2.jpg
case_images: f2
case_images: RNA analysis was performed using the same methods that were employed for the proband and similarly demonstrated aberrant splicing (Figure 2B).
case_images: Case 1 left upper parathyroidectomy pathology. (A) Gross pathology following surgical parathyroid exploration in which the left upper parathyroid gland (arrow) and a portion of the thymus were removed. The excised parathyroid gland measured 1.5 x 1.2 x 0.7 cm and weighed 0.95 g. (B) H&E-stained sections revealed hypercellular parathyroid parenchyma consistent with a parathyroid adenoma. (C) Immunohistochemical staining for parafibromin revealed focally weak to negative nuclear expression in lesional cells (two-toned arrows) with retained staining in surrounding cells (internal positive control, solid arrows).
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case_images: PMC11646312_01_ziae149f3.jpg
case_images: f3
case_images: There were no gross features of parathyroid cancer intraoperatively, and the resected parathyroid gland measured 1.5 cm and weighed 0.95 g (Figure 3A). Parathyroid pathology revealed a hypercellular gland consistent with an adenoma, with loss of nuclear parafibromin immunohistochemical staining (Figure 3B and C).
case_images: PMC11646312_02
case_images: Sashimi plots drawn from RNA-sequencing data. (A) A sample of the proband's peripheral blood demonstrated the native splice site (arrow, ~80% use) and introduction of a cryptic splice site (~20% use). Read densities at splice junction sites are shown; junction reads are plotted as arcs. (B) A zoomed-in image of the splice junction site reveals the insertion of two intronic nucleotides (dashed box) in the affected family members but not in an unaffected control patient (proband, (top); sister, (middle); control, (bottom)).
case_images: ziae149f2.jpg
case_images: PMC11646312_02_ziae149f2.jpg
case_images: f2
case_images: RNA analysis was performed using the same methods that were employed for the proband and similarly demonstrated aberrant splicing (Figure 2B).
case_images: Case 2 parathyroid localization studies. (A) Thyroid US revealed a left inferior thyroid lobe lesion measuring 1.5 cm deep x 1.6 cm wide x 2.0 cm long (arrow, sagittal view). The lesion had a complex cystic and solid appearance with layering internal debris. (B) The solid component of the lesion demonstrated vascularity (arrow, sagittal view with Doppler). (C) Sestamibi scintigraphy showed physiologic radiotracer uptake of the thyroid gland on the immediate images (arrow). (D) One hour delayed sestamibi images showed radiotracer washout without areas of focal sestamibi retention (arrow). (E) The lesion observed on thyroid US correlated with a hypoattenuating lesion posterior to the left thyroid lobe on the CT scan that was done for (arrow). (F) The hypoattenuating lesion did not have increased radiotracer uptake on the fused SPECT/CT image (arrow).
case_images: ziae149f4.jpg
case_images: PMC11646312_02_ziae149f4.jpg
case_images: f4
case_images: Neck US showed a 2 cm complex cystic and solid structure posterior and inferior to the left thyroid lobe (Figure 4A and B). Sestamibi scintigraphy did not show any areas of abnormal radiotracer uptake (Figure 4C-F).
case_images: Case 2 left lower parathyroidectomy pathology. (A) The specimen measured 2.5 x 1.5 x 1.2 cm, weighed 2.8 g, and contained a cystic structure consisting of dark brown fluid. (B) H&E-stained sections displayed hypercellular parathyroid parathyroid with associated areas of fibrosis and cyst formation. No significant cytologic atypia, mitotic activity, or angioinvasion was identified. (C) Immunohistochemical staining for parafibromin revealed negative nuclear expression in the lesional cells (two-toned arrows) and retained staining in surrounding cells (internal positive control, solid arrows).
case_images: ziae149f5.jpg
case_images: PMC11646312_02_ziae149f5.jpg
case_images: f5
case_images: The left lower parathyroid gland was excised, measuring 2.5 cm with cystic degeneration (Figure 5A). H&E staining showed a hypercellular parathyroid gland with cystic change, without malignant features (Figure 5B). Immunohistochemistry showed loss of nuclear parafibromin staining (Figure 5C).