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Pycnodysostosis with novel gene mutation and sporadic medullary thyroid carcinoma: A case report.

ABSTRACT: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia caused by a mutation in the cathepsin K encoded by cathepsin K gene (CTSK). Medullary thyroid carcinoma (MTC) is also a relatively rare type of primary thyroid carcinoma.A 31-year-old woman presenting a short stature and a palpable nodule in the front of her neck that had gradually increased in size during the last 2 years was referred to our department. She has experienced multiple fractures at lower limbs in the last 2 decades.The patient's clinical examination revealed short stature, underweight, a prominent forehead, stubby fingers, and a fixed nodule in the right thyroid lobe. Intraoral examination revealed multiple clinically malposed and missing teeth, as well as chronic periodontitis with a narrow and grooved palate. Radiographic examination revealed typical widely separated cranial sutures and an open anterior/posterior fontanel with an obtuse gonial angle, acroosteolysis, and osteosclerosis with narrowed medullary cavities. Ultrasonography of the thyroid gland showed a marked hypoechoic solid nodule in the right lobe in which tumor cell clusters were confirmed by ultrasound-guided fine needle aspiration biopsy and was suspected to be MTC. Laboratory tests revealed dramatically elevated serum calcitonin >2000?pg/L (reference range: 0-5?pg/L) and carcinoembryonic antigen (CEA) 134.37?ng/mL (reference range: 0-5?ng/mL). Genotypic screening revealed compound heterozygous mutations in the CTSK gene (c.158delA, P.Asn53Thr/c.C830T, P.Ala277Val) but no mutation associated with the familial forms of MTC.The patient underwent a total thyroidectomy with right-sided functional neck dissection.CEA and serum calcitonin decreased significantly postthyroidectomy, and no further fracture has been reported by the patient so far.The present study is the first to report a rare case of the coexistence of pycnodysostosis with a compound CTSK gene mutation and sporadic MTC. Radiological techniques and gene analysis play key roles in the definitive diagnosis.

SUBMITTER: Shi X

PROVIDER: S-EPMC5815678 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Pycnodysostosis with novel gene mutation and sporadic medullary thyroid carcinoma: A case report.

Shi Xiulin X Huang Caoxin C Xiao Fangsen F Liu Wei W Zeng Jinyang J Li Xuejun X

Medicine 20171201 50

<h4>Rationale</h4>Pycnodysostosis is a rare autosomal recessive skeletal dysplasia caused by a mutation in the cathepsin K encoded by cathepsin K gene (CTSK). Medullary thyroid carcinoma (MTC) is also a relatively rare type of primary thyroid carcinoma.<h4>Patient concerns</h4>A 31-year-old woman presenting a short stature and a palpable nodule in the front of her neck that had gradually increased in size during the last 2 years was referred to our department. She has experienced multiple fractu ...[more]

PMID: 29390266

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Project description:BackgroundThe cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease.MethodsTumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RETM918T mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival.ResultsSixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22-81 years). The median tumor size was 30 mm (range 6-145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1-27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93-NA] versus 18.27 [CI 17.24-NA] years (p < 0.0001). Median overall survival of patients with a combined somatic RETM918T mutation and CDKN2C loss versus no somatic RETM918T mutation and CDKN2C loss versus somatic RETM918T mutation and CDKN2C 2N versus no somatic RETM918T mutation and CDKN2C 2N was 2.38 [CI 1.67-NA] years versus 10.81 [CI 2.46-NA] versus 17.24 [CI 9.82-NA] versus not reached [CI 13.46-NA] years (p < 0.0001).ConclusionsThe detection of somatic CDKN2C loss is associated with the presence of distant metastasis at presentation as well decreased overall survival, a relationship enhanced by concomitant RETM918T mutation. Further defining the genes involved in the progression of metastatic MTC will be an important step toward identifying pathways of disease progression and new therapeutic targets.

Project description:Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.The clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed.Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5?mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3?cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.From this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

Dataset Information

Pycnodysostosis with novel gene mutation and sporadic medullary thyroid carcinoma: A case report.

Publications

Pycnodysostosis with novel gene mutation and sporadic medullary thyroid carcinoma: A case report.

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