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Open access

Michela Del Prete, Fabrizio Muratori, Irene Campi, Gianleone Di Sacco, Federico Vignati, Domenico Pellegrino, and Luca Persani

Summary

Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.

Learning points

  • Resistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH).
  • Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test.
  • RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.
Open access

Keita Tatsushima, Akira Takeshita, Shuji Fukata, Noriaki Fukuhara, Mitsuo Yamaguchi-Okada, Hiroshi Nishioka, and Yasuhiro Takeuchi

Summary

A 50-year-old woman with thyroid-stimulating hormone (TSH)-producing pituitary adenoma (TSHoma) was diagnosed due to symptoms of thyrotoxicosis. Preoperatively, she showed thyrotoxicosis with the syndrome of inappropriate secretion of TSH (SITSH) and had a 5 cm nodule in her thyroid gland. Octreotide was administered preoperatively, which helped lower her serum TSH level but not her thyroid hormone level. These findings were atypical for a patient with TSHoma. The TSHoma was completely resected, and the TSH level dropped below the sensitivity limit shortly after surgery. Interestingly, however, thyroid hormone levels remained high. A clear clue to the aetiology was provided by consecutive thyroid scintigraphy. Although preoperative thyroid scintigraphy did not show a hot nodule and the mass was thought to be a non-functional thyroid nodule, the nodule was found to be hot in the postoperative phase of TSH suppression. By focusing on the atypical postoperative course of the TSHoma, we were able to conclude that this was a case of TSHoma combined with an autonomously functioning thyroid nodule (AFTN).

Learning points

  • The diagnosis of autonomously functioning thyroid nodules (AFTNs) depends on suppressed serum TSH levels.
  • If thyroid hormones are resistant to somatostatin analogue therapy or surgery for TSHoma, complications of AFTN as well as destructive thyroiditis need to be considered.
  • It is important to revisit the basics when facing diagnostic difficulties and not to give up on understanding the pathology.
Open access

N Mohammadnia, S Simsek, and F Stam

Summary

Gynecomastia is a symptom with a potential high disease burden. It has a variety of underlying causes, such as malignant, drug-related or hormonal. The presence of gynecomastia can be explained in thyrotoxicosis due to a concomitant disbalance of sex hormones. Interestingly, it rarely is the presenting symptom of Graves’ disease. A 49-year-old man presented to our outpatient clinic with right-sided gynecomastia. After thorough history taking, more symptoms of thyrotoxicosis were present. Treatment was started with thiamazole and later levothyroxine. Three months after this treatment the gynecomastia and other symptoms resolved completely. A disbalance of sex hormones due to an increased expression of the protein sex hormone-binding globulin (SHBG) caused by thyrotoxicosis could result in gynecomastia. In vitro and in vivo research in mice suggest that the pathophysiology of thyrotoxicosis-associated gynecomastia is due to upregulation of hepatocyte nuclear factor-4α (HNF4A) in liver cells. Subsequent increase of SHBG results in a decrease of free testosterone levels.

Learning points

  • Gynecomastia is a common finding (up to almost 40%) on physical examination in patients with hyperthyroidism.
  • In gynecomastia, thyroid function tests should be examined on initial presentation because of the relative simple treatment.
  • The pathophysiology of thyrotoxicosis-associated gynecomastia is well understood by a sex-hormonal disbalance due to an increased expression of SHBG.
  • Due to the well explainable pathophysiology, reduction of symptoms can be expected after treatment.
  • The underlying mechanism of an increased expression of SHBG is not well understood. However, in vitro and in vivo research in mice suggests that thyrotoxicosis causes an increased expression of HNF4A in liver cells. Thus, upregulating the expression of SHBG.
  • Interestingly, HNF4A is suspected to play an important role in MODY. Future research will clarify the importance of this gene and might open up new insights for therapy.
Open access

Hannah E Forde, Niamh Mehigan-Farrelly, Katie Ryan, Tom Moran, Megan Greally, Austin G Duffy, and Maria M Byrne

Summary

A 41-year-old male presented to the Emergency Department with a 6-month history of back and hip pain. Skeletal survey revealed bilateral pubic rami fractures and MRI of the spine demonstrated multiple thoracic and lumbar fractures. Secondary work up for osteoporosis was undertaken. There was no evidence of hyperparathyroidism and the patient was vitamin D replete. Testosterone (T) was low at 1.7 nmol/L (8.6–29.0) and gonadotrophins were undetectable. The patient failed a 1 mg dexamethasone suppression test (DST) with a morning cortisol of 570 nmol/L (<50) and subsequently a low dose DST with a cortisol post 48 h of dexamethasone of 773 nmol/L (<50) and an elevated ACTH 98 ng/L. A corticotropin-releasing factor (CRF) test suggested ectopic ACTH secretion. The patient was commenced on teriparatide for osteoporosis and metyrapone to control the hypercortisolaemia. A positron emission tomography (PET) scan to look for the source of ACTH secretion demonstrated right neck adenopathy. Biopsy and subsequent lymph node dissection were performed and histology revealed a metastatic neuroendocrine tumour. Immunostaining was positive for calcitonin and thyroid transcription factor 1 (TTF1). Serum calcitonin was also significantly elevated at 45 264 ng/L (<10). The patient proceeded to a total thyroidectomy and left neck dissection. Histology confirmed a 7 mm medullary thyroid carcinoma (MTC). Post-operatively, the patient commenced vandetanib therapy and achieved a clinical and biochemical response. After approximately 18 months of vandetanib therapy, the patient developed recurrent disease in his neck. He is currently on LOXO-292 and is doing well 36 months post-diagnosis.

Learning points

  • Unexplained osteoporosis requires thorough investigation and the workup for secondary causes is not complete without excluding glucocorticoid excess.
  • MTC should be considered when searching for sources of ectopic ACTH secretion.
  • Resistance to tyrosine kinase inhibitors is well described with MTC and clinicians should have a low threshold for screening for recurrent disease.
Open access

Tetsuji Wakabayashi, Akihito Takei, Nobukazu Okada, Miki Shinohara, Manabu Takahashi, Shuichi Nagashima, Kenta Okada, Ken Ebihara, and Shun Ishibashi

Summary

The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells.

Learning points

  • Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development.
  • SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome.
  • Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.
Open access

Ahmad Housin, Marc P Pusztaszeri, and Michael Tamilia

Summary

Fever of unknown origin is a commonly encountered medical problem. Most common causes include infections, malignancy, and connective tissue diseases. Endocrine causes are rare but are well documented. While fever is common in some endocrine disorders, fever of unknown origin as the sole presenting feature is very rare. We describe a case report of a 63-year-old male who presents with fever of unknown origin. Imaging and biopsy results confirmed the diagnosis of subacute thyroiditis. He was started on prednisone with a good response. We conclude that subacute thyroiditis should be considered in the work up of fever of unknown origin even in the absence of classical signs and symptoms.

Learning points:

  • Fever of unknown origin is a rare sole presentation of subacute thyroiditis.
  • The classic signs and symptoms may not be manifest at the time of presentation.
  • Normal thyroid function tests and elevated markers of inflammation often make infections, malignancy and autoinflammatory conditions the prime consideration.
  • Imaging of the thyroid gland may point to a morphologic aberration and prompt a thyroid biopsy.
  • After exclusion of infection, a rapid response to steroids may be both diagnostic and therapeutic.
Open access

Viktoria F Koehler, Patrick Keller, Elisa Waldmann, Nathalie Schwenk, Carolin Kitzberger, Kathrin A Schmohl, Thomas Knösel, Christian Georg Stief, and Christine Spitzweg

Summary

Struma ovarii is a teratoma of the ovaries predominantly composed of thyroid tissue. Hyperthyroidism associated with struma ovarii is rare, occurring in approximately 8% of cases. Due to the rarity of struma ovarii, available data are limited to case reports and small case series.We report on a 61-year-old female patient with known Hashimoto’s thyroiditis on levothyroxine replacement therapy for years with transition to clinical and biochemical hyperthyroidism despite antithyroid medication with carbimazole (10 mg/day), new diagnosis of urothelial carcinoma and an adnexal mass suspicious of ovarian cancer. The patient underwent resection of the adnexal mass and histopathology revealed a mature teratoma predominantly composed of thyroid tissue showing high levels of sodium iodide symporter protein expression. Following struma ovarii resection and disappearance of autonomous production of thyroid hormones, the patient developed hypothyroidism with severely decreased thyroid hormone levels fT4 and fT3 (fT4 0.4 ng/dL, reference interval 0.9–1.7 and fT3 < 1.0 pg/mL, reference interval 2.0–4.4). This has previously been masked by continued thyroid-stimulating hormone suppression due to long-term hyperthyroidism pre-surgery indicating secondary hypothyroidism, in addition to primary hypothyroidism based on the known co-existing chronic lymphocytic thyroiditis of the orthotopic thyroid gland. Levothyroxine administration was started immediately restoring euthyroidism.This case illustrates possible diagnostic pitfalls in a patient with two concurrent causes of abnormal thyroid function.

Learning points:

  • Struma ovarii is an ovarian tumor containing either entirely or predominantly thyroid tissue and accounts for approximately 5% of all ovarian teratomas.
  • In rare cases, both benign and malignant struma ovarii can secrete thyroid hormones, causing clinical and biochemical features of hyperthyroidism.
  • Biochemical features of patients with struma ovarii and hyperthyroidism are similar to those of patients with primary hyperthyroidism. In such cases, thyroid scintigraphy should reveal low or absent radioiodine uptake in the thyroid gland, but the presence of radioiodine uptake in the pelvis in a whole body radioiodine scintigraphy.
  • We give advice on possible diagnostic pitfalls in a case with two simultaneous causes of abnormal thyroid function due to the co-existence of struma ovarii.
Open access

Stephanie J Kim, Eric Morris Bomberg, Joshua Menke, Marika Russell, and Elizabeth J Murphy

Differentiated thyroid cancers generally have favorable prognoses, though follicular thyroid cancer is overall associated with a worse prognosis due in part to increased incidence of distant metastasis. We report a case of a 51-year-old woman with a history of widely invasive follicular thyroid carcinoma treated with a total thyroidectomy, radioactive iodine and external beam radiation. Five and a half years following her surgery, she was found to have an axillary lymph node mass, multiple lung masses, and a hilar mass in the setting of declining thyroglobulin (Tg) antibodies. Her metastases were initially thought to be due to a primary lung adenocarcinoma given a neoplastic cell immunophenotype that included an absence of Tg expression and co-expression of TTF-1 and Napsin A. However, PAX8 expression demonstrated that the axillary and hilar metastases were actually thyroid in origin rather than lung. Axillary metastases in differentiated thyroid carcinoma are exceedingly rare and previous reports have typically involved widely disseminated disease with extensive neck lymphadenopathy. With a decline in Tg antibodies levels in high-risk patients, one should consider progression and loss of differentiation of thyroid carcinoma rather than a response to treatment.

Learning points:

  • Axillary metastases in differentiated thyroid carcinoma are uncommon.
  • In patients with high-risk thyroid carcinomas, a decline in thyroglobulin antibody may not signal disease improvement, but rather a progression to a poorly differentiated form of cancer.
  • PAX8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas.
Open access

Anda Mihaela Naciu, Martina Verri, Anna Crescenzi, Chiara Taffon, Filippo Longo, Luca Frasca, Gaia Tabacco, Lavinia Monte, Andrea Palermo, Pierfilippo Crucitti, and Roberto Cesareo

Summary

We present the case of a 47-year-old Caucasian previously healthy woman with a voluminous thyroid nodule occupying almost the entire anterior neck region. The lesion had progressively increased in size during the previous 3 months and the patient presented intermittent symptoms of dysphagia and odynophagia with a slight change in voice. Fine needle aspiration showed papillary carcinoma. Based on imaging and cytological findings, the patient underwent total thyroidectomy. The surgical sample revealed a totally enlarged thyroid gland (weight: 208 g) with the presence of a poly-lobulated lesion centrally located and involving the isthmus and both lobes. Hobnail features were present in more than 30% of the neoplastic cells in agreement with the criteria for this subtype. Psammoma bodies and focal necrosis were also present. The extra-thyroidal extension included strap muscles and peri-esophageal glands. Immunohistochemistry using VE1 antibody for detecting BRAF-V600E mutation resulted positive. The final diagnosis was papillary thyroid carcinoma (PTC) hobnail variant (HVPTC)-pT4a. The HVPTC is a rare entity and, in most cases, appears like a unifocal lesion with a maximum tumor size of 8 cm reported so far. To our knowledge, this represents the largest tumor ever described (14 cm), showing rapid growth and with multinodular goiter-like aspect.

Learning points:

  • HVPTC is an aggressive variant of PTC, usually associated with radioactive iodine refractoriness, and a higher mortality rate compared to classic PTC. However, there is a marked individual variability in this association.
  • HVPTC usually appears as small unifocal lesion but a multinodular goiter presentation may occur.
  • The present case highlights that despite of the histology, our patient achieved a high ablation success rate after radioactive iodine therapy.
Open access

Edmond Puca, Entela Puca, Pellumb Pipero, Holta Kraja, and Najada Como

Summary

Comorbidities are a risk factor for patients with COVID-19 and the mechanisms of disease remain unclear. The aim of this paper is to present a case report of an COVID-19 patient with severe hypocalcaemia. This is a report of an 81-year-old female, suffered from myalgia and fatigue for more than 3–4 weeks. Fever and cough appear 2 days before she presented to the emergency room. On physical examination, she was febrile with a temperature of 38.8°C, accompanied by cough, sore throat, headache, fatigue, and muscle ache. Her past medical history was remarkable with no chronic disease. She had lymphopenia. Laboratory test revealed moderate liver dysfunction, hypoalbuminemia, and severe hypocalcaemia (serum corrected calcium level: 5.7  mg/dL). Parathyroid hormone (PTH) was 107.9 pg/mL (range: 15–65) and 25(OH)2D levels was 4.5 ng/mL (range: 25–80). Chest CT scan detected peripheral ground-glass opacity. Throat swab for coronavirus by RT-PCRassay tested positive for the virus. She was treated with lopinavir/ritonavir, third generation cephalosporin, anticoagulant, daily high-dose calcium acetate, vitamin D3, fresh frozen plasma and oxygen therapy. She was discharged after two negative throat swab tests for coronavirus by conventional RT-PCR.

Learning points:

  • Comorbidities are a risk factor for patients with COVID-19.
  • Laboratory findings are unspecific in COVID-19 patients; laboratory abnormalities include lymphopenia, elevated of LDH, CPK and the inflammatory markers, such as C reactive protein, ferritinemia and the erythrocyte sedimentation rate.
  • In addition to inflammatory markers, in COVID-19 patients it is crucial to check the level of vitamin D and calcium.
  • There may be a correlation between vitamin D deficiency and the severity of COVID-19 disease.