Diagnosis and Treatment > Investigation > DNA sequencing

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Pradeep Vasudevan Leicester Clinical Genetics, Women’s and Children’s Services, Leicester Royal Infirmary, Leicester, UK

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Corrina Powell Leicester Clinical Genetics, Women’s and Children’s Services, Leicester Royal Infirmary, Leicester, UK

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Adeline K Nicholas University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Ian Scudamore Department of Obstetrics and Gynaecology, Women’s and Prenatal Services, Leicester General Hospital, Leicester, UK

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James Greening Department of Paediatric Endocrinology, Leicester Royal Infirmary, Leicester, UK

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Soo-Mi Park Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

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Nadia Schoenmakers University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Summary

In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.

Learning points:

  • CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.

  • CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.

  • Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.

  • Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

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Run Yu Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, USA

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Danielle Sharaga Cancer Center of Santa Barbara with Sansum Clinic, Santa Barbara, California, USA

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Christopher Donner Sansum Clinic, Santa Barbara, California, USA

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M Fernando Palma Diaz Department of Pathology

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Masha J Livhits Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, USA

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Michael W Yeh Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, USA

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Summary

Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1–1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case.

Learning points:

  • Pheochromocytomatosis is a very rare form of pheochromocytoma recurrence.

  • Pheochromocytomatosis refers to new, multiple and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma.

  • Tumor capsule rupture during adrenalectomy predisposes a patient to develop pheochromocytomatosis.

  • Surgical resection of the multiple tumors of pheochromocytomatosis is recommended.

  • Pheochromocytoma recurrence should prompt genetic testing for syndromic pheochromocytoma.

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Ruth Mangupli Department of Neurosurgery, Section of Neuroendocrinology, Hospital Universitario de Caracas, Caracas, Venezuela

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Adrian F Daly Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium

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Elvia Cuauro Department of Neurosurgery, Section of Neuroendocrinology, Hospital Universitario de Caracas, Caracas, Venezuela

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Paul Camperos Department of Neurosurgery, Section of Neuroendocrinology, Hospital Universitario de Caracas, Caracas, Venezuela

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Jaime Krivoy Department of Neurosurgery, Section of Neuroendocrinology, Hospital Universitario de Caracas, Caracas, Venezuela

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Albert Beckers Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium

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Summary

A 20-year-old man with an 8-year history of progressive enlargement of his hands and feet, coarsening facial features, painful joints and thickened, oily skin was referred for investigation of acromegaly. On examination, the subject was of normal height and weight. He had markedly increased skin thickness around the forehead, eyelids and scalp with redundant skin folds. Bilateral painful knee swelling was accompanied by enlargement of the extremities, and his fingers were markedly clubbed. Routine hematological, biochemical and hormonal blood tests, including GH and IGF-1 were normal. The clinical picture suggested primary hypertrophic osteoarthropathy (PHOA) rather than acromegaly and radiological studies were supportive of this, demonstrating increased subperiosteal bone formation and increased bone density and cortical thickening. There was widespread joint disease, with narrowing of joint spaces, whereas the knees demonstrated effusions and calcification. A skull X-ray revealed calvarial hyperostosis and a normal sellar outline. Family history was negative. Genetic studies were performed on peripheral blood leukocyte DNA for mutations in the two genes associated with PHOA, 15-hydroxyprostaglandin dehydrogenase (HPGD; OMIM: 601688) and solute carrier organic anion transporter family member 2A1 (SLCO2A1; OMIM: 601460). The sequence of HPGD was normal, whereas the subject was homozygous for a novel pathological variant in SLCO2A1, c.830delT, that predicted a frameshift and early protein truncation (p.Phe277Serfs*8). PHOA, also known as pachydermoperiostosis, is a rare entity caused by abnormal prostaglandin E2 metabolism, and both HPGD and SLCO2A1 are necessary for normal prostaglandin E2 handling. High prostaglandin levels lead to bone formation and resorption and connective tissue inflammation causing arthropathy, in addition to soft tissue swelling.

Learning points:

  • The differential diagnosis of enlarged extremities, coarsened facial features, skin changes and increased sweating in suspected acromegaly is quite limited and primary hypertrophic osteoarthropathy (PHOA) is one of the few conditions that can mimic acromegaly at presentation.

  • PHOA is not associated with abnormalities in GH and IGF-1 secretion and can be readily differentiated from acromegaly by hormonal testing.

  • Clubbing in the setting of diffuse enlargement of joints and extremities in addition to skin changes should alert the physician to the possibility of PHOA, as clubbing is not a usual feature of acromegaly. Underlying causes of secondary hypertrophic osteoarthroapthy (e.g. bronchial neoplasia) should be considered.

  • PHOA is a very rare condition caused by abnormalities in prostaglandin metabolism and has two known genetic causes (HPGD and SLCO2A1 mutations).

  • SLCO2A1 gene mutations lead usually to autosomal recessive PHOA; fewer than 50 SLCO2A1 mutations have been described to date and the current case is only the second in a Hispanic patient.

  • Treatment of primary hypertrophic osteoarthropathy is focused on the management of joint pain usually in the form of non-steroidal anti-inflammatory drug therapy.

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Shinsuke Uraki The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Hiroyuki Ariyasu The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Asako Doi The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Hiroto Furuta The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Masahiro Nishi The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Takeshi Usui Department of Medical Genetics, Shizuoka General Hospital, Shizuoka City, Japan

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Hiroki Yamaue The 2nd Department of Surgery, Wakayama Medical University, Wakayama, Japan

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Takashi Akamizu The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Summary

A 54-year-old man had gastrinoma, parathyroid hyperplasia and pituitary tumor. His family history indicated that he might have multiple endocrine neoplasia type 1 (MEN1). MEN1 gene analysis revealed a heterozygous germline mutation (Gly156Arg). Therefore, we diagnosed him with MEN1. Endocrinological tests revealed that his serum prolactin (PRL) and plasma adrenocorticotropic hormone (ACTH) levels were elevated to 1699 ng/mL and 125 pg/mL respectively. Immunohistochemical analysis of the resected pancreatic tumors revealed that the tumors did not express ACTH. Overnight 0.5 and 8 mg dexamethasone suppression tests indicated that his pituitary tumor was a PRL-ACTH-producing plurihormonal tumor. Before transsphenoidal surgery, cabergoline was initiated. Despite no decrease in the volume of the pituitary tumor, PRL and ACTH levels decreased to 37.8 ng/mL and 57.6 pg/mL respectively. Owing to the emergence of metastatic gastrinoma in the liver, octreotide was initiated. After that, PRL and ACTH levels further decreased to 5.1 ng/mL and 19.7 pg/mL respectively. He died from liver dysfunction, and an autopsy of the pituitary tumor was performed. In the autopsy study, histopathological and immunohistochemical (IHC) analysis showed that the tumor was single adenoma and the cells were positive for ACTH, growth hormone (GH), luteinizing hormone (LH) and PRL. RT-PCR analysis showed that the tumor expressed mRNA encoding all anterior pituitary hormones, pituitary transcription factor excluding estrogen receptor (ER) β, somatostatin receptor (SSTR) 2, SSTR5 and dopamine receptor D (D2R). PRL-ACTH-producing tumor is a very rare type of pituitary tumor, and treatment with cabergoline and octreotide may be useful for controlling hormone levels secreted from a plurihormonal pituitary adenoma, as seen in this case of MEN1.

Learning points:

  • Although plurihormonal pituitary adenomas were reported to be more frequent in patients with MEN1 than in those without, the combination of PRL and ACTH is rare.

  • RT-PCR analysis showed that the pituitary tumor expressed various pituitary transcription factors and IHC analysis revealed that the tumor was positive for PRL, ACTH, GH and LH.

  • Generally, the effectiveness of dopamine agonist and somatostatin analog in corticotroph adenomas is low; however, if the plurihormonal pituitary adenoma producing ACTH expresses SSTR2, SSTR5 and D2R, medical therapy for the pituitary adenoma may be effective.

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Anil Piya Laboratory of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA
Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA

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Jasmeet Kaur Laboratory of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

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Alan M Rice Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA
Augusta University School of Medicine, Augusta, Georgia, USA

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Himangshu S Bose Laboratory of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

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Summary

Cholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH). Although the STAR protein consists of seven exons, biochemical analysis in nonsteroidogenic COS-1 cells showed that the first two were not essential for pregnenolone synthesis. Here, we present a patient with ambiguous genitalia, salt-lossing crisis within two weeks after birth and low cortisol levels. Sequence analysis of the STAR, including the exon–intron boundaries, showed the complete deletion of exon 1 as well as more than 50 nucleotides upstream of STAR promoter. Mitochondrial protein import with the translated protein through synthesis cassette of the mutant STAR lacking exon 1 showed protein translation, but it is less likely to have synthesized without a promoter in our patient. Thus, a full-length STAR gene is necessary for physiological mitochondrial cholesterol transport in vivo.

Learning points:

  • STAR exon 1 deletion caused lipoid CAH.

  • Exon 1 substitution does not affect biochemical activity.

  • StAR promoter is responsible for gonadal development.

Open access
Rowena Speak Departments of Oncology and Metabolism, University of Sheffield

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Jackie Cook Department of Genetics, Sheffield Children’s Hospital, Sheffield, UK

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Barney Harrison Endocrine Surgery, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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John Newell-Price Departments of Oncology and Metabolism, University of Sheffield
Endocrinology

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Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification.

Learning points:

  • C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.

  • C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.

  • There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.

Open access
Jasmeet Kaur Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

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Alan M Rice Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA
Augusta University School of Medicine, Augusta, Georgia, USA
Neonatology Intensive Care Unit, Memorial University Medical Center, Georgia, USA

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Elizabeth O’Connor Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA

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Anil Piya Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA
Neonatology Intensive Care Unit, Memorial University Medical Center, Georgia, USA

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Bradley Buckler Neonatology Intensive Care Unit, Memorial University Medical Center, Georgia, USA

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Himangshu S Bose Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

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Congenital adrenal hyperplasia (CAH) is caused by mutations in cytochrome P450 side chain cleavage enzyme (CYP11A1 and old name, SCC). Errors in cholesterol side chain cleavage by the mitochondrial resident CYP11A1 results in an inadequate amount of pregnenolone production. This study was performed to evaluate the cause of salt-losing crisis and possible adrenal failure in a pediatric patient whose mother had a history of two previous stillbirths and loss of another baby within a week of birth. CAH can appear in any population in any region of the world. The study was conducted at Memorial University Medical Center and Mercer University School of Medicine. The patient was admitted to Pediatric Endocrinology Clinic due to salt-losing crisis and possible adrenal failure. The patient had CAH, an autosomal recessive disease, due to a novel mutation in exon 5 of the CYP11A1 gene, which generated a truncated protein of 286 amino acids compared with wild-type protein that has 521 amino acids (W286X). Although unrelated, both parents are carriers. Mitochondrial protein import analysis of the mutant CYP11A1 in steroidogenic MA-10 cells showed that the protein is imported in a similar fashion as observed for the wild-type protein and was cleaved to a shorter fragment. However, mutant’s activity was 10% of that obtained for the wild-type protein in non-steroidogenic COS-1 cells. In a patient of Mexican descent, a homozygous CYP11A1 mutation caused CAH, suggesting that this disease is not geographically restricted even in a homogeneous population.

Learning points:

  • Novel mutation in CYP11A1 causes CAH;

  • This is a pure population from Central Mexico;

  • Novel mutation created early truncated protein.

Open access
Motoyuki Igata Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Kaku Tsuruzoe Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Junji Kawashima Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Daisuke Kukidome Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Tatsuya Kondo Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Hiroyuki Motoshima Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Seiya Shimoda Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Noboru Furukawa Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Takeshi Nishikawa Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Nobuhiro Miyamura Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Eiichi Araki Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Summary

Resistance to thyroid hormone (RTH) is a syndrome of reduced tissue responsiveness to thyroid hormones. RTH is majorly caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. Here, we report a rare case of RTH with a papillary thyroid carcinoma (PTC). A 26-year-old woman was referred to our hospital due to a thyroid tumor and hormonal abnormality. She had elevated serum thyroid hormones and non-suppressed TSH levels. Genetic analysis of THRB identified a missense mutation, P452L, leading to a diagnosis of RTH. Ultrasound-guided fine-needle aspiration biopsy of the tumor and lymph nodes enabled the cytological diagnosis of PTC with lymph node metastases. Total thyroidectomy and neck lymph nodes dissection were performed. Following surgery, thyroxine replacement (≥500 μg) was necessary to avoid the symptoms of hypothyroidism and to maintain her TSH levels within the same range as before the operation. During the follow-up, basal thyroglobulin (Tg) levels were around 6 ng/ml and TSH-stimulated Tg levels were between 12 and 20 ng/ml. Up to present, the patient has had no recurrence of PTC. This indicates that these Tg values are consistent with a biochemical incomplete response or an indeterminate response. There is no consensus regarding the management of thyroid carcinoma in patients with RTH, but aggressive treatments such as total thyroidectomy followed by radioiodine (RAI) and TSH suppression therapy are recommended.

Learning points

  • There are only a few cases reporting the coexistence of RTH and thyroid carcinoma. Moreover, our case would be the first case presenting one with lymph node metastases.

  • Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear.

  • When total thyroidectomy is performed in patients with RTH, a large amount of thyroxine is needed to maintain their thyroid function.

  • There is no consensus regarding the management of thyroid carcinoma in patient with RTH, but effective treatments such as total thyroidectomy followed by RAI and TSH suppression therapy are recommended.

Open access
Jerena Manoharan Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Caroline L Lopez Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Karl Hackmann Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Fetscherstrasse 7401307, Dresden, Germany
German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany

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Max B Albers Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Anika Pehl Department of Pathology, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Peter H Kann Division of Endocrinology and Diabetology, Department of Gastroenterology and Endocrinology, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Emily P Slater Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Evelin Schröck Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Fetscherstrasse 7401307, Dresden, Germany
German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany

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Detlef K Bartsch Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Summary

We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation.

Learning points

  • Our patient presents an extraordinary course of disease.

  • Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.

  • This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

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Jasmeet Kaur Division of Biomedical Science, Department of Biochemistry, Mercer University School of Medicine and Memorial University Medical Center, Hoskins Research Building, 4700 Waters Avenue, Savannah, Georgia, 31404, USA

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Luis Casas Division of Endocrinology, Department of Pediatrics, University of North Dakota, Fargo, North Dakota, USA

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Himangshu S Bose Division of Biomedical Science, Department of Biochemistry, Mercer University School of Medicine and Memorial University Medical Center, Hoskins Research Building, 4700 Waters Avenue, Savannah, Georgia, 31404, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, 31404, USA

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Summary

Lipoid congenital adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is most commonly caused by mutations in steroidogenic acute regulatory protein (STAR), which is required for the movement of cholesterol from the outer to the inner mitochondrial membranes to synthesize pregnenolone. This study was performed to evaluate whether the salt-losing crisis and the adrenal inactivity experienced by a Scandinavian infant is due to a de novo STAR mutation. The study was conducted at the University of North Dakota, the Mercer University School of Medicine and the Memorial University Medical Center to identify the cause of this disease. The patient was admitted to a pediatric endocrinologist at the Sanford Health Center for salt-losing crisis and possible adrenal failure. Lipoid CAH is an autosomal recessive disease, we identified two de novo heterozygous mutations (STAR c.444C>A (STAR p.N148K) and STAR c.557C>T (STAR p.R193X)) in the STAR gene, causing lipoid CAH. New onset lipoid CAH can occur through de novo mutations and is not restricted to any specific region of the world. This Scandinavian family was of Norwegian descent and had lipoid CAH due to a mutation in S TAR exons 4 and 5. Overexpression of the STAR p.N148K mutant in nonsteroidogenic COS-1 cells supplemented with an electron transport system showed activity similar to the background level, which was ∼10% of that observed with wild-type (WT) STAR. Protein-folding analysis showed that the finger printing of the STAR p.N148K mutant is also different from the WT protein. Inherited STAR mutations may be more prevalent in some geographical areas but not necessarily restricted to those regions.

Learning points

  • STAR mutations cause lipoid CAH.

  • This is a pure population from a caucasian family.

  • Mutation ablated STAR activity.

  • The mutation resulted in loosely folded conformation of STAR.

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