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Open access

Hiroki Nakajima, Yasuhiro Niida, Eriko Hamada, Kuwata Hirohito, Masahide Ota, Sadanori Okada, Takako Mohri, Yukako Kurematsu, Shigeto Hontsu, Shigeo Muro, and Yutaka Takahashi

Summary

Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted.

Learning points

  • The immune checkpoint inhibitor atezolizumab has recently been approved for the treatment of small-cell lung cancer (SCLC).

  • Approximately 1–6% of tumour ectopically produce ACTH and cause ectopic ACTH syndrome (EAS) as an endocrine paraneoplastic syndrome.

  • The use of combined chemotherapy and atezolizumab in the ectopic ACTH syndrome secondary to small-cell lung cancer may cause a precipitous fall in circulating ACTH/cortisol, resulting in symptomatic adrenal insufficiency

  • The advances in cancer therapy and treatment for endocrine paraneoplastic syndrome need to be adapted.

Open access

Nobuyuki Nishi, Ken Takeshima, Shuhei Morita, Hiroshi Iwakura, Masahiro Nishi, and Takaaki Matsuoka

Summary

IgG4-related hypophysitis is an autoimmune hypophysitis associated with IgG4-related disease. Swelling of the pituitary gland is responsive to steroid therapy, but the prognosis of pituitary function after the treatment remains unclear. The present case implies that transiently improved pituitary function can re-worsen during long-term follow-up in IgG4-related hypophysitis. A 71-year-old male patient with IgG4-related hypophysitis visited a nearby hospital with malaise, anorexia, and polyuria. Pituitary dysfunction was suspected, so he was referred to our hospital for further examination. Imaging studies and laboratory data showed swelling of the pituitary gland and panhypopituitarism, which dramatically improved following steroid therapy. There was no evidence of relapsing IgG4-related disease during prednisolone tapering. Pituitary function was examined after 4 years under treatment with low-dose prednisolone; surprisingly, anterior pituitary function had worsened again. Our case suggests a need for continuous monitoring of pituitary function after steroid therapy for IgG4-related hypophysitis. This report illustrates the natural course of pituitary function in IgG4-related hypophysitis and may be informative when considering the introduction of steroid therapy.

Learning points

  • Steroid therapy is an effective first-line therapy for pituitary dysfunction and pituitary swelling in IgG4-related hypophysitis.

  • Pituitary function can worsen again during follow-up, despite transient improvement after steroid therapy in IgG4-related hypophysitis.

  • Continuous monitoring of pituitary function is necessary for IgG4-related hypophysitis, regardless of disease activity.

Open access

Kei Ito, Jun Ito, Yuki Yamamoto, Rikako Nakajima, Masanao Fujii, Yukino Katakura, Aiko Muramatsu, Norio Takayashiki, Kazuhiro Toyama, Mineo Kurokawa, and Hiroaki Yagyu

Summary

A 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests.

Learning points

  • Erdheim–Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions.

  • MH caused both GH deficiency and central diabetes insipidus.

  • Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years.

  • Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.

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

Tomomi Taguchi, Sachiko Kimizuka, and Koji Takano

Summary

Acromegaly is associated with a low quality of life (QoL), which is partially attributable to appearance. However, appearance changes are only partially reversible with treatments of growth hormone excess. This case study describes a 41-year-old Japanese man who presented with mandibular prognathism. Acromegaly was suspected because of the patient’s facial features. Subsequent examination revealed a pituitary tumour with elevated levels of growth hormone and insulin-like growth factor 1 (IGF1), confirming a diagnosis of acromegaly. We assessed his QoL with the acromegaly QoL questionnaire (AcroQoL) before transsphenoidal surgery, and all AcroQoL scores were low. Although the pituitary adenoma was resected, his serum IGF1 levels started to increase again and MRI identified a residual pituitary lesion. After lanreotide and pegvisomant injection therapies improved his serum IGF1 levels, we reassessed his AcroQoL scores, however, the results showed worsening scores regarding appearance and personal relationships, and the patient expressed interest in surgery for mandibular prognathism. We performed sagittal split ramus osteotomy (SSRO) with Le Fort I osteotomy, thus, the patient’s AcroQoL scores improved. This case shows that SSRO with Le Fort I osteotomy for mandibular prognathism, rather than control of serum IGF1 level alone, improved the patient’s AcroQoL score, especially for both psychological well-being and approval of appearance. Acromegaly has many complications, including its negative impact on patients’ perception of their appearance and patients’ QoL can be improved using multiple options, in addition to controlling growth hormone levels.

Learning points

  • The patient’s AcroQoL scores worsened despite biochemical normalization of IGF-1 levels.

  • Mandibular prognathism due to acromegaly can be successfully operated by performing sagittal split ramus osteotomy with Le Fort I osteotomy.

  • Frequent monitoring of AcroQoL scores and appropriate response to negative results can improve the overall QoL.

Open access

Katsuo Tao, Midori Awazu, Misa Honda, Hironori Shibata, Takayasu Mori, Shinichi Uchida, Tomonobu Hasegawa, and Tomohiro Ishii

Summary

We report a male infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypercalcemia and hyperphosphatemia since birth. Serum sodium started to increase at 39 days. Although there was no polyuria, urine osmolality was 71 mOsm/kg, when serum osmolality was 296 mOsm/kg with plasma arginine vasopressin 22.5 pg/mL. He was thus diagnosed as NDI. An undetectable level of urine calcium and unsuppressed intact parathyroid hormone suggested hyperparathyroidism including calcium-sensing receptor mutations that could cause hypercalcemia-induced NDI. Polyuria became apparent after the initiation of i.v. infusion for the treatment of hypernatremia. Low calcium and low sodium formula with hypotonic fluid infusion did not correct hypernatremia, hypercalcemia, or hyperphosphatemia. Hydrochlorothiazide and subsequently added celecoxib effectively decreased urine output and corrected electrolytes abnormalities. Normal serum electrolytes were maintained after the discontinuation of low calcium formula. The genetic analysis revealed a large deletion of the arginine vasopressin receptor-2 (AVPR2) gene but no pathogenic variant in the calcium-sensing receptor (CASR) gene. Whether hypercalcemia and hyperphosphatemia were caused by dehydration alone or in combination with other mechanisms remains to be clarified.

Learning points

  • Congenital NDI can present with neonatal hypercalcemia and hyperphosphatemia.

  • Hypercalcemia and hyperphosphatemia can be treated with low calcium and low sodium formula, hydration, hydrochlorothiazide, and celecoxib.

  • Genetic testing is sometimes necessary in the differentiating diagnosis of hypercalcemia associated with NDI.

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

Shunsuke Shimazaki, Itsuro Kazukawa, Kyoko Mori, Makiko Kihara, and Masanori Minagawa

Summary

Ammonium acid urate (AAU) crystals are rare in industrialized countries. Furthermore, the number of children with diabetic ketoacidosis (DKA) who develop severe acute kidney injury (AKI) after hospitalization is small. We encountered two patients with AKI caused by AAU crystals during the recovery phase of DKA upon admission. They were diagnosed with severe DKA and hyperuricemia. Their urine volume decreased and AKI developed several days after hospitalization; however, acidosis improved in both patients. Urine sediment analysis revealed AAU crystals. They were treated with urine alkalization and diuretics. Excretion of ammonia in the urine and urine pH levels increased after treatment of DKA, which resulted in the formation of AAU crystals. In patients with severe DKA, the urine and urine sediment should be carefully examined as AAU can form in the recovery phase of DKA.

Learning points:

  • Ammonium acid urate crystals could be formed in the recovery phase of diabetic ketoacidosis.

  • Diabetic ketoacidosis patients may develop acute kidney injury caused by ammonium acid urate crystals.

  • Urine and urine sediment should be carefully checked in patients with severe DKA who present with hyperuricemia and volume depletion.

Open access

Shuhei Baba, Arina Miyoshi, Shinji Obara, Hiroaki Usubuchi, Satoshi Terae, Masao Sunahara, Takahiro Oshima, Kazuhito Misawa, Takahiro Tsuji, Bunya Takahashi, Yuto Yamazaki, Hironobu Sasano, and Norio Wada

Summary

A 31-year-old man with Williams syndrome (WS) was referred to our hospital because of a 9-year history of hypertension, hypokalemia, and high plasma aldosterone concentration to renin activity ratio. A diagnosis of primary aldosteronism (PA) was clinically confirmed but an abdominal CT scan showed no abnormal findings in his adrenal glands. However, a 13-mm hypervascular tumor in the posterosuperior segment of the right hepatic lobe was detected. Adrenal venous sampling (AVS) subsequently revealed the presence of an extended tributary of the right adrenal vein to the liver surrounding the tumor. Segmental AVS further demonstrated a high plasma aldosterone concentration (PAC) in the right superior tributary vein draining the tumor. Laparoscopic partial hepatectomy was performed. The resected tumor histologically separated from the liver was composed of clear cells, immunohistochemically positive for aldesterone synthase (CYP11B2), and subsequently diagnosed as aldosterone-producing adrenal adenoma. After surgery, his blood pressure, serum potassium level, plasma renin activity and PAC were normalized. To the best of our knowledge, this is the first report of WS associated with PA. WS harbors a high prevalence of hypertension and therefore PA should be considered when managing the patients with WS and hypertension. In this case, the CT findings alone could not differentiate the adrenal rest tumor. Our case, therefore, highlights the usefulness of segmental AVS to distinguish adrenal tumors from hepatic adrenal rest tumors.

Learning points:

  • Williams syndrome (WS) is a rare genetic disorder, characterized by a constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension.

  • WS is a disease with a high frequency of hypertension but the renin-aldosterone system in WS cases has not been studied at all.

  • If a patient with WS had hypertension and severe hypokalemia, low PRA and high ARR, the coexistence of primary aldosteronism (PA) should be considered.

  • Adrenal rest tumors are thought to arise from aberrant adrenal tissues and are a rare cause of PA.

  • Hepatic adrenal rest tumor (HART) should be considered in the differential diagnosis when detecting a mass in the right hepatic lobe.

  • Segmental adrenal venous sampling could contribute to distinguish adrenal tumors from HART.

Open access

Yuki Fujita, Daisuke Tanaka, Hisato Tatsuoka, Miho Matsubara, Takanori Hyo, Yoshiyuki Hamamoto, Toshiyuki Komiya, Nobuya Inagaki, Yutaka Seino, and Yuji Yamazaki

Summary

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient’s MODY5.

Learning points:

  • Genetic diagnosis of MODY is relevant for appropriate treatment.

  • Dominantly inherited early-onset diabetes mellitus with renal cysts suggests MODY5.

  • Scanning the non-coding regions is important for not missing a mutation in HNF1B.