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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

Tina Kienitz, Jörg Schwander, Ulrich Bogner, Michael Schwabe, Thomas Steinmüller, and Marcus Quinkler

Summary

Apart from adrenal myelolipomas, adrenal lipomatous tumors are rare and only seldom described in the literature. We present the case of a 50-year-old man, with a classical form of congenital adrenal hyperplasia (CAH), which was well treated with prednisolone and fludrocortisone. The patient presented with pollakisuria and shortness of breath while bending over. On MRI, fat-equivalent masses were found in the abdomen (14 × 19 × 11 cm on the right side and 10 × 11 × 6 cm on the left side). The right adrenal mass was resected during open laparotomy and the pathohistological examination revealed the diagnosis of an adrenal lipoma. Symptoms were subdued totally postoperatively. This is the first report of a bilateral adrenal lipoma in a patient with CAH that we are aware of.

Learning points:

  • Macronodular hyperplasia is common in patients with congenital adrenal hyperplasia (CAH).
  • Solitary adrenal tumors appear in approximately 10% of adult CAH patients and are often benign myelolipomas.
  • The Endocrine Society Clinical Practice Guideline does not recommend routine adrenal imaging in adult CAH patients.
  • Adrenal imaging should be performed in CAH patients with clinical signs for an adrenal or abdominal mass.
  • Adrenal lipoma is rare and histopathological examinations should rule out a differentiated liposarcoma.
Open access

Jin Hui Ho, Ana Vetriana Abd Wahab, Yin Khet Fung, and Serena Sert Kim Khoo

Summary

Polycystic ovarian syndrome (PCOS) is associated with menstrual irregularities, ovulatory dysfunction, hirsutism, insulin resistance, obesity and metabolic syndrome but is rarely associated with severe hyperandrogenaemia and virilisation resulting in male pattern baldness and clitoromegaly. Total serum testosterone greater than twice the upper limit of the reference range or free androgen index of over five-fold elevated suggests a diagnosis other than PCOS. We reported a case of a 15 years old obese girl presented with secondary amenorrhoea, virilising signs: frontal baldness, clitoromegaly and prominent signs of insulin resistance and marked acanthosis nigricans. Her total testosterone level was markedly elevated at 9.4 nmol/L (0.5–1.7 nmol/L) and MRI pelvis revealed a right ovarian mass with fat and cystic component and a left polycystic ovary. The patient underwent laparoscopic right ovarian cystectomy and histologically confirmed mature cystic teratoma. Post-operatively, her testosterone level declined but did not normalise, menses resumed but remained irregular. Her fasting insulin was elevated 85.2 mIU/L (3–25 mIU/L) and HOMA-IR was high at 13.1 (>2) with persistent acanthosis nigricans suggesting co-existing HAIR-AN syndrome, an extreme phenotype of polycystic ovarian syndrome.

Learning points:

  • Rapid onset of hyperandrogenic symptoms, especially if associated with signs of virilisation must raise the suspicion of an androgen-secreting tumour.
  • Total serum testosterone greater than twofold the upper limit of the reference range or free androgen indices over fivefold suggest a diagnosis other than polycystic ovarian syndrome (PCOS).
  • High levels of testosterone with normal levels of the DHEA-S suggest an ovarian source.
  • Ovarian androgen-secreting tumour and HAIR-AN syndrome, an extreme spectrum of PCOS can co-exist.
Open access

Michele Fosci, Francesca Pigliaru, Antonio Stefano Salcuni, Massimo Ghiani, Maria Valeria Cherchi, Maria Antonietta Calia, Andrea Loviselli, and Fernanda Velluzzi

Summary

A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.

Learning points:

  • A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists.
  • In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical.
  • The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis.
  • This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Open access

Ana M Lopes and Sofia Teixeira

Summary

Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.

Learning points:

  • HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations.
  • Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype.
  • Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis.
  • HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes.
  • The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
  • Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Open access

Sajjad Ahmad, Thomas Best, Andrew Lansdown, Caroline Hayhurst, Fiona Smeeton, Steve Davies, and Aled Rees

Summary

Excess cortisol is associated with hypertrophy and redistribution of adipose tissue leading to central obesity which is c