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Open access

Mariana Aveiro-Lavrador, Adriana De Sousa Lages, Luísa Barros, and Isabel Paiva


Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway leading to impaired corticosteroid biosynthesis. Depending on the extension of enzyme defect, there may be variable severities of CAH – classic and non-classic. We report the case of a 37-year-old male patient with a previously unknown diagnosis of classic CAH referred to Endocrinology evaluation due to class III obesity and insulin resistance. A high diagnostic suspicion was raised at the first Endocrinology consultation after careful past medical history analysis especially related to the presence of bilateral adrenal myelolipomas and primary infertility. A genetic test confirmed the presence of a variant of the CYP21A2 in homozygous with an enzymatic activity of 0–1%, corresponding to a classic and severe CAH form. Our case represents an unusually late definitive diagnose of classic CAH since the definition was established only during adulthood in the fourth decade of life. The missing diagnosis of classic 21 hydroxylase deficiency during infancy led to important morbidity, with a high impact on patients’ quality of life.

Learning points

  • Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive enzyme disorders responsible for an impaired cortical adrenal hormonal synthesis.

  • CAH may be divided into two major forms: classic and non-classic CAH.

  • If untreated, CAH may be fatal or may be responsible for important multi-organ long-term consequences that can be undervalued during adulthood.

  • Adrenal myelolipomas are associated with chronic exposure to high ACTH levels and continuous androgen hyperstimulation typically found in undertreated CAH patients.

  • Testicular adrenal rest tumours (TART) and primary infertility can be the first manifestation of the disease during adulthood.

Open access

Ana M Lopes, Josué Pereira, Isabel Ribeiro, Ana Martins da Silva, Henrique Queiroga, and Cláudia Amaral


Pituitary metastasis (PM) can be the initial presentation of an otherwise unknown malignancy. As PM has no clinical or radiological pathognomonic features, diagnosis is challenging. The authors describe the case of a symptomatic PM that revealed a primary lung adenocarcinoma. A 62-year-old woman with multiple sclerosis and no history of malignancy, incidentally presented with a diffusely enlarged and homogeneously enhancing pituitary gland associated with stalk enlargement. Clinical and biochemical evaluation revealed anterior hypopituitarism and diabetes insipidus. Hypophysitis was considered the most likely diagnosis. However, rapid visual deterioration and pituitary growth raised the suspicion of metastatic involvement. A search for systemic malignancy was performed, and CT revealed a lung mass, which proved to be a lung adenocarcinoma. Accordingly, the patient was started on immunotherapy. Resection of the pituitary lesion was performed, and histopathology analysis revealed metastatic lung adenocarcinoma. Following surgery, the patient underwent radiotherapy. More than 2 years after PM detection, the patient shows a clinically relevant response to antineoplastic therapy and no evidence of PM recurrence.

Learning points:

  • Although rare, metastatic involvement of the pituitary gland has been reported with increasing frequency during the last decades.

  • Pituitary metastasis can be the initial presentation of an otherwise unknown malignancy and should be considered in the differential diagnosis of pituitary lesions, irrespective of a history of malignancy.

  • The sudden onset and rapid progression of visual or endocrine dysfunction from a pituitary lesion should strongly raise the suspicion of metastatic disease.

  • MRI features of pituitary metastasis can overlap with those of other pituitary lesions, including hypophysitis; however, rapid pituitary growth is highly suggestive of metastatic disease.

  • Survival after pituitary metastasis detection has improved over time, encouraging individualized interventions directed to metastasis to improve quality of life and increase survival.

Open access

João José Nunes Roque, Irina Borisovna Samokhvalova Alves, Ana Maria de Almeida Paiva Fernandes Rodrigues, and Maria João Bugalho


Menopause is a relative hyperandrogenic state but the development of hirsutism or virilizing features should not be regarded as normal. We report the case of a 62-year-old woman with a 9-month history of progressive frontotemporal hair loss and hirsutism, particularly on her back, arms and forearms. Blood tests showed increased total testosterone of 5.20 nmol/L that remained elevated after an overnight dexamethasone suppression test. Free Androgen Index was 13.1 and DHEAS was repeatedly normal. Imaging examinations to study adrenals and ovaries were negative. The biochemical profile and the absence of imaging in favor of an adrenal tumor made us consider the ovarian origin as the most likely hypothesis. After informed consent, bilateral salpingectomy-oophorectomy and total hysterectomy were performed. Gross pathology revealed ovaries of increased volume and histology showed bilateral ovarian stromal hyperplasia. Testosterone levels normalized after surgery and hirsutism had completely subsided 8 months later.

Learning points:

  • Menopause is a relative hyperandrogenic state

  • Hirsutism and/or virilizing features, in a postmenopausal woman, should raise the hypothesis of a malignant cause

  • In the absence of an identifiable ovarian or adrenal tumor, the ovarian origin remains the most likely

  • Peripheral aromatization of excess androgen may conduct to high levels of estrogen increasing the risk of endometrial cancer

  • Bilateral oophorectomy results in significant clinical improvement.

Open access

Ana M Lopes and Sofia Teixeira


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

Joana Lima Ferreira, Francisco Simões de Carvalho, Ana Paula Marques, and Rosa Maria Príncipe


Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.

Learning points:

  • Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.

  • Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.

  • APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.

  • APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.

  • Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.

  • Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

Open access

Mariana Barbosa, Sílvia Paredes, Maria João Machado, Rui Almeida, and Olinda Marques


Gonadotropin-releasing hormone (GnRH) agonists, currently used in the treatment of advanced prostate cancer, have been described as a rare cause of pituitary apoplexy, a potentially life-threatening clinical condition. We report the case of a 69-year-old man with a known pituitary macroadenoma who was diagnosed with prostate cancer and started treatment with GnRH agonist leuprorelin (other hormones were not tested before treatment). Few minutes after drug administration, the patient presented with acute-onset severe headache, followed by left eye ptosis, diplopia and vomiting. Pituitary MRI revealed tumor enlargement and T1-hyperintense signal, compatible with recent bleeding sellar content. Laboratory endocrine workup was significant for low total testosterone. The patient was managed conservatively with high-dose steroids, and symptoms significantly improved. This case describes a rare phenomenon, pituitary apoplexy induced by GnRH agonist. We review the literature regarding this condition: the pathophysiological mechanism involved is not clearly established and several hypotheses have been proposed. Although uncommon, healthcare professionals and patients should be aware of this complication and recognize the signs, preventing a delay in diagnosis and treatment.

Learning points:

  • Pituitary apoplexy (PA) is a potentially life-threatening complication that can be caused by gonadotropin-releasing hormone agonist (GnRHa) administration for the treatment of advanced prostate cancer.

  • This complication is rare but should be taken into account when using GnRHa, particularly in the setting of a known pre-existing pituitary adenoma.

  • PA presents with classic clinical signs and symptoms that should be promptly recognized.

  • Patients should be instructed to seek medical care if suspicious symptoms occur.

  • Healthcare professionals should be aware of this complication, enabling its early recognition, adequate treatment and favorable outcome.

Open access

J Pedro, F M Cunha, V Neto, V Hespanhol, D F Martins, S Guimarães, A Varela, and D Carvalho


We describe the case of a 56 year-old woman with the almost simultaneous appearance of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and a carotid body paraganglioma. Of interest, 6 years earlier, the patient underwent total thyroidectomy due to papillary thyroid carcinoma and, in the meantime, she was submitted to mastectomy to treat an invasive ductal carcinoma of the breast. In order to explain these lesions, an extensive genetic study was performed. Results showed positivity for the presence of the tumor suppressor gene PALB2, whose presence had already been detected in a niece with breast cancer. The patient underwent different procedures to treat the lesions and currently she is symptom-free over 2 years of follow-up.

Learning points:

  • The presence of two rare neoplasms in a single person should raise the suspicion of a common etiology.

  • To the best of our knowledge, this is the first case that shows the coexistence of DIPNECH and paraganglioma.

  • The contribution of the PALB2 gene in the etiology of these rare neoplasms is a possibility.

Open access

Sara Lomelino-Pinheiro, Bastos Margarida, and Adriana de Sousa Lages


Familial hypomagnesemia with secondary hypocalcemia (FHSH) is a rare autosomal recessive disorder (OMIM# 602014) characterized by profound hypomagnesemia associated with hypocalcemia. It is caused by mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6). It usually presents with neurological symptoms in the first months of life. We report a case of a neonate presenting with recurrent seizures and severe hypomagnesemia. The genetic testing revealed a novel variant in the TRPM6 gene. The patient has been treated with high-dose magnesium supplementation, remaining asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to prevent irreversible neurological damage.

Learning points:

  • Loss-of-function mutations of TRPM6 are associated with FHSH.

  • FHSH should be considered in any child with refractory hypocalcemic seizures, especially in cases with serum magnesium levels as low as 0.2 mM.

  • Normocalcemia and relief of clinical symptoms can be assured by administration of high doses of magnesium.

  • Untreated, the disorder may be fatal or may result in irreversible neurological damage.

Open access

Diana Catarino, Cristina Ribeiro, Leonor Gomes, and Isabel Paiva


Pituitary infections, particularly with fungus, are rare disorders that usually occur in immunocompromised patients. Cushing’s syndrome predisposes patients to infectious diseases due to their immunosuppression status. We report the case of a 55-year-old woman, working as a poultry farmer, who developed intense headache, palpebral ptosis, anisocoria, prostration and psychomotor agitation 9 months after initial diabetes mellitus diagnosis. Cranioencephalic CT scan showed a pituitary lesion with bleeding, suggesting pituitary apoplexy. Patient underwent transsphenoidal surgery and the neuropathologic study indicated a corticotroph adenoma with apoplexy and fungal infection. Patient had no preoperative Cushing’s syndrome diagnosis. She was evaluated by a multidisciplinary team who decided not to administer anti-fungal treatment. The reported case shows a rare association between a corticotroph adenoma and a pituitary fungal infection. The possible contributing factors were hypercortisolism, uncontrolled diabetes and professional activity. Transsphenoidal surgery is advocated in these infections; however, anti-fungal therapy is still controversial.

Learning points:

  • Pituitary infections are rare disorders caused by bacterial, viral, fungal and parasitic infections.

  • Pituitary fungal infections usually occur in immunocompromised patients.

  • Cushing’s syndrome, as immunosuppression factor, predisposes patients to infectious diseases, including fungal infections.

  • Diagnosis of pituitary fungal infection is often achieved during histopathological investigation.

  • Treatment with systemic anti-fungal drugs is controversial.

  • Endocrine evaluation is recommended at the time of initial presentation of pituitary manifestations.

Open access

Joanna Prokop, João Estorninho, Sara Marote, Teresa Sabino, Aida Botelho de Sousa, Eduardo Silva, and Ana Agapito


POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a rare multisystemic disease. Clinical presentation is variable, the only mandatory criteria being polyneuropathy and monoclonal gammapathy in association with one major and one minor criterion. Primary adrenal insufficiency is rarely reported. We describe a case of a 33-year-old patient, in whom the presenting symptoms were mandibular mass, chronic sensory-motor peripheral polyneuropathy and adrenal insufficiency. The laboratory evaluation revealed thrombocytosis, severe hyperkalemia with normal renal function, normal protein electrophoresis and negative serum immunofixation for monoclonal protein. Endocrinologic laboratory work-up confirmed Addison’s disease and revealed subclinical primary hypothyroidism. Thoracic abdominal CT showed hepatosplenomegaly, multiple sclerotic lesions in thoracic vertebra and ribs. The histopathologic examination of the mandibular mass was nondiagnostic. Bone marrow biopsy revealed plasma cell dyscrasia and confirmed POEMS syndrome. Axillary lymphadenopathy biopsy: Castleman’s disease. Gluco-mineralocorticoid substitution and levothyroxine therapy were started with clinical improvement. Autologous hematopoietic cell transplantation (HCT) was planned, cyclophosphamide induction was started. Meanwhile the patient suffered two ischemic strokes which resulted in aphasia and hemiparesis. Cerebral angiography revealed vascular lesions compatible with vasculitis and stenosis of two cerebral arteries. The patient deceased 14 months after the diagnosis. The young age at presentation, multiplicity of manifestations and difficulties in investigation along with the absence of serum monoclonal protein made the diagnosis challenging. We report this case to highlight the need to consider POEMS syndrome in differential diagnosis of peripheral neuropathy in association with endocrine abnormalities even in young patients.

Learning points:

  • POEMS syndrome is considered a ‘low tumor burden disease’ and the monoclonal protein in 15% of cases is not found by immunofixation.

  • Neuropathy is the dominant characteristic of POEMS syndrome and it is peripheral, ascending, symmetric and affecting both sensation and motor function.

  • Endocrinopathies are a frequent feature of POEMS syndrome, but the cause is unknown.

  • The most common endocrinopathies are hypogonadism, primary hypothyroidism and abnormalities in glucose metabolism.

  • There is no standard therapy; however, patients with disseminated bone marrow involvement are treated with chemotherapy with or without HCT.