Summary

Bariatric surgery is increasingly being accepted as a viable treatment for managing the growing obesity epidemic. Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed procedures. Perforated duodenal ulcer following RYGB is a rare condition with a low incidence. We report a case of a patient with a perforated duodenal ulcer post RYGB, and the surgical approach. A 66-year-old man with hypertension and a history of laparoscopic RYGB for class III obesity was admitted to the emergency department with severe epigastric pain radiating to the right side of his abdomen and right shoulder, associated with nausea and vomiting. Computed tomography (CT) showed intraperitoneal free fluid, a thickened wall of the duodenum and free air, duodenal perforation was suspected. The patient underwent exploratory laparoscopy that revealed a perforated duodenal ulcer that was closed with an absorbable barbed suture and omental patch. Perforated ulcers in excluded segments after RYGB are a rare entity with a challenging diagnosis, and clinicians should be aware of and have a low threshold for diagnostic laparoscopy.

Learning points

• Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed procedures in bariatric surgery.

• Perforated ulcers in excluded segments after RYGB are a rare entity with a challenging diagnosis.

• The pathophysiology of this perforation is not clear, but several mechanisms have been proposed. Helicobacter pylori has been implicated.

• Clinicians should be aware and have a low threshold for diagnostic laparoscopy for a patient who has acute abdominal pain after RYGB, despite negative diagnostic measures.

Summary

We report a 61-year-old male patient without personal history of thyroid carcinoma or radiation exposure. In 2011, he presented with a cervical mass whose biopsy diagnosed a papillary thyroid carcinoma (PTC) in a lymph node metastasis (LNM). Total thyroidectomy with lymphadenectomy of central and ipsilateral compartment was performed. Histopathology identified a 2 mm follicular variant of PTC and LNM in 25/25 lymph nodes. The patient was treated with 150 mCi of radioactive iodine (RAI), followed by levothyroxine suppressive therapy. In 2016, a retrotracheal mass was diagnosed, suggesting local recurrence; patient was submitted to surgical excision and RAI therapy (120 mCi). Due to seizures, in 2019, a brain CT was performed that diagnosed brain metastases. The patient underwent debulking of the main lesion. Histopathology analysis confirmed a metastatic lesion with variated morphology: classical PTC and follicular pattern and hobnail and tall cell features. Molecular analysis revealed BRAFV600E in LNM at presentation and BRAFV600E and TERT promoter (TERTp) mutations in the recurrent LNM and brain metastasis. Based upon this experience we review the reported cases of subcentimetric PTC with brain metastases and discuss the molecular progression of the present case.

Learning points

• Papillary microcarcinoma (PMCs) usually have very good prognosis with low impact on patient survival.

• PMCs presenting in elderly patients with LNM at diagnosis may carry a guarded outcome.

• Brain metastasis although rare indicate aggressive phenotypic features.

• Patient risk stratification of PMCs based on histopathological analysis and genetic testing may have a significant impact on prognosis providing therapeutic markers, that may predict disease progression and overall outcome.

Summary

Leptin is secreted by adipocytes in response to fat storage and binds to its receptor (LEPR), which is ubiquitously expressed throughout the body. Leptin regulates energy expenditure and is anorexigenic. In this study, we describe the clinical and hormonal findings of three siblings with a personal history of rapid weight gain during the first months of life. They had delayed puberty, high levels of FSH (15.6 ± 3.7 mUI/mL; reference: 1.5–12.4) and LH (12.3 ± 2.2 mUI/mL; reference: 1.7–8.6), normal oestradiol and total testosterone and successful fertility. None of the patients had dyslipidemia, diabetes or thyroid disease. Next-generation sequencing identified a pathogenic homozygous variant c.2357T>C, p.(Leu786Pro) in LEPR. Their parents and children were heterozygous for this mutation. We compared clinical and biochemical findings of homozygous carriers with first-degree heterozygous family members and ten randomly selected patients with adult-onset morbid obesity. Homozygous carriers of the mutation had significantly higher BMI (32.2 ± 1.7 kg/m² vs 44.5 ± 7.1 kg/m², P = 0.023) and increased serum levels of leptin (26.3 ± 9.3 ng/mL vs 80 ± 36.4 ng/mL, P = 0.028) than their heterozygous relatives. Compared with the ten patients with adult-onset morbid obesity, serum levels of leptin were not significantly higher in homozygous carriers (53.8 ± 24.1 ng/mL vs 80 ± 36.4 ng/mL, P = 0.149), and thus serum levels of leptin were not a useful discriminative marker of LEPR mutations. We described a rare three-generation family with monogenic obesity due to a mutation in LEPR. Patients with early onset obesity should be considered for genetic screening, as the identification of mutations may allow personalized treatment options (e.g. MC4R-agonists) and targeted successful weight loss.

Learning points

• The early diagnosis of monogenic forms of obesity can be of great interest since new treatments for these conditions are becoming available.

• Since BMI and leptin levels in patients with leptin receptor mutations are not significantly different from those found in randomly selected morbid obese patients, a careful medical history is mandatory to suspect this condition.

• Loss of leptin receptor function has been associated with infertility. However, our patients were able to conceive, emphasizing the need for genetic counselling in affected patients with this condition.

Summary

Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1–34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability.

Learning points

• Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene.

• The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1.

• Teriparatide (recombinant human parathyroid hormone 1–34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

Summary

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.

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.

Summary

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.

Summary

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.

Summary

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.

Summary

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.