Diagnosis and Treatment > Signs and Symptoms
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Search for other papers by Peter Novodvorsky in
Google Scholar
PubMed
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Search for other papers by Emma Walkinshaw in
Google Scholar
PubMed
Search for other papers by Waliur Rahman in
Google Scholar
PubMed
Search for other papers by Valerie Gordon in
Google Scholar
PubMed
Search for other papers by Karen Towse in
Google Scholar
PubMed
Search for other papers by Sarah Mitchell in
Google Scholar
PubMed
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Search for other papers by Dinesh Selvarajah in
Google Scholar
PubMed
Search for other papers by Priya Madhuvrata in
Google Scholar
PubMed
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Search for other papers by Alia Munir in
Google Scholar
PubMed
Summary
Bariatric surgery is an effective therapy for obesity but is associated with long-term complications such as dumping syndromes and nutritional deficiencies. We report a case of a 26-year-old caucasian female, with history of morbid obesity and gestational diabetes (GDM), who became pregnant 4 months after Roux-en-Y bypass surgery. She developed GDM during subsequent pregnancy, which was initially managed with metformin and insulin. Nocturnal hypoglycaemia causing sleep disturbance and daytime somnolence occured at 19 weeks of pregnancy (19/40). Treatment with rapid-acting carbohydrates precipitated further hypoglycaemia. Laboratory investigations confirmed hypoglycaemia at 2.2 mmol/L with appropriately low insulin and C-peptide, intact HPA axis and negative IgG insulin antibodies. The patient was seen regularly by the bariatric dietetic team but concerns about compliance persisted. A FreeStyle Libre system was used from 21/40 enabling the patient a real-time feedback of changes in interstitial glucose following high or low GI index food intake. The patient declined a trial of acarbose but consented to an intraveneous dextrose infusion overnight resulting in improvement but not complete abolishment of nocturnal hypoglycaemia. Hypoglycaemias subsided at 34/40 and metformin and insulin had to be re-introduced due to high post-prandial blood glucose readings. An emergency C-section was indicated at 35 + 1/40 and a small-for-gestational-age female was delivered. There have been no further episodes of hypoglycaemia following delivery. This case illustrates challenges in the management of pregnancy following bariatric surgery. To our knowledge, this is the first use of FreeStyle Libre in dumping syndrome in pregnancy following bariatric surgery with troublesome nocturnal hypoglycaemia.
Learning points:
-
Bariatric surgery represents the most effective treatment modality in cases of severe obesity. With increasing prevalence of obesity, more people are likely to undergo bariatric procedures, many of which are women of childbearing age.
-
Fertility generally improves after bariatric surgery due to weight reduction, but pregnancy is not recommended for at least 12–24 months after surgery. If pregnancy occurs, there are currently little evidence-based guidelines available on how to manage complications such as dumping syndromes or gestational diabetes (GDM) in women with history of bariatric surgery.
-
Diagnosis of GDM relies on the use of a 75 g oral glucose tolerance test (OGTT). The use of this test in pregnant women is not recommended due to its potential to precipitate dumping syndrome. Capillary glucose monitoring profiles or continuous glucose monitoring (CGM) is being currently discussed as alternative testing modalities.
-
As the CGM technology becomes more available, including the recently introduced FreeStyle Libre Flash glucose monitoring system, more pregnant women, including those after bariatric surgery, will have access to this technology. We suggest urgent development of guidelines regarding the use of CGM and flash glucose monitoring tools in these circumstances and in the interim recommend careful consideration of their use on a case-to-case basis.
Search for other papers by Irene Berges-Raso in
Google Scholar
PubMed
Search for other papers by Olga Giménez-Palop in
Google Scholar
PubMed
Search for other papers by Elisabeth Gabau in
Google Scholar
PubMed
Search for other papers by Ismael Capel in
Google Scholar
PubMed
Search for other papers by Assumpta Caixàs in
Google Scholar
PubMed
Search for other papers by Mercedes Rigla in
Google Scholar
PubMed
Summary
Kallmann syndrome is a genetically heterogeneous form of hypogonadotropic hypogonadism caused by gonadotropin-releasing hormone deficiency and characterized by anosmia or hyposmia due to hypoplasia of the olfactory bulbs; osteoporosis and metabolic syndrome can develop due to longstanding untreated hypogonadism. Kallmann syndrome affects 1 in 10 000 men and 1 in 50 000 women. Defects in 17 genes, including KAL1, have been implicated. Kallmann syndrome can be associated with X-linked ichthyosis, a skin disorder characterized by early onset dark, dry, irregular scales affecting the limb and trunk, caused by a defect of the steroid sulfatase gene (STS). Both KAL1 and STS are located in the Xp22.3 region; therefore, deletions in this region cause a contiguous gene syndrome. We report the case of a 32-year-old man with ichthyosis referred for evaluation of excessive height (2.07 m) and weight (BMI: 29.6 kg/m2), microgenitalia and absence of secondary sex characteristics. We diagnosed Kallmann syndrome with ichthyosis due to a deletion in Xp22.3, a rare phenomenon.
Learning points:
-
Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism with anosmia or hyposmia associated with defects in the production or action of gonadotropin-releasing hormone (GnRH) and hypoplasia of the olfactory bulbs.
-
Several genes have been implicated in Kallmann syndrome, including KAL1, located in the Xp22.3 region, which is responsible for X-linked Kallmann syndrome. KAL1 encodes the protein anosmin-1. X-linked ichthyosis is caused by deficiency of the steroid sulfatase enzyme, encoded by STS, which is also located in the Xp22.3 region. Deletions involving this region can affect both genes and result in contiguous gene syndromes.
-
Phenotype can guide clinicians toward suspicion of a specific genetic mutation. KAL1 mutations are mostly related to microgenitalia, unilateral renal agenesis and synkinesia, although patients need not present all these abnormalities.
-
Longstanding untreated hypogonadism is associated with poor sexual health, osteoporosis and metabolic syndrome with the concomitant risk of developing type 2 diabetes mellitus and obesity.
-
Treatment aims to promote the development of secondary sex characteristics, build and sustain normal bone and muscle mass and restore fertility. Treatment can also help minimize some psychological consequences.
-
Treatments available for patients with congenital GnRH deficiency such as Kallmann syndrome include gonadal steroid hormones, human gonadotropins and GnRH. The choice of therapy depends on the goal or goals.
Search for other papers by Ahmad Haider in
Google Scholar
PubMed
Search for other papers by Karim S Haider in
Google Scholar
PubMed
Research Department, Gulf Medical University, Ajman, UAE
Search for other papers by Farid Saad in
Google Scholar
PubMed
Summary
In daily practice, clinicians are often confronted with obese type 2 diabetes mellitus (T2DM) patients for whom the treatment plan fails and who show an inadequate glycemic control and/or no sustainable weight loss. Untreated hypogonadism can be the reason for such treatment failure. This case describes the profound impact testosterone therapy can have on a male hypogonadal patient with metabolic syndrome, resulting in a substantial and sustained loss of body weight, pronounced improvement of all critical laboratory values and finally complete remission of diabetes.
Learning points:
-
Hypogonadism occurs frequently in men with T2DM.
-
In case of pronounced abdominal fat deposition and T2DM, the male patient should be evaluated for testosterone deficiency.
-
Untreated hypogonadism can complicate the successful treatment of patients with T2DM.
-
Under testosterone therapy, critical laboratory values are facilitated to return back to normal ranges and even complete remission of diabetes can be achieved.
Search for other papers by Kingsley Okolie in
Google Scholar
PubMed
Australian National University Medical School, Canberra, ACT, Australia
Search for other papers by Sumathy Perampalam in
Google Scholar
PubMed
Search for other papers by Anthony Barker in
Google Scholar
PubMed
Australian National University Medical School, Canberra, ACT, Australia
Search for other papers by Christopher J Nolan in
Google Scholar
PubMed
Klinefelter syndrome (KS) is a chromosomal disorder affecting males, with the typical karyotype of 47,XXY due to a supernumerary X chromosome, which causes progressive testicular failure resulting in androgen deficiency and infertility. Despite it being the most common sex chromosomal disorder, its diagnosis is easily missed. In addition to its classical clinical features of tall stature, gynaecomastia, small testes, and symptoms and signs of hypogonadism including infertility, KS is also often associated with neurocognitive, behavioural and psychiatric disorders.
We present a 44-year-old man with KS who, despite having erectile dysfunction, paradoxically had increased libido. He used sildenafil to overcome his erectile dysfunction. Hypersexuality was manifested by very frequent masturbation, multiple sexual partners most of whom were casual, and a sexual offence conviction at the age of 17 years.
Discussion focuses on the frequent failure of clinicians to diagnose KS, the neurocognitive, behavioural and psychiatric aspects of KS, this unusual presentation of hypersexuality in a man with KS, and the challenges of medical management of hypogonadism in a man with a history of a sexual offence.
Learning points:
-
Klinefelter syndrome (KS) is common in men (about 1 in 600 males), but the diagnosis is very often missed.
-
In addition to classic features of hypogonadism, patients with KS can often have associated neurocognitive, behavioural and/or psychiatric disorders.
-
More awareness of the association between KS and difficulties related to verbal skills in boys could improve rates of early diagnosis and prevent longer-term psychosocial disability.
-
Hypersexuality in the context of hypogonadism raises the possibility of sex steroid independent mechanistic pathways for libido.
-
Testosterone replacement therapy in KS with hypersexuality should be undertaken with caution using a multidisciplinary team approach.
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Search for other papers by B Cangiano in
Google Scholar
PubMed
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Search for other papers by C Cacciatore in
Google Scholar
PubMed
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Search for other papers by L Persani in
Google Scholar
PubMed
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Search for other papers by M Bonomi in
Google Scholar
PubMed
We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic–pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion.
Learning points:
-
Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.
-
In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.
-
In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.
-
Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.
Search for other papers by Regina Streuli in
Google Scholar
PubMed
Search for other papers by Ina Krull in
Google Scholar
PubMed
Search for other papers by Michael Brändle in
Google Scholar
PubMed
Search for other papers by Walter Kolb in
Google Scholar
PubMed
Search for other papers by Günter Stalla in
Google Scholar
PubMed
Search for other papers by Marily Theodoropoulou in
Google Scholar
PubMed
Search for other papers by Annette Enzler-Tschudy in
Google Scholar
PubMed
Search for other papers by Stefan Bilz in
Google Scholar
PubMed
Summary
Ectopic ACTH/CRH co-secreting tumors are a very rare cause of Cushing’s syndrome and only a few cases have been reported in the literature. Differentiating between Cushing’s disease and ectopic Cushing’s syndrome may be particularly difficult if predominant ectopic CRH secretion leads to pituitary corticotroph hyperplasia that may mimic Cushing’s disease during dynamic testing with both dexamethasone and CRH as well as bilateral inferior petrosal sinus sampling (BIPSS). We present the case of a 24-year-old man diagnosed with ACTH-dependent Cushing’s syndrome caused by an ACTH/CRH co-secreting midgut NET. Both high-dose dexamethasone testing and BIPSS suggested Cushing’s disease. However, the clinical presentation with a rather rapid onset of cushingoid features, hyperpigmentation and hypokalemia led to the consideration of ectopic ACTH/CRH-secretion and prompted a further workup. Computed tomography (CT) of the abdomen revealed a cecal mass which was identified as a predominantly CRH-secreting neuroendocrine tumor. To the best of our knowledge, this is the first reported case of an ACTH/CRH co-secreting tumor of the cecum presenting with biochemical features suggestive of Cushing’s disease.
Learning points:
-
The discrimination between a Cushing’s disease and ectopic Cushing’s syndrome is challenging and has many caveats.
-
Ectopic ACTH/CRH co-secreting tumors are very rare.
-
Dynamic tests as well as BIPSS may be compatible with Cushing’s disease in ectopic CRH-secretion.
-
High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH.
-
Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing’s syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing’s syndrome and lead to further investigations.
Search for other papers by Alessandro Mantovani in
Google Scholar
PubMed
Search for other papers by Fabrizia Perrone in
Google Scholar
PubMed
Search for other papers by Vincenzo Stoico in
Google Scholar
PubMed
Search for other papers by Isabella Pichiri in
Google Scholar
PubMed
Search for other papers by Laura Salvotelli in
Google Scholar
PubMed
Search for other papers by Ilaria Teobaldi in
Google Scholar
PubMed
Search for other papers by Massimiliano Bruti in
Google Scholar
PubMed
Search for other papers by Michela Conti in
Google Scholar
PubMed
Search for other papers by Luca Cima in
Google Scholar
PubMed
Search for other papers by Albino Eccher in
Google Scholar
PubMed
Search for other papers by Enzo Bonora in
Google Scholar
PubMed
Summary
The incidences of type 2 diabetes mellitus and many cancers are rapidly increasing worldwide. Diabetes is a strong risk factor for some cancers (including lymphomas) and is also associated with adverse cancer outcomes. After gastrointestinal tract, the skin is the second most frequent extranodal site involved by non-Hodgkin lymphomas and the cutaneous B-cell lymphomas (CBCLs) range from 25% to 30% of all primary cutaneous lymphomas. The primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is an aggressive lymphoma with a poor prognosis, representing roughly 20% of all primary CBCLs. Classically, the cutaneous manifestation of this lymphoma is a red or violaceous tumors arising on a leg. To date, despite the large body of evidence suggesting that diabetes is strongly associated with an increased risk of some cancers, very little information is available regarding a possible association between type 2 diabetes and primary cutaneous diffuse large B-cell lymphoma. In this report, we will present the case of a white adult patient with type 2 diabetes with chronic leg ulcers complicated by a primary cutaneous diffuse large B-cell lymphoma.
Learning points:
-
Diabetes mellitus is increasing worldwide as well as the incidence of many cancers.
-
Diabetes mellitus is a powerful risk factor for some cancers (including lymphomas) and is strongly associated with adverse cancer outcomes.
-
Seen that diabetes is strongly associated with an increased risk of cancers (including cutaneous lymphomas), clinicians should always keep in mind this complication in elderly patients with type 2 diabetes, even in a chronic leg ulcer with hypertrophy of the wound edge, which is hard to heal and does not have the typical characteristics of a diabetic or vascular ulcer. In these cases, a biopsy should be performed to rule out a neoplasm.
-
Early diagnosis and correct management of cancer in a patient with type 2 diabetes are crucial to improve clinical outcomes.
Search for other papers by Noman Ahmad in
Google Scholar
PubMed
Search for other papers by Abdulmonem Mohammed Almutawa in
Google Scholar
PubMed
Search for other papers by Mohamed Ziyad Abubacker in
Google Scholar
PubMed
Search for other papers by Hossam Ahmed Elzeftawy in
Google Scholar
PubMed
Search for other papers by Osama Abdullah Bawazir in
Google Scholar
PubMed
Summary
An insulinoma is a rare tumour with an incidence of four cases per million per year in adults. The incidence in children is not established. There is limited literature available in children with insulinoma, and only one case is reported in association with Down’s syndrome in adults. Insulinoma diagnosis is frequently missed in adults as well as in children. The Whipple triad is the most striking feature although it has limited application in young children. Hypoglycaemia with elevated insulin, C-peptide and absent ketones is highly suggestive of hyperinsulinism. We present a case of 10-year-old boy with Down’s syndrome with recurrent insulinoma. He was initially misdiagnosed as having an adrenal insufficiency and developed cushingoid features and obesity secondary to hydrocortisone treatment and excessive sugar intake. The tumour was successfully localised in the head of the pancreas with an MRI and octreotide scan on first presentation. Medical treatment with diazoxide and octreotide could not achieve normal blood glucose levels. The insulinoma was laparoscopically enucleated and pathological examination confirmed a neuroendocrine tumour. Subsequently, he had complete resolution of symptoms. He had a recurrence after 2 years with frequent episodes of hypoglycaemia. The biochemical workup was suggestive of hyperinsulinism. MRI and PET scan confirmed the recurrence at the same site (head of the pancreas). He had an open laparotomy for insulinoma resection. The pathology was consistent with benign insulinoma, and subsequently, he had complete resolution of symptoms.
Learning points:
-
Insulinoma is a very rare tumour in children; it should be considered in the differential diagnosis of hypoglycaemia with absent ketones.
-
Refractory neurological symptoms like seizure, migraine, mood changes and regression of learning abilities should suggest evaluation for hypoglycaemia.
-
MRI with contrast and PET scan would localise the majority of pancreatic beta islet cell lesions.
-
Medical treatment with diazoxide, octreotide and the addition of corn starch in feeds is not curative but can be supportive to maintain normoglycemia until the surgical resection.
-
Surgical resection is the only curative treatment. The surgical procedure of choice (laparoscopic/open laparotomy) depends on local expertise, preoperative localisation, tumour size and number.
-
Surgical treatment results in complete resolution of symptoms, but all cases should be closely followed up to monitor for recurrence. The recurrence rate is four times higher in MEN1 cases.
Search for other papers by Murray B Gordon in
Google Scholar
PubMed
Search for other papers by Kellie L Spiller in
Google Scholar
PubMed
Summary
Long-acting pasireotide is an effective treatment option for acromegaly, but it is associated with hyperglycemia, which could impact its use in patients with diabetes. We present a case of a 53-year-old man with acromegaly and type 2 diabetes mellitus (glycated hemoglobin (HbA1c): 7.5%), who refused surgery to remove a pituitary macroadenoma and enrolled in a Phase 3 clinical trial comparing long-acting pasireotide and long-acting octreotide in acromegalic patients. The patient initially received octreotide, but insulin-like growth factor 1 (IGF-1) levels remained elevated after 12 months (383.9 ng/mL; 193.0 ng/mL; reference range: 86.5–223.8 ng/mL), indicating uncontrolled acromegaly. He switched to pasireotide 40 mg and subsequently increased to 60 mg. Within 6 months, IGF-1 levels normalized (193.0 ng/mL), and they were mostly normal for the next 62 months of treatment with pasireotide (median IGF-1: 190.7 ng/mL). Additionally, HbA1c levels remained similar to or lower than baseline levels (range, 6.7% to 7.8%) during treatment with pasireotide despite major changes to the patient’s antidiabetic regimen, which included insulin and metformin. Uncontrolled acromegaly can result in hyperglycemia due to an increase in insulin resistance. Despite having insulin-requiring type 2 diabetes, the patient presented here did not experience a long-term increase in HbA1c levels upon initiating pasireotide, likely because long-term control of acromegaly resulted in increased insulin sensitivity. This case highlights the utility of long-acting pasireotide to treat acromegaly in patients whose levels were uncontrolled after long-acting octreotide and who manage diabetes with insulin.
Learning points
-
Long-acting pasireotide provided adequate, long-term biochemical control of acromegaly in a patient with insulin-requiring type 2 diabetes mellitus who was unresponsive to long-acting octreotide.
-
Glycemic levels initially increased after starting treatment with pasireotide but quickly stabilized as acromegaly became controlled.
-
Long-acting pasireotide, along with an appropriate antidiabetic regimen, may be a suitable therapy for patients with acromegaly who also have insulin-requiring type 2 diabetes mellitus.
Search for other papers by Teresa Rego in
Google Scholar
PubMed
Search for other papers by Fernando Fonseca in
Google Scholar
PubMed
Search for other papers by Stéphanie Espiard in
Google Scholar
PubMed
Search for other papers by Karine Perlemoine in
Google Scholar
PubMed
Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed
Search for other papers by Ana Agapito in
Google Scholar
PubMed
Summary
PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH <5 pg/mL; urinary free cortisol (UFC), 532 µg/24 h (normal range: 20–90); failure to suppress the low-dose dexamethasone test (0.5 mg every 6 h for 48 h): cortisol 21 µg/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55 × 54 × 30 mm; left, 85 × 53 × 35 mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient’s 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15 cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients.
Learning points:
-
PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.
-
The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.
-
Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene.
-
The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.
-
As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.
