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Open access

Nicholas J Theis, Toby Calvert, Peter McIntyre, Stephen P Robertson and Benjamin J Wheeler

Summary

Cantu syndrome, or hypertrichotic osteochondrodysplasia, is a rare, autosomal dominant genetically heterogeneous disorder. It is characterized by hypertrichosis, cardiac and skeletal anomalies and distinctive coarse facial features. We report a case where slowed growth velocity at 13 years led to identification of multiple pituitary hormone deficiencies. This adds to other reports of pituitary abnormalities in this condition and supports inclusion of endocrine monitoring in the clinical surveillance of patients with Cantu syndrome.

Learning points:

  • Cantu syndrome is a rare genetic disorder caused by pathogenic variants in the ABCC9 and KCNJ8 genes, which result in gain of function of the SUR2 or Kir6.1 subunits of widely expressed KATP channels.
  • The main manifestations of the syndrome are varied, but most commonly include hypertrichosis, macrosomia, macrocephaly, coarse ‘acromegaloid’ facies, and a range of cardiac defects.
  • Anterior pituitary dysfunction may be implicated in this disorder, and we propose that routine screening should be included in the clinical and biochemical surveillance of patients with Cantu syndrome.
Open access

Charlotte Delcourt, Halil Yildiz, Alessandra Camboni, Eric Van den Neste, Véronique Roelants, Alexandra Kozyreff, Jean Paul Thissen, Dominique Maiter and Raluca Maria Furnica

Summary

A 26-year-old woman presented with persistent headache and tiredness. Biological investigations disclosed a moderate inflammatory syndrome, low PTH-hypercalcemia and complete anterior hypopituitarism. A magnetic resonance imaging (MRI) of the pituitary gland was performed and revealed a symmetric enlargement with a heterogeneous signal. Ophthalmological examination showed an asymptomatic bilateral anterior and posterior uveitis, and a diagnosis of pituitary sarcoidosis was suspected. As the localization of lymphadenopathies on the fused whole-body FDG-PET/computerized tomography (CT) was not evoking a sarcoidosis in first instance, an excisional biopsy of a left supraclavicular adenopathy was performed showing classic nodular sclerosis Hodgkin’s lymphoma (HL). A diagnostic transsphenoidal biopsy of the pituitary gland was proposed for accurate staging of the HL and surprisingly revealed typical granulomatous inflammation secondary to sarcoidosis, leading to the diagnosis of a sarcoidosis–lymphoma syndrome. The co-existence of these diseases constitutes a diagnostic challenge and we emphasize the necessity of exact staging of disease in order to prescribe adequate treatment.

Learning points:

  • The possibility of a sarcoidosis–lymphoma syndrome, although rare, should be kept in mind during evaluation for lymphadenopathies.
  • In the case of such association, lymphoma usually occurs after sarcoidosis. However, sarcoidosis and lymphoma can be detected simultaneously and development of sarcoidosis in a patient with previous lymphoma has also been reported.
  • An accurate diagnosis of the disease and the respective organ involvements, including biopsy, is necessary in order to prescribe adequate treatment.
Open access

Andrew R Tang, Laura E Hinz, Aneal Khan and Gregory A Kline

Summary

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.

Learning points:

  • Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.
  • HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.
  • HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.
  • Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.
Open access

Catherine D Zhang, Pavel N Pichurin, Aleh Bobr, Melanie L Lyden, William F Young Jr and Irina Bancos

Summary

Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant.

Learning points:

  • PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal.
  • The diagnosis of PPNAD should prompt screening for CNC.
  • CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene.
  • Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.
Open access

Mara Ventura, Leonor Gomes, Joana Rosmaninho-Salgado, Luísa Barros, Isabel Paiva, Miguel Melo, Diana Oliveira and Francisco Carrilho

Summary

Intracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background.

Learning points:

  • Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism.
  • The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation.
  • Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology.
  • 16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders.
  • Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion.
  • Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.
Open access

Danielle R Bullock, Bradley S Miller, H Brent Clark and Patricia M Hobday

Summary

IgG4-related hypophysitis is an important diagnostic consideration in patients with a pituitary mass or pituitary dysfunction and can initially present with headaches, visual field deficits and/or endocrine dysfunction. Isolated IgG4-related pituitary disease is rare, with most cases of IgG4-related disease involving additional organ systems. We report the case of a teenage female patient with isolated IgG4-related hypophysitis, diagnosed after initially presenting with headaches. Our patient had no presenting endocrinologic abnormalities. She was treated with surgical resection, prednisolone and rituximab with no further progression of disease and sustained normal endocrine function. This case, the youngest described patient with isolated IgG4-related hypophysitis and uniquely lacking endocrinologic abnormalities, adds to the limited reports of isolated pituitary disease. The use of rituximab for isolated pituitary disease has never been described. While IgG4-related hypophysitis has been increasingly recognized, substantial evidence concerning the appropriate treatment and follow-up of these patients is largely lacking.

Learning points:

  • IgG4-related hypophysitis most often occurs in the setting of additional organ involvement but can be an isolated finding. This diagnosis should therefore be considered in a patient presenting with pituitary abnormalities.
  • Most patients with IgG4-related hypophysitis will have abnormal pituitary function, but normal functioning does not exclude this diagnosis.
  • Corticosteroids have been the mainstay of therapy for IgG4-related disease, with other immunosuppressive regimens being reserved for refractory cases. Further research is needed to understand the effectiveness of corticosteroid-sparing regimens and whether there is utility in using these agents as first-line therapies.
Open access

Benedetta Zampetti, Giorgia Simonetti, Roberto Attanasio, Antonio Silvani and Renato Cozzi

Summary

We describe the 20-year course of a 63-year-old male with a macroprolactinoma that acquired resistance to treatment and aggressive behavior after a 4-year successful treatment with cabergoline. He was submitted to multiple surgical resections by a skilled surgeon, fractionated radiotherapy and was eventually treated with temozolomide. After a first 6-month standard cycle, a relapse occurred and he was treated again successfully.

Learning points:

  • Prolactinomas are the most frequent type of pituitary adenoma.
  • They usually have a benign course.
  • In most cases dopamine-agonist drugs, mainly cabergoline, are first-line (and usually only) treatment.
  • Occasionally prolactinomas can have or acquire resistance to treatment and/or aggressive behavior.
  • Temozolomide (TMZ), an oral alkylating drug, can be effective in such aggressive tumors.
  • Multimodal treatment (surgery, radiation, cabergoline and TMZ) is warranted in aggressive pituitary tumors.
  • We describe here successful rechallenge with TMZ after relapse occurring 18 months after a first TMZ cycle.
Open access

Harmony Thompson, Helen Lunt, Cate Fleckney and Steven Soule

Summary

An adolescent with type 1 diabetes and a history of self-harm, which included intentional overdoses and insulin omission, presented with an insulin degludec overdose. She had been commenced on the ultra-long-acting insulin, degludec, with the aim of reducing ketoacidosis episodes in response to intermittent refusal to take insulin. Insulin degludec was administered under supervision as an outpatient. Because it was anticipated that she would attempt a degludec overdose at some stage, the attending clinicians implemented a proactive management plan for this (and related) scenarios. This included long-term monitoring of interstitial glucose using the Abbott Freestyle Libre flash glucose monitor. The patient took a witnessed overdose of 242 units of degludec (usual daily dose, 32 units). She was hospitalised an hour later. Inpatient treatment was guided primarily by interstitial glucose results, with capillary and venous glucose tests used as secondary measures to assess the accuracy of interstitial glucose values. Four days of inpatient treatment was required. The patient was managed with high glycaemic loads of food and also intermittent intravenous dextrose. No hypoglycaemia was documented during the admission. In summary, while a degludec overdose may require several days of inpatient management, in situations where proactive management is an option and the dose administered is relatively modest, it may be possible to avoid significant hypoglycaemia. In addition, this case demonstrates that inpatient interstitial glucose monitoring may have a role in managing insulin overdose, especially in situations where the effect of the insulin overdose on glucose levels is likely to be prolonged.

Learning points:

  • Degludec overdoses have a prolonged effect on blood glucose levels, but if the clinical situation allows for early detection and management, treatment may prove easier than that which is typically needed following overdoses of a similar dose of shorter acting insulins.
  • Inpatient real-time interstitial monitoring helped guide management, which in this context included the prescription of high dietary carbohydrate intake (patient led) and intravenous 10% dextrose (nurse led).
  • Use of inpatient interstitial glucose monitoring to guide therapy might be considered ‘off label’ use, thus, both staff and also patients should be aware of the limitations, as well as the benefits, of interstitial monitoring systems.
  • The Libre flash glucose monitor provided nurses with low cost, easy-to-use interstitial glucose results, but it is nevertheless advisable to check these results against conventional glucose tests, for example, capillary ‘finger-stick’ or venous glucose tests.
Open access

Eleanor P Thong, Sarah Catford, Julie Fletcher, Phillip Wong, Peter J Fuller, Helena Teede and Frances Milat

Summary

The association between type 1 diabetes mellitus (T1DM) and bone health has garnered interest over the years. Fracture risk is known to be increased in individuals with T1DM, although bone health assessment is not often performed in the clinical setting. We describe the case of a 21-year-old male with longstanding T1DM with multilevel vertebral fractures on imaging, after presenting with acute back pain without apparent trauma. Dual-energy X-ray absorptiometry (DXA) revealed significantly reduced bone mineral density at the lumbar spine and femoral neck. Extensive investigations for other secondary or genetic causes of osteoporosis were unremarkable, apart from moderate vitamin D deficiency. High-resolution peripheral quantitative computed tomography and bone biospy revealed significant alterations of trabecular bone microarchitecture. It later transpired that the patient had sustained vertebral fractures secondary to unrecognised nocturnal hypoglycaemic seizures. Intravenous zoledronic acid was administered for secondary fracture prevention. Despite anti-resorptive therapy, the patient sustained a new vertebral fracture after experiencing another hypoglycaemic seizure in his sleep. Bone health in T1DM is complex and not well understood. There are significant challenges in the assessment and management of osteoporosis in T1DM, particularly in young adults, where fracture prediction tools have not been validated. Clinicians should be aware of hypoglycaemia as a significant risk factor for fracture in patients with T1DM.

Learning points:

  • Type 1 diabetes mellitus (T1DM) is a secondary cause of osteoporosis, characterised by reduced bone mass and disturbed bone microarchitecture.
  • Hypoglycaemic seizures generate sufficient compression forces along the thoracic column and can cause fractures in individuals with compromised bone quality.
  • Unrecognised hypoglycaemic seizures should be considered in patients with T1DM presenting with fractures without a history of trauma.
  • Patients with T1DM have increased fracture risk and risk factors should be addressed. Evaluation of bone microarchitecture may provide further insights into mechanisms of fracture in T1DM.
  • Further research is needed to guide the optimal screening and management of bone health in patients with T1DM.
Open access

Taieb Ach, Hela Marmouch, Dorra Elguiche, Asma Achour, Hajer Marzouk, Hanene Sayadi, Ines Khochtali and Mondher Golli

Summary

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism in combination with a defect in sense of smell, due to abnormal migration of gonadotropin-releasing hormone-producing neurons. We report a case of a 17-year-old Tunisian male who presented with eunuchoid body proportions, absence of facial, axillary and pubic hair, micropenis and surgically corrected cryptorchidism. Associated findings included anosmia. Karyotype was 46XY and hormonal measurement hypogonadotropic hypogonadism. MRI of the brain showed bilateral agenesis of the olfactory bulbs and 3.5 mm pituitary microadenoma. Hormonal assays showed no evidence of pituitary hypersecretion.

Learning points:

  • The main clinical characteristics of KS include hypogonadotropic hypogonadism and anosmia or hyposmia.
  • MRI, as a non-irradiating technique, should be the first radiological step for investigating the pituitary gland as well as abnormalities of the ethmoid, olfactory bulbs and tracts in KS.
  • KS may include anterior pituitary hypoplasia or an empty sella syndrome. The originality of our case is that a microadenoma also may be encountered in KS. Hormonal assessment indicated the microadenoma was non-functioning. This emphasizes the importance of visualizing the pituitary region in KS patients to assess for hypoplastic pituitary malformations or adenomas.