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Open access

Bifocal germinoma in a patient with 16p11.2 microdeletion syndrome

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

Transient diabetes insipidus in a post-partum woman with pre-eclampsia associated with residual placental vasopressinase activity

Natassia Rodrigo and Samantha Hocking

Summary

This case illustrates the exceedingly rare phenomenon of transient diabetes insipidus, in association with pre-eclampsia, occurring in the post-partum period following an in vitro fertilisation pregnancy, in an otherwise well 48-year-old lady. Diabetes insipidus can manifest during pregnancy, induced by increased vasopressinase activity secreted by placental trophoblasts and usually manifests in the third trimester. This presentation elucidates not only the intricate balance between the physiology of pregnancy and hormonal homeostasis, but also the importance of post-partum care as the physiological changes of pregnancy still hold pathological potential in the weeks immediately following delivery.

Learning points:

  • Diabetes insipidus (DI) is a rare complication of pregnancy occurring in 1 in 30 000 pregnancies.

  • It is associated with excessive vasopressinase activity, secreted by placental trophoblasts, which increases the rate of degradation of anti-diuretic hormone.

  • It is responsive to synthetic desmopressin 1-deanimo-8-d-arginine vasopressin as this form is not degraded by placental vasopressinase.

  • Vasopressinase is proportional to placental weight, which is increased in pregnancies conceived with assisted reproductive techniques including in vitro fertilisation.

  • Vasopressinase-induced DI is associated with pre-eclampsia.

Open access

Difficulties in cerebrospinal fluid βhCG interpretation in a patient with an infundibular lesion

Alicia R Jones, Alan McNeil, Christopher Yates, Bala Krishnamurthy and Peter S Hamblin

Summary

A variety of neoplastic, inflammatory and congenital conditions can cause pituitary stalk thickening. Differentiating between these causes is important as targeted treatment may be offered. Diagnostic work-up consists of a thorough history, examination, biochemical analysis and imaging. We present the case of a 33-year-old male who presented with diabetes insipidus and had pituitary stalk thickening on magnetic resonance imaging. Further investigations revealed an elevated CSF βhCG, which raised the possibility of an intracranial germ cell tumor. However, when repeated on four different assays, the βhCG levels were discordant. On serial imaging, the pituitary stalk thickening reduced slightly, which would be unexpected for a germ cell tumor. This case raises the difficulties interpreting CSF βhCG, as not all immunoassays for βhCG have been validated for use in CSF. The Roche Diagnostics Elecsys and Siemens Centaur assays have been validated for CSF βhCG, and so we advocate using one of these methods. If unavailable or serum/CSF results are ambiguous, serial MRI is appropriate, with pituitary stalk biopsy considered if the stalk measures >6.5 mm or other imaging abnormalities are present.

Learning points:

  • Most adult patients with central diabetes insipidus have imaging abnormalities on a pituitary MRI. The most common abnormalities are loss of the posterior pituitary bright spot and pituitary stalk thickening, both of which are non-specific.

  • Causes of pituitary stalk thickening include neoplastic, inflammatory, infective and congenital lesions.

  • Investigation of pituitary stalk thickening should encompass the many possible causes and include biochemical analyses as well as imaging of the chest, abdomen and pelvis. Further investigations should be guided by the clinical context, but may include testicular ultrasound, CSF analysis and pituitary stalk biopsy.

  • Germ cell tumors involving the pituitary stalk may be suspected on clinical grounds, but in the absence of a tissue diagnosis (biopsy) confirmation may be difficult and relies on biochemical assessment of blood and possibly CSF as well as serial MRI imaging.

  • CSF βhCG levels should be analyzed on an instrument validated for use in CSF or on multiple instruments, and the pitfalls of testing this marker (false negative in some germ cell tumors, false positives in other conditions, lack of internationally agreed reference ranges for diagnosing germ cell tumors) should be considered when interpreting the results.

Open access

Recurrent pituitary abscess: case report and review of the literature

Raluca Maria Furnica, Julie Lelotte, Thierry Duprez, Dominique Maiter and Orsalia Alexopoulou

Summary

A 26-year-old woman presented with severe postpartum headaches. Magnetic resonance imaging (MRI) revealed a symmetric, heterogeneous enlargement of the pituitary gland. Three months later, she developed central diabetes insipidus. A diagnosis of postpartum hypophysitis was suspected and corticosteroids were prescribed. Six months later, the pituitary mass showed further enlargement and characteristics of a necrotic abscess with a peripheral shell and infiltration of the hypothalamus. Transsphenoidal surgery was performed, disclosing a pus-filled cavity which was drained. No bacterial growth was observed, except a single positive blood culture for Staphylococcus aureus, considered at that time as a potential contaminant. A short antibiotic course was, however, administered together with hormonal substitution for panhypopituitarism. Four months after her discharge, severe headaches recurred. Pituitary MRI was suggestive of a persistent inflammatory mass of the sellar region. She underwent a new transsphenoidal resection of a residual abscess. At that time, the sellar aspiration fluid was positive for Staphylococcus aureus and she was treated with antibiotics for 6 weeks, after which she had complete resolution of her infection. The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies.

Learning points:

  • The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies.

  • In a significant proportion of cases no pathogenic organism can be isolated.

  • A close follow-up is necessary given the risk of recurrence and the high rate of postoperative pituitary deficiencies.

Open access

IgG4-related hypophysitis presenting as diabetes insipidus with tubulo-interstital nephritis and mediastinal lymphadenopathy

Rayna Patel, Waheed Mustafa, Michael T Sheaff and Sami Khan

Summary

IgG4-related disease (IgG4-RD) is a rare but increasingly recognised condition, emerging as a clinical entity following the observation of the associations of autoimmune pancreatitis. IgG4-RD is characterised by extensive infiltration of IgG4-positive plasma cells into multiple organs and raised serum IgG4 levels. Clinical manifestations of IgG4 disease classically include autoimmune pancreatitis, lacrimal or salivary gland infiltration (formerly known as Mikulicz disease) and retroperitoneal fibrosis. More rarely, IgG4 disease can cause pituitary hypophysitis. Although most frequently described in middle-aged males, the epidemiology and pathogenesis of the disease remain largely undefined. Nevertheless, an understanding of the wide variety of clinical manifestations of this multi-system condition is undeniably important given the often excellent outcomes following treatment. We describe an unusual presentation of IgG4 disease with isolated diabetes insipidus secondary to pituitary hypophysitis. The patient in question subsequently developed chest pain secondary to mediastinal lymphadenopathy and tubulo-interstitial nephritis leading to renal dysfunction. He was successfully treated with oral steroids and had regular follow-up, and remains well at follow-up 2 years later.

Learning points

  • IgG4 disease, although rare, is increasing in prevalence largely due to increased recognition of its clinical manifestations, including autoimmune pancreatitis, lacrimal or salivary gland infiltration, retroperitoneal fibrosis and, more rarely, lymphocytic hypophysitis presenting as diabetes insipidus.

  • IgG4 disease is highly treatable, and symptoms may show complete resolution with administration of steroids, highlighting the importance of correct and timely diagnosis.

  • Causes of lymphocytic hypophysitis are varied and not distinguishable radiologically. Given the difficulty in biopsying the pituitary, careful attention must be paid to the systemic clinical presentation to provide clues as to the underlying disorder.

Open access

Chinese Erdheim-Chester disease: clinical-pathology-PET/CT updates

Huanyu Ding, Yang Li, Caishun Ruan, Yuan Gao, Hehua Wang, Xiangsong Zhang and Zhihong Liao

Summary

Erdheim-Chester disease (ECD), one type of systemic non-Langerhans cell histiocytosis, has been rarely seen and is characterized by the accumulation of foamy CD68+CD1a- histiocytes. We reported a case of ECD and reviewed the clinical features of 13 cases of ECD reported so far in China. A 53-year-old male was diagnosed with central diabetes insipidus in March 2014, followed by fever, splenomegaly and anemia in July 2014. His initial pituitary magnetic resonance imaging (MRI) revealed the absence of high signal at T1-weighted image in posterior pituitary without any lesion. A further positron emission tomography/computer tomography (PET/CT) images showed elevated metabolic activity of 18F-2-fluro-D-deoxy-glucose (FDG) and low 13N-NH3 uptake in the posterior pituitary, and multi-organ involvement. Biopsy at right femur lesion revealed that granulomatous infiltration of foamy histiocytes and Touton giant cells surrounded by fibrosis tissues. Immunohistochemistry stain was positive for CD68, negative for CD207/Langerin and S-100. The diagnosis of ECD was confirmed and the treatment with pegylated interferon was effective. ECD was a possible immune-related disorder concluding from the IgG4 immunohistochemistry results. We summarized the pathological manifestations for ECD and its differential diagnosis from Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). ECD should be considered by both pathologists and clinicians in the differential diagnosis when central diabetes insipidus is accompanied with multi-organ involvement, especially skeletal system involvement, or recurrent fever.

Learning points

  • ECD should be considered when central diabetes insipidus is accompanied with multisystem involvement, especially symmetric/asymmetric bone lesions, or recurrent fever.

  • PET/CT scanning was helpful for locating pituitary lesion, discovering multiple system involvement and indicating the biopsy sites.

  • Conducting proper immunohistochemistry stains was important for diagnosing ECD. ECD might be correlated with immune disorder.

Open access

Utility of genetic testing in suspected familial cranial diabetes insipidus

Ramesh Srinivasan, Stephen Ball, Martin Ward-Platt, David Bourn, Ciaron McAnulty and Tim Cheetham

Summary

Aim: Differentiating familial cranial diabetes insipidus (CDI) from primary polydipsia can be difficult. We report the diagnostic utility of genetic testing as a means of confirming or excluding this diagnosis.

Patient and methods: The index case presented at 3 months with polydipsia. He was diagnosed with familial CDI based on a positive family history combined with what was considered to be suspicious symptomatology and biochemistry. He was treated with desmopressin (DDAVP) but re-presented at 5 months of age with hyponatraemia and the DDAVP was stopped. Gene sequencing of the vasopressin gene in father and his offspring was undertaken to establish the underlying molecular defect.

Results: Both father and daughter were found to have the pathogenic mutation c.242T>C (p.Leu81Pro) in exon 2 of the AVP gene consistent with a diagnosis of familial diabetes insipidus. The index case did not have the pathogenic mutation and the family could be reassured that he would not require intervention with DDAVP.

Conclusions: Gene sequencing of AVP gene can have a valuable role in predicting whether or not a child is at risk of developing CDI in future. This can help to prevent family uncertainty and unnecessary treatment with its associated risks.

Learning points

  • Differentiating patients with familial cranial diabetes insipidus from those with primary polydipsia is not always straightforward.

  • Molecular genetic analysis of the vasopressin gene is a valuable way of confirming or refuting a diagnosis of familial CDI in difficult cases and is a valuable way of identifying individuals who will develop CDI in later childhood. This information can be of great value to families.