Clinical Overview > Condition/ Syndrome
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Summary
IgG4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory condition which can affect various organs including the pituitary gland. The true annual incidence of this condition remains widely unknown. In addition, it is unclear whether IgG4 antibodies are causative or the end result of a trigger. With no specific biomarkers available, the diagnosis of IgG4-related hypophysitis remains a challenge. Additionally, there is a wide differential diagnosis. We report a case of biopsy-proven IgG4-related hypophysitis in a young man with type 2 diabetes mellitus.
Learning points:
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IgG4-related hypophysitis is part of a spectrum of IgG4-related diseases.
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Clinical manifestations result from anterior pituitary hormone deficiencies with or without diabetes insipidus, which can be temporary or permanent.
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A combination of clinical, radiological, serological and histological evidence with careful interpretation is required to make the diagnosis.
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Tissue biopsy remains the gold standard investigation.
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Disease monitoring and long-term management of this condition is a challenge as relapses occur frequently.
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Summary
A previously healthy 24-year-old female underwent an emergent caesarean section without a major bleeding described. During the first post-operative days (POD) she complained of fatigue, headache and a failure to lactate with no specific and conclusive findings on head CT. On the following days, fever rose with a suspicion of an obstetric surgery-related infection, again with no evidence to support the diagnosis. On POD5 a new-onset hyponatremia was documented. The urine analysis suggested SIADH, and following a treatment failure, further investigation was performed and demonstrated both central hypothyroidism and adrenal insufficiency. The patient was immediately treated with hydrocortisone followed by levothyroxine with a rapid resolution of symptoms and hyponatremia. Further laboratory investigation demonstrated anterior hypopituitarism. The main differential diagnosis was Sheehan’s syndrome vs lymphocytic hypophysitis. Brain MRI was performed as soon as it was available and findings consistent with Sheehan’s syndrome confirmed the diagnosis. Lifelong hormonal replacement therapy was initiated. Further complaints on polyuria and polydipsia have led to a water deprivation testing and the diagnosis of partial central insipidus and appropriate treatment with DDAVP.
Learning points:
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Sheehan’s syndrome can occur, though rarely, without an obvious major post-partum hemorrhage.
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The syndrome may resemble lymphocytic hypophysitis clinically and imaging studies may be crucial in order to differentiate both conditions.
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Hypopituitarism presentation may be variable and depends on the specific hormone deficit.
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Euvolemic hyponatremia workup must include thyroid function test and 08:00 AM cortisol levels.
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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:
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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.
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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.
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Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology.
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16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders.
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Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion.
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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.
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Summary
In this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient’s clinical course as well as a review of LHX3 mutations and the associated phenotype.
Learning points:
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Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life
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Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3
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Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations
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Division of Endocrinology and Metabolism Division of Endocrinology and Metabolism, International University of Health and Welfare Hospital, Tochigi, Japan
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Summary
Lymphocytic hypophysitis (LyH) has been known to be associated with pregnancy. We herein report the case of a 33-year-old woman who underwent vaginal delivery without massive bleeding at 40 weeks of gestation. Because of the presence of headache and terrible fatigue after childbirth, she visited our hospital. Severe hyponatremia (Na, 118 mEq/L) and visual field abnormality was noted upon examination. MRI revealed pituitary enlargement with a swollen pituitary stalk, albeit at low signal intensity. Basal pituitary hormone levels were all reduced and remained low after exogenous administration of hypothalamic-releasing hormones. She was diagnosed with LyH and was started on prednisolone 60 mg/day. A month later, her pituitary function had gradually improved together with a decrease in pituitary enlargement and recovery of her visual field. The dose of prednisolone was gradually reduced and finally withdrawn 27 months later. After prednisolone withdrawal, her pituitary function remained normal despite the absence of any hormonal replacement. A year later, she became pregnant without medication and delivered a second baby without LyH recurrence. Thereafter, her pituitary function has been normal for more than 5 years. Two valuable observations can be highlighted from the case. First, the patient completely recovered from LyH through prompt prednisolone therapy during its initial phase and had almost normal pituitary function. Second, after recovery from LyH, she was able to undergo spontaneous pregnancy and deliver a baby. We believe that reporting incidences of spontaneous pregnancy after complete normalization of pituitary function in patients with LyH is of great significance.
Learning points:
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Females are more affected by LyH than males given its strong association with pregnancy.
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LyH possesses characteristic findings on pituitary MRI.
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Glucocorticoid therapy for LyH has been recommended as an effective treatment.
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A history of previous pregnancies does not increase the risk of developing AH in subsequent pregnancies.
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Early induction of high-dose prednisolone was therapeutically effective in treating LyH.
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Summary
Granular cell tumours (GCT) are rare, slow-growing, benign neoplasms that are usually located in the head and neck. They are more frequent in the female gender and typically have an asymptomatic clinical course, being diagnosed only at autopsy. Symptomatic GCT of the neurohypophysis are exceedingly rare, being less than 70 cases described so far. The authors report on a case of a 28-year-old male that presented to the Endocrinology clinic with clinical and biochemical evidence of hypogonadism. He also reported minor headaches without any major visual symptoms. Further laboratory tests confirmed hypopituitarism (hypogonadotrophic hypogonadism, central hypothyroidism and hypocortisolism) and central nervous system imaging revealed a pituitary macroadenoma. The patient underwent transcranial pituitary adenoma resection and the pathology report described a GCT of the neurohypophysis with low mitotic index. The reported case is noteworthy for the rarity of the clinicopathological entity.
Learning points:
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Symptomatic GCTs are rare CNS tumours whose cell of origin is not well defined that usually give rise to visual symptoms, headache and endocrine dysfunction.
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Imaging is quite unspecific and diagnosis is difficult to establish preoperatively.
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Surgical excision is challenging due to lesion’s high vascularity and propensity to adhere to adjacent structures.
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The reported case is noteworthy for the rarity of the clinicopathological entity.
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Sellar plasmacytomas are rare and the differential diagnosis with non-functioning pituitary adenomas might be difficult because of clinical and radiological resemblance. They usually present with neurological signs and intact anterior pituitary function. Some may already have or eventually progress to multiple myeloma. We describe a case associated with extensive anterior pituitary involvement, which is a rare form of presentation. A 68-year-old man was referred to our Endocrinology outpatient clinic due to gynecomastia, reduced libido and sexual impotence. Physical examination, breast ultrasound and mammography confirmed bilateral gynecomastia. Blood tests revealed slight hyperprolactinemia, low testosterone levels, low cortisol levels and central hypothyroidism. Sellar MRI showed a heterogeneous sellar mass (56 × 60 × 61 mm), initially suspected as an invasive macroadenoma. After correcting the pituitary deficits with hydrocortisone and levothyroxine, the patient underwent transsphenoidal surgery. Histological examination revealed a plasmacytoma and multiple myeloma was ruled out. The patient was unsuccessfully treated with radiation therapy (no tumor shrinkage). Myeloma ultimately developed, with several other similar lesions in different locations. The patient was started on chemotherapy, had a bone marrow transplant and is now stable (progression free) on lenalidomide and dexamethasone. The presenting symptoms and panhypopituitarism persisted, requiring chronic replacement treatment with levothyroxine, hydrocortisone and testosterone.
Learning points:
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Plasmacytomas, although rare, are a possible type of sellar masses, which have a completely different treatment approach, so it is important to make the correct diagnosis.
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Usually, they present with neurological signs and symptoms and a well-preserved pituitary function, but our case shows that anterior pituitary function can be severely compromised.
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Making a more extensive evaluation (clinical and biochemical) might provide some clues to this diagnosis.
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Summary
Isolated Growth Hormone Deficiency (IGHD) is a rare cause of short stature, treated with the standard regimen of subcutaneous synthetic growth hormone (GH). Patients typically achieve a maximum height velocity in the first year of treatment, which then tapers shortly after treatment is stopped. We report a case of a 9-year-old male who presented with short stature (<3rd percentile for age and race). Basal hormone levels showed undetectable serum IGF1. Skeletal wrist age was consistent with chronologic age. Cranial MRI revealed no masses or lesions. Provocative arginine-GH stimulation testing demonstrated a peak GH level of 1.4 ng/mL. Confirmatory genetic testing revealed a rare autosomal recessive single-nucleotide polymorphism (SNP) with mutational frequency of 2%. GH supplementation was started and pursued for 2 years, producing dramatically increased height velocity. This velocity persisted linearly through adolescence, several years after treatment had been discontinued. Final adult height was >95th percentile for age and race. In conclusion, this is a case of primary hypopituitarism with differential diagnosis of IGHD vs Idiopathic Short Stature vs Constitutional Growth Delay. This case supports two objectives: Firstly, it highlights the importance of confirmatory genetic testing in patients with suspected, though diagnostically uncertain, IGHD. Secondly, it demonstrates a novel secondary growth pattern with implications for better understanding the tremendous variability of GH treatment response.
Learning points:
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GHD is a common cause of growth retardation, and IGHD is a specific subtype of GHD in which patients present solely with short stature.
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The standard treatment for IGHD is subcutaneous synthetic GH until mid-parental height is reached, with peak height velocity attained in the 1st year of treatment in the vast majority of patients.
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Genetic testing should be strongly considered in cases of diagnostic uncertainty prior to initiating treatment.
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Future investigations of GH treatment response that stratify by gene and specific mutation will help guide treatment decisions.
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Response to treatment in patients with IGHD is variable, with some patients demonstrating little to no response, while others are ‘super-responders.’
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Summary
Central diabetes insipidus (DI) is a rare clinical entity characterized by low circulating levels of antidiuretic hormone (ADH) presenting with polyuria and volume depletion. Pituitary surgery is the most common cause of central DI in adults. Pituitary and hypothalamic disease, particularly invasive neoplasms, rarely cause DI, being idiopathic cases responsible for the majority of non-surgical cases. HIV patients, especially those with poor virulogical control, are prone to the development of CNS neoplasms, particularly lymphomas. These neoplasms usually become manifest with mass effects and seizures. Central DI and hypopituitarism are uncommon initial manifestations of primary CNS lymphomas. The authors describe the case of 29-year-old female, HIV-positive patient whose CNS lymphoma presented with DI.
Learning points:
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Central diabetes insipidus has multiple causes and central nervous system lymphomas are not often considered in the differential diagnosis due to their low prevalence.
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Accurate biochemical diagnosis should always be followed by etiological investigation.
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The HIV population is at risk for many neoplasms, especially CNS lymphomas.
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New-onset polyuria in an HIV-positive patient in the absence of focal neurological signs should raise the suspicion for a central nervous system process of neoplastic nature.
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This clinical entity usually constitutes a therapeutical challenge, often requiring a multidisciplinary approach for optimal outcome.
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Summary
The craniopharyngiomas are solid cystic suprasellar tumors that can present extension to adjacent structures, conditioning pituitary and hypothalamic dysfunction. Within hypothalamic neuroendocrine dysfunction, we can find obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, imbalances in the regulation of body temperature, thirst, heart rate and/or blood pressure and alterations in dietary intake (like anorexia). We present a rare case of anorexia–cachexia syndrome like a manifestation of neuroendocrine dysfunction in a patient with a papillary craniopharyngioma. Anorexia–cachexia syndrome is a complex metabolic process associated with underlying illness and characterized by loss of muscle with or without loss of fat mass and can occur in a number of diseases like cancer neoplasm, non-cancer neoplasm, chronic disease or immunodeficiency states like HIV/AIDS. The role of cytokines and anorexigenic and orexigenic peptides are important in the etiology. The anorexia–cachexia syndrome is a clinical entity rarely described in the literature and it leads to important function limitation, comorbidities and worsening prognosis.
Learning points:
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Suprasellar lesions can result in pituitary and hypothalamic dysfunction.
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The hypothalamic neuroendocrine dysfunction is commonly related with obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, but rarely with anorexia–cachexia.
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Anorexia–cachexia syndrome is a metabolic process associated with loss of muscle, with or without loss of fat mass, in a patient with neoplasm, chronic disease or immunodeficiency states.
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Anorexia–cachexia syndrome results in important function limitation, comorbidities that influence negatively on treatment, progressive clinical deterioration and bad prognosis that can lead the patient to death.
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Anorexia–cachexia syndrome should be suspected in patients with emaciation and hypothalamic lesions.
