RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.

Myxedema crisis and ovarian hyperstimulation in a child with Down syndrome

Objectives Myxedema crisis, a fatal complication of severe hypothyroidism, is extremely rare in children and treatment guidelines are lacking. Since availability of intravenous levothyroxine is limited in resource poor settings, myxedema crisis can be treated with oral levothyroxine and/or oral liothyronine (if necessary), in the absence of cardiac risk factors, thus hastening the recovery and significantly decreasing the associated morbidity and mortality. In the background of untreated hypothyroidism, a possible association of ovarian hyperstimulation syndrome (OHSS) and reactive pituitary hyperplasia should be kept in mind, thus preventing unnecessary interventions. Case presentation A 13-year-old girl child with Down syndrome, presented with myxedema crisis, as initial presentation of untreated hypothyroidism. Conclusions Annual screening, timely diagnosis of hypothyroidism, and early initiation of thyroid hormone supplementation will prevent associated physical and neurocognitive morbidity in children, especially those with Down syndrome. Importance of oral liothyronine supplementation in myxedema crisis, has been highlighted in this case report.

Pituitary Macroadenoma and Severe Hypothyroidism: The Link between Brain Imaging and Thyroid Function

In case of primary hypothyroidism, reactive pituitary hyperplasia can manifest as pituitary (pseudo) macroadenoma. We report the case of a 12-year-old boy who was evaluated for impaired growth velocity and increased body weight. Because of low insulin-like growth factor 1 levels and poor response to the growth hormone stimulation test, brain magnetic resonance imaging was performed and a pituitary macroadenoma was found. Treatment with levothyroxine was started, and thyroid function was evaluated approximately every 40 days to titrate the dosage. After few months of therapy, the size of the macroadenoma decreased and growth hormone secretion normalized. The pituitary returned to normal size in approximately 5 years. The boy went through puberty spontaneously and reached a normal adult height. In a patient affected by primary hypothyroidism, reactive pituitary hyperplasia can cause growth hormone deficiency; however, growth hormone secretion usually normalizes after starting levothyroxine treatment. Pituitary macroadenoma can be difficult to distinguish from severe pituitary hyperplasia; however, pituitary macroadenomas are rare in childhood, and our clinical case underlines how the hormonal evaluation is essential to achieve a correct diagnosis and prevent unnecessary surgery in a context of pituitary mass.

Sellar Gangliocytoma: Case Report and Review of an Extremely Rare Tumour

Sellar gangliocytomas (SGs) are rare, well-differentiated, low-grade neoplasias that commonly present along with a pituitary adenoma (PA). We describe a case of a 52-year-old woman with a 2-year history of headache, body weight increase, and recent onset of arterial hypertension and type 2 diabetes mellitus. Work-up tests revealed a normal hypophyseal profile, except for mild ACTH elevation, and a sellar mass on magnetic resonance imaging (MRI). A diagnosis of an enlarging pituitary macroadenoma was established, and to prevent symptom progression, the tumour was resected. Pathology showed 2 cell populations: ganglion and corticotrope cells. Three years after surgery, the patient no longer had a headache but persisted with arterial hypertension and type 2 diabetes mellitus. A literature review produced 207 cases of SGs. They typically present in women at 40 years of age and the most common clinical presentation are symptoms of acromegaly. Of the documented cases, 74 and 93% were treated with surgery alone or combined treatments (radiotherapy, radiosurgery, or pharmacotherapy), respectively. The majority of deaths associated with a SG came from the first half of the 20th century. In conclusion, this patient presented with a silent SG with likely pituitary hyperplasia. SGs are a challenging diagnosis, have a benign course, and may provide insights into PA tumourigenesis.

COVID-19 Induced Myxedema Madness

Background: Corona Virus Disease 2019 (COVID-19) pandemic was first reported in December 31st, 2019 in Wuhan, China. The clinical presentation is variable, including a variety of neuropsychiatric related symptoms. Myxedema Madness is a rare and severe neuropsychiatric complication of hypothyroidism manifested as psychosis. Case Presentation: A 25-year-old female with past medical history significant for treated Papillary Thyroid Cancer, presented with near syncopal event associated with weakness, lower extremity swelling, constipation, cold intolerance and dry skin. The patient was not compliant with her thyroid replacement therapy. Upon collateral history taken from the patient’s mother; the patient became dysphoric and tearful. On examination, patient had slightly decreased blood pressure and non-pitting edema on lower extremities. On neurological evaluation she exhibited forgetfulness and retardation of speech and motoric activity. Lab was remarkable for TSH greater than 100 uU/mL (reference range 0.30-4.20 uU/mL), FT4 0.4 ng/dL (reference range 0.6-1.5 ng/dL), and FT3 0.7 pg/mL (reference range 2.3-4.2 pg/mL). Patient tested negative for COVID-19 PCR. She was started on her home dose of Levothyroxine 150 mcg daily. Patient was discharged home after she was assessed by a psychiatrist, with no further interventions. Three days later, the patient was readmitted for confusion, disorientation and memory loss. Patient was found to be positive for COVID-19 PCR and negative for SARS-CoV-2 antibodies. She was found to be disoriented with paranoid delusions. Laboratory studies showed negative urine drug screen, syphilis and NMDA antibodies. CSF analysis were within normal ranges. Brain Magnetic resonance imaging was only positive for pituitary hyperplasia. Patient was started on T4 and T3 replacement therapy (Levothyroxine 50 mcq Intravenous, Liothyronine 5 mcg daily orally, respectively) followed by Risperdal 1 mg nightly. After significant improvement in her mood and delusions, patient was discharged home on Levothyroxine 150 mg daily and Risperdal 1mg for two weeks. Patient and family members were counseled on medications compliance. In a two-week follow-up visit, patient reported to be compliant with medications and improvement of mood. She denied hallucination or delusions. Her lab work was significant for TSH 5.57 uU/mL, FT4 1.3 ng/dL and FT3 3.2 pg/mL. Conclusion: Both psychosis secondary to COVID-19 and Myxedema Madness are rare conditions. Appropriate and timely supplementation of thyroid hormone facilitated speedy return of patient’s cognitive and psychiatric functions to appropriate baseline. This case report may increase physician’s awareness for potentially increased susceptibility of patients with severe hypothyroidism to neuropsychiatric manifestations of COVID-19.

Pituitary Hyperplasia: To Operate or Not to Operate, That Is the Question

Pituitary hyperplasia is defined as an absolute increase in the number of one or more adenohypophyseal cell subtypes, manifesting radiologically as pituitary enlargement beyond what is considered normal. It has been noted in certain physiological conditions like pregnancy however can also be seen in pathological conditions with end organ insufficiency like severe hypothyroidism. 21- year old female with a past medical history of Primary Hypothyroidism secondary to Hashimoto’s thyroiditis presented initially for evaluation of worsening headache and blurry vision. She was diagnosed with hypothyroidism at 10 years of age and had an extensive family history of hypothyroidism. At the time of presentation, she was 11 months post- partum and had been on and off her levothyroxine supplementation, having stopped it completely for a few months after delivery. MRI brain showed an 18 mm homogeneously enhancing intrasellar mass with suprasellar extension. She was referred to Neurosurgery for further evaluation. Workup revealed a TSH >100 (0.27 - 4.2 mIU/L) and FT4 <0.4 (0.8 - 2 ng/dL). In the context of severe untreated hypothyroidism and MRI findings consistent with pituitary hyperplasia with abutment but no mass effect on the optic apparatus, initial plan was to treat the hypothyroidism medically and observe closely. Patient was started on levothyroxine supplementation. Her TSH improved to 3.367 (0.550 - 4.780 uIU/mL) and FT4 to 2.00 (0.89 - 1.76 ng/dL), ηοωεϖερ she continued to have worsening of visual symptoms. Surgery was considered to decompress the optic nerve, but pre-operative MRI showed a significant decrease in size of the pituitary gland with decreased suprasellar bulging and no mass effect on the optic chiasm. Surgery was subsequently cancelled. Prolonged primary hypothyroidism leads to pituitary hyperplasia due to loss of negative feedback from lack of circulating T4 and T3, leading to excessive TRH secretion from the hypothalamus. The high TRH can lead to thyrotroph as well as lactotroph hyperplasia. Subsequently patients can present with headache, vision changes along with signs and symptoms of hypothyroidism and increased prolactin secretion. It is important to differentiate hyperplasia from other sellar lesions like pituitary macroadenoma or hypophysitis. Patients with hypothyroidism, who have pituitary enlargement diagnosed on brain imaging, should be promptly diagnosed and treated with thyroid hormone replacement. With a higher frequency and improved quality of imaging techniques, we are increasingly coming across scenarios of abnormal findings on imaging. Correlation of radiographic imaging results with a thorough history and biochemical testing is essential prior to proceeding with surgical intervention.

Sox2 Is Required Independently in Both Stem and Differentiated Cells for Pituitary Tumour Genesis in P27 Null Mice

Tumour development can depend on cell intrinsic dysfunction, but, in some cases, extrinsic factors are important drivers. Here, we have established a genetically tractable model demonstrating that the same gene is relevant both cell-autonomously and non-cell-autonomously for tumorigenesis. P27, a cell cycle inhibitor, is also able to drive repression of the transcription factor Sox2. This interaction plays a crucial role during development of p27-/- pituitary tumours because loss of one copy of Sox2 impairs tumorigenesis (1). However, SOX2 is expressed in both endocrine and stem cells (SC), and its contribution to tumorigenesis in either cell type is unknown. We have thus explored the cellular origin and mechanisms underlying endocrine tumorigenesis in p27-/- pituitaries. We found that pituitary hyperplasia is associated with reduced cellular differentiation, in parallel with increased levels of SOX2 in stem and endocrine cells. Using conditional loss-of-function and lineage tracing approaches, we show that SOX2 is required cell-autonomously in p27-/- endocrine cells for these to give rise to tumours, and in SCs for promotion of tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), the target of P27 repressive action. Single cell transcriptomic analysis further reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for tumorigenesis. Altogether, our data highlight different aspects of the role of SOX2 following loss of p27, according to cellular context, and uncover an unexpected SOX2-dependent tumour-promoting role for SCs. Our results imply that targeting SCs, in addition to tumour cells, may represent an efficient anti-tumoral strategy in certain contexts. (1) Li H, et al. (2012) p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation. Cell Stem Cell 11(6):845-852.

Acromegaly in a Young Women With Pituitary Hyperplasia Secondary to a Neuroendocrine Tumor

Acromegaly is rarely due to an excess of the GH-releasing hormone (GHRH) and pituitary hyperplasia on histology should alert to its presence. Clinical Case: A 35-year-old was referred to surgery with a confirmed diagnosis of symptomatic acromegaly. Her GH failed to suppress during an oral glucose tolerance test (OGTT), her IGF-1 and prolactin was high. Her serum calcium was normal and her chromogranin B was high. MRI scan suggested microadenoma. Her surgery was deferred because of Covid 19, and she was treated with somatostatin analog (SSA). She finally had surgery in July. The histology and immunocytochemistry suggested pituitary hyperplasia with diffuse positivity for chromogranin and synaptophysin. GH was positive in the majority of the cells with many cells positive for Prolactin and ACTH. FSH and LH were positive in scattered cells with patchy positivity of TSH. A solitary nodule was noted in her neck during an examination. We arranged to look for conditions associated with pituitary hyperplasia resulting in GHRH production, including the genetic tests for inherited conditions. Her calcitonin level was normal. She had an ultrasound scan guided fine needle aspiration of the thyroid nodule, this showed Thy3f oncocytic nodule with no features of medullary thyroid carcinoma. She had an NMGa68DOTATATE whole body PET CTand the scan showed a large DOTATAE avid mass from the right adrenal gland compatible with Pheochromocytoma. Her 24 hours total urinary metadrenaline and normetadrenalin was high. Her genetic test for MEN1, CDKN1B, and MEN2 are negative. We have requested the GHRH measurement. After a pituitary surgery, her GH suppressed adequately on OGTT. Her IGF-1 and prolactin is low and her hypogonadism is resolved. Conclusion: Excess production GHRH can result from neuroendocrine tumors of the lung, pancreas, thyroid (medullary thyroid cancer), or pheochromocytomas and hypothalamic gangliocytomas. Several familial syndromes, multiple endocrine neoplasia type 1 (MEN1) and 4 (MEN4), familial isolated pituitary adenoma (FIPA), Carney complex, and sporadic germline mosaic disorder McCune-Albright disease predispose to pituitary hyperplasia. GHRH acromegaly should be suspected in a patient with biochemical/clinical features of acromegaly in the presence of co-existing neuroendocrine tumors when there is diffuse pituitary enlargement on imaging or resolution of acromegaly after the surgical resection of the primary neuroendocrine tumour or persistent acromegaly after surgery if there is histological evidence of somatotroph hyperplasia. References: Akirov A, ASA SL, AMER L Shimon I and Ezzat S. The clinicopathological spectrum of acromegaly. J. Clin. Med. 8(11), 1962 (2019) J. Clin. Med. 2019; 8: 11, 1962