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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

Susan Ahern, Mark Daniels and Amrit Bhangoo

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:

  • Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life

  • Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3

  • Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations

Open access

Yew Wen Yap, Steve Ball and Zubair Qureshi

Summary

The coexistence of primary hypothyroidism and thyroid-stimulating hormone (TSH)-stimulating pituitary macroadenoma can be a rare occurrence and can make diagnosis very challenging. We describe a case of a 44-year-old female with a history of fatigue, poor concentration, weight gain and amenorrhoea together with biochemical evidence of primary autoimmune hypothyroidism. Her initial TSH levels were elevated with low normal free thyroxine (T4) levels. Levothyroxine treatment was initiated and the dose was gradually titrated to supraphysiologic doses. This led to the normalisation of her TSH levels but her free T4 and triiodothyronine (T3) levels remained persistently elevated. This prompted a serum prolactin check which returned elevated at 2495 µ/L, leading onto pituitary imaging. A MRI of the pituitary gland revealed a pituitary macroadenoma measuring 2.4 × 2 × 1.6 cm. Despite starting her on cabergoline therapy with a reduction in her prolactin levels, her TSH levels began to rise even further. Additional thyroid assays revealed that she had an abnormally elevated alpha subunit at 3.95 (age-related reference range <3.00). This corresponded to a thyroid-secreting hormone pituitary macroadenoma. She went on to have a transphenoidal hypophysectomy. Histology revealed tissues staining for TSH, confirming this to be a TSH-secreting pituitary macroadenoma. This case highlighted the importance of further investigations with thyroid assay interferences, heterophile antibodies, alpha subunit testing and anterior pituitary profile in cases of resistant and non-resolving primary hypothyroidism.

Learning points:

  • Levothyroxine treatment in primary hypothyroidism can potentially unmask the presence of a latent TSH-secreting pituitary macroadenoma, which can make diagnosis very challenging.

  • A high index of suspicion should prompt clinicians to further investigate cases of primary hypothyroidism which despite increasing doses of levothyroxine treatment with normalisation of TSH, the free T4 and T3 levels remain persistently elevated.

  • Clinicians should consider investigating for adherence to levothyroxine, thyroid assay interference, heterophile antibodies, TSH dilution studies, alpha subunit and anterior pituitary profile testing to further clarity the diagnosis in these patients.

  • Although coexistent cases of TSHoma with primary hypothyroidism are rare, it should always be in the list of differential diagnoses in cases of unresolving primary hypothyroidism.

Open access

Wael M Almistehi and Mussa H Almalki

Summary

Giant prolactinomas are a rare entity; during pregnancy, the risk for complications associated with these tumors is higher. Here, we report a case of a young woman who had an invasive, giant prolactinoma post resection with residual disease who became pregnant. This patient was treated with cabergoline to prevent tumor expansion in pregnancy, resulting in the uneventful delivery of a healthy baby boy.

Learning points:

  • Giant prolactinoma can cause both diagnostic and therapeutic challenges given their atypical presentation.

  • Accurate diagnosis is paramount to avoid unnecessary surgical intervention or pituitary irradiation.

  • This case demonstrates the effectiveness and safety of CAB therapy during pregnancy.

Open access

Philip D Oddie, Benjamin B Albert, Paul L Hofman, Craig Jefferies, Stephen Laughton and Philippa J Carter

Summary

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.

Learning points:

  • Adrenocortical carcinoma is an important differential diagnosis for virilization in young children

  • Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis

  • Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.

  • Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed

  • In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

Open access

Kewan Hamid, Neha Dayalani, Muhammad Jabbar and Elna Saah

Summary

A 6-year-old female presented with chronic intermittent abdominal pain for 1 year. She underwent extensive investigation, imaging and invasive procedures with multiple emergency room visits. It caused a significant distress to the patient and the family with multiple missing days at school in addition to financial burden and emotional stress the child endured. When clinical picture was combined with laboratory finding of macrocytic anemia, a diagnosis of hypothyroidism was made. Although chronic abdominal pain in pediatric population is usually due to functional causes such as irritable bowel syndrome, abdominal migraine and functional abdominal pain. Hypothyroidism can have unusual presentation including abdominal pain. The literature on abdominal pain as the main presentation of thyroid disorder is limited. Pediatricians should exclude hypothyroidism in a patient who presents with chronic abdominal pain. Contrast to its treatment, clinical presentation of hypothyroidism can be diverse and challenging, leading to a delay in diagnosis and causing significant morbidity.

Learning points:

  • Hypothyroidism can have a wide range of clinical presentations that are often nonspecific, which can cause difficulty in diagnosis.

  • In pediatric patients presenting with chronic abdominal pain as only symptom, hypothyroidism should be considered by the pediatricians and ruled out.

  • In pediatric population, treatment of hypothyroidism varies depending on patients’ weight and age.

  • Delay in diagnosis of hypothyroidism can cause significant morbidity and distress in pediatrics population.

Open access

Ehtasham Ahmad, Kashif Hafeez, Muhammad Fahad Arshad, Jimboy Isuga and Apostolos Vrettos

Summary

Primary hypothyroidism is a common endocrine condition, most commonly caused by autoimmune thyroiditis (Hashimoto’s disease) while Graves’ disease is the most common cause of hyperthyroidism. Hypothyroidism is usually a permanent condition in most patients requiring lifelong levothyroxine treatment. Transformation from Hashimoto’s disease to Graves’ disease is considered rare but recently been increasingly recognised. We describe a case of a 61-year-old lady who was diagnosed with hypothyroidism approximately three decades ago and treated with levothyroxine replacement therapy. Approximately 27 years after the initial diagnosis of hypothyroidism, she started to become biochemically and clinically hyperthyroid. This was initially managed with gradual reduction in the dose of levothyroxine, followed by complete cessation of the medication, but she remained hyperthyroid, ultimately requiring anti-thyroid treatment with Carbimazole. This case highlights that there should be a high index of suspicion for a possible conversion of hypothyroidism to hyperthyroidism, even many years after the initial diagnosis of hypothyroidism. To our knowledge, this case illustrates the longest reported time interval between the diagnosis of hypothyroidism until the conversion to hyperthyroidism.

Learning points:

  • Occurrence of Graves’ disease after primary hypothyroidism is uncommon but possible.

  • In this case, there was a time-lapse of almost 28 years and therefore this entity may not be as rare as previously thought.

  • Diagnosis requires careful clinical and biochemical assessment. Otherwise, the case can be easily confused for over-replacement of levothyroxine.

  • We suggest measuring both anti-thyroid peroxidase (TPO) antibodies and TSH receptor antibodies (TRAB) in suspected cases.

  • The underlying aetiology for the conversion is not exactly known but probably involves autoimmune switch by an external stimulus in genetically susceptible individuals.

Open access

Shigenori Nakamura, Teruyuki Masuda and Masatoshi Ishimori

Summary

We report a case of a 15-year-old girl with a midline neck mass that was first noted 2 or 3 years previously. She had been treated with levothyroxine (L-T4) for congenital hypothyroidism until 11 years of age. Ultrasonography revealed an atrophic right thyroid (1.0 × 1.6 × 2.6 cm in size) and a mass (2.3 × 1.0 × 3.5 cm in size) in the upper part of the neck. No left lobe of the thyroid was detected. On further evaluation, Tc-99m pertechnetate thyroid scintigraphy and CT showed ectopic thyroid tissue in the lingual region and infrahyoid region. Thus, she was diagnosed as having dual ectopic thyroid and thyroid hemiagenesis. The atrophic right thyroid was thought be non-functional. Treatment with L-T4 was started to reduce the size of the dual ectopic thyroid tissue. This may be the first reported case of dual ectopic thyroid associated with hemiagenesis detected only by ultrasonography.

Learning points:

  • Ultrasonography can confirm the presence or absence of orthotopic thyroid tissue in patients with ectopic thyroid.

  • The cause of congenital hypothyroidism should be examined.

  • Clinical manifestation of ectopic thyroid may appear when the treatment with L-T4 is discontinued.

  • Annual follow-up is needed in all children when their thyroid hormone replacement is stopped.

Open access

Carlos Tavares Bello, Patricia Cipriano, Vanessa Henriques, João Sequeira Duarte and Conceição Canas Marques

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:

  • 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.

  • Imaging is quite unspecific and diagnosis is difficult to establish preoperatively.

  • Surgical excision is challenging due to lesion’s high vascularity and propensity to adhere to adjacent structures.

  • The reported case is noteworthy for the rarity of the clinicopathological entity.

Open access

Joseph A Chorny, John J Orrego and José Manuel Cameselle-Teijeiro

Summary

Most medullary thyroid carcinomas (MTCs) are low grade and produce calcitonin. There are some calcitonin-negative MTCs that produce only calcitonin gene-related peptide (CGRP). Rarely, MTCs are negative for calcitonin and CGRP peptides, but contain their corresponding mRNAs. Primary thyroid neuroendocrine neoplasms other than MTCs are extremely rare. We describe a primary high-grade neuroendocrine carcinoma that was negative for CGRP and calcitonin at both the protein and mRNA levels. A 42-year-old woman presented with a rapidly enlarging thyroid mass replacing most of the left lobe and isthmus. A computed tomography-guided core-needle biopsy was performed. The tumor was composed of sheets of small-to-medium sized epithelial cells. The cells were immunoreactive for pancytokeratin, synaptophysin, CD56 and thyroid transcription factor-1, but negative for CK7, CK20, CD45, CD99, ERG, chromogranin A, thyroglobulin, calcitonin, CGRP and carcinoembryonic antigen. The Ki-67 proliferation index was ~90%. In situ hybridization was negative for calcitonin mRNA. The patient was initially diagnosed as having a small cell carcinoma. She was treated with cisplatin and etoposide (VP16), followed by radiation therapy. Given the excellent clinical course, the tumor was reviewed and reclassified as a high-grade neuroendocrine carcinoma (non-small-cell type). Heretofore, only a few other similar high-grade neuroendocrine tumors with negative markers of C-cell derivation have been reported. In our case, the patient is cancer free five years after diagnosis, but in the other cases, the outcome was poor.

Learning points:

  • There are neuroendocrine carcinomas of the thyroid that do not produce calcitonin or calcitonin gene-related peptide.

  • This category of calcitonin-negative neuroendocrine carcinomas is heterogeneous, consisting of low- and high-grade tumors.

  • The high-grade neuroendocrine carcinomas of the thyroid are rare and generally have a poor prognosis. They are divided into small cell and non-small cell or large cell types.