Summary

Pituitary adenomas are intracranial neoplasms, usually demonstrating a benign phenotype. We present the case of 21-year-old male with an 18-month history of reduced visual function (acuity and field) in the left eye. Based on neuroimaging and endocrine profile, a giant prolactinoma causing hypogonadotropic hypogonadism was diagnosed and cabergoline was commenced. After a month of treatment, the tumour size reduced, and visual function improved to normal; however, he developed Foster Kennedy syndrome with a swollen right optic disc. After almost 1 year of follow-up, he regained full visual functioning. Two years since his diagnosis, his prolactin remains normal with no adverse effects or further visual complications.

Learning points

• Foster Kennedy syndrome is a rare entity but can be a feature of pituitary adenomas.

• Visual deterioration secondary to a compressive optic neuropathy can be reversible, provided that diagnosis and treatment are prompt.

• This case highlights the importance of frequent monitoring of visual function during follow-up of these lesions, particularly when there are deficits at diagnosis.

Summary

Biallelic pathological variants in the thyroid stimulating hormone (TSH) subunit β gene (TSHB) result in isolated TSH deficiency and secondary hypothyroidism, a rare form of central congenital hypothyroidism (CCH), with an estimated incidence of 1 in 65 000 births. It is characterised by low levels of free thyroxine and inappropriately low serum TSH and may therefore be missed on routine neonatal screening for hypothyroidism, which relies on elevated TSH. We describe a patient with CCH who developed recurrence of pituitary hyperplasia and symptomatic hypothyroidism due to poor compliance with thyroxine replacement. She was diagnosed with CCH as a neonate and had previously required trans-sphenoidal hypophysectomy surgery for pituitary hyperplasia associated with threatened chiasmal compression at 17 years of age due to variable adherence to thyroxine replacement. Genetic testing of TSHB identified compound heterozygosity with novel variant c.217A>C, p.(Thr73Pro), and a previously reported variant c.373delT, p.(Cys125Valfs*10). Continued variable adherence to treatment as an adult resulted in recurrence of significant pituitary hyperplasia, which subsequently resolved with improved compliance without the need for additional medications or repeat surgery. This case describes a novel TSHB variant associated with CCH and demonstrates the importance of consistent compliance with thyroxine replacement to treat hypothyroidism and prevent pituitary hyperplasia in central hypothyroidism.

Learning points

• Pathogenic variants in the TSH subunit β gene (TSHB) are rare causes of central congenital hypothyroidism (CCH).

• c.217A>C, p.(Thr73Pro), is a novel TSHB variant, presented in association with CCH in this case report.

• Thyroxine replacement is critical to prevent clinical hypothyroidism and pituitary hyperplasia.

• Pituitary hyperplasia can recur post-surgery if adherence to thyroxine replacement is not maintained.

• Pituitary hyperplasia can dramatically reverse if compliance with thyroxine replacement is improved to maintain free thyroxine (FT4) levels in the middle-to-upper normal range, without the need for additional medications or surgeries.

Summary

Pituitary apoplexy (PA) is a medical emergency with complex diagnosis and management. In this study, we describe a case of PA in a 63-year-old male treated with oral anticoagulant therapy for atrial fibrillation. In the patient, PA manifested itself with asthenia and severe headache not responsive to common analgesics. Despite the finding of a pituitary mass through CT, and in anticipation of the endocrinological evaluation and pituitary MRI, the patient’s clinical condition worsened with an escalation of headache and asthenia associated with deterioration of the visual field and impairment of consciousness level. The emergency assessments revealed an adrenal failure, whereas MRI showed a haemorrhagic pituitary macroadenoma with compression of the optic chiasm. Intravenous fluids repletion and high-dose hydrocortisone were started with a rapid improvement of the patient’s health and visual field abnormalities. Hydrocortisone was gradually reduced to a replacement dose. During the follow-up, panhypopituitarism was documented, and replacement therapies with l-thyroxine and testosterone were introduced. Three months later, a pituitary MRI showed a 50% reduction in the pituitary adenoma volume.

Learning points

• Pituitary apoplexy (PA) is a medical emergency that can result in haemodynamic instability and abnormalities in the level of consciousness.

• The management of PA requires a multidisciplinary team that includes endocrinologists, ophthalmologists, neuro-radiologists, and neuro-surgeons.

• Pituitary MRI with gadolinium is the diagnostic gold standard for PA.

• PA therapy aims to improve general conditions and treat compression symptoms, especially visual field abnormalities.

• Adrenocorticotrophic hormone deficiency is a common and severe complication of PA. Thus, all patients with PA must be promptly treated with injective synthetic glucocorticoids (e.g. hydrocortisone 100 mg) and i.v. saline.

• PA must be taken into consideration in case of sudden headache in patients with a pituitary macroadenoma, especially if other risk factors are recognized.

Summary

Thyroid dermopathy is an uncommon manifestation of thyroid disease that impairs the quality of life in certain cases. Currently, the available treatments offer limited results and a chance of recurrence. Teprotumumab, a novel medication that results in the regression of thyroid ophthalmopathy, may have similar effects on dermopathy. We describe four patients treated with teprotumumab for their thyroid ophthalmopathy who concomitantly had dermatopathy upon initiation of their infusions. Patients improved after two to three infusions and three out of the four patients have not suffered a recurrence.Teprotumumab is a monoclonal antibody (MAB) that attenuates an inflammatory response, resulting in decreased edema and tissue expansion. Given the similarities of their pathophysiology, we believe that the resolution of thyroid dermatopathy and regression of thyroid eye disease occurs via the same mechanism. We encourage further investigation utilizing teprotumumab for patients whose dermopathy is associated with impaired quality of life.

Learning points

• Thyroid dermopathy (TD), an uncommon manifestation of thyroid disease, may occasionally impair function and quality of life.

• There are only a few treatments for TD, with limited results and high rates of recurrence.

• Teprotumumab is a Food and Drug Administration-approved medication used for thyroid eye disease (TED).

• Our patients treated with teprotumumab for TED showed improvement of TD, which demonstrates its potential use for this condition.

Summary

Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves’ disease (GD). Additional/concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 µg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range <1.75). MRI revealed an enhancing lesion infiltrating the left superior rectus, with concurrent characteristic muscle belly involvement bilaterally. Orbital biopsy showed atypical lymphoid cells (CD20+), suggesting marginal zone lymphoma. CT thorax and abdomen, fluorodeoxyglucose-positron emission tomography and bone marrow examination were normal. The patient was administered orbital radiotherapy for her localised lymphoma and carbimazole was continued. TED is the most common cause of orbital involvement overall and in GD. However, additional or alternative pathology may be present which requires evaluation. MRI can be a useful adjunct in these patients. Orbital lymphoma needs to be staged with workup for disseminated disease. Radiotherapy is the treatment of choice for localized disease. The index case provides evidence for synchronous presentation of dual pathology and highlights the importance of astute clinical examination as well as keeps a low threshold for MRI in selected cases.

Learning points

• Thyroid eye disease can co-exist with other ocular pathology, especially in elderly individuals.

• Eccentric proptosis, absent lid lag and restriction of eye movements (suggesting tendon involvement) should alert towards the presence of alternative pathology.

• Orbital imaging using MRI not only has greater sensitivity in diagnosing radiologically bilateral disease in patients who have unilateral involvement clinically but is also useful to identify concurrent neoplasms.

Summary

A 37-year-old female of South Asian origin was referred to our diabetes clinic for evaluation of an unusual finding during her retinal screening. Her retinal blood vessels appeared white in contrast to the normal pink-red colour. She had type I hyperlipidaemia, confirmed by genotype, and was recently diagnosed with diabetes, secondary to pancreatic insufficiency, for which she had suboptimal control and multiple hospitalisations with recurrent pancreatitis. On examination, she had multiple naevi on her skin; the rest of the examination was unremarkable. The patient did not report any visual disturbances and had intact visual acuity. Investigations showed raised total cholesterol (12.5 mmol/L) and triglycerides (57.7 mmol/L). Following evaluation, the patient was diagnosed with lipaemia retinalis, secondary to type I hyperlipidaemia. The patient was managed conservatively to reduce the cholesterol and triglyceride burdens. However, therapies with orlistat, statin, fibrates and cholestyramine failed. Only a prudent diet, omega-3 fish oil, medium-chain triglycerides oil and glycaemic control optimised with insulin showed some improvements in her lipid profile. Unfortunately, this led her to becoming fat-soluble vitamin deficient; hence, she was treated with appropriate supplementation. She was also recently started on treatment with volanesorsen. Following this, her lipid parameters improved and lipaemia retinalis resolved.

Learning points

• Lipaemia retinalis is an uncommon incidental finding of type I hyperlipidaemia that may not affect vision.

• Management of associated dyslipidaemia is challenging with minimal response to conventional treatment.

• Increased awareness of lipaemia retinalis and specialist management is needed as part of regular patient monitoring and personalised management.

Summary

Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS.

Learning points

• Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood.

• The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation.

• The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30.

• The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible.

• Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

Summary

The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells.

Learning points

• Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development.

• SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome.

• Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.

Summary

Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.

Learning points:

• Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.

• Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.

• APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.

• APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.

• Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.

• Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

Summary

Silent corticotroph adenoma (SCA) is an unusual type of nonfunctioning pituitary adenoma (NFA) that is silent both clinically and biochemically and can only be recognized by positive immunostaining for ACTH. Under rare circumstances, it can transform into hormonally active disease presenting with severe Cushing syndrome. It might often produce diagnostic dilemma with difficult management issue if not thoroughly investigated and subtyped accordingly following surgery. Here, we present a 21-year-old male who initially underwent pituitary adenomectomy for presumed NFA with compressive symptoms. However, he developed recurrent and invasive macroadenoma with severe clinical as well as biochemical hypercortisolism during post-surgical follow-up. Repeat pituitary surgery was carried out urgently as there was significant optic chiasmal compression. Immunohistochemical analysis of the tumor tissue obtained on repeat surgery proved it to be an aggressive corticotroph adenoma. Though not cured, he showed marked clinical and biochemical improvement in the immediate postoperative period. Anticipating recurrence from the residual tumor, we referred him for cyber knife radio surgery.

Learning points:

• Pituitary NFA commonly present with compressive symptoms such as headache and blurred vision.

• Post-surgical development of Cushing syndrome in such a case could be either drug induced or endogenous.

• In the presence of recurrent pituitary tumor, ACTH-dependent Cushing syndrome indicates CD.

• Rarely a SCA presenting initially as NFA can transform into an active corticotroph adenoma.

• Immunohistochemical marker for ACTH in the resected tumor confirms the diagnosis.