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

The iconic photograph ‘A Jewish giant at home with his parents in the Bronx, N.Y. 1970’ by the famous American photographer Diane Arbus (1923–1971) shows the 2.34 m (7 ft. 8¼ in.) acromegalic giant Eddie Carmel (1936–1972) and his parents in the living room of their New York home. The picture is a typical example of Arbus’ style. The relationship between the artist and the tall subject is described. A growth hormone-secreting pituitary macroadenoma was unsuccessfully treated with two cycles of pituitary radiotherapy achieving a 7000 rad cumulative dose and by incomplete pituitary surgery. Hypopituitarism was treated according to medical standards in the 1960s and 1970s. The giant patient died of increased intracranial pressure and at autopsy a residual acidophil pituitary macroadenoma was found, but also a perisellar meningioma which was most probably induced by the high dose of pituitary radiotherapy. The case report illustrates the possibilities and impossibilities of treating acromegaly 50 years ago and demonstrates the potential risks of high dose pituitary radiotherapy (in acromegaly).

Learning points

• Acromegaly is a very old disease.

• Therapy for acromegaly has evolved over the decades.

• In art museums one can come across artistic impressions of endocrine disorders.

• People suffering from disfiguring endocrine disorders like acromegaly were pre-WW2 ‘exposed’ in theaters and circuses.

• High dose pituitary radiotherapy can be associated with secondary brain tumor formation.

Summary

Immobilization-induced hypercalcemia is an uncommon cause of elevated calcium which is usually diagnosed following extensive systemic workup and exclusion of more common etiologies. Previously reported cases have largely described this phenomenon in adolescents and young adults a few weeks to months after the initial onset of immobilization. Metabolic workup tends to demonstrate hypercalcemia, hypercalciuria, and eventual osteoporosis. While the exact mechanism remains largely unclear, a dysregulation between bone resorption and formation is central to the pathogenesis of this disease. Decreased mechanical loading from prolonged bedrest tends to increase osteoclast induced bone resorption while promoting osteocytes to secrete proteins such as sclerostin to reduce osteoblast mediated bone formation. We describe the case of an 18-year-old male who was admitted following intraabdominal trauma. He underwent extensive abdominal surgery including nephrectomy resulting in initiation of dialysis. After 6 months of hospitalization, the patient gradually began developing uptrending calcium levels. Imaging and laboratory workup were unremarkable for any PTH-mediated process, malignancy, thyroid disorder, adrenal disorder, or infection. Workup did reveal significant elevated bone turnover markers which in combination with the clinical history led the physicians to arrive at the diagnosis of immobilization induced hypercalcemia. In order to prevent decreased rates of bone loss, the patient was administered denosumab for treatment. Hypocalcemia followed treatment expectedly and was repleted with supplementation via the patient’s total parenteral nutrition.

Learning points

• Immobilization-induced hypercalcemia should remain as a differential diagnosis of patients with prolonged hospitalizations with hypercalcemia.

• Extensive workup of common etiologies of hypercalcemia should be considered prior to arriving at this diagnosis.

• Denosumab, while off-label for this usage, offers an effective treatment option for immobilization-induced hypercalcemia though it carries a risk of hypocalcemia especially among patients with renal disease.

Summary

We describe a case of an infant who presented with clinical features of hyperthyroidism. The child was found to be tachycardic, hypertensive and diaphoretic, she was noted to have poor weight gain and difficulty in sleeping. The child was admitted to the pediatric intensive care unit for care. She was found to have biochemical evidence of hyperthyroidism with positive thyroid stimulating immunoglobulin. She responded well to methimazole and propranolol and had a remarkable recovery. She is the youngest patient to be diagnosed with Graves disease in the English literature, at 12 months of life.

Learning points

• Hyperthyroidism must always be considered even at very young age, for patient presenting with poor weight gain and hyperdynamic state.

• Autoimmune diseases are becoming more common in infancy.

• Craniosynostosis and increased height for age are well-documented consequences of untreated hyperthyroidism in developing children.

Summary

Hypothyroidism is a common medical condition and is often easily managed with excellent outcomes, when treated adequately. Compliance with levothyroxine (LT4) therapy is often compromised because of the need for a daily and lasting schedule. Overt rhabdomyolysis due to under-treatment or non-compliance is a rare occurrence. We report a case of rhabdomyolysis leading to acute kidney injury (AKI) on chronic kidney disease (CKD) requiring hemodialysis (HD) in a 68-year-old Caucasian male due to non-compliance with levothyroxine (LT4) therapy. Our patient 'ran out of levothyroxine' for approximately 4 weeks and developed gradually progressive muscle pain. The diagnosis of severe AKI due to rhabdomyolysis was made based on oliguria, elevated creatinine kinase (CK), and renal failure. Resuming the home dose of LT4 failed to correct CK levels, and there was a progressive decline in renal function. Although increasing doses of LT4 and three cycles of HD improved CK levels, they remained above baseline at the time of discharge. The patient recovered gradually and required HD for 4 weeks. CK levels normalized at 6 weeks. Through this case report, we highlight that non-compliance with LT4 therapy can lead to life-threatening complications such as renal failure and hence the need to educate patients on the significance of compliance with LT4 therapy should be addressed.

Learning points

• Non-compliance to levothyroxine therapy is common and can lead to serious complications, including rhabdomyolysis.

• Rhabdomyolysis is an uncommon presentation of hypothyroidism and severe rhabdomyolysis can result in renal failure requiring hemodialysis.

• Rhabdomyolysis associated with hypothyroidism can be further exacerbated by concomitant use of statins.

Summary

Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.

Learning points

• The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes.

• Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs.

• Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants.

• Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.

Learning points:

• The c.57delG SDHD mutation may confer a more aggressive phenotype than other mutations associated with familial paraganglioma syndrome type 1.

• A capillary hemangioma, a component of other pseudohypoxia states, was observed in the lung of a single member of the c.57delG SDHD kindred.

• This report supports the hypothesis of others that mutations found near the beginning of the SDHD open reading frame are more likely to demonstrate an aggressive phenotype.

Learning points:

• Axillary metastases in differentiated thyroid carcinoma are uncommon.

• In patients with high-risk thyroid carcinomas, a decline in thyroglobulin antibody may not signal disease improvement, but rather a progression to a poorly differentiated form of cancer.

• PAX8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas.

Summary

SOX5 plays an important role in chondrogenesis and chondrocyte differentiation. SOX5 defects in humans (often deletions) result in a Lamb-Shaffer syndrome (LSS), presenting with speech delay, behavioral problems and minor dysmorphic features. We present a patient with idiopathic short stature (ISS) who carried a heterozygous novel variant in SOX5. The patient had no dysmorphic features, but a skeletal survey revealed minor skeletal abnormalities. Laboratory and endocrine evaluation for known causes of growth disorders was negative. The missense variant in SOX5 gene (c.1783A>G, p.K595E) was de novo and was predicted to be deleterious by in silico programs. In summary, we present a patient whose presentation may provide evidence that gene defects in SOX5 may contribute to the etiology of short stature and/or mild skeletal defects beyond LSS.

Learning points:

• We report a girl with idiopathic short stature and mild skeletal defects presenting with a de novo variant in SOX5 gene, predicted in silico to be deleterious.

• Although SOX5 has not been previously specifically associated with short stature, several evidences support its contributing effect on dyschondrogenesis.

• Missense variants in SOX5 gene may lead to mild phenotypes, differing from typical presentation of patients with Lamb-Shaffer syndrome.

Summary

Single-minded homolog 1 (SIM1) is a transcription factor that plays a role in the development of both the hypothalamus and pituitary. SIM1 gene mutations are known to cause obesity in humans, and chromosomal deletions encompassing SIM1 and other genes necessary for pituitary development can cause a Prader–Willi-like syndrome with obesity and hypopituitarism. There have been no reported cases of hypopituitarism linked to a single SIM1 mutation. A 21-month-old male presented to endocrinology clinic with excessive weight gain and severe obesity. History was also notable for excessive drinking and urination. Endocrine workup revealed central hypothyroidism, partial diabetes insipidus, and central adrenal insufficiency. Genetic evaluation revealed a novel mutation in the SIM1 gene. No other genetic abnormalities to account for his obesity and hypopituitarism were identified. While we cannot definitively state this mutation is pathogenic, it is notable that SIM1 plays a role in the development of all three of the patient’s affected hormone axes. He is now 6 years old and remains on treatment for his pituitary hormone deficiencies and continues to exhibit excessive weight gain despite lifestyle interventions.

Learning points:

• Mutations in SIM1 are a well-recognized cause of monogenic human obesity, and there have been case reports of Prader–Willi-like syndrome and hypopituitarism in patients with chromosomal deletions that contain the SIM1 gene.

• SIM1 is expressed during the development of the hypothalamus, specifically in neuroendocrine lineages that give rise to the hormones oxytocin, arginine vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin.

• Pituitary testing should be considered in patients with severe obesity and a known genetic abnormality affecting the SIM1 gene, particularly in the pediatric population.