Summary

In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium–glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications.

Learning points

• While the PNPLA3 I148M mutation is well-established, accumulation of other mutations may accelerate susceptibility to non-alcoholic steatohepatitis (NASH).

• NASH and dyslipidemia may be intertwined biochemically and genetically through several key genes.

• SGLT2 inhibitors emerge as promising treatment for NASH albeit with interindividual variation in efficacy. Genetic background may explain the mechanisms behind the variation.

• A novel dysfunctional mutation in MUL1 may lead to metabolic inflexibilities through impaired mitochondrial dynamics and function.

Summary

The most common sites of distant metastases of papillary thyroid carcinoma (PTC) are lung and bone. Widespread distant metastases of PTC are rare and associated with poor overall prognosis. Metastases to sites such as liver and pancreas are extremely rare, and literature is sparse on overall survival. In this report, we present a 57-year-old man whose initial presentation of PTC was with pancreatic, liver, and lung metastases, and subsequently developed metastases to bone and brain. He underwent a total thyroidectomy, neck dissection, and tracheal resection. Pathology revealed a predominant columnar cell variant PTC with focal areas of tall cell variant, and genomic sequencing showed both PIK3CA and BRAF gene mutations. Radioactive iodine ablation with I-131 did not show any uptake in metastatic sites and he had progression of the metastases within 6 months. Therefore, therapy with lenvatinib was initiated for radioactive iodine refractory disease. Our patient has tolerated the lenvatinib well, and all his sites of metastases decreased in size. His liver and pancreatic lesions took longer to respond but showed response 6 months after initiation of lenvatinib, and he remains on full dose lenvatinib 18 months into treatment.

Learning points

• Papillary thyroid carcinoma (PTC) usually metastasizes to lung and bone but can rarely occur in many other sites.

• Patients with distant metastases have significantly worse long-term prognosis.

• Lenvatinib can be an effective treatment of radioactive iodine refractory PTC with rare sites of distant metastases.

• Lenvatinib can be an effective treatment of PTC with BRAF V600E and PIK3CA mutation.

Summary

We present the case of a 60-year-old female who developed repeated atraumatic stress fractures. She was initially diagnosed with osteoporosis based on her dual-energy X-ray absorptiometry (DXA) scan bone mineral density (BMD) T-scores and started on denosumab therapy. Secondary osteoporosis screen revealed abnormal myeloma screen and low serum phosphate levels. It was thought that the patient had multiple myeloma with associated Fanconi-related tubular dysfunction. However, fibroblast growth factor-23 (FGF-23) levels were grossly elevated, making Fanconi syndrome unlikely. The patient was subsequently diagnosed with two separate conditions, namely cardiac amyloid light-chain (AL) amyloidosis and FGF-23-related hypophosphataemia, likely due to tumour-induced osteomalacia. This case highlights the importance of excluding osteomalacia as a cause of low BMD and checking FGF-23 levels in the workup for hypophosphataemia.

Learning Points

• Tumour-induced osteomalacia is a difficult diagnosis as the tumour is often small and slow growing. Imaging may fail to identify a tumour, and treatment therefore consists of calcitriol and phosphate replacement.

• Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting.

• Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted.

• DXA cannot distinguish low bone mineral density due to osteoporosis from osteomalacia. Antiresorptive therapy should be avoided in osteomalacia due to the risk of clinical and radiographic deterioration.

Summary

Diabetes mellitus type 2 (DM-2) is one of the important causes of low-grade chronic inflammation (meta inflammation) seen in almost all tissues in the body. Other possible mechanisms involved in the development of lower urinary tract symptoms (LUTS) with DM-2 are the hypertonicity of the peripheral sympathetic nerves and hyperinsulinemia effects on the autonomous nervous system activity. These further suggests that abnormalities in glucose homeostasis influence the hyperproliferation of the prostate cells resulting in benign prostatic hyperplasia (BPH). Similarly, hepatic steatosis, a form of non-alcoholic fatty liver disease (NAFLD) prevalence among patients with DM-2, is as high as 75%. NAFLD has no symptoms in most diabetic patients. In this study, we present a case of a 64-year-old Black male who had worsening urinary urgency and hesitancy for 4 months, with increasing abdominal girth. Patient was found to have symptoms, diagnostic studies, and physical exam findings indicative of BPH and fatty liver disease. He was treated with hepato-protective medications, tighter control of his blood glucose levels, and blood pressure meds for 13 months. Upon follow-up, most of his symptoms were resolved. Timeline of BPH resolution and decrease in liver size following treatment suggest that DM-2 has a strong correlation with the development of BPH and fatty liver disease in most patients living with diabetes.

Learning points

• Men with type 2 diabetes mellitus (DM-2) tend to have significantly lower serum PSA level, lower testosterone levels, and larger prostate volume compared to non-diabetic male patients.

• Patients with DM-2 have higher prevalence of hepatic steatosis, liver cirrhosis, and end-stage liver failure.

• The role of metformin in reducing hepatic steatosis as stated by several studies is yet to be validated as our patient has been on metformin for 22 years for the management of DM-2 with fatty liver disease.

Summary

Human T-cell lymphotropic virus-1 (HTLV-1) causes adult T-cell leukemia and lymphoma (ATLL) and is a rare but important cause of hypercalcemia. A 53-year-old male with HTLV-1-associated myelopathy presented with acute on chronic bilateral lower extremity weakness and numbness. Initial blood work revealed hypercalcemia with corrected calcium of 16.2 mg/dL (8.5–11.5) with normal levels of phosphorus and alkaline phosphatase. Workup for hypercalcemia revealed parathyroid hormone (PTH) of 14 pg/mL (10–65), 25 hydroxy vitamin D at 19.6 ng/mL (30–100), 1,25 dihydroxy vitamin D at 6.7 pg/mL (19.9–79.3), thyroid-stimulating hormone of 1.265 μIU/mL (0.5–5), undetectable PTH-related protein (PTHrP) and lactate dehydrogenase of 433 U/L (100–220). The urine calcium creatinine ratio was 0.388. Reverse transcriptase PCR was positive for HTLV-1 and negative for HTLV-2. Peripheral blood flow cytometry and lymph node biopsy confirmed ATLL. He received treatment with fluids, calcitonin and denosumab after which serum calcium levels fell (nadir: 7.7 mg/dL) and then normalized. Humoral hypercalcemia in this setting is mediated by receptor activator of nuclear factor-kappa B ligand (RANKL), PTHrP and other cytokines. PTHrP levels depend on levels of the TAX gene product, cell type and lymphocyte-specific factors. Thus, a low level, like in our patient, does not rule out HTLV-1 infection/ATLL as the cause of hypercalcemia. Hypercalcemia is known to be responsive to monoclonal antibodies against RANKL given the compound’s role in mediating hypercalcemia in these cases.

Learning points

• Human T-cell lymphotropic virus-1 infection and adult T-cell leukemia and lymphoma are associated with high rates of hypercalcemia and hypercalcemic crises.

• Hypercalcemia in these cases is mediated by osteoclastic bone resorption carried out by several agents including receptor activator of nuclear factor-kappa B ligand, parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein 1 alpha, interleukins, etc. A normal PTHRrP does not rule out humoral hypercalcemia of malignancy in this setting, as indicated by this case.

• Hypercalcemia in such settings is highly responsive to monoclonal antibodies against RANKL given the role the ligand plays in resorptive hypercalcemia.

Summary

Primary hyperparathyroidism (PHP) is the most common aetiology for hypercalcaemia. The incidence of PHP in pregnant women is reported to be 8/100 000 population/year. It presents a threat to the health of both mother (hyperemesis, nephrolithiasis) and fetus (fetal death, congenital malformations, and neonatal severe hypocalcaemia-induced tetany). However, there is a lack of clear guidance on the management of primary hyperparathyroidism in pregnancy. In this study, we describe the case of a 26-year-old female patient who presented with severe hypercalcaemia secondary to PHP and underwent successful parathyroid adenectomy under local anaesthesia.

Learning points

• Primary hyperparathyroidism is a rare complication in pregnancy, but the consequences for mother and fetus can be severe.

• A perceived risk of general anaesthesia to the fetus in the first trimester has resulted in a general consensus to delay parathyroid surgery to the second trimester when possible – although the increased risk of fetal loss may occur before planned surgery.

• If the patient presents with severe or symptomatic hypercalcaemia, minimally invasive surgery under local anaesthetic should be considered regardless of the gestational age of the pregnancy.

Learning points

• Nodular glomerular lesions in diabetes mellitus are thought to be associated with long-term severe hyperglycemia.

• This case shows that although mild, long-term hyperglycemia for more than 10 years may also contribute to the formation of nodular lesions and that repeated chronic kidney infections over the years and chronic acidosis may be facilitating factors in the formation of diabetic nephropathy, including nodular glomerular lesions.

• This case appears to be idiopathic nodular glomerulosclerosis of the medullary sponge kidney associated with chronic urinary tract infection.

Summary

There is a close association between obesity and type 2 diabetes (T2D). The value of weight loss in the management of patients with T2D has long been known. Loss of 15% or more of body weight can have a disease-modifying effect in people with diabetes inducing remission in a large proportion of patients. Very low-carbohydrate ketogenic diets (VLCKDs) have been proposed as an appealing nutritional strategy for obesity management. The diet was shown to result in significant weight loss in the short, intermediate, and long terms and improvement in body composition parameters as well as glycemic and lipid profiles. The reported case is a 35-year-old man with obesity, dyslipidemia, and T2D for 5 years. Despite the use of five antidiabetic medications, including insulin, HbA1c was 10.1%. A VLCKD through a commercial multidisciplinary weight loss program (PnK method) was prescribed and all medications were discontinued. The method is based on high-biological-value protein preparations and has 5 steps, the first 3 steps (active stage) consist of a VLCKD (600–800 kcal/d) that is low in carbohydrates (<50 g daily from vegetables) and lipids. The amount of proteins ranged between 0.8 and 1.2 g/kg of ideal body weight. After only 3 months, the patient lost 20 kg with weight normalization and diabetes remission, and after 2 years of follow-up, the patient remained without the pathologies. Due to the rapid and significant weight loss, VLCKD emerges as a useful tool in T2D remission in patients with obesity.

Learning points

• Obesity and type 2 diabetes (T2D) are conditions that share key pathophysiological mechanisms.

• Loss of 15% or more of body weight can have a disease-modifying effect in people with T2D inducing remission in a large proportion of patients.

• Diabetes remission should be defined as a return of HbA1c to <6.5% and which persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.

• The very low-carbohydrate ketogenic diet (VLCKD) is a nutritional approach that has significant beneficial effects on anthropometric and metabolic parameters.

• Due to the rapid and significant weight loss, VLCKD emerges as a useful tool in T2D remission in patients with obesity.

Summary

A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 μg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic β-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients.

Learning points

• PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes.

• Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations.

• Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.

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.