Hiroaki IwasakiDivision of Endocrinology and Metabolism, Department of Internal Medicine, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan Division of Endocrinology and Metabolism, Department of Internal Medicine, Minamiyamato Hospital, Yamato, Kanagawa, Japan
A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around the left shoulder and the right hip joint. The patient could not fully extend her fingers because of skin sclerosis in both hands. Laboratory studies showed hyperphosphataemia and a high ratio of renal tubular maximum reabsorption of phosphate to glomerular filtration rate. There were no abnormalities in serum calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone levels, whereas serum fibroblast growth factor 23 was low. Hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome (HFTC/HHS) was diagnosed using whole genome sequencing that revealed a novel frameshift beyond the 584th threonine located in the lectin domain of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 associated with a duplication of the 1748th thymine in the coding region of the corresponding gene. Furthermore, anti-nuclear, anti-centromere, and anti-cardiolipin antibodies were positive, implying that comorbid limited type scleroderma might play a role in tumoural calcinosis (TC) development. A low phosphate diet was prescribed with phosphate-lowering medications, including aluminium hydroxide, acetazolamide, and sevelamer hydrochloride. The patient displayed a decrease in serum phosphate levels from 6.5 to 5.5 mg/dL 10 months after the initiation of treatment, but her TC had not improved during treatment for more than 1 year. This case was interesting because the patient with HFTC/HHS exhibited TC despite being over her 60s, and subsequent scleroderma might contribute to the specific clinical course. When HFTC/HHS presents with elderly-onset TC, the involvement of comorbidities in exacerbating TC should be considered.
HFTC/HHS occurs on an autosomal recessive basis, but its clinical course and manifestations differ significantly throughout the cases.
HFTC/HHS may be undiagnosed until later in life because of its rarity, unfamiliarity, and phenotype diversity; therefore, HFTC/HHS should be included in the differential diagnosis of elderly patients with unexplained hyperphosphataemia or ectopic calcinosis.
Comorbidities, including rheumatologic disorders, may contribute to developing HFTC/HHS-associated calcinosis.
A 67-year-old man was referred to our department for thyrotoxicosis with intermittent palpitation and 4-kg weight loss during the previous month. At the first visit, the patient was treated with cyclosporine A (CyA) for membranous nephropathy during the last 3 years and 8 months. Laboratory studies revealed that the serum TSH level was <0.005 μU/ml, and free thyroxine (fT4) and triiodothyronine (fT3) levels were elevated at 2.76 ng/dl and 5.96 pg/ml respectively. Anti-TSH receptor antibody (TRAb) level was increased at 26.4%. A clinical diagnosis of Graves' hyperthyroidism was given, and then thyrostatic treatment with thiamazole (MMI) at a dose of 10 mg daily was initiated after CyA withdrawal. After the initiation of MMI therapy, serum fT4 and fT3 attained the normal level within 1.5 months, with relief of symptoms followed by a remarkable decrease in urinary protein excretion from 2.0–5.2 g/day to ≤0.03 g/day. The patient maintained euthyroid with a low titre of TRAb for the succeeding 2 years and then MMI was finally stopped. Neither a relapse of hyperthyroidism nor a flare-up of nephrotic syndrome was observed for 3 years after MMI discontinuation. CyA has conflicting effects on immunologic self-tolerance by modulation of self-reactive T cells and natural CD4+CD25+Foxp3+ regulatory T cell (Treg) functions, and possibly becomes a triggering factor in the development of autoimmune disorders. This case may be interesting when considering the effect of each T cell subset on the development of Graves' disease.
The balance between intrathyroidal self-reactive T cell and natural CD4+CD25+Foxp3+ Treg functions determine self-tolerance in the thyroid.
CyA not only halts the expansion of self-reactive T cells but also impairs the function of Treg, which can provoke an unwanted immune response.
A change in thyroid autoimmunity during treatment with CyA may result in the development of autoimmune thyroid diseases (AITD).
Renal involvement in AITD frequently manifests as nephrotic syndrome, and thyrostatic treatment with thiamazole may be effective for excessive proteinuria.
A 45-year-old female was referred for endocrine evaluation of an incidental mass (31×24 mm in diameter) on the right adrenal gland. The patient was normotensive and nondiabetic, and had no history of generalised obesity (body weight, 46 kg at 20 years of age and 51.2 kg on admission); however, her waist-to-hip ratio was 0.97. Elevated urinary free cortisol levels (112–118 μg/day) and other findings indicated adrenocorticotrophic hormone-independent Cushing's syndrome due to right adrenocortical adenoma. Echocardiography before adrenalectomy revealed concentric left ventricular (LV) hypertrophy with a particular increase in interventricular septum thickness leading to impaired systolic and diastolic functions. Upon surgical remission of hypercortisolism, the asymmetric hypertrophy disappeared and the cardiac dysfunctions were considerably ameliorated. Although the mechanism(s) by which excessive cortisol contributes to LV wall thickness remain(s) unclear, serial echocardiography and cardiac multidetector-row computed tomography may support the notion that abnormal fat deposition in the myocardium owing to hypercortisolism appears to be an important factor for the reversible change in the cardiac morphology.
Patients with Cushing's syndrome occasionally exhibit severe LV hypertrophy related to systolic and diastolic dysfunctions although they have neither hypertension nor diabetes mellitus.
Biological remission of hypercortisolism can normalise structural and functional cardiac parameters and help in differentiating the cardiac alterations induced by excessive cortisol from those induced by other diseases.
Excessive lipid accumulation within the heart before myocardial fibrosis may be implicated in reversible alterations in the cardiac morphology by Cushing's syndrome.
Early diagnosis and treatment of Cushing's syndrome appear to be pivotal in preventing irreversible cardiac dysfunctions subsequent to cardiovascular events and heart failure.
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.
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.
Takashi MatsuzakaDepartment of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan
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.
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.