Akihiro Sakurai

Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant hereditary tumor syndrome characterized by synchronous or metachronous occurrence of primary hyperparathyroidism (PHPT), ossifying fibroma of the maxilla and/or mandible, renal tumor and uterine tumors. Early diagnosis of this syndrome is essential because it is associated with increased risk of parathyroid cancer. A 30-year-old man with urolithiasis had severe hypercalcemia (15.0 mg/dL after correction) induced by inappropriate parathyroid hormone (PTH) secretion (intact PTH 1390 pg/mL), indicating severe PHPT. An underlying parathyroid tumor was surgically removed and was histologically confirmed to be an adenoma. However, PHPT due to another parathyroid tumor reoccurred two years after the surgery. Although no HPT-JT-associated manifestations other than PHPT were detected, HPT-JT was strongly suspected based on the exclusion of multiple endocrine neoplasia (MEN) and the young age of disease occurrence. Genetic analysis revealed a novel nonsense mutation (p.Arg91X; c.271C>T) in exon 3 of the causative gene, CDC73, which encodes the tumor suppressor protein parafibromin. The residual parathyroid glands were all removed without autotransplantation of parathyroid gland taking into consideration prospective parathyroid carcinogenesis. The resected parathyroid tumor was also an adenoma. The present case highlights that HPT-JT should be considered and CDC73 mutation analysis should be performed, especially in cases of early-onset PHPT, recurrent PHPT, PHPT with polyglandular parathyroid involvement, and PHPT presenting with severe hypercalcemia even if there is no positive family history.

A novel nonsense mutation in the NOG gene causes familial NOG -related symphalangism spectrum disorder

The human noggin (NOG) gene is responsible for a broad spectrum of clinical manifestations of NOG-related symphalangism spectrum disorder (NOG-SSD), which include proximal symphalangism, multiple synostoses, stapes ankylosis with broad thumbs (SABTT), tarsal–carpal coalition syndrome, and brachydactyly type B2. Some of these disorders exhibit phenotypes associated with congenital stapes ankylosis. In the present study, we describe a Japanese pedigree with dactylosymphysis and conductive hearing loss due to congenital stapes ankylosis. The range of motion in her elbow joint was also restricted. The family showed multiple clinical features and was diagnosed with SABTT. Sanger sequencing analysis of the NOG gene in the family members revealed a novel heterozygous nonsense mutation (c.397A>T; p.K133*). In the family, the prevalence of dactylosymphysis and hyperopia was 100% while that of stapes ankylosis was less than 100%. Stapes surgery using a CO2 laser led to a significant improvement of the conductive hearing loss. This novel mutation expands our understanding of NOG-SSD from clinical and genetic perspectives.

An adolescent case of familial hyperparathyroidism with a germline frameshift mutation of the CDC73 gene

Abstract. A 13-yr-old boy who complained of persistent nausea, vomiting and weight loss had hypercalcemia and an elevated intact PTH level. Computed tomography confirmed two tumors in the thyroid gland. The tumors were surgically removed and pathologically confirmed as parathyroid adenoma. Because his maternal aunt and grandmother both had histories of parathyroid tumors, genetic investigation was undertaken for him, and a germline frameshift mutation of the CDC73 gene was identified. CDC73 gene analysis should be done on individuals who are at risk of familial hyperparathyroidism, including those who are asymptomatic, and they should be followed for potential primary hyperparathyroidism and associated disorders including resultant parathyroid carcinoma.

Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination

BackgroundMuir-Torre syndrome (MTS) is characterized by sebaceous neoplasms with internal malignancies and regarded as a variant of hereditary nonpolyposis colorectal cancer (HNPCC). Pathogenic variations of MTS have been identified in the MSH2, MLH1, and MSH6 genes, with the majority of variations located in MSH2.ObjectivesTo present an MTS patient who was the only individual with skin malignancies within a cancer-prone pedigree and to showthe usefulness ofRNA-based genetic analysis in the investigation of MTS.Materials & methodsA 77-year-old man who had operated X-ray equipment at his workplace in his twenties was clinically diagnosed with MTS and investigated by RNA-based analysis, multiplex ligation-dependent probe amplification, and genomic DNA sequencing.ResultsThe patient had suffered from sebaceous tumours, squamous cell carcinomas of the skin, and colon cancer. The patient’s family history was remarkable for visceral malignant diseases. Genetic analysis revealed homologous recombination between two Alu elements within intron 4 and 5 of the MLH1 gene. The rearrangement caused a 1,222-bp deletion, including the entire exon 5. Deletion of exon 5 has previously been reported only in two patients with HNPCC, and not in patients with MTS.ConclusionsFor the genetic analysis of MTS, the possibility of rare copy number variations of MLH1, as well as MSH2 variations, should be considered. RNA-based screening using puromycin is recommended in order to identify such variations. It remains unclear why only the proband among the pedigree had skin malignancies, however, the skin carcinogenesis might have been related to occupational radiation exposure.

Detection of Urinary Mulberry Bodies Leads to Diagnosis of Fabry Cardiomyopathy: A Simple Clue in the Urine Sediment

Fabry disease is an X-linked lysosomal storage disease characterized by globotriaosyceramide accumulation because of genetic loss/deficiency of α-galactosidase A (α-Gal A) activity. Clinical symptoms of classic Fabry disease, such as acroparethesia and neuropathic pain, typically become apparent in childhood and adolescence. Clinical manifestations in adulthood include cardiac and renal diseases, which are the main causes of death. Life expectancy of untreated Fabry males is ≈50 years. Myocardial involvement in Fabry disease is potentially misdiagnosed as hypertrophic cardiomyopathy unless careful workup of the patient, including pathological and genetic tests, is performed. The presence of chronic kidney disease with proteinuria in patients with ventricular hypertrophy leads to further analyses for diagnosis of Fabry disease. Although deterioration of renal function, leading to end-stage renal disease, is a typical manifestation of classical Fabry disease, a cardiac variant of Fabry disease, often accompanied by mild proteinuria, has also been reported.nnA 52-year-old man with ventricular hypertrophy and a history of acroparethesia during childhood was referred …

Evaluation of the minimally invasive parathyroidectomy in patients with primary hyperparathyroidism: A retrospective cohort study

Introduction An accurate differential diagnosis between single adenoma (SA) and multiglandular disease (MGD) remains difficult in Technetium-99m sestamibi scintigraphy (MIBI)-negative patients with primary hyperparathyroidism (PHPT). The aim of the present study was to evaluate the minimally invasive parathyroidectomy (MIP) in patients with PHPT. Methods Clinical records of 48 patients who underwent neck exploration between November 2002 and June 2012 in Kochi Medical School Hospital were reviewed retrospectively to identify candidates that underwent for MIP which was defined as the selective removal of a SA using less invasive surgery. Results The preoperative detection rate of lesions using ultrasonography, MIBI, computed tomography, and magnetic resonance imaging was 90%, 83%, 76%, and 55%, respectively. Although all 39 patients in the MIBI-positive group were diagnosed with an SA and subsequently underwent curative MIP, 3 patients in MIBI-negative group (n = 6) were MGD, who underwent neck exploration. Preoperative mean intact parathyroid hormone (419 pg/ml vs. 149 pg/ml; P < 0.01) and alkaline phosphatase levels (746 U/l vs. 277 U/l; P < 0.01) were significantly higher in the SA than MGD group. Conclusions In MIBI-negative patients with indications for surgery, MIP should not be carried out without a clear localization of SA, or in MGD.