Familial Dysalbuminemic Hyperthyroxinemia that was Inappropriately Treated with Thiamazole Due to Pseudo-thyrotoxic Symptoms.

We herein report the case of a Japanese woman with familial dysalbuminemic hyperthyroxinemia (FDH) who was initially diagnosed with Graves' disease. Direct genomic sequencing revealed a guanine to cytosine transition in the second nucleotide of codon 218 in exon 7 of the albumin gene, which then caused a proline to arginine substitution. She was finally diagnosed with FDH, which did not require treatment. FDH is - superficially - an uncommon cause of syndrome of inappropriate secretion of thyrotropin (SITSH) in Japan. A misdiagnosis of pseudo-hyperthyroidism will lead to inappropriate treatment. Thus, physicians should strongly note the possibility of FDH as a differential diagnosis of SITSH.

Dopamine-Secreting Paraganglioma in the Retroperitoneum.

Pheochromocytomas and paragangliomas, which exclusively produce dopamine, are very rare. Herein, we report for the first time a Japanese case of an exclusively dopamine-producing paraganglioma accompanied by detailed immunohistochemical analyses. A 70-year-old Japanese woman was referred to our hospital for functional examination of her left retroperitoneal mass. Her adrenal functions were normal, except for excessive dopamine secretion. After the tumorectomy, her dopamine level normalized. The histopathological diagnosis of the tumor was paraganglioma; this was confirmed by positive immunostaining of chromogranin A (CgA), tyrosine hydroxylase (TH), dopamine ß-hydroxylase (DBH), and succinate dehydrogenase gene subunit B (SDHB). However, the immunostaining of CgA in the tumor cells showed peculiar dot-like staining located corresponding to Golgi complex in the perinuclear area, rather than the diffuse cytoplasmic staining usually observed in epinephrine- or norepinephrine-producing functional pheochromocytomas and paragangliomas. The immunohistochemical results suggested that the tumor cells had sparse neuroendocrine granules in the cytoplasm, resulting in inhibition of catecholamine synthesis from dopamine to norepinephrine in neurosecretory granules. This may be the mechanism responsible for exclusive dopamine secretion in the present case.

Ectopic ACTH syndrome caused by desmopressin-responsive thymic neuroendocrine tumor.

A 32-year-old Chinese woman with rapid weight gain and progressive edema was found to have typical Cushingoid features. Her endocrine data were consistent with a diagnosis of ACTH-dependent Cushing's syndrome. To differentiate ectopic ACTH syndrome (EAS) from Cushing's disease (CD), various dynamic endocrine and imaging tests were performed. Her ACTH response was negative to corticotropin-releasing hormone (CRH) and positive to desmopressin. Magnetic resonance imaging of the pituitary showed no mass lesion. Computed tomography scan of the chest revealed a large mass (21 × 15 mm) in the anterior mediastinum, where positron emission tomography showed accumulation of [(18)F] fluorodeoxyglucose. Selective venous sampling showed marked step-up in ACTH level in the internal thoracic vein but not in the cavernous sinus after CRH stimulation. These data are compatible with the diagnosis of EAS. The resected tumor was pathologically consistent with thymic neuroendocrine tumor (NET) positive for ACTH by immunohistochemistry and abundant V1b receptor gene expression by RT-PCR. Postoperatively, her circulating ACTH/cortisol levels became normalized, and responded to stimulation with CRH but not with desmopressin. Her Cushingoid appearance gradually disappeared, and she was free from recurrence 5 years after surgery. This is a rare case of desmopressin-responsive EAS caused by thymic NET with predominant V1b gene expression, which was successfully localized by imaging modalities combined with selective venous sampling.

[Results of the model project to determine the cause of deaths related to medical practice].

A model project to determine the cause of deaths related to medical practice began in 2005. Since 2010, it has been managed by the Japan Medical Safety Research Organization (JMSRO), which is supported financially by the government and a majority of medical societies and organizations. There is a central office in Tokyo and nine local offices nationwide. When the JMSRO accepts a case, it makes a report on the cause of death and measures to prevent recurrence after detailed autopsy and clinical evaluation. So far, 180 cases have been accepted, of which 156 have been completed. A system to achieve the goals of the project has been established. About 80% of families of the deceased and medical organizations stated that they were satisfied with the results. Four families have initiated civil actions, and another four could potentially do so. No criminal charges have been filed. A new concept to establish an official third-party organization to analyze causes of medical practice-related deaths has been proposed by a committee under the JMSRO, and efforts should be made to put that proposal into practice.

Sibling cases of Addison's disease caused by DAX-1 gene mutations.

We report two sibling cases of Addison's disease without any evidence of sexual precocity, adrenal hyperplasia, or autoimmune disease. The diagnosis of primary adrenocortical insufficiency was made at the age of 5 in the younger brother and at the age of 18 in the elder brother. The younger brother had been inactive during infancy and had diffuse skin pigmentation without abnormal external genitalia, while the elder brother had been healthy until the age of 17 when he noticed skin pigmentation and small testes. Both boys had delayed puberty due to hypogonadotropic hypogonadism. The diagnosis of adrenal hypoplasia congenita (AHC) was established by genetic analysis of DAX-1 gene (dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene 1) with the same single frameshift mutation (305delG). However, yet-uncharacterized epigenetic, nongenetic and/or genetic factors other than the DAX-1 gene may be responsible for the differential onset of AHC in these sibling cases.

Reverse 'see-saw' relationship between Graves' disease and myasthenia gravis; clinical and immunological studies.

Although the association of two distinct autoimmune diseases, Graves' disease (GD) and myasthenia gravis (MG), is rare, the relationships of clinical and immunological activities between the two diseases remain unknown. In the present study, we investigated whether there exist any relationships between clinical and immunological activities of GD and MG as well as any common characteristics of their HLA antigens in five patients with concomitant association with GD and MG. The present study clearly showed positive relationships between the clinical activities of GD and MG in all five cases. Except for two cases, one with undetectable acetylcholine receptor antibody and another with few sample number, there were positive relationships between two circulating auto-antibodies against TSH receptor and acetylcholine receptor as well as their immunological and clinical activities in the remaining three cases. Furthermore, the present serological HLA typing study revealed that all five cases had common HLA-DQ3. Therefore, our study clearly demonstrates a reverse 'see-saw' relationship between GD and MG based on their clinical and immunological features, and suggests that HLA-DQ3 may play a potential pathogenic role in the concomitant development of the two diseases.

[A case of pulmonary infection induced by both Aspergillus sp. and Mycobacterium tuberculosis during corticosteroid therapy].

An 83-year-old woman with idiopathic thrombocytopenic purpura had received corticosteroid drugs since December 1998. Pulmonary aspergillosis appeared three months later, but improved with administration of itraconazole. When the dose of corticosteroid had to be increased again because of aggravation of the underlying disease after a 20-month gradually decreased use of the drugs, a new infiltration shadow in the left upper and middle fields appeared after one month of increase. Therefore, a detailed examination was performed. Mycobacterium tuberculosis was identified by the DDH method, Aspergillus sp. was isolated from the sputum culture, and aspergillus antigen was positive serologically, leading to a diagnosis of pulmonary infection induced by both Aspergillus sp. and Mycobacterium tuberculosis. Because of the prolonged administration of corticosteroid drugs, the patient was highly susceptible to infectious diseases. We considered this a case of interest because 20 months after the diagnosis of pulmonary aspergillosis, a mixed pulmonary infection of Mycobacterium tuberculosis and Aspergillus sp. was identified.

[A case of mixed pulmonary infection with Mycobacterium tuberculosis and M. intracellulare due to familial prevalence].

A 76-year-old woman was admitted to our hospital because of an abnormal shadow on chest radiography and a suspected familial prevalence of pulmonary tuberculosis. Her son had previously been admitted to our hospital with pulmonary tuberculosis and tuberculous pleuritis. In the present case, a diagnosis of pulmonary tuberculosis and atypical pulmonary mycobacteriosis was made on the basis of detection of both Mycobacterium tuberculosis and M. intracellulare several times in a sputum culture of anti-fast bacilli. Restriction fragment length polymorphism (RFLP) analysis was then performed for both the woman and her son. The RFLP analysis revealed the same pattern in both mother and son, and confirmed that this was a case of mixed pulmonary infection passed from son to mother.

[Clinical evaluation of the cause of death in patients with active pulmonary tuberculosis].

We made a clinical analysis of the cause of death of forty deceased patients with active pulmonary tuberculosis who were admitted to Kawasaki Medical School Hospital, Kawasaki Medical School Kawasaki Hospital, and Asahigaoka Hospital during the period from January 1996 to December 2001. The age of 40 deceased patients (29 males/11 females) ranged from 55 to 93 years old, and were mostly bedridden. Underlying diseases existed in all except one case, and they were respiratory diseases in 9 patients and non-respiratory diseases in 34 patients. Laboratory findings revealed poor nutritional conditions. The diagnosis of pulmonary tuberculosis was established within one month from the appearance of symptoms in over half of these patients because most of them were smear positive for Mycobacterium tuberculosis. None of the strains of Mycobacterium tuberculosis isolated from these patients were multidrug resistant for antituberculous drugs and only one strain was completely resistant for Rifampicin. Radiological findings of the tuberculosis were bilateral in 30 patients. Consolidation shadows without cavity were noted in 22 patients, and extension within the unilateral lung field was observed in 24 patients. Regarding the cause of death, advanced pulmonary tuberculosis was the cause in 17 patients and non-tuberculous diseases were the cause in 23 patients. There were 15 patients with bacterial superinfections such as bacterial pneumonia, 4 with malignancy, and 4 with other disease. The number of pulmonary tuberculosis patients in poor general and nutritional condition has been increasing with the aging of the Japanese population. Treatment for pulmonary tuberculosis has been successful in most cases, however, the number of the deaths unrelated to tuberculosis including those due to bacterial superinfection has been increasing. Therefore, treatment should be considered against resistant microoganisms such as MRSA.