GATA3 abnormalities and the phenotypic spectrum of HDR syndrome.

We report on GATA3 analysis and the phenotypic spectrum in nine Japanese families with the HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) (MIM 146255). Fluorescence in situ hybridisation and microsatellite analyses showed heterozygous gross deletions including GATA3 in four families. Sequence analysis showed heterozygous novel mutations in three families: a missense mutation within the first zinc finger domain at exon 4 (T823A, W275R), an unusual mutation at exon 4 (900insAA plus 901insCCT or C901AACCCT) resulting in a premature stop at codon 357 with loss of the second zinc finger domain, and a nonsense mutation at exon 6 (C1099T, R367X). No GATA3 abnormalities were identified in the remaining two families. The triad of HDR syndrome was variably manifested by patients with GATA3 abnormalities. The results suggest that HDR syndrome is primarily caused by GATA3 haploinsufficiency and is associated with a wide phenotypic spectrum.

Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia.

We describe a 27-year-old woman with familial idiopathic hypoparathyroidism, bilateral sensorineural deafness and right renal aplasia. There was a family history of deafness in her father and two other family members with sensorineural deafness, one of whom had hypoparathyroidism. To our knowledge, there have been four previous reports of idiopathic hypoparathyroidism associated with sensorineural deafness and renal dysplasia. The clinical features were not identical to any of the four previous reports. Although no chromosome abnormalities were present in the patient using standard trypsin G-banding analysis, we speculate that some common genetic mutation caused hypoparathyroidism, sensorineural deafness and renal dysplasia.

Reversibility of autonomic nerve function in relation to rapid improvement of glycemic control.

To determine the reversibility of autonomic nerve function in relation to the rapid improvement of glycemic control, we studied 54 patients with type 2 diabetes mellitus (33 men and 21 women; mean age, 49+/-8 years; mean duration of diabetes, 10+/-7 years). For 4 weeks of admission, the subjects were placed on strict dietary therapy, and 10 of them were under dietary therapy, 16 initially continued treatment with oral hypoglycemic agents, while 28 were treated with insulin. We measured the dark-adapted pupillary area (DAPA) by infrared photography, an indicator of diabetic autonomic neuropathy, on the second and 28th day after hospitalization. The change in FPG (delta FPG = - 111+/-49 mg/dl; mean +/- SD, p<0.001) and the change in HbA1c (delta HbA1c = -1.3+/-0.3%, p<0.001) were significantly improved. We observed significant improvements in the change in DAPA (delta DAPA) of all patients (25.1+/-11.0 vs. 25.7+/-11.6 mm2, delta DAPA = 0.6+/-1.4 mm2, p<0.01) and in those of patients without retinopathy (delta DAPA = 1.0+/-0.6 mm2, p<0.01). No change was observed in those of patients with retinopathy (delta DAPA= -0.02+/-0.3 mm2, NS). The delta DAPA was related to the delta HbA1c (r = -0.479, p<0.001) and also to the diabetic duration (years, r = -0.517, p<0.001). These findings suggest that a rapid improvement of glycemic control improves autonomic nerve function observed in type 2 diabetes with shorter duration. Particular attention should be paid to maintaining strict glycemic control at the stage of diabetic patients without retinopathy and those with shorter duration.

McCune-Albright syndrome associated with non-autoimmune type of hyperthyroidism with development of thyrotoxic crisis.

We report on a patient having McCune-Albright syndrome (MAS) associated with non-autoimmune hyperthyroidism associated with thyrotoxic crisis. Polyostotic fibrous dysplasia developed at age 8, and café-au-lait pigmentation was noted on the skin. At age 18, he developed hyperthyroidism with multiple adenomatous changes. The hyperthyroidism had been controlled with an antithyroid drug, but the antithyroid medication was discontinued by the patient at age 23. One year later, thyrotoxic crisis developed with fever, convulsions and loss of consciousness. Thyroid function tests showed serum concentrations of free T(4) of 5.1 ng/dl, and serum TSH of <0.1 microU/ml. Serum thyroglobulin concentrations were markedly increased (1,280 ng/ml). Three major thyroid-related autoantibodies (TSH receptor antibody, antithyroglobulin, and antimicrosomal antibodies) were not detected in serum. Serum GH concentrations were increased, and not suppressed by the glucose tolerance test, but increased paradoxically by TRH. The thyrotoxic crisis was ameliorated by treatment with a beta-adrenergic receptor-blocking agent, glucocoroticoid, iodine, antithyroid drug, and antibiotics. The cause of thyroidal defect in our patient is not considered to be autoimmune hyperthyroidism, but hyperthyroidism due to constitutive activation of G(s)alpha by inhibition of its GTPase. This paper describes, as far as we know, the first case of MAS associated with thyrotoxic crisis. Because hyperthyroidism in this patient recurred quickly after discontinuation of the antithyroid drug, the mode of treatment for MAS-associated hyperthyroidism appears to be total surgical ablation or repetitive radioiodine therapy.

Pulmonary diffusing capacity, serum angiotensin-converting enzyme activity and the angiotensin-converting enzyme gene in Japanese non-insulin-dependent diabetes mellitus patients.

We investigated the independent change in pulmonary diffusing capacity (DLCO) as one manifestation of pulmonary microangiopathy and to analyze the correlation between DLCO and serum ACE. We also examined the association between DLCO and the ACE genes. We examined pulmonary functions, especially %DLCO/VA (DLCO corrected by alveolar volume, percent predicted) in 54 NIDDM patients and 34 age-matched normal control subjects. Subjects were subdivided according to the degree of retinopathy. Serum ACE level was assayed by a colorimetric method in 54 patients and an insertion/deletion polymorphism in the ACE gene was amplified using the polymerase chain reaction in 52 of the 54 patients. There was a significant reduction of %DLCO/VA (percent predicted P < 0.05) in diabetic patients. In the proliferative retinopathy (PDR) group. %DLCO/VA was significantly (P < 0.05) lower than in the no diabetic retinopathy (NDR) and simple diabetic retinopathy (SDR) groups. Although the levels of serum ACE were within normal ranges in all diabetic groups, %DLCO/VA was negatively correlated with serum ACE values (r = 0.49, P < 0.0002, y = -1.4x + 109.3). Differences among DD, ID and II type of the ACE gene, with respect to the incidence of abnormal values of each clinical parameter, were not significant. DLCO was significantly reduced in patients with PDR and the serum ACE was significantly related to impaired DLCO. Our study suggests the existence of microangiopathic involvement of pulmonary vessels in NIDDM patients.

Novel mitochondrial DNA mutation in tRNA(Lys) (8296A-->G) associated with diabetes.

Mutation in the mitochondrial gene at position 3243 was recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondria play an important role in glucose-stimulated insulin secretion in pancreatic beta-cells, we therefore searched for such mutations to detect a candidate gene for diabetes. We screened 10 diabetic subjects with clinical features suggesting mitochondrial DNA mutations. An adenine to guanine point mutation in tRNA(Lys) in at position 8296 (the 8296 mutation) was newly identified. Subsequently, we screened 1216 diabetic subjects, 44 patients with sensorineural deafness subjects and 300 non-diabetic control subjects for this mutation. We identified the mutation in 11 (0.90%) unrelated diabetic subjects, one (2.3%) patient with deafness and no non-diabetic control subject. Seven of these 12 subjects showed maternal inheritance. Deafness was seen in 7 of 12 probands. Four family pedigrees showed maternal inheritance of diabetes over two or three generations. Subjects carrying the 8296 mutation may develop diabetes and the mutation can explain as high as ca. 1% of the causes of diabetes.

Daily profile of serum leptin in Prader-Willi syndrome complicated by diabetes mellitus--a case report.

High leptin levels in Prader-Willi (P-W) syndrome may occur as a result of the existence of leptin resistance, because a hypothalamic disturbance may underlay this disorder. In order to study whether there is a defective action of leptin on the hypothalamus in P-W syndrome, we have measured leptin and insulin twice during the daily profile of blood glucose, comparing the results with the recent reports. The patient was a 22-year-old female, who showed the typical feature of P-W syndrome complicated overt diabetes. This case of P-W syndrome was only made to maintain a diet of 1840 kcal/day of examination under hospitalization and was not made to maintain a calorie diet on any other day of examination in clinic. There was no reduction of leptin observed during the day, especially around noon and mid-afternoon, both under hospitalization and in clinic. Our experience suggests that an absence of the normal fall in leptin during the day was not related to eating pattern in this case, but to the defective action of leptin on the hypothalamus as well as excessive production by adipose tissue.

Treatment with rhG-CSF for osteomyelitis in a patient with p47-phox-deficient chronic granulomatous disease.

A 24-year-old woman with osteomyelitis was diagnosed as having p47-phox-deficient chronic granulomatous disease (CGD). The patient showed a marked deficiency of p47-phox, which is very rare in Japan. As the clinical response to various antibiotics including sulfamethoxazole-trimethoprim was not satisfactory, we added recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the treatment protocol. We report the beneficial clinical course of the patient, together with the effect of rhG-CSF on the granulocyte function, and the present report indicates that rhG-CSF is useful for the treatment of antibiotic-resistant infection in the variant type of p47-phox-defective CGD.

Hypoparathyroidism and insulin-dependent diabetes mellitus in a patient with Kearns-Sayre syndrome harbouring a mitochondrial DNA deletion.

We report a 17-year-old girl with short stature, external ophthalmoplegia, atypical retinal pigmentary degeneration, sensorineural hearing loss, and cardiac conduction defect (Kearns-Sayre syndrome). A large-scale deletion (6741 base pairs) in mitochondrial DNA was found in her muscle specimen. She also had insulin-dependent diabetes mellitus (IDDM). On admission, her plasma glucose level was elevated at 31.0mmol/l with mild ketoacidosis, and haemoglobinA1c elevated at 16.5%. After improvement of diabetic ketoacidosis, she was placed on insulin 24-30 units/day despite her small body weight of 25 kg. There was reduced excretion of urinary C-peptide at 3.97 nmol/day. In addition, she had idiopathic hypoparathyroidism with a serum calcium level of 2.15 mmol/l, phosphate 1.7 mmol/l, and intact PTH below 10 ng/l. Human leucocyte associated antigen typing showed A24, A26; B54, B61; CW1, CW3; DR8, DR14; DQ1 and DQ3, suggesting that the presence of HLA-A24 and CW3 antigen contributed to the association of IDDM and hypoparathyroidism, similar to Japanese patients with polyglandular autoimmune syndrome, complicated by hypoparathyroidism and IDDM. We suggest that a genetic linkage, as well as mitochondrial dysfunction, may be responsible for the association of the two disease states. This is an extremely rare case of Kearns-Sayre syndrome, presenting in association with IDDM and idiopathic hypoparathyroidism.