家族性尿崩和甲旁减

Clin Pediatr Endocrinol 2002; 11(1), 25-27 Copyright© 2002 by The Japanese Society for Pediatric Endocrinology s l, ad i ar ex f D ss n g Introduction Familial diabetes isipidus (FDI) is a syndrome of central arginine vasopressin (AVP) deficiency that is transmitted as an autosomal dominant trait with a high degree of penetrance. Hypo- parathyroidism has been described in association with numerous disorders such as anterior hypopituitarism, Addison’s disease, Hashimoto’s thyroiditis, pernicious anemia, mucocutaneous candidiasis. Here we reported a female with FDI and idiopathic hypoparathyroidism and analyzed the AVP-NPII gene in her family. Case Report The patient was a female aged 17 9/12 years. Her mother and maternal uncle also had central diabetes insipidus. But there was no family history of thyroid and parathyroid diseases, other endocrine disorders, renal diseases, autoimmune diseases and deafness. At the age of about 2 years she began to complain of polydipsia (2,000–3,000 ml/day) and polyuria. But her growth was normal. At the age of 6 4/12 years, she was admitted to our hospital for evaluation of polydipsia and polyuria. On admission, her height was 113.0 cm (–0.5 SD) and weight 20.2 kg (–1.3 SD). Blood pressure was 98/42 mmHg. Physical examination revealed unremarkable findings. Her daily fluid intake was 2,000 to 3,000 ml and daily urine output was 2,000 to 3,500 ml. Urine and plasma osmolarity were 90– 640 and 280–292 mOsm/kg, respectively. Plasma AVP and osmolarity were 0.5 pg/ml and 292 mOsm/kg, respectively. Before water deprivation, Received: August 3, 2001 Accepted: October 17, 2001 Correspondence: Dr. Yoshikazu Nishi, Department of Pediatrics, Hiroshima Red Cross Hospital, 1–9–6 Senda- machi, Naka-ku, Hiroshima 730-8619, Japan Original A Patient with Familial Diabete Idiopathic Hypoparathyroidism Yoshikazu Nishi1, and Yutaka Oiso2 1Department of Pediatrics, Hiroshima Red Cross Hospita 2Department of Internal Medicine, Nagoya University Gr Abstract. A 17 9/12-year-old female with fam hypoparathyroidism is described. We analyzed the in her family, and a novel heterozygous mutation in and her mother. This deletion mutation results in a termination at codon 80. Only two cases of non-F reported so far, but there has been no report on the a The causes of this association are not known and it is Key words: familial diabetes insipidus, AVP-NPII Insipidus and Hiroshima, uate School of Medicine, Nagoya, Japan lial diabetes insipidus (FDI) and idiopathic ginine vasopressin-neurophysin II (AVP-NPII) gene on 2 of the AVP-NPII gene was noted in the patient rame shift beginning at codon 70 and a premature I and idiopathic hypoparathyroidism have been ociation of FDI and idiopathic hypoparathyroidism. ot known whether it is accidental or not. ene, hypoparathyroidism Nishi et al.26 Vol.11 / No.1 plasma osmolarity was 278 mOsm/kg and urine osmolar i ty 90 mOsm/kg . D uring water deprivation the urine output was constantly 60-70 ml per hour. After 4 hours of water deprivation, two consecutive hourly urine osmolarity tests showed less than a 30 mOsm/kg rise; plasma osmolarity was 283 mOsm/kg and urine osmolarity 169 mOsm/kg. At this time 0.1 U/kg of aqeous vasopressin was given subcutaneously. One hour later, urine osmolarity increased to 306 mOsm/kg (81% increase) and urine output decreased to 24 ml. The ratio of urine osmolarity and plasma osmolarity was 0.6 before vasopressin injection. Other pituitary function tests and routine renal function tests were normal. Head MRI did not show any space-occupying lesions in the hypothalamus or pituitary regions. These results were consistent with a diagnosis of central diabetes insipidus and DDAVP (1-deamino-8D- arginine vasopressin) therapy was initiated. She had been doing well under DDAVP therapy until the age of 17 9/12 years, when she felt numbness of the hands. She had no symptoms of anorexia, weight loss and weakness. At this time her height was 156.5 cm (–0.3 SD) and weight 58.5 kg (+0.8 SD). She had no dietary problems. Serum Ca and P were 2.8 mEq/l and 6.5 mg/dl , respectively. Serum Mg was 2.0 mg/dl. Serum alkaline phosphatase was 222 IU/l. Serum PTH and intact PTH were less than 100 pg/ml (normal adults; 160–520 pg/ml) and 5 pg/ml (normal adults; 10–65 pg/ml), respectively. Plasma 1, 25 (OH)2 vitamin D was 37.0 pg/ml (normal adults; 20–70 pg/ml). Serum TSH, free T3 and free T4 were normal. She had no antithyroid peroxidase antibody, antithyroglobulin antibody, antinuclear antibody, anti-DNA antibody and anti-RNP antibody. Antibodies against the vasopressin- producing cells of the hypothalamus were not measured. Head CT and EEG were normal. Ophthalmologic examination was also normal. She had no Albright signs and no symptoms such as round face, short neck, brachydactylia. A diagnosis of idiopathic hypoparathyroidism was made. 1αD3 therapy ( 1.5 ug/day) was commenced and numbness of the hands disappeared and serum Ca and P levels became normal. D NA seque nce ana ly s i s o f the AVP- neurophysin II (AVP-NPII) gene was performed by the direct sequencing method with a dsDNA cycle sequencing system (ABI cycle sequencer). One of the two consecutive cytosine sequences (nucleotides 1893–1894) was deleted in one allele of exon 2 in the patient and her mother. This deletion mutation results in a frame shift beginning at codon 70 and a premature termination at codon 80. But the mutation was absent in her father and two younger sisters aged 6 11/12 years and 15 9/12 years who did not have polydipsia or polyuria. Ca-sensing receptor gene analysis was normal. Discussion To date, approximately 40 different mutations associated with FDI have been located in the AVP- NPII gene (1–3). We describe a novel deletion mutation in exon 2 of the AVP-NPII gene in a Japanese family with central diabetes insipidus. Following the first description of idiopathic hypoparathyroidism in 1926, this condition has been described in association with numerous disorders, especially in autoimmune disorders such as Addison ’s di sease , ante r ior hypopituitarism, Hashimoto’s thyroiditis, pernic ious anemia , and mucocutaneous candidiasis (4). This patient has shown no evidence of these conditions so far, although these may take years to manifest and hypopara- thyroidism may be an early manifestation in this patient. This pat ient has FDI and idiopathic hypoparathyroidism. There have been only two reports on the association of non-FDI with idiopathic hypoparathyroidism. In 1941, Lichtwitz (5) mentioned a 51-year-old patient with diabetes in s ip idus who subseque nt ly deve loped hypocalcemia and tetany, but detailed supporting A Patient with FDI and Idiopathic Hypoparathyroidism 27June 2002 data were not presented. In 1994 Jabbar et al. (6) reported a 20-year-old man with central diabetes insipidus and idiopathic hypoparathyroidism. He had had polydipsia and polyuria since childhood. At the age of 20 years hypocalcemia and hyperphosphatemia with serum PTH (mid- molecule RIA), inappropriately low for the level of Ca. However, the present report details the first case with FDI and idiopathic hypoparathyroidism. The causes of the association of FDI or non-FDI with idiopathic hypoparathyroidism are not known, and it is not known whether this association is accidental or not. Only three cases including this patient with FDI or non-FDI and idiopathic hypopara- thyroidism have been reported, but some cases References 1. Nijenhuis M, van den Akker ELT, Zalm R, et al. Familial neurohypophyseal diabetes insipidus in a large dutch kindred: effect of the onset of diabetes on growth in children and cell biological defects of the mutant vasopressin prohormone. J Clin Endocrinol Metab 2001; 86: 3410–20. 2. Fujii H, Iida S, Moriwake K. Familial neurohypophyseal diabetes insipidus associated with a novel mutation in the vasopressin- neurophysin II gene. Int J Mol Med 2000; 5: 229– 34. 3. Abbes AP, Bruggeman B, van den Akker EL, et al. Identification of two distinct mutations at the same nucleotide position, concomitantly with a novel polymorphism in the vasopress in - may have gone unreported. Further studies may be needed to clarify this association. Acknowledgement The author thanks Dr. T. Yasuda, Department of Pediatrics, Chiba University School of Medicine for Ca-sensing receptor gene analysis. neurophysin II gene (AVP-NP II) in two dutch families with familial neurohypophyseal diabetes insipidus. Clin Chem. 2000; 46: 1699–702. 4. Perheentupa J. Hypoparathyroidism and mineral homeostasis. In: Lifshitz F, editor, Pediatric endocrinology, New York: Marcel Dekker, Inc. 1996; 433–71. 5. Lichtwitz L. Functional pathology, New York: Grune and Station, 1941; 345. 6. Jabbar A, Akhter J. Idiopathic cranial diabetes insip id us assoc ia ted w i th id iopathic hypoparathyroidism. Post Med J 1994; 70: 523–4.