Nephrogenic Diabetes Insipidus and Intracerebral Arch Dis Child: First Published As 10.1136/Adc.65.8.885 on 1 August 1990

Archives ofDisease in Childhood 1990; 65: 885-887 885

Nephrogenic diabetes insipidus and intracerebral Arch Dis Child: first published as 10.1136/adc.65.8.885 on 1 August 1990. Downloaded from calcification

0 Schofer, R Beetz, K Kruse, C Rascher, C Schutz, J Bohl

Abstract system, intracranial haemorrhage, and hypo- Three children who presented with two rare parathyroidism or pseudohypoparathyroid- conditions, nephrogenic diabetes insipidus ism.5 7 8 and intracerebral calcification, were studied. We report three children (two boys and one The lack of evidence for the presence of a girl) who presented with the combination of metabolic defect other than nephrogenic nephrogenic diabetes insipidus and massive diabetes insipidus suggests that it can lead to intracerebral calcification. To our knowledge, the development of intracerebral calcifica- the concurrence of primary nephrogenic diabe- tion. Perhaps the main risk factor is inadequate tes insipidus and intracerebral calcification has fluid intake during early infancy. not been reported before.

Nephrogenic diabetes insipidus is characterised Case reports by unresponsiveness of the distal tubule and the collecting duct to normal or increased con- CASE 1 centrations of antidiuretic hormone. The A girl was born at full term weighing 3200 g. renal concentrating defect may be partial or She was 49 cm long, and had a head circumfer- complete. 1-3 ence of 34 cm (45th centile). The pregnancy had In the primary, hereditary form of the dis- been uncomplicated and the family history was ease, specific cells in the membrane of the distal unremarkable. According to her paediatrician convoluted tubule and collecting duct are incap- she had developed normally for the first two to able of increasing their permeability to water in three months, and had then experienced recur- response to the action of antidiuretic hormone. rent episodes of dehydration that became gra- The mode ofinheritance ofprimary nephrogenic dually more serious and eventually led to her diabetes insipidus is believed to be X linked first admission to hospital at the age of 6 with a variable expression in girls. 1-3 Secondary months. She presented with hyperosmotic nephrogenic diabetes insipidus may develop in dehydration with dilute urine, and by then was numerous disorders including certain neopla- already malnourished and showing neurodeve- http://adc.bmj.com/ sias, medullary cystic disease, and hypercal- lopmental retardation. Subsequently, frequent caemia. episodes of severe dehydration occurred, which In a series of 34 941 paediatric skull radio- were usually precipitated by infection. Clinical graphs, pathological calcification was seen in examination at 4 years of age showed short sta- 293 (0-84%).4 The incidence of pathological ture (91 cm, 8 cm below the 3rd centile), normal intracranial calcification in 18 000 paediatric body weight for height (13-5 kg), microcephaly

computed tomograms was 1-6%.5 Calcification (45-9 cm, 1P9 cm below the 3rd centile), low set on October 1, 2021 by guest. Protected copyright. was most often seen in children who had had ears, delayed dentition, normal blood pressure, prenatal infections with Toxoplasma gondii and discrete motor coordination defects with an University Children's (22%) or other inflammatory brain diseases.4'6 awkward gait. Her intelligence quotient (IQ) Hospital, It was also found in association with, or as a was 40-45 and did not deteriorate thereafter. Langenbeckstrasse 1, consequence of, tumours of the central nervous Results of laboratory tests are summarised in D-6500 Mainz 1, Federal Republic of Germany Laboratory results of cases 1-3 O Schofer Variable (reference range) Case No R Beetz University Children's 1 2 3 Hospital, Wiirzburg Serum: K Kruse Sodium (135-145 mmol/l) 144-173 139-160 142-165 Chloride (9-106 mmol/1) 108-121 108-120 108-121 University Children's Potassium (3-0-4-5 mmol/1) 1-8-3-6 3-2-4-4 2-9-4-2 Hospital, Heidelberg Calcium (2-0-2-5 mmol/l) 2 3-2-5 2-3 2-2 W Rascher Inorganic phosphate (1-42-2 mmol/1) 1-4-1-5 1-6-2-4 1-5-2-2 Children's Hospital, Osmolality (280-295 mmol/kg) 306-320 297-316 285-322 Regensburg Antidiuretic hormone (2-4 pg/ml)* 51-1 10-7 45-6 C Schutz Parathyroid hormone (30-90 pmol/l) 53 60 44 Urine: Department of Osmolality (120-800 mmol/kg) 120-233 72-92 132 Neuropathology, Osmolality after antidiuretic hormone (>150 of baseline) 160 (105%) Not tested Not tested University of Mainz Cyclic AMP (200-450 pmol/24h or 2-6 nmol/100 mit) Not tested 1340 (24h) 5-3t J Bohl Glomerular filtration rate (as creatinine clearance) (80-120 ml/min/173 i2) 80 106 113 88% 94% 86% Correspondence to: Tubular reabsorption of phosphate (80-97%) Dr Schofer. *Measured at the following serum osmolalities: 306 mmol/kg in case 1, 297 mmol/kg in case 2, and 287 mmol/kg in case 3. Accepted 20 March 1990 tCyclic AMP is measured as nmol/100 ml glomerular filtration rate as creatinine clearance, 886 Schofer, Beetz, Kruse, Rascher, Schutz, Bohl

renal concentrating capability when deprived of water, but there was no other family history of renal disease, particularly nephrogenic diabetes

insipidus, or other congenital diseases, move- Arch Dis Child: first published as 10.1136/adc.65.8.885 on 1 August 1990. Downloaded from ment disorders, or consanguinity. He was first admitted to hospital at the age of 4 weeks because of hypertonic dehydration during an upper respiratory tract infection. The diagnosis of inherited primary nephrogenic diabetes insipidus was eventually confirmed by com- bined mannitol challenge and vasopressin test. Possible secondary nephrogenic diabetes insipi- Figure I Cranial computed tomography showing: (A) symmetrical calcification dus was excluded. His daily urine output when predominantly in thefrontal white matter (case 1), (B) symmetric calcification mainly in the receiving maintenance treatment with either caudate nucleus, lentiform nucleus, and thefrontal white matter (case 2); and (C) massive but frusemide and spironolactone, or hydrochlor- non-progressive calcification particularly in the white matter ofthefrontal, parietal, and othiazide and spironolactone, was 2 1 at the end occipital lobes (case 3). ofhis first year, 3 1 when he was 2 years old, and 4-5 1 at the age of 8 years. After infancy episodes of dehydration occurred only during feb- rile infections. At the age of 4 years he had a seizure. Two years later, cranial computed tomography showed symmetric intracerebral calcification predominantly within the caudate nucleus, the lentiform nucleus, and the frontal white matter (fig 1). His mental and motor development was retarded by 2-2 5 years at that time, but he was making progress. When last seen at the age of 8 years, he was in good health with increased body weight and improved psychomotor development. His blood pressure was normal throughout. Results of laboratory tests are summarised in the table. The kidneys showed no evidence of calcification; there were no skeletal abnormalities, and no evidence of prenatal or postnatal infection with T gondii or cytomegalovirus was found.

CASE 3

A boy was born at full term after an uncompli- http://adc.bmj.com/ Figure 2 Sections ofthe rostral basal ganglia (caudate nucleus and putamen stained with cated pregnancy and delivery. He weighed 3600 periodic acid Schiffat a magnification of160) showing: (A) fine granulated perivascular g at birth, and was 51 cm long. The family his- calcification-the wall and lumen ofthe vessel as well as the nuclei ofthe endothelial cells are 7 months preserved; and (B): large, confluencing perivascular deposits ofcalcium-the wall ofthe tory was uneventful. At the age of he included vessel is destroyed in most parts (case 1). was admitted to hospital because of recurrent vomiting, constipation, intermittent fever, failure to thrive, growth retardation, irritability,

and convulsions. He was severely malnourished on October 1, 2021 by guest. Protected copyright. the table. Renal morphology on ultrasound being 64 cm long (4 cm below the 3rd centile), scanning, chromosome analysis, and skeletal weighing 6 5 kg (3rd centile), and with a head radiographs were normal. At the age of 4 years circumference of 41 cm (0 5 cm below the 3rd she developed seizures, and symmetric intra- centile). Nephrogenic diabetes insipidus was cerebral calcification was found on computed suspected because of persistent hypotonic urine tomography, predominantly within the frontal in spite of increased serum sodium concentra- white matter (fig 1). tion and osmolality. She died when she was 8-8 years old of septi- Results of laboratory tests are summarised in caemia with severe electrolyte disturbances, and the table. The diagnosis of primary nephrogenic at necropsy there were signs of generalised bac- diabetes insipidus was established by increased terial infection. Her kidneys contained a few serum concentrations of antidiuretic hormone small tubular cysts within the cortex, but no cal- and failure of the adequately hydrated patient to cification. Disseminated intracerebral perivas- increase his urinary osmolality in response to cular and pericapillar calcification were found repeated nasal administration of desmopressin in the cortex and the basal ganglia (fig 2). acetate (DDAVP). Other disorders with secon- Neuronal cells were unaffected but there were dary resistance to antidiuretic hormone were discrete signs of demyelination as well as reac- excluded. The extracellular calcium and phos- tive gliosis. phate metabolism, which was investigated at 20 months, was normal; impairment of the kidney response to parathyroid hormone was excluded. CASE 2 Treatment with a restricted protein and salt A boy was born without complications after a intake and hydrochlorothiazide (2 mg/kg/day) normal pregnancy. His mother had a decreased resulted in pronounced improvement of water Nephrogenic diabetes insipidus and intracerebral calcification 887

and electrolyte balance, growth, weight gain, has not previously been reported as a consequ- and psychomotor development. ence or possible complication of nephrogenic Computed tomography at 7 and 14 months diabetes insipidus.1-3 The distribution of the showed massive, but non-progressive, brain cal- calcification (often lining small vessels) found Arch Dis Child: first published as 10.1136/adc.65.8.885 on 1 August 1990. Downloaded from cification, particularly in the white matter of at necropsy (case 1) lends some weight to the the frontal, parietal, and occipital lobes (fig 1). following hypothetical sequence: nephrogenic Serological investigations gave no evidence of diabetes insipidus leads to recurrent severe prenatal infection with T gondii, cytomegalo- hyperosmolar dehydration that damages virus, rubella, herpes simplex virus, or Tre- endothelial and other cells. This exposes mate- ponema pallidum. rial with nucleating properties (for example, mitochondria or collagen) to calcium and phosphate in solution and perhaps alters calcification Discussion inhibitors such as glycosaminoglycans or inor- All three children had nephrogenic diabetes ganic pyrophosphate.'8 As a consequence, cal- insipidus and intracerebral calcification. The cium phosphate and other such substances are association of two such rare conditions suggests deposited particularly within or around the that there may be a common pathogenesis. walls of small vessels, or both. 8 Diseases causing secondary nephrogenic From the clinical point of view it could be diabetes insipidus-such as medullary cystic worthwhile to investigate a larger group of kidney disease, chronic obstructive uropathy, patients with nephrogenic diabetes insipidus nephrocalcinosis, hypercalciuria, polycystic and severe episodes of dehydration during early kidneys, chronic severe hypokalaemia, and infancy, to find out the incidence of intracere- malignant tumours that can be associated with bral calcification. nephrogenic diabetes insipidus (for example, oat cell carcinoma of the lung)-were 1 Culpepper RM, Hebert SC, Andreoli TE. Nephrogenic excluded. 1-3 Nephrogenic diabetes insipidus diabetes insipidus. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The was therefore classified as a primary lack of metabolic basis of inherited disease. 5th Ed. New York: tubular response to antidiuretic hormone. McGraw-Hill, 1983:1867-88. 2 Kaplan SA. Nephrogenic diabetes insipidus. In: Holliday Underlying disorders associated with intra- MA, Barratt TM, Vernier RL, eds. Pediatric nephrology. cerebral calcification are mainly prenatal or 2nd Ed. Baltimore: Williams and Wilkins, 1987:623-5. 3 Stern P. Nephrogenic defects of urinary concentration. In: postnatal infections with T gondii or Edelmann CM, ed. Diseases of the kidney. Vol II. Boston: cytomegalovirus,4 6 endocrine abnormalities Little, Brown and Company, 1978:987-95. 4 Willich E, Sellier W, Weigel W. Die intrakraniellen Verkal- such as all forms of hypoparathyroidism and kungen des Kindesalters. Fortschrifte auf dem Gebiete der pseudohypoparathyroidism,79 toxic or hypoxic Rontgenstrahlen 1972;116:735-50. 5 Kendall B, Cavanagh N. Intracranial calcification in paediat- damage to the central nervous system,'1'2 and ric computed tomography. Neuroradiology 1986;28:324-30. some congenital disorders with a yet unknown 6 Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders, 1981. metabolic cause.1l5 Within this last group of 7 Drezner MK, Neelon FA. Pseudohypoparathyroidism. In: disorders, Fahr-Volhard disease,'4 16 oculocra- Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein niosomatic disease,'5 17 and Cockayne's JL, Brown MS, eds. The metabolic basis ofinherited disease.

5th Ed. New York: McGraw-Hill, 1983:1508-27. http://adc.bmj.com/ syndrome'3 have to be principally considered. 8 Camp JD. Symmetrical calcification of cerebral basal ganglia; would be the its roentgenologic significance in diagnosis of parathyroid Obviously hypoparathyroidism insufficiency. Radiology 1947;49:568-77. most attractive choice of underlying pathology 9 Steinbach HL, Young DA. The roentgen appearance of because both main symptoms (nephrogenic pseudohypoparathyroidism (PH) and pseudopseudohypoparathyroidism (PPH). Differentiation from other syndro- diabetes insipidus and intracerebral calcifica- mes associated with short metacarpals, metatarsals, and tion) could be explained, but this was ruled out phalanges. AJR 1966;97:49-66. 10 Ilium F. Calcification of the basal ganglia following carbon by the finding of normal parathyroid hormone monoxide poisoning. Neuroradiology 1980;19:213-4.

and calcium concentrations in all patients. Evi- 11 Numaguchi Y, Hoffman JC, Sones PJ. Basal ganglia calcifica- on October 1, 2021 by guest. Protected copyright. tion as a late radiation effect. AJR 1975;123:27-30. dence against pseudohypoparathyroidism and 12 Peylan-Ramu N, Poplack DG, Blei CL, Herdt JR, Vermess pseudopseudohypoparathyroidism was based on M, Di Chiro G. Computer assisted tomography in methro- trexate encephalopathy. J Comput Assist Tomogr 1977;1: the normal concentrations of calcium and phos- 216-21. phate in serum 13 Cockayne EA. Dwarfism with retinal atrophy and deafness. and urine, the absence of renal Arch Dis Child 1946;21:52-4. calcification, and the absence of skeletal 14 Fahr T. Idiopathische Verkalkungen der Hirngefafle. Zen- abnormalities.7-9 Thus no underlying pathology tralblAllgPathol 1930;50:129-33. 15 Kearns TP, Sayre GP. Retinitis pigmentosa, external other than nephrogenic diabetes insipidus could ophthalmoplegia, and complete heart block. Arch Ophthal- be found to explain the intracerebral calcifica- mol 1958;60:280-9. 16 Kazis AD. Contribution of CT scan to the diagnosis of Fahr's tion. All patients had, however, experienced syndrome. Acta NeurolScand 1985;71:206-1 1. recurrent episodes of severe dehydration due to 17 Seigel RS, Seeger JF, Gabrielson TO, Allen RJ. Computed tomography in oculocraniosomatic disease (Kearns-Sayre the relative or absolute unresponsiveness of syndrome). Radiology 1979;130:159-64. their renal tubules to antidiuretic hormone. 18 Russel RGG, Caswell AM, Hearn PR, Sharrad RM. Calcium in mineralized tissues and pathological calcification. Br To our knowledge intracerebral calcification MedBull 1986;42:435-46.