American Journal of Medical Genetics 36:275-278 (1990)
Hypodipsic Hypernatremia and Hypertriglyceridemia Associated With Cleft Lip and Cleft Palate: A New Hypothalamic Dysfunction Syndrome? Dan Ben-Amitai, Avinoam Rachmel, Yael Levy, Yakov Sivan, Menachem Nitzan, and Reuben Steinherz Department of Pediatrics (D.B-A., A.R., Y.L., Y.S., M.N., R.S.), Section on Human Biochemical and Developmental Genetics (R.S.I. Beilinson Medical Center. Petah-Tikva. and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
We report on a 4-month-oldgirl with congenital hypodipsic hypernatremia resulting from decreased sensitivity of the hypothalamic osmoreceptors with increased tonicity in association with hyperlipemia and cleft lip and cleft palate. We postulate that the link among these various derangements is hypothalamic Dysfunction.
KEY WORDS: hypothalamus, hyperlipidemia, mid-face defect, osmolarity INTRODUCTION Cleft lip and palate have been associated with various metabolic disorders. The combination of this developmental field defect with hypernatremia and hypertriglyceridemia in the presence of inappropriate low plasma vasopressin concentration for the corresponding plasma tonicity has not been reported previously. We report on a patient with these manifestations and suggest that hypothalamic dysfunction may be the casual link between the metabolic abnormalities and the anatomical lesions. CLINICAL REPORT R.M., a 4-month-old girl, was admitted to Beilinson Medical Center for evaluation of unexplained elevated body temperature. The child was born after a n uneventful pregnancy and delivery to unrelated healthy parents of Ashkenazi-Jewish origin. On physical examination she appeared healthy. Length was 58 cm, weight was 4,800 g, (both below the 3rd centile). Body temperature was elevated to 38.7"C with signs of bilateral acute otitis Received for publication March 20,1989; revision received October 23, 1989. Address reprint requests to Reuben Steinherz, M.D., Head, Division on Biochemical Genetics, Department of Pediatrics, Bellinson Medical Center, 49100 Petah Tikva, Irsael.
0 1990 Wiley-Liss, Inc.
media, cleft lip and palate, and subtle signs of developmental delay; i.e., does not roll from front to back and hardly responds to familiar people. At age 3 years the child remained microcephalic with head circumference of 43 cm, length 79 cm, and weight 8,900 g (all below 3rd centile) (Fig. 1).The interpupilar distance and the inner canthi distances were 45 mm and 25 mm (20th and 3rd centiles), respectively. Except for surgically corrected cleft lip and palate there were no other anomalies. Chromosomal study, done twice, was normal. At age 3 years the child is hypertonic with severe psychomotor retardation (acts and behaves like a 6-month-old baby). Routine blood chemistry tests on admission showed a serum sodium level of 153 mEqlL. Repeated serum sodium measurements confirmed the original observation of chronic hypernatremia; sodium levels ranged from 140 to 170 mEqiL. Only occasionally were serum sodium levels in the upper normal range reported (i.e., 145 mEqi L). The infant's appearance or performance had no correlation to the serum sodium levels. Complete blood counts; renal and liver function tests; cultures of urine, blood, stool, serum electrolytes except sodium, calcium, phosphorus, blood proteins, lactic dehydrogenase, and alkaline phosphatase; and chest radiographs were normal. Plasma lipids taken simultaneously with serum sodium measurements demonstrated severe hypertriglyceridemia in the range of 370 to 2,640 mgldl. The plasma triglycerides did not change by diet manipulation or with varying sodium concentrations. VLDL, LDL, and HDL were normal for age. Possibly associated genetic lipid disorders were excluded by the normal levels of the child's parents' plasma lipids. Since, in certain individuals with mid-face defects such as cleft lip and cleft palate, malformations of the hypophysis and the hypothalamic regions might occur [Roitman and Laron, 19781, we did growth hormone and basal prolactin assays which were normal. Thyrotropin-releasing hormone (TRH) stimulated prolactin release and a t the same time stimulated the thyroid-stimulating hormone (TSH) level, which increased from 2.1 to 30
276
Ben-Amitai et al. almost constant (data not presented), but when plasma osmolality reached 310 mOsm/kg, urine osmolality increased. To exclude any possible contribution of kidney disease to the changes in plasma osmolality, vasopressin analog 1-deamino, 8-D-arginine vasopressin (DDAVP)was injected intramuscularly at the dose of 0.5 IUlkg body weight. Under these conditions urine osmolality increased from 100 to 900 mOsm/kg within 6 hours, while plasma osmolality and sodium concentration showed insignificant decreases from 294 to 289 mOsm/kg and from 147 to 144 mEq/L, respectively.
Fig. 1. The patient, R.M., at age 3 years.
pUlmL. Plasma aldosterone and renin as well as the levels of LH, FSH, and T4 were normal. Computerized tomography and nuclear magnetic resonance (NMR) of the brain were normal. A few months after initial admission, informed parental consent was obtained for further studies: A water deprivation test was conducted for 10 hours’(Tab1e I). The patient’s low basal vasopressin concentration of 1 pg/ml was only slightly increased after 6 and 10 hours of water deprivation to the levels of 1.9 and 2.1 pg/ml, respectively. Serum sodium during the whole examination period remained consistently high. Urine osmolality did not change much after 6 hours. It should also be mentioned that during the first 4 hours of water deprivation, urine osmolality remained
TABLE I. Water DeDrivation Test ~
Plasma arginine Vasopressin (pg/ml) Serum sodium (mEqiL) Serum osmolality (mOsrdkg) Uriune osmolality (mOsmikg) Body weight (a)
~
Initial 1.0
6 hr of water deprivation 1.9
10 hr of water deprivation 2.1
150
159
153
306
314
313
325
438
525
8,150
-
7,900
DISCUSSION The manifestations in this patient are: bilateral cleft lip and palate, hypernatremia, hypertriglyceridemia, and vasopressin concentrations inappropriately low for the increased plasma osmolality. Combination of some of the signs, though not in a single patient, have been reported in a limited number of publications; a plausible explanation which might provide a link between the patient’s sign and symptoms is a hypothalamic lesion or dysfunction. The observations of excretion of diluted urine in spite of elevated plasma osmolality and th a t urine concentration increased only by increasing plasma osmolality to very high levels by water deprivation imply subnormal ADH response. Patients with partial diabetes insipidus concentrate and dilute their urine at abnormally high levels of plasma osmolality. Normally, these patients can be diagnosed a s having polydipsia and polyuria in the face of normal plasma osmolality [Robertson et al., 19821. In contrast, lack of thirst may lead to hypernatremia and hyperosmolality [Robertson, 19841.It has been suggested that hypodipsic hypernatremia reflects decreased sensitivity of the hypothalamic osmoreceptors to increased tonicity, which causes abnormal perception of thirst and decreased vasopressin secretion [Conley e t al., 1976; Robertson et al., 1982; Robertson, 19841. Loss of thirst is often, if not always, associated with defects in ADH secretion due to proximity between the hypothalamic neural centers for water regulation and ADH production [Robertson et al., 19821. The failure to demonstrate a substantial anatomic hypothalamic lesion in our patient is in agreement with other authors who described hypothalamic adipsia without demonstrable structural lesions [Blank and Fransworth, 1974; Conley et al., 1976; Shaad et al., 1979; Christensen et al., 1981; Hayek and Peake, 19821. Other possible evidence for hypothalamic lesion is the known association between cleft lip and palate and hypothalamic malfunction [Roitman and Laron, 19781. The association of thirst-deficient hypernatremia with hyperlipidemia has previously been described in a few cases [Christensen et al., 1981; Hayek and Peake, 1982; DeRubertis et al., 1974; Sridhar et al., 1974; Halter et al., 1977; Sklar et al., 19811. All 10 reported patients were either adolescents or adults. In 7 of them tumors in the hypothalamic region were detected [DeRubertis et al., 1974; Sridhar et al., 1974; Halter et al., 1977; Sklar et al., 19811 In 2 cases [Hayek and Peake, 1982; Christensen e t al., 19811 there was no anatomic lesion in the hypothalamic region.
A New Hypothalamic Dysfunction Syndrome
277
Several explanations have been suggested to interpret hypernatremia and hyperlipidemia. On the basis of the the association between hypernatremia and hyper- experimental data, we postulate that the thirst-defitriglyceridemia. One explanation is that hypernatremia cient hypernatremia and hyperlipidemia in our patient per se leads to hyperlipidemia. It was demonstrated in are not fortuitous. The present patient combines for the first time hypoanimals that hypernatremia can induce hyperlipidemia and fatty liver [Hayek et al., 19831.Furthermore, hyper- dipsic hypernatremia, cleft lip and palate, and hypernatremia can also enhance triglyceride formation in the lipidemia. We cannot exclude the possibility that all the liver either directly or indirectly through hormonal me- sequential and developmental changes observed in the diators [Greenbaum and McLean, 1953; Fielding and patient represent an autosomal recessive disorder. Fielding, 1976; Hotta et al., 1981; Brindley, 19811. InhiACKNOWLEDGMENTS bition of lipoprotein lipase in adipose tissue, heart, lung, The secreterial assistance of Mrs. Pnina Falk is and other tissues by hypernatremic conditions probably plays some role in the production of hyperlipidemia greatly appreciated. [Fielding and Fielding, 19761. REFERENCES Another suggested theory is that fat mobilization from adipose t&ue is modulated by ventromedial hypo- Blank MS. Fransworth PB (1974): IdioDathic svmutomatic hvDer“I natremia in a 9-year-old boy: A clinicai and phisioiogic evaluation. thalamus [Bray and Nishizawa, 19781. Thus, hyperJ Pediatr 85:215-219. natremia can mediate hyperlipidemia through its acNishizawa Y (1978):Ventromedial hypothalamus modulates tion on the hypothalamus. Except for the few mentioned BrayfatGA, mobilisation during fasting. Nature 274:900-902. reports [DeRubertis et al., 1974; Sridhar et al., 1974; Bray GA, Inous S, Nishizawa Y (1981): Hypothalamic obesity. Diabetologia 20:366-377. Halter et al., 1977; Sklar et al., 1981;Christensen et al., DN (1981): Regulation of hepatic triacylglycerol synthesis 1981;Hayek and Peake, 19821of adipsic hypernatremia, Brindley and lipoprotein metabolism by glucocorticoids. Clin Sci 61: we could not trace any in vivo association between hy129-133. pernatremia and hyperlipidemia. Furthermore, in all Christensen NC, Hagen C, Nielsen MD, Petersen S (1981): Hypernatremia, diabetes mellitus, hyperprolactinemia, retarded growth the adipsic cases (including our patient) there was no and delayed puberty in a 14-year-oldgirl. Effect of bromocriptine correlation between the plasma sodium levels and the treatment. Acta Endocrinol (Copenh) 96:30-35. triglyceride concentrations. The lack of correlation Conley SB, Brocklebank JT, Tatlor IT, Robson AM (1976): Recurrent hypernatremia: A proposed mechanism in a patient with absence of raises the assumption that more than one factor creates thirst and abnormal excretion of water. J Pediatr 89:898-903. hypertriglyceridemia in the face of hypernatremia. The DeRubertis FR, Michells MF, David BB (1974): “Essential” hyperassociation between hypernatremia and hypernatremia. Arch Intern Med 134:889-895. triglyceridemia can also be explained by lesion at the Durr J, Karakash C, Vallotton MB, Jeanrenaud B (1981): Abnormal water turnover associated with hypothalamic obesity. Endocrinolhypothalamic region. A destructive lesion of the venogy 108:1228-1232. tromedial hypothalamus (VMH)causes hyperlipidemia Fielding CJ, Fielding PE (1976): Mechanism of salt-mediated inhibition of lipoprotein lipase. J Lipid Res 17:248-256. in rats [Frohman et al., 19691and humans [Sklar et al., LA, Bernardis LL (1968): Growth hormone and insulin levels 19811. The mechanism by which this lesion increases Frohman in weaning rats with ventromedial hypothalamic lesions. Endotriglyceride concentration is still speculative. One thecrinology 82:1125-1132. ory is that destruction of the VMH leads to decrease in Frohman LA, Bernardis LL, Schnatz JD, Burok L (1969): Plasma insulin and triglyceride levels after hypothalamic lesions in weansympathetic activity or alternatively increases the ing rats. Am J Physiol 216:1496-1501. parasympathetic tone which directly inhibits lipolysis Greenbaum AL, McLean P (1953):The mobilization of lipid by anterior pituitary growth hormone. Biochem J 54:407-413. and enhances lipogenesis [Shimazu, 19811. Another exJB, Goldberg AP, Robertson GL, Porte D (1977):Selective osmoplanation is that VMH lesion increases insulin secretion Halter receptor dysfunction in the syndrome of chromic hypernatremia. J [Frohman et al., 19691 either through derangement in Clin Endocrinol Metab 44:609-616. the autonomic nervous system [Bray et al., 19811 or Hayek A, Bryant PD, Woodside WF (1983): Hypernatremia induces hyperlipemia and fatty liver. Metabolism 32:l-3. through a hypothalamic humoral factor [Moltz et al., A, Peake TG (1982): Hypothalamic adipsia without demonstra19771. The hyperinsulinemia augments deposition of Hayek ble structural lesion. Pediatrics 70:275-278. lipids in adipose tissue, enhances lipogenesis in the liver Hotta N, Kakuta H, Kunieda T, Ida A, Sakamoto N (1981):Inhibitory effect of hyperosmolarity of ketogenesis. Diabetes 30 (Suppl and adipose tissue, and reduces lypolysis in adipose 1):128A. tissue [Bray et al., 19811. At the same time hyperin- Karakash C, Rohner-Jeanrenaud F, Hustvedt BE, Jeanrenaud B sulinemia stimulates hepatic triglyceride secretion [Re(1980):Nitrogen handling in adult hypoophthalmic obese rats. Am J Physiol 238:E32-E37. aven et al., 19671. A second hormone found in excess in JH, Dobbs RE, McCann SM, Fawcett CP (1977): Effects of hypoVMH lesions is glucagon. These 2 pancreatic hormones Moltz thalamic factors on insulin and glucagon release from the islets of favor uptake and deamination of amino acids and their Langerhans. Endocrinology 101:196-202. diversion toward lipid synthesis [Karakash et al., 19801. Reaven GM, Lerner RL, Stern MP, Farquhar JW (1967):Role of insulin in endogenous hypertriglyceridemia. J Clin Invest 46:1756-1767. VMH lesions were also connected with thyroid hormone Robertson GL (1984): Abnormalities of thirst regulation. Kidney Int [Tulloch et al., 19731and growth hormone [Frohman and 25:460-469. Bernardis, 19681 deficiencies; the lack of either might Robertson GL, Aycinena P, Zerbe RL (1982): Neurogenic disorders of osmoregulation. Am J Med 72:339-353. explain the hypertriglyceridemia. Roitman A, Laron Z (1978): Hypothalamo-pituitary hormone insufiIn the present case none of the hormonal factors could ciency associated with cleft lip and palate. Arch Dis Child 53: 952-955. account for the hypertriglyceridemia since the child’s endocrine profile was completely normal. Durr et al. Schaad U, Vassella F, Zuppinger K, Oetliker 0 11979): Hypodipsiahypernatremia syndrome. Helv Paediatr Acta 34:63-76. [1981] found that an experimental VMH lesion in rats Shimazu T (1981): Central nervous system regulation of liver and can cause both impairment of ADH secretion leading to adipose tissue metabolism. Diabetologia 20:343-356.
278
Ben-Amitai et al.
Sklar CA, Grumbach MM, Kaplan SL, Conte FA (1981): Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: Report of 10 patients. J Clin Endocrinol Metab 52:9-16. Sridhar CB, Calvert GD, Ibbertson HK (1974): Syndrome of hyper-
natremia, hypodipsia and partial diabetes insipidus: A new interpretation. J Clin Endocrinol Metab 38:890-901. Tulloch BR, Lewis B, Russell FT (1973): Triglyceride metabolism in thyroid disease. Lancet 1:391-394.
Hypodipsic Hypernatremia and Hypertriglyceridemia Associated With Cleft Lip and Cleft Palate: A New Hypothalamic Dysfunction Syndrome? Dan Ben-Amitai, Avinoam Rachmel, Yael Levy, Yakov Sivan, Menachem Nitzan, and Reuben Steinherz Department of Pediatrics (D.B-A., A.R., Y.L., Y.S., M.N., R.S.), Section on Human Biochemical and Developmental Genetics (R.S.I. Beilinson Medical Center. Petah-Tikva. and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
We report on a 4-month-oldgirl with congenital hypodipsic hypernatremia resulting from decreased sensitivity of the hypothalamic osmoreceptors with increased tonicity in association with hyperlipemia and cleft lip and cleft palate. We postulate that the link among these various derangements is hypothalamic Dysfunction.
KEY WORDS: hypothalamus, hyperlipidemia, mid-face defect, osmolarity INTRODUCTION Cleft lip and palate have been associated with various metabolic disorders. The combination of this developmental field defect with hypernatremia and hypertriglyceridemia in the presence of inappropriate low plasma vasopressin concentration for the corresponding plasma tonicity has not been reported previously. We report on a patient with these manifestations and suggest that hypothalamic dysfunction may be the casual link between the metabolic abnormalities and the anatomical lesions. CLINICAL REPORT R.M., a 4-month-old girl, was admitted to Beilinson Medical Center for evaluation of unexplained elevated body temperature. The child was born after a n uneventful pregnancy and delivery to unrelated healthy parents of Ashkenazi-Jewish origin. On physical examination she appeared healthy. Length was 58 cm, weight was 4,800 g, (both below the 3rd centile). Body temperature was elevated to 38.7"C with signs of bilateral acute otitis Received for publication March 20,1989; revision received October 23, 1989. Address reprint requests to Reuben Steinherz, M.D., Head, Division on Biochemical Genetics, Department of Pediatrics, Bellinson Medical Center, 49100 Petah Tikva, Irsael.
0 1990 Wiley-Liss, Inc.
media, cleft lip and palate, and subtle signs of developmental delay; i.e., does not roll from front to back and hardly responds to familiar people. At age 3 years the child remained microcephalic with head circumference of 43 cm, length 79 cm, and weight 8,900 g (all below 3rd centile) (Fig. 1).The interpupilar distance and the inner canthi distances were 45 mm and 25 mm (20th and 3rd centiles), respectively. Except for surgically corrected cleft lip and palate there were no other anomalies. Chromosomal study, done twice, was normal. At age 3 years the child is hypertonic with severe psychomotor retardation (acts and behaves like a 6-month-old baby). Routine blood chemistry tests on admission showed a serum sodium level of 153 mEqlL. Repeated serum sodium measurements confirmed the original observation of chronic hypernatremia; sodium levels ranged from 140 to 170 mEqiL. Only occasionally were serum sodium levels in the upper normal range reported (i.e., 145 mEqi L). The infant's appearance or performance had no correlation to the serum sodium levels. Complete blood counts; renal and liver function tests; cultures of urine, blood, stool, serum electrolytes except sodium, calcium, phosphorus, blood proteins, lactic dehydrogenase, and alkaline phosphatase; and chest radiographs were normal. Plasma lipids taken simultaneously with serum sodium measurements demonstrated severe hypertriglyceridemia in the range of 370 to 2,640 mgldl. The plasma triglycerides did not change by diet manipulation or with varying sodium concentrations. VLDL, LDL, and HDL were normal for age. Possibly associated genetic lipid disorders were excluded by the normal levels of the child's parents' plasma lipids. Since, in certain individuals with mid-face defects such as cleft lip and cleft palate, malformations of the hypophysis and the hypothalamic regions might occur [Roitman and Laron, 19781, we did growth hormone and basal prolactin assays which were normal. Thyrotropin-releasing hormone (TRH) stimulated prolactin release and a t the same time stimulated the thyroid-stimulating hormone (TSH) level, which increased from 2.1 to 30
276
Ben-Amitai et al. almost constant (data not presented), but when plasma osmolality reached 310 mOsm/kg, urine osmolality increased. To exclude any possible contribution of kidney disease to the changes in plasma osmolality, vasopressin analog 1-deamino, 8-D-arginine vasopressin (DDAVP)was injected intramuscularly at the dose of 0.5 IUlkg body weight. Under these conditions urine osmolality increased from 100 to 900 mOsm/kg within 6 hours, while plasma osmolality and sodium concentration showed insignificant decreases from 294 to 289 mOsm/kg and from 147 to 144 mEq/L, respectively.
Fig. 1. The patient, R.M., at age 3 years.
pUlmL. Plasma aldosterone and renin as well as the levels of LH, FSH, and T4 were normal. Computerized tomography and nuclear magnetic resonance (NMR) of the brain were normal. A few months after initial admission, informed parental consent was obtained for further studies: A water deprivation test was conducted for 10 hours’(Tab1e I). The patient’s low basal vasopressin concentration of 1 pg/ml was only slightly increased after 6 and 10 hours of water deprivation to the levels of 1.9 and 2.1 pg/ml, respectively. Serum sodium during the whole examination period remained consistently high. Urine osmolality did not change much after 6 hours. It should also be mentioned that during the first 4 hours of water deprivation, urine osmolality remained
TABLE I. Water DeDrivation Test ~
Plasma arginine Vasopressin (pg/ml) Serum sodium (mEqiL) Serum osmolality (mOsrdkg) Uriune osmolality (mOsmikg) Body weight (a)
~
Initial 1.0
6 hr of water deprivation 1.9
10 hr of water deprivation 2.1
150
159
153
306
314
313
325
438
525
8,150
-
7,900
DISCUSSION The manifestations in this patient are: bilateral cleft lip and palate, hypernatremia, hypertriglyceridemia, and vasopressin concentrations inappropriately low for the increased plasma osmolality. Combination of some of the signs, though not in a single patient, have been reported in a limited number of publications; a plausible explanation which might provide a link between the patient’s sign and symptoms is a hypothalamic lesion or dysfunction. The observations of excretion of diluted urine in spite of elevated plasma osmolality and th a t urine concentration increased only by increasing plasma osmolality to very high levels by water deprivation imply subnormal ADH response. Patients with partial diabetes insipidus concentrate and dilute their urine at abnormally high levels of plasma osmolality. Normally, these patients can be diagnosed a s having polydipsia and polyuria in the face of normal plasma osmolality [Robertson et al., 19821. In contrast, lack of thirst may lead to hypernatremia and hyperosmolality [Robertson, 19841.It has been suggested that hypodipsic hypernatremia reflects decreased sensitivity of the hypothalamic osmoreceptors to increased tonicity, which causes abnormal perception of thirst and decreased vasopressin secretion [Conley e t al., 1976; Robertson et al., 1982; Robertson, 19841. Loss of thirst is often, if not always, associated with defects in ADH secretion due to proximity between the hypothalamic neural centers for water regulation and ADH production [Robertson et al., 19821. The failure to demonstrate a substantial anatomic hypothalamic lesion in our patient is in agreement with other authors who described hypothalamic adipsia without demonstrable structural lesions [Blank and Fransworth, 1974; Conley et al., 1976; Shaad et al., 1979; Christensen et al., 1981; Hayek and Peake, 19821. Other possible evidence for hypothalamic lesion is the known association between cleft lip and palate and hypothalamic malfunction [Roitman and Laron, 19781. The association of thirst-deficient hypernatremia with hyperlipidemia has previously been described in a few cases [Christensen et al., 1981; Hayek and Peake, 1982; DeRubertis et al., 1974; Sridhar et al., 1974; Halter et al., 1977; Sklar et al., 19811. All 10 reported patients were either adolescents or adults. In 7 of them tumors in the hypothalamic region were detected [DeRubertis et al., 1974; Sridhar et al., 1974; Halter et al., 1977; Sklar et al., 19811 In 2 cases [Hayek and Peake, 1982; Christensen e t al., 19811 there was no anatomic lesion in the hypothalamic region.
A New Hypothalamic Dysfunction Syndrome
277
Several explanations have been suggested to interpret hypernatremia and hyperlipidemia. On the basis of the the association between hypernatremia and hyper- experimental data, we postulate that the thirst-defitriglyceridemia. One explanation is that hypernatremia cient hypernatremia and hyperlipidemia in our patient per se leads to hyperlipidemia. It was demonstrated in are not fortuitous. The present patient combines for the first time hypoanimals that hypernatremia can induce hyperlipidemia and fatty liver [Hayek et al., 19831.Furthermore, hyper- dipsic hypernatremia, cleft lip and palate, and hypernatremia can also enhance triglyceride formation in the lipidemia. We cannot exclude the possibility that all the liver either directly or indirectly through hormonal me- sequential and developmental changes observed in the diators [Greenbaum and McLean, 1953; Fielding and patient represent an autosomal recessive disorder. Fielding, 1976; Hotta et al., 1981; Brindley, 19811. InhiACKNOWLEDGMENTS bition of lipoprotein lipase in adipose tissue, heart, lung, The secreterial assistance of Mrs. Pnina Falk is and other tissues by hypernatremic conditions probably plays some role in the production of hyperlipidemia greatly appreciated. [Fielding and Fielding, 19761. REFERENCES Another suggested theory is that fat mobilization from adipose t&ue is modulated by ventromedial hypo- Blank MS. Fransworth PB (1974): IdioDathic svmutomatic hvDer“I natremia in a 9-year-old boy: A clinicai and phisioiogic evaluation. thalamus [Bray and Nishizawa, 19781. Thus, hyperJ Pediatr 85:215-219. natremia can mediate hyperlipidemia through its acNishizawa Y (1978):Ventromedial hypothalamus modulates tion on the hypothalamus. Except for the few mentioned BrayfatGA, mobilisation during fasting. Nature 274:900-902. reports [DeRubertis et al., 1974; Sridhar et al., 1974; Bray GA, Inous S, Nishizawa Y (1981): Hypothalamic obesity. Diabetologia 20:366-377. Halter et al., 1977; Sklar et al., 1981;Christensen et al., DN (1981): Regulation of hepatic triacylglycerol synthesis 1981;Hayek and Peake, 19821of adipsic hypernatremia, Brindley and lipoprotein metabolism by glucocorticoids. Clin Sci 61: we could not trace any in vivo association between hy129-133. pernatremia and hyperlipidemia. Furthermore, in all Christensen NC, Hagen C, Nielsen MD, Petersen S (1981): Hypernatremia, diabetes mellitus, hyperprolactinemia, retarded growth the adipsic cases (including our patient) there was no and delayed puberty in a 14-year-oldgirl. Effect of bromocriptine correlation between the plasma sodium levels and the treatment. Acta Endocrinol (Copenh) 96:30-35. triglyceride concentrations. The lack of correlation Conley SB, Brocklebank JT, Tatlor IT, Robson AM (1976): Recurrent hypernatremia: A proposed mechanism in a patient with absence of raises the assumption that more than one factor creates thirst and abnormal excretion of water. J Pediatr 89:898-903. hypertriglyceridemia in the face of hypernatremia. The DeRubertis FR, Michells MF, David BB (1974): “Essential” hyperassociation between hypernatremia and hypernatremia. Arch Intern Med 134:889-895. triglyceridemia can also be explained by lesion at the Durr J, Karakash C, Vallotton MB, Jeanrenaud B (1981): Abnormal water turnover associated with hypothalamic obesity. Endocrinolhypothalamic region. A destructive lesion of the venogy 108:1228-1232. tromedial hypothalamus (VMH)causes hyperlipidemia Fielding CJ, Fielding PE (1976): Mechanism of salt-mediated inhibition of lipoprotein lipase. J Lipid Res 17:248-256. in rats [Frohman et al., 19691and humans [Sklar et al., LA, Bernardis LL (1968): Growth hormone and insulin levels 19811. The mechanism by which this lesion increases Frohman in weaning rats with ventromedial hypothalamic lesions. Endotriglyceride concentration is still speculative. One thecrinology 82:1125-1132. ory is that destruction of the VMH leads to decrease in Frohman LA, Bernardis LL, Schnatz JD, Burok L (1969): Plasma insulin and triglyceride levels after hypothalamic lesions in weansympathetic activity or alternatively increases the ing rats. Am J Physiol 216:1496-1501. parasympathetic tone which directly inhibits lipolysis Greenbaum AL, McLean P (1953):The mobilization of lipid by anterior pituitary growth hormone. Biochem J 54:407-413. and enhances lipogenesis [Shimazu, 19811. Another exJB, Goldberg AP, Robertson GL, Porte D (1977):Selective osmoplanation is that VMH lesion increases insulin secretion Halter receptor dysfunction in the syndrome of chromic hypernatremia. J [Frohman et al., 19691 either through derangement in Clin Endocrinol Metab 44:609-616. the autonomic nervous system [Bray et al., 19811 or Hayek A, Bryant PD, Woodside WF (1983): Hypernatremia induces hyperlipemia and fatty liver. Metabolism 32:l-3. through a hypothalamic humoral factor [Moltz et al., A, Peake TG (1982): Hypothalamic adipsia without demonstra19771. The hyperinsulinemia augments deposition of Hayek ble structural lesion. Pediatrics 70:275-278. lipids in adipose tissue, enhances lipogenesis in the liver Hotta N, Kakuta H, Kunieda T, Ida A, Sakamoto N (1981):Inhibitory effect of hyperosmolarity of ketogenesis. Diabetes 30 (Suppl and adipose tissue, and reduces lypolysis in adipose 1):128A. tissue [Bray et al., 19811. At the same time hyperin- Karakash C, Rohner-Jeanrenaud F, Hustvedt BE, Jeanrenaud B sulinemia stimulates hepatic triglyceride secretion [Re(1980):Nitrogen handling in adult hypoophthalmic obese rats. Am J Physiol 238:E32-E37. aven et al., 19671. A second hormone found in excess in JH, Dobbs RE, McCann SM, Fawcett CP (1977): Effects of hypoVMH lesions is glucagon. These 2 pancreatic hormones Moltz thalamic factors on insulin and glucagon release from the islets of favor uptake and deamination of amino acids and their Langerhans. Endocrinology 101:196-202. diversion toward lipid synthesis [Karakash et al., 19801. Reaven GM, Lerner RL, Stern MP, Farquhar JW (1967):Role of insulin in endogenous hypertriglyceridemia. J Clin Invest 46:1756-1767. VMH lesions were also connected with thyroid hormone Robertson GL (1984): Abnormalities of thirst regulation. Kidney Int [Tulloch et al., 19731and growth hormone [Frohman and 25:460-469. Bernardis, 19681 deficiencies; the lack of either might Robertson GL, Aycinena P, Zerbe RL (1982): Neurogenic disorders of osmoregulation. Am J Med 72:339-353. explain the hypertriglyceridemia. Roitman A, Laron Z (1978): Hypothalamo-pituitary hormone insufiIn the present case none of the hormonal factors could ciency associated with cleft lip and palate. Arch Dis Child 53: 952-955. account for the hypertriglyceridemia since the child’s endocrine profile was completely normal. Durr et al. Schaad U, Vassella F, Zuppinger K, Oetliker 0 11979): Hypodipsiahypernatremia syndrome. Helv Paediatr Acta 34:63-76. [1981] found that an experimental VMH lesion in rats Shimazu T (1981): Central nervous system regulation of liver and can cause both impairment of ADH secretion leading to adipose tissue metabolism. Diabetologia 20:343-356.
278
Ben-Amitai et al.
Sklar CA, Grumbach MM, Kaplan SL, Conte FA (1981): Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: Report of 10 patients. J Clin Endocrinol Metab 52:9-16. Sridhar CB, Calvert GD, Ibbertson HK (1974): Syndrome of hyper-
natremia, hypodipsia and partial diabetes insipidus: A new interpretation. J Clin Endocrinol Metab 38:890-901. Tulloch BR, Lewis B, Russell FT (1973): Triglyceride metabolism in thyroid disease. Lancet 1:391-394.
