Hum. Hcrcd. 25: 30-34 (1975)
Possible Dominant Inheritance of the Idiopathic Hypercalcémie Syndrome K. Mi nis. Zs. Szhi.ii) and P. Tom Department of Pediatrics, County Hospital, Gyôr
Key Words. Idiopathic hypercalcemia • Family study Abstract. A girl, aged 16 months, with idiopathic hypercalcemia (failure to thrive, characteristic face, supravalvular aortic stenosis) was observed. Her serum calcium level was between 14 and 20 mg 100 ml. Both her father and brother were mentally retarded and had calcium deposits in their corncac. Their serum calcium values were 11.9 and 13.0 mg/ 100 ml. respectively, with increased urinary output of calcium. The family history is sug gestive of autosomal dominant inheritance of the disease.
The idiopathic hypercalcemic syndrome first described by F anconi el a/. [1952] and L ig h t w o o d [1952] is characterized by severe infantile hyper calcemia, failure to thrive, anorexia, vomiting, constipation, polyuria, thirst, recurring dehydration, and muscular hypotonia. Typical facies and supra valvular aortic stenosis develop in the majority of the cases. In older patients dwarfing, mental retardation and the peculiar facies of hypercalcemia are present, and there may be osteosclerosis, parenchymal calcification, renal and cardiovascular damage. In children and adults the infantile hypercal cemia turns to a normocalcemic stage. An important condition of the diag nosis is that overdosage of vitamin D could be excluded. In spile of the well-known clinical picture, the inheritance of the syndrome is still not clarified. We report here on a family in which the idiopathic hypercalcemic syndrome seemed to be inherited as an autosomal dominant trait.
O.T. 111272 was born after 40 weeks' gestation. Pregnancy and delivery were un eventful; however, the newborn weighed only 2,000 g and showed clinical signs of dys-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
Case Repon
M éhks/Szelid /T óth
31
maturity. On the 6th day of her life a holosystolic murmur was noticed, yet the baby’s circulation remained compensated and she thrived well until the age of 3 months. From the 4th month she had to be repeatedly hospitalized because of fever, vomiting and failure to thrive. Detailed clinical and laboratory investigations revealed idiopathic hypercalcémie syndrome of the baby. Her phenotype was characteristic of the disease: she had a typical ‘eltin’ face (tig. I), calcium deposits in the cornea, supravalvular aortic stenosis, and peri pheral pulmonic stenosis. Her serum calcium level was between 14 and 20 mg/100 ml, which could not be decreased by any therapeutic efforts including calcium-free diet, ad ministration of Calcitonin, Prednisolone, sodium sulfate and phosphate. Vitamin D in toxication could be excluded: the child got only 200,000 units of vitamin D;, at two occasions at the age of 3 and 5 months. According to the results of calcium- and Furosemidc-loading tests, primary hyperparalhyreoidism could not he suggested. In accordance with this, two histologically normal parathyroid glands were found when she was operated on at the age of 14 months. Urinary hydroxyprolin and glucose-aminoglycan excretion was within the normal limits. When submitting this report she was 16 months old and severely atrophic. She weighed only 4,080 g and seemed to be both physically and mentally retarded. Her hypercalcemia persisted with values of 15 17 mg, 100 ml. and a slow impairment of renal function could be observed.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
Fig. I. The proposita at the age of 13 months.
32
Mini s Szi i.io T oth
Fig. 2. Pedigree of the family. *, * = Personally examined, biochemically tested. ■. • = Affected persons with both clinical and biochemical features of the idiopathic hypercalcémie syndrome. I *_|, O = Suspicious for the syndrome according to verbal in formation only.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
The mother was 37 years old at the ehild's birth. She was short in stature ( 154 cm), but otherwise physically and mentally normal. Blood chemistry showed no pathological results. The father was 38 years when the proposita was born. He seemed to be slightly mentally retarded, but psychological tests had never been made. He had previously been treated for gastric ulcer; the serum calcium level was not determined at that occasion, but a conspi cuously high amount of calcium oxalate crystals in the urine sediment was described. We did not find any signs of cardiac anomaly, but calcium deposits in his lens and corneac were observed. His serum calcium level was 11.9 mg/100 ml. The brother of the proposita, aged 17, was obviously mentally retarded. His physical appearance corresponded to that of a 12-year-old boy. His ophlhalmological examination revealed corneal and lenticular opacities and tortuosity of retinal vessels. Cardiologic and roentgenologic examinations resulted in normal findings. The laboratory results were characteristic of the idiopathic hypercalcémie syndrome: serum calcium 13.0 mg 100 ml, phosphorus 4.1 mg 100 ml. urinary calcium output 540 mg/24 h. The family of the mother could not be reached. According to verbal information, no mental retardation, infantile atrophy or deaths had occurred among her relatives. The father had 5 siblings. Only the youngest sister could be personally examined and biochemically tested. She proved to be healthy and intelligent, just like her two sons. The father's brother, born in 1938. died in 1953. His history was rather suspicious for the hypercalcémie syndrome. He was a very weak, dystrophic infant, susceptible to in fections. Even later he remained physically and mentally retarded and was treated for 'renal disease'. When he was 15 years old, the parents were told that the child had 'calci fication of the inner organs'. The boy died at home, and unfortunately neither medical nor autopsy reports about his disease are available. The other sisters and brothers of the father and their children were said to be healthy. The paternal grandmother, on the other hand, had been treated since the age of 35 years for ‘premature arteriosclerosis'. She refused cooperation. The pedigree of the family is shown in figure 2.
Idiopathic hypercalcemia
33
Discussion As recently reviewed by Beuren [1972]. a total of about 240 patients with supravalvular aortic stenosis have been reported until now. A part of these is probably due to administration of vitamin D in huge doses during pregnancy and infancy. The other part may correspond to a component of the idiopathic hypercalcemic syndrome. Supravalvular aortic stenosis is regarded as an autosomal dominant phenotype, while hypercalcemia with ‘elfin' face, mental retardation and supravalvular aortic stenosis is thought to be non-familial and a phenocopy of familial supravalvular aortic stenosis [M c K u sic k . 1971], B euren [1972] is against this distinction and suggests that also idiopathic hypercalcemia is a familial disease. This idea was supported by the findings of M orrison and M c N ally [1967] and A n ha el at. [1967] which also showed considerable variations of manifestation within the same family. Suspicion of a genetic basis of hypercalcemia was provided by the family first reported by S mith et at. [1959] and later by Ki nny el al. [1963]. Besides two affected sisters, the parents had normal serum calcium levels, thus an autosomal recessive mode of inheritance could be supposed. The examina tions of B l iz z a r d et at. [1963] and E h r h a r d t and M oney [1967] indicated that the defect may be connected with vitamin D inactivation, and the hyper sensitivity to vitamin D may be dominant and not recessive. In a recent summary of features of idiopathic hypercalcemia, S in g leto n and D utton [1973] strictly stated ‘heredity: none’, thus the data on the inheritance of the syndrome arc still controversial. Our index patient was a typical case of the idiopathic hypercalcemic syndrome. According to clinical, laboratory and histological examinations, her very high serum calcium level was not due to primary or secondary hyperparathyreoidism. Both the patient’s brother and father had a signi ficantly elevated serum calcium level and. as a consequence of this, signs of parenchymal calcification. Overdosage of vitamin D could be excluded in all the persons examined: thus, not only the clinical symptoms, but also biochemical evidence are suggestive of dominant inheritance of idiopathic hypercalcemia in the family observed.
References
J. Pediat. 71: 431-441 (1967).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
A n n a , A . U.: W i u s k , H. I£.; R ow k , R. D.; P it t , K. L.; L kvin , S.: O i i i s i n , O. !£., and C ookk , R. L.: Pathogenesis of the supravalvular aortic stenosis syndrome in children.
34
M emes/S z e l id T o m
B e u r e n , A. J.: Supravalvular aortic stenosis: a complex syndrome with and without
mental retardation. Birth Defects, Orig. A. Ser. 8/5: 45 56 (1972). B l iz z a r d . R. M. (1963): cited by M c K u s ic k 11971). E iik h a r d t , A. A. and M o n e y , J.: Hypercalcemia a family study of psychologic func
tioning. Johns Hopk. med. J. 121: 14 20 (1967). F an co n i , G .: G ir a r d e t , P.; S c h l e s in g e r , R.; B u t l e r , N. und B l a c k , J.: Chronische
Dr. K. M eh es , Department of Pediatrics, County Hospital, Megyei Korhaz, II 4002 (Ivor, Pf. 92 (Hungary)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
Hypercalcamie, kombinierl mil Osteosklerose, Hypcrazotamie, Minderwuchs und kongenitalen Missbildungen. Helv. paediat. Acta 7. 314-349 (1952). KfNNY, F. M .: A c e t o , T.: P ijr is c h , M .: H a r r iso n , H .: H a r r iso n , H. C'.. and B l iz z a r d , R. M.: Metabolic studies in a patient with idiopathic hypercalcemia of infancy. J. Pediat. 62: 531 537 (1963). L ig h tw o o d , R.: Idiopathic hypercalcemia with failure to thrive. Proc. rov. Soc. Med. 45: 401 410 (1952). Mc K usick, V.: Mendelian inheritance in man (Johns Hopkins Press. Baltimore 1971). M o rriso n . R. C. and M c N a l l y , H. E.: The spectrum of abnormalities in supravalvular aortic stenosis. Abstract. Amer. J. Cardiol. 19: 143 (1967). S in g let o n , E. B. and D u t t o n , R. V.: Idiopathic hypercalcemia. Semin. Roentgenol. 8: 212-213 (1973). S m ith , D. W.: B l iz z a r d , R. M„ and H arriso n , H. E.: Idiopathic hypercalcemia. A case report with assays of vitamin D in the serum. Pediatrics 24: 258 269 (1959).
Possible Dominant Inheritance of the Idiopathic Hypercalcémie Syndrome K. Mi nis. Zs. Szhi.ii) and P. Tom Department of Pediatrics, County Hospital, Gyôr
Key Words. Idiopathic hypercalcemia • Family study Abstract. A girl, aged 16 months, with idiopathic hypercalcemia (failure to thrive, characteristic face, supravalvular aortic stenosis) was observed. Her serum calcium level was between 14 and 20 mg 100 ml. Both her father and brother were mentally retarded and had calcium deposits in their corncac. Their serum calcium values were 11.9 and 13.0 mg/ 100 ml. respectively, with increased urinary output of calcium. The family history is sug gestive of autosomal dominant inheritance of the disease.
The idiopathic hypercalcemic syndrome first described by F anconi el a/. [1952] and L ig h t w o o d [1952] is characterized by severe infantile hyper calcemia, failure to thrive, anorexia, vomiting, constipation, polyuria, thirst, recurring dehydration, and muscular hypotonia. Typical facies and supra valvular aortic stenosis develop in the majority of the cases. In older patients dwarfing, mental retardation and the peculiar facies of hypercalcemia are present, and there may be osteosclerosis, parenchymal calcification, renal and cardiovascular damage. In children and adults the infantile hypercal cemia turns to a normocalcemic stage. An important condition of the diag nosis is that overdosage of vitamin D could be excluded. In spile of the well-known clinical picture, the inheritance of the syndrome is still not clarified. We report here on a family in which the idiopathic hypercalcemic syndrome seemed to be inherited as an autosomal dominant trait.
O.T. 111272 was born after 40 weeks' gestation. Pregnancy and delivery were un eventful; however, the newborn weighed only 2,000 g and showed clinical signs of dys-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
Case Repon
M éhks/Szelid /T óth
31
maturity. On the 6th day of her life a holosystolic murmur was noticed, yet the baby’s circulation remained compensated and she thrived well until the age of 3 months. From the 4th month she had to be repeatedly hospitalized because of fever, vomiting and failure to thrive. Detailed clinical and laboratory investigations revealed idiopathic hypercalcémie syndrome of the baby. Her phenotype was characteristic of the disease: she had a typical ‘eltin’ face (tig. I), calcium deposits in the cornea, supravalvular aortic stenosis, and peri pheral pulmonic stenosis. Her serum calcium level was between 14 and 20 mg/100 ml, which could not be decreased by any therapeutic efforts including calcium-free diet, ad ministration of Calcitonin, Prednisolone, sodium sulfate and phosphate. Vitamin D in toxication could be excluded: the child got only 200,000 units of vitamin D;, at two occasions at the age of 3 and 5 months. According to the results of calcium- and Furosemidc-loading tests, primary hyperparalhyreoidism could not he suggested. In accordance with this, two histologically normal parathyroid glands were found when she was operated on at the age of 14 months. Urinary hydroxyprolin and glucose-aminoglycan excretion was within the normal limits. When submitting this report she was 16 months old and severely atrophic. She weighed only 4,080 g and seemed to be both physically and mentally retarded. Her hypercalcemia persisted with values of 15 17 mg, 100 ml. and a slow impairment of renal function could be observed.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
Fig. I. The proposita at the age of 13 months.
32
Mini s Szi i.io T oth
Fig. 2. Pedigree of the family. *, * = Personally examined, biochemically tested. ■. • = Affected persons with both clinical and biochemical features of the idiopathic hypercalcémie syndrome. I *_|, O = Suspicious for the syndrome according to verbal in formation only.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
The mother was 37 years old at the ehild's birth. She was short in stature ( 154 cm), but otherwise physically and mentally normal. Blood chemistry showed no pathological results. The father was 38 years when the proposita was born. He seemed to be slightly mentally retarded, but psychological tests had never been made. He had previously been treated for gastric ulcer; the serum calcium level was not determined at that occasion, but a conspi cuously high amount of calcium oxalate crystals in the urine sediment was described. We did not find any signs of cardiac anomaly, but calcium deposits in his lens and corneac were observed. His serum calcium level was 11.9 mg/100 ml. The brother of the proposita, aged 17, was obviously mentally retarded. His physical appearance corresponded to that of a 12-year-old boy. His ophlhalmological examination revealed corneal and lenticular opacities and tortuosity of retinal vessels. Cardiologic and roentgenologic examinations resulted in normal findings. The laboratory results were characteristic of the idiopathic hypercalcémie syndrome: serum calcium 13.0 mg 100 ml, phosphorus 4.1 mg 100 ml. urinary calcium output 540 mg/24 h. The family of the mother could not be reached. According to verbal information, no mental retardation, infantile atrophy or deaths had occurred among her relatives. The father had 5 siblings. Only the youngest sister could be personally examined and biochemically tested. She proved to be healthy and intelligent, just like her two sons. The father's brother, born in 1938. died in 1953. His history was rather suspicious for the hypercalcémie syndrome. He was a very weak, dystrophic infant, susceptible to in fections. Even later he remained physically and mentally retarded and was treated for 'renal disease'. When he was 15 years old, the parents were told that the child had 'calci fication of the inner organs'. The boy died at home, and unfortunately neither medical nor autopsy reports about his disease are available. The other sisters and brothers of the father and their children were said to be healthy. The paternal grandmother, on the other hand, had been treated since the age of 35 years for ‘premature arteriosclerosis'. She refused cooperation. The pedigree of the family is shown in figure 2.
Idiopathic hypercalcemia
33
Discussion As recently reviewed by Beuren [1972]. a total of about 240 patients with supravalvular aortic stenosis have been reported until now. A part of these is probably due to administration of vitamin D in huge doses during pregnancy and infancy. The other part may correspond to a component of the idiopathic hypercalcemic syndrome. Supravalvular aortic stenosis is regarded as an autosomal dominant phenotype, while hypercalcemia with ‘elfin' face, mental retardation and supravalvular aortic stenosis is thought to be non-familial and a phenocopy of familial supravalvular aortic stenosis [M c K u sic k . 1971], B euren [1972] is against this distinction and suggests that also idiopathic hypercalcemia is a familial disease. This idea was supported by the findings of M orrison and M c N ally [1967] and A n ha el at. [1967] which also showed considerable variations of manifestation within the same family. Suspicion of a genetic basis of hypercalcemia was provided by the family first reported by S mith et at. [1959] and later by Ki nny el al. [1963]. Besides two affected sisters, the parents had normal serum calcium levels, thus an autosomal recessive mode of inheritance could be supposed. The examina tions of B l iz z a r d et at. [1963] and E h r h a r d t and M oney [1967] indicated that the defect may be connected with vitamin D inactivation, and the hyper sensitivity to vitamin D may be dominant and not recessive. In a recent summary of features of idiopathic hypercalcemia, S in g leto n and D utton [1973] strictly stated ‘heredity: none’, thus the data on the inheritance of the syndrome arc still controversial. Our index patient was a typical case of the idiopathic hypercalcemic syndrome. According to clinical, laboratory and histological examinations, her very high serum calcium level was not due to primary or secondary hyperparathyreoidism. Both the patient’s brother and father had a signi ficantly elevated serum calcium level and. as a consequence of this, signs of parenchymal calcification. Overdosage of vitamin D could be excluded in all the persons examined: thus, not only the clinical symptoms, but also biochemical evidence are suggestive of dominant inheritance of idiopathic hypercalcemia in the family observed.
References
J. Pediat. 71: 431-441 (1967).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
A n n a , A . U.: W i u s k , H. I£.; R ow k , R. D.; P it t , K. L.; L kvin , S.: O i i i s i n , O. !£., and C ookk , R. L.: Pathogenesis of the supravalvular aortic stenosis syndrome in children.
34
M emes/S z e l id T o m
B e u r e n , A. J.: Supravalvular aortic stenosis: a complex syndrome with and without
mental retardation. Birth Defects, Orig. A. Ser. 8/5: 45 56 (1972). B l iz z a r d . R. M. (1963): cited by M c K u s ic k 11971). E iik h a r d t , A. A. and M o n e y , J.: Hypercalcemia a family study of psychologic func
tioning. Johns Hopk. med. J. 121: 14 20 (1967). F an co n i , G .: G ir a r d e t , P.; S c h l e s in g e r , R.; B u t l e r , N. und B l a c k , J.: Chronische
Dr. K. M eh es , Department of Pediatrics, County Hospital, Megyei Korhaz, II 4002 (Ivor, Pf. 92 (Hungary)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/22/2018 3:27:14 PM
Hypercalcamie, kombinierl mil Osteosklerose, Hypcrazotamie, Minderwuchs und kongenitalen Missbildungen. Helv. paediat. Acta 7. 314-349 (1952). KfNNY, F. M .: A c e t o , T.: P ijr is c h , M .: H a r r iso n , H .: H a r r iso n , H. C'.. and B l iz z a r d , R. M.: Metabolic studies in a patient with idiopathic hypercalcemia of infancy. J. Pediat. 62: 531 537 (1963). L ig h tw o o d , R.: Idiopathic hypercalcemia with failure to thrive. Proc. rov. Soc. Med. 45: 401 410 (1952). Mc K usick, V.: Mendelian inheritance in man (Johns Hopkins Press. Baltimore 1971). M o rriso n . R. C. and M c N a l l y , H. E.: The spectrum of abnormalities in supravalvular aortic stenosis. Abstract. Amer. J. Cardiol. 19: 143 (1967). S in g let o n , E. B. and D u t t o n , R. V.: Idiopathic hypercalcemia. Semin. Roentgenol. 8: 212-213 (1973). S m ith , D. W.: B l iz z a r d , R. M„ and H arriso n , H. E.: Idiopathic hypercalcemia. A case report with assays of vitamin D in the serum. Pediatrics 24: 258 269 (1959).
