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Zinc deficiency in achondroplastic children and their parents
Volume 94 Number 4
Brief clinical and laboratory observations
609
Zinc deficiency in achondroplastic children and their parents P. J. Collipp, S. Y. Chen, V. T. Maddaiah, S. Amin, and M. Castro-Magana, East Meadow, N. Y.
HUMAN ACHONDROPLASIA is inherited as a simple autosomal dominant trait. Approximately 80% of new cases result from mutations, 1 and increased parental age is associated with the birth of achondroplastic children, z Infertility and increased fetal and perinatal mortality contribute to the fact that most cases originate by mutation rather than as children of parents who have achondroplasia?
METHODS
AND RESULTS
Using atomic absorption spectrophotometry, we have assayed zinc and copper concentrations in the hair of children with typical achondroplasia, familial short stature, or constitutional growth delay, and of unaffected parents of achondroplastic children and healthy adults of similar age and sex as the parents (Table). Specimens consisted of the terminal 2 to 3 inches o f hair, obtained from the posterior scalp. Duplicate 60 to 80 mg hair specimens were digested in concentrated nitric:perchloric (3:1) acid mixture. The results are the mean of at least two determinations per specimen. The achondroplastic children were all confirmed as typical examples by physical examination and radiographs of skull, spine, long bones, and pelvis. Several of the parents were noted to have white flecks in their fingernails, which has been reported to be associated with zinc deficiency. The data indicate significantly reduced zinc and increased copper values, and reduced zinc:copper ratio, in the hair of parents and children with achondroplasia. DISCUSSION Congenital hydrocephalus and other anomalies associated with maternal zinc deficiency in rats has been reported to result from deficiency throughout pregnancy as well as from transitory deficiencies limited to a few days during gestation. '-6 Short periods of zinc deficiency result in a rapid fall of zinc levels in maternal blood plasma, since pregnant rats cannot mobilize zinc from body tissues in amounts sufficient to supply the needs of the fetuses. Human ~chondroplasia is consistently associated with increased head circumference, which has recently been documented to result from hydrocephalus. 7 Zinc concentration of human serum declines with advancing age) The possibility that human congenital malformaFrom the Department of Pediatrics, Nassau County Medical Center.
0022-3476/79/400609+02500.20/0 9 1979 The C. V. Mosby Co.
Table. Hair zinc and copper concentration ~ g / g m ) Age (mean)
Normal adults (38) Achondroplasia Parents (27) With children (11) Constitutional
Zn
Cu
I
Zn/Cu
42
185.9 -+ 40.0 37.9 - 24
39
161.8 -+ 31.5" 42.4 --- 24.1
3.8*
9
130.0 +- 50.2* 48.3 +-- 12.8"
2'.7*
12
162.7 -+ 32.6
12
179.6+ 27.3
4.9
growth delay (109) Familial short stature (43)
-
*P < 0.01 differentfrom normal adults and children. tions may result from maternal zinc depletion was suggested by Hambidge et al. 9 Immune deficiency has been reported as an occasional problem in children with achondroplasia, and has been associated with zinc deficiency also. Glucose intolerance has been reported to be associated with zinc deficiency'~ and we have reported glucose intolerance and increased plasma free fatty acids in children with achondroplasia. 11 The association between growth retardation and zinc deficiency in children was first reported by Prasad et al. ~2 Infertility and hypogonadism are well-established complications of chronic zinc deficiency which are also associated with achondroplasia. The role of zinc as an essential trace element, as a cofactor in more than 70 metalloenzymes and its role in the biochemical and morphologic events of the cell cycle, have been reported elsewhere. In summary, normal parents of children with achondroplasia have significantly reduced zinc and increased copper concentration in their hair, suggesting that zinc deficiency may be a contributing factor in the pathogenesis of this mutation. Zinc deficiency may also contribute to some of the problems associated with the condition after the mutation has occurred. REFERENCES
1. Bailey JA: Disproportionate short stature, Philadelphia, 1973, W B Saunders Company. 2. Collipp PJ, Gupta K, and Belier E: Parental age and achondroplasia, NY State J Med 76:1810, 1976. 3. Johnston FE: Achondroplastic dwarfs through history, Clin Pediatr 2:703, 1963.
6 10
Brief clinical and laboratory observations
4. Adeloye A, and Warkany J: Experimental congenital hydrocephalus, Childs Brain 2:325, 1976. 5. Hurley LS, Gowan J, and Swenerton H: Teratogenic effects of short-term and transitory zinc deficiency in rats, Teratology 4:199, 1971. 6. Warkany J, and Petering HG: Congenital malformations of the brain produced by short zinc deficiencies in rats, Am J Ment Defic 77:645, 1973. 7. Mueller S, Bell W, Cornell S, Hamsher K, and Dolan K: Achondroplasia and hydrocephalus, Neurology 27:430, 1977. 8. Chooi MK, Todd JK, and Boyd ND: Influence of age and sex on plasma zinc levels in normal and diabetic individuals, Nutr Metab 20:135, 1976.
The Journal of Pediatrics April 1979
9. Hambidge KM, Nelner KH, and Walravens PA: Zinc acrodermatitis enteropathica, and congenital malformations, Lancet 2:577, 1975. 10. Hendricks DG, and Mahoney AW: Glucose tolerance in zinc deficient rats, J Nutr 102:1078, 1972. 11. Collipp PJ, Sharma RK, Thomas J, Maddaiah VT, and Chen SY: Abnormal glucose tolerance in children with achondroplasia, Am J Dis Child 124:682, 1972. 12. Prasad AS, Halsted JA, and Nadimi M: Syndrome of iron deficiency dwarfism, and geophagia, Am J Med 31:532, 1961.
Vascular ring presenting as asthma." The value of a flow-volume curve Michael L. Loren, M.D.,* Richard L. Cooley, M.D., Candice Rohr, M.D., and Richard O. Buck, M.D., Denver, Colo. Tt~E FOLLOWING CASE REPORT demonstrates the value of a flow-volume curve in making the diagnosis o f a vascular ring in a child with Wheezing and recurrent pneumonias.
Table, demonstrated both large and small airway obstruction, with minimal response to isoproterenol, The expiratory flowvolume curve is pictured in Figure, B. The flow rates and time constants are also listed in the Table.
CASE REPORT Patient P.A. was an 8-year-old boy with a history of wheezing beginning at 3 years of age following an episode of flulike symptoms. After upper respiratory tract symptoms, he would develop coughing and wheezing which responded partially to theophylline preparations and beta-2-agonists. From the age of 6, there were six hospitalizations for pneumonia, usually beginning in the left or right lower lung lobes and associated with fever, wheezing, and coughing. Symptoms resolved with the use of antibiotics and bronchodilators. There was no history of ear or sinus infections. The mother has a history of season allergic rhinitis. The child was referred to the National Asthma Center for further evaluation. A physical examination demonstrated mild wheezing on forced expiration and a prolonged expiratory time. Following the inhalation of 2.4 mg of methacholine, there was no change in pulmonary function? The hematocrit was 39%. IgG was 540 mg/dl (normal range 559 to 1,590); IgA, 45 mg/dl (normal 46 to 332); IgM, 50 mg/dl (normal 27 to 214). Prick skin tests to inhalants were negative. Spirometry and plethysmography were done with an Ohio 840 Spirometer and an Ohio 3000 body plethysmograph. Flow-volume curves were generated by an in-line computer. Standard pulmonary functions, listed in the From The National Asthma Center, Division of Medicine, and the University of Colorado, Department of Pediatrics. *Reprint address: 1999 Julian St., Denver. CO 80204.
Abbreviations used F/V: flow volume MEFR 25% VC: maximum expiratory flow rate of 25% at vital capacity
After reviewing the F/V curve, it was postulated that the patient might have an intrathoracie obstruction. Repeat physical examination demonstrated a blood pressure of 110/80 in the right arm with a palpable systolic pressure of 80 in the left arm. Radial pulses were thought to be either equal or slightly less in the left arm. Chest roentgenogram demonstrated a right aortic arch. A barium esophagogram revealed an indentation in the posterior esophagus. An air tracheobronchogram did not demonstrate tracheal compression, Angiograms and corrective surgery, done later at Hospital Sainte Justine in Montreal, demonstrated a vascular ring which consisted of a right aortic arch and a left ligamentum arteriosum. Following the operation, the patient has been free of infections and wheezing symptoms for 12 months. DISCUSSION The flow-volume curve is a useful pictorial demonstration of airway obstruction. A b n o r m a l patterns o f air obstruction, such as from tumors, tracheal stenosis, and chronic obstructive lung disease, have been described.~. 3 At our institution, F / V curves are done routinely on all
0022-3476/79/400610+02500.20/0
9 1979 The C. V. Mosby Co.
Brief clinical and laboratory observations
609
Zinc deficiency in achondroplastic children and their parents P. J. Collipp, S. Y. Chen, V. T. Maddaiah, S. Amin, and M. Castro-Magana, East Meadow, N. Y.
HUMAN ACHONDROPLASIA is inherited as a simple autosomal dominant trait. Approximately 80% of new cases result from mutations, 1 and increased parental age is associated with the birth of achondroplastic children, z Infertility and increased fetal and perinatal mortality contribute to the fact that most cases originate by mutation rather than as children of parents who have achondroplasia?
METHODS
AND RESULTS
Using atomic absorption spectrophotometry, we have assayed zinc and copper concentrations in the hair of children with typical achondroplasia, familial short stature, or constitutional growth delay, and of unaffected parents of achondroplastic children and healthy adults of similar age and sex as the parents (Table). Specimens consisted of the terminal 2 to 3 inches o f hair, obtained from the posterior scalp. Duplicate 60 to 80 mg hair specimens were digested in concentrated nitric:perchloric (3:1) acid mixture. The results are the mean of at least two determinations per specimen. The achondroplastic children were all confirmed as typical examples by physical examination and radiographs of skull, spine, long bones, and pelvis. Several of the parents were noted to have white flecks in their fingernails, which has been reported to be associated with zinc deficiency. The data indicate significantly reduced zinc and increased copper values, and reduced zinc:copper ratio, in the hair of parents and children with achondroplasia. DISCUSSION Congenital hydrocephalus and other anomalies associated with maternal zinc deficiency in rats has been reported to result from deficiency throughout pregnancy as well as from transitory deficiencies limited to a few days during gestation. '-6 Short periods of zinc deficiency result in a rapid fall of zinc levels in maternal blood plasma, since pregnant rats cannot mobilize zinc from body tissues in amounts sufficient to supply the needs of the fetuses. Human ~chondroplasia is consistently associated with increased head circumference, which has recently been documented to result from hydrocephalus. 7 Zinc concentration of human serum declines with advancing age) The possibility that human congenital malformaFrom the Department of Pediatrics, Nassau County Medical Center.
0022-3476/79/400609+02500.20/0 9 1979 The C. V. Mosby Co.
Table. Hair zinc and copper concentration ~ g / g m ) Age (mean)
Normal adults (38) Achondroplasia Parents (27) With children (11) Constitutional
Zn
Cu
I
Zn/Cu
42
185.9 -+ 40.0 37.9 - 24
39
161.8 -+ 31.5" 42.4 --- 24.1
3.8*
9
130.0 +- 50.2* 48.3 +-- 12.8"
2'.7*
12
162.7 -+ 32.6
12
179.6+ 27.3
4.9
growth delay (109) Familial short stature (43)
-
*P < 0.01 differentfrom normal adults and children. tions may result from maternal zinc depletion was suggested by Hambidge et al. 9 Immune deficiency has been reported as an occasional problem in children with achondroplasia, and has been associated with zinc deficiency also. Glucose intolerance has been reported to be associated with zinc deficiency'~ and we have reported glucose intolerance and increased plasma free fatty acids in children with achondroplasia. 11 The association between growth retardation and zinc deficiency in children was first reported by Prasad et al. ~2 Infertility and hypogonadism are well-established complications of chronic zinc deficiency which are also associated with achondroplasia. The role of zinc as an essential trace element, as a cofactor in more than 70 metalloenzymes and its role in the biochemical and morphologic events of the cell cycle, have been reported elsewhere. In summary, normal parents of children with achondroplasia have significantly reduced zinc and increased copper concentration in their hair, suggesting that zinc deficiency may be a contributing factor in the pathogenesis of this mutation. Zinc deficiency may also contribute to some of the problems associated with the condition after the mutation has occurred. REFERENCES
1. Bailey JA: Disproportionate short stature, Philadelphia, 1973, W B Saunders Company. 2. Collipp PJ, Gupta K, and Belier E: Parental age and achondroplasia, NY State J Med 76:1810, 1976. 3. Johnston FE: Achondroplastic dwarfs through history, Clin Pediatr 2:703, 1963.
6 10
Brief clinical and laboratory observations
4. Adeloye A, and Warkany J: Experimental congenital hydrocephalus, Childs Brain 2:325, 1976. 5. Hurley LS, Gowan J, and Swenerton H: Teratogenic effects of short-term and transitory zinc deficiency in rats, Teratology 4:199, 1971. 6. Warkany J, and Petering HG: Congenital malformations of the brain produced by short zinc deficiencies in rats, Am J Ment Defic 77:645, 1973. 7. Mueller S, Bell W, Cornell S, Hamsher K, and Dolan K: Achondroplasia and hydrocephalus, Neurology 27:430, 1977. 8. Chooi MK, Todd JK, and Boyd ND: Influence of age and sex on plasma zinc levels in normal and diabetic individuals, Nutr Metab 20:135, 1976.
The Journal of Pediatrics April 1979
9. Hambidge KM, Nelner KH, and Walravens PA: Zinc acrodermatitis enteropathica, and congenital malformations, Lancet 2:577, 1975. 10. Hendricks DG, and Mahoney AW: Glucose tolerance in zinc deficient rats, J Nutr 102:1078, 1972. 11. Collipp PJ, Sharma RK, Thomas J, Maddaiah VT, and Chen SY: Abnormal glucose tolerance in children with achondroplasia, Am J Dis Child 124:682, 1972. 12. Prasad AS, Halsted JA, and Nadimi M: Syndrome of iron deficiency dwarfism, and geophagia, Am J Med 31:532, 1961.
Vascular ring presenting as asthma." The value of a flow-volume curve Michael L. Loren, M.D.,* Richard L. Cooley, M.D., Candice Rohr, M.D., and Richard O. Buck, M.D., Denver, Colo. Tt~E FOLLOWING CASE REPORT demonstrates the value of a flow-volume curve in making the diagnosis o f a vascular ring in a child with Wheezing and recurrent pneumonias.
Table, demonstrated both large and small airway obstruction, with minimal response to isoproterenol, The expiratory flowvolume curve is pictured in Figure, B. The flow rates and time constants are also listed in the Table.
CASE REPORT Patient P.A. was an 8-year-old boy with a history of wheezing beginning at 3 years of age following an episode of flulike symptoms. After upper respiratory tract symptoms, he would develop coughing and wheezing which responded partially to theophylline preparations and beta-2-agonists. From the age of 6, there were six hospitalizations for pneumonia, usually beginning in the left or right lower lung lobes and associated with fever, wheezing, and coughing. Symptoms resolved with the use of antibiotics and bronchodilators. There was no history of ear or sinus infections. The mother has a history of season allergic rhinitis. The child was referred to the National Asthma Center for further evaluation. A physical examination demonstrated mild wheezing on forced expiration and a prolonged expiratory time. Following the inhalation of 2.4 mg of methacholine, there was no change in pulmonary function? The hematocrit was 39%. IgG was 540 mg/dl (normal range 559 to 1,590); IgA, 45 mg/dl (normal 46 to 332); IgM, 50 mg/dl (normal 27 to 214). Prick skin tests to inhalants were negative. Spirometry and plethysmography were done with an Ohio 840 Spirometer and an Ohio 3000 body plethysmograph. Flow-volume curves were generated by an in-line computer. Standard pulmonary functions, listed in the From The National Asthma Center, Division of Medicine, and the University of Colorado, Department of Pediatrics. *Reprint address: 1999 Julian St., Denver. CO 80204.
Abbreviations used F/V: flow volume MEFR 25% VC: maximum expiratory flow rate of 25% at vital capacity
After reviewing the F/V curve, it was postulated that the patient might have an intrathoracie obstruction. Repeat physical examination demonstrated a blood pressure of 110/80 in the right arm with a palpable systolic pressure of 80 in the left arm. Radial pulses were thought to be either equal or slightly less in the left arm. Chest roentgenogram demonstrated a right aortic arch. A barium esophagogram revealed an indentation in the posterior esophagus. An air tracheobronchogram did not demonstrate tracheal compression, Angiograms and corrective surgery, done later at Hospital Sainte Justine in Montreal, demonstrated a vascular ring which consisted of a right aortic arch and a left ligamentum arteriosum. Following the operation, the patient has been free of infections and wheezing symptoms for 12 months. DISCUSSION The flow-volume curve is a useful pictorial demonstration of airway obstruction. A b n o r m a l patterns o f air obstruction, such as from tumors, tracheal stenosis, and chronic obstructive lung disease, have been described.~. 3 At our institution, F / V curves are done routinely on all
0022-3476/79/400610+02500.20/0
9 1979 The C. V. Mosby Co.