Acta Pzdiatr Scand 65: 487493, 1976
PSEUDOHYPOPARATHYROIDISM A DifficultDiagnosis in Early Childhood E I R I K MONN, JAN BJIbRN OSNES, IVAR @YE and KARL WILHELM WEFRING From the Department of Paediatrics, ~ i k s ~ o s ~ i t a Wniversity lei, of Oslo, Department of Pharmacology, University of Oslo and Department of Paediatrics, Vestfold Sentralsykehus, Tensberg, Norwlay
ABSTRACT. Monn, E., Osnes, J. B., @ye, I. and Wefring, K. W. (Department of Paediatrics, Rikshospitalet, University of Oslo, Department of Pharmacology, University of Oslo and Department of Paediatrics, Vestfold Sentralsykehus, Tonsberg, Norway). Pseudohypoparathyroidism. A difficult diagnosis in early childhood. Acta Paediatr Scand, 65: 487, 1976.-We have studied one adult and three children with pseudohypoparathyroidism and observed that the physical character of short metacarpal bones is not evident in the first 4-5 years of life, that hypocalcaemia and hyperphasphataemia may be absent in the first years of life, but that the renal unresponsiveness to parathyroid hormone can still be demonstrated. Our data confirm earlier observation that in evaluating the renal responsiveness to parathyroid hormone, urinary cyclic AMP is a better parameter than urinary phosphorus. Thus in early childhood, it may be difficult to differentiate between a normal child, a child with pseudohypoparathyroidism and a child with pseudo-pseudohypoparathyroidism unless the renal parathyroid hormone responsiveness is studied. KEY WORDS: Pseudohypoparathyroidism, cyclic AMP, children
In 1942 Albright et al. (1) described the syndrome of pseudohypoparathyroidism (PHP) characterized by the physical characteristics of round face and short, thick-set figure, early epiphyseal closure of some metacarpal or metatarsal bones with resulting shortening of the involved fingers and toes, subcutaneous foci of ectopic calcification and calcium deposits in basal ganglia. The incidence of the different physical characteristics varies ( 1 , 15). In addition, patients with PHP had high serum phosphorus, low serum calcium and showed a blunted phosphaturic response to exogenous parathyroid hormone (PTH) (1). High endogenous serum parathyroid hormone levels have been observed before the hypocalcaemic state is corrected (14).
In 1952 Albright et al. (2) described the syndrome of pseudo-pseudohypoparathyroidism (PPHP) characterized by the four physical signs mentioned above, but with normal serum phosphorus and calcium values. Although Albright’s patient did not respond to exogenous PTH, other studies have shown that patients with PPHP do have a normal renal PTH-response ( 5 , 15). In 1969 Chase et al. demonstrated that the mechanism of action of PTH is mediated through cyclic AMP which in the kidneys causes phosphaturia through a series of unknown intermediate steps. Normal individuals and patients with PPHP or hypoparathyroidism showed a pronounced increase in urinary cyclic AMP after injection of PTH, whereas patients with PHP showed a reduced or absent Acta Pzdiatr Scand 65
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response ( 5 ) . The findings led to the conclusion that the metabolic defect in PHP is a partial o r total lack of the PTH-sensitive receptor/adenyl cyclase complex in renal and/or skeletal tissue. In adults the main physical and biochemical characteristics of the PHP and PPHP syndromes thus are well delineated. Few reports have appeared concerning these syndromes in young children (7, 9, 16). and to our knowledge there is no report on the urinary cyclic AMP response to PTH in children in the first decade. We have had the opportunity of following some patients with such syndromes from early life: one mother, her two daughters and one non-related girl. The purpose of this article is to describe our studies on these 4 patients. Our studies show that in early life it may be difficult to differentiate between a normal child, a child with PHP and a child with PPHP. MATERIALS AND METHODS Controls were 6 patients (age 6 weeks to 13 years) without renal or metabolic disorders, who had indwelling urinary catheters for various reasons (operations for hypospadia, 4; cerebral damage, 2). Informed consent was obtained from all patients. Chemical analyses were done by standard methods. Normal values for alkaline phosphatase: adults less than 270 I.U./l, children less than 750 I.U./l. Urinary cyclic AMP was measured by the protein-binding assay of Gilman as previously described (6). The urine samples were diluted 5-100 times in SO mM sodium acetate buffer (pH 4.0) before assaying. Serum PTH and calcitonin were measured by radio-immunoassay (Dr. Gautvik, Oslo). Normal values: calcitonin less than 0.5 nglml, PTH less than 1.3 ng/ml. The protocols for testing the urinary cyclic AMP response to hormones were as follows. Individuals were fasted from 7 p.m. the previous night. At 7 a.m. they were given 15-20 ml of water/kg perorally, and thereafter about 10 ml of water/kg/hour. Urine samples were collected hourly by spontaneous voiding or by indwelling catheter. After three control specimens were obtained, the hormone was infused.
Parathyroid hormone Parathormon (Lilly) was dissolved in 20 ml of 5 % glucose, and infused intravenously in 10 minutes in an amount of 5 I.U./kg. A maximum dose of 200 I.U. was given. After infusion, urine was collected after 30, 60 and 120 minutes. The same batch of hormone was used in all experiments. Aclu Pzdiutr Scand 65
CASE REPORTS AND RESULTS Putient 1
A woman, born 1937. She had no subjective symptoms of her disease during childhood, and passed high school with average marks. Since puberty she noticed periodically some muscular stiffness and paraesthesiae. She became pregnant in December 1964, developed right-sided cataract in April 1965 and underwent an operation for its removal. Later she developed a moderate left-sided cataract. Two days after delivery in 1965 she noticed moderate involuntary muscular contractions in both arms for a few days. After her daughter (patient 2) was taken to hospital in 1966, the patient was admitted to the medical department. Her height was 159 cm, weight 54 kg, the blood pressure was 120/80. She had a round face, short lateral fingers and some hard small nodules over the sternum and over the left wrist. A biopsy showed osteoma cutis. She had normal haemoglobin, creatinine and serum sodium, potassium and chloride. Serum calcium was 2.7 mEq/l, serum phosphorus 7.0 mg/100 ml, alkaline phosphatase 480 I.U./I. EEG showed generalized dysrhythmia. X-ray of the skeleton showed moderate generalized osteoporosis, calcifications in the basal ganglia of the brain and subcutaneously over sternum, left wrist and in the feet. All metacarpal bones were short (Fig. I ) , and lateral metatarsal bones were short. She received 70000 U. vitamin D, daily since 1966, and calcium and phosphorus values normalized. Since then she has had two normal pregnancies with delivery of a normal healthy girl in 1969 and of patient 3 in 1972. In October 1974 she was admitted to hospital for testing hormone responsiveness. Her serum calcium was 4.7 mEq/l. serum phosphorus 4.8 mgl100 ml and serum PTH 0. I2 ng/ml and serum calcitonin 0.30 ng/ml.
Patient 2
A girl, born September 1965, first child of patient I . She was delivered at term, weight 4080 g, length 53 cm. When she was 2 months old, nodules 1-2 mm in diameter were noticed subcutaneously on the trunk and lower extremities. A biopsy was taken and showed osteoma cutis. She was admitted to the paediatric department at the age of 9 months and was then 74 cm long and weighed 11.7 kg. Except for the osteomas, which later disappeared, the clinical examination was normal, including ophthalmoscopy. She was considered to have normal psychomotor development. She had normal haemoglobin, normal serum creatinine, sodium, potassium and chloride. Serum calcium 4.4 mEq/l, phosphorus 4.7 mgl100 ml, alkaline phosphatase 670 I.U./l. X-ray of the skeleton showed normal findings, including the metacarpal bones, which also appeared normal when she was 20 months old (Fig. 2). The serum calcium and phosphorus values in relation to age were normal until 61 years of age. She was then considered slightly retarded in her psychomotor development. Serum calcium was 3.8 mEq/
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Fig. 1 . X-ray of the hand of patient 1 at 28 years of age.
I , phosphorus 7.8 mg/lOO ml, alkaline phosphatase 890 l.U./I. X-ray of the skeleton now showed short lateral metacarpal bones and the skeleton appeared osteoporotic (Fig. 2). She has received 50000 U. vitamin D2 daily since. Her serum calcium and phosphorus values normalized and she appeared less retarded. In March 1974, when she was 84 years old, serum calcium was 4.4 mEq/l and phosphorus 3.8 mg/lOO ml. Examination of hormone responsiveness was carried out, and was repeated in October 1974 with similar results. Serum calcium was then 4.8 mEq/l, phosphorus 6.5 mg/ 100 ml, PTH 0.1 ng/ml and calcitonin 0.12 ng/ml. She is now in second grade of primary school and is doing well with some supportive teaching. Patient 3 A girl born September 1972, third and youngest daughter of patient 1. A normal delivery at term, length 55 cm, weight 4600 g. Except for a round face the clinical examination was normal, her serum calcium was 4.4 mEq/l and X-ray of the hands showed normal metacarpal bones (Fig. 3). Her serum calcium and phosphorus values remained normal throughout the first year, and she was admitted to the paediatric department in March 1974 for further studies. At 18 months she was slightly hypotonic, but could walk a few steps by herself. She was overweight, 14.5 kg and 76 cm long. X-ray of the skeleton did not reveal
Fig. 2 . X-rays of the hand of patient 2 at different ages. The short lateral metacarpal bones are not evident before 6 years of age. At 9 years of age the skeletal age is 11 years
anything pathological (Fig. 3). Serum calcium was 5.5 mEq/l. The renal response to PTH was measured. This test was repeated in October 1974 with similar results. She was then 24 months old, length 88 cm, weight 18.4 kg. She was considered to have slight psychomotor retardation. No osteoma could be revealed. She had normal EEG, and X-ray of the skeleton was normal (Fig. 3). Serum calcium was 3.8 mEq/l, phosphorus 6.8 mg/lOO ml, alkaline phosphatase 510 I.U./I. Serum PTH was 0.1 nglml and calcitonin 0.14 nglml. Acta Pzdiatr Scand 65
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Fig. 3. X-rays of the hand of patient 3 at different ages. No shortening of metacarpal bones is evident. At 2 years of age the skeletal age is 4 years.
Patient 4 A girl, born December 1967. She is of a healthy family, with three elder siblings. The parents and siblings all have normal serum calcium and phosphorus values, and normal X-rays of the hands. She was delivered at term after a normal pregnancy, length 45 cm, weight 2 450 g. She was admitted to the paediatric department when 5 months old due to transitory diarrhoea. The clinical examination was normal, as were serum calcium and phosphorus and X-ray of the hand (Fig. 4). She developed normally until she was 4 years old when she had convulsions of few minutes’ duration. EEG showed generalized dysrhythmia, and she was given phenytoin. She was admitted to the paediatric department in April 1972. She was 4 years 5 months old, thick-set, 21.8 kg and 100 cm. She had a round face and short lateral fingers. Ophthalmoscopy was normal. The deep tendon reflexes were brisk, and she had a positive Chvostek sign. Haemoglobin was 7995, serum calcium 2.7 mEq/l, phosphorus 9 mg/100 ml, alkaline phosphatase 1150 I.U./I. X-ray of the skeleton showed osteoporosis, subcutaneous calcium deposits in the left foot, and short lateral metacarpal bones (Fig. 4). An EEG showed moderate generalized dysrhythmia. She was given 100000 U. vitamin D, and 500 mg calcium daily, and the phenytoin was continued. She was readmitted in February 1974, when the clinical examination was negative and she was in good condition. Serum calcium was 4.8 mEq/l, phosphorus 4 mg/100 ml, alkaline phosphatase 600 I.U./I. Tests for hormone responsiveness were carried out
DISCUSSION Based on the blunted urinary cyclic AMP response to PTH, all 4 patients are classified as having PHP. Our studies show that the diagnosis of PHP is difficult in early life, and as to the diagnosis, the physical characteristics are less important than the biochemical. The pathogenesis of the former characteristics are also less understood than those of the latter. Although the incidence of the different physical characteristics i,n PHP and PPHP varies, the most classical finding is the abnormally short fourth or fifth metacarpal or metatarsal bones ( 1 , 15). The X-rays of the hand of patient 2, 3 and 4 indicate that in early life the typical shortening of the metacarpal bones is not present, but is evident at about 4 . 5 years of age. Elrick et al. (9) studied one patient and suggested that premature closure
Puruthyroid hormone responsitieness After injection of PTH, all six controls showed a rapid and distinct increase in urinary cyclic AMP, whereas the phosphaturic effect was much more variable (Fig. 5). Compared with the controls, all 4 patients showed a reduced cyclic AMP excretion. Patient I did not respond to PTH at all, whereas patient 4 had the highest response, but well below that of the controls. As to the phosphaturic response, the group of patients were more homogeneous than the controls and on the whole showed a relatively small response. Acta Pzdiutr Scund 65
Fig. 4. X-rays of the hand of patient 4 at different ages. Short metacarpal bones are not present at 5 months of age. At 5 years of age the skeletal age is 6-61 years.
Pseudohypoparathyroidism CONTROLS
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Fig. 5. Effect of parathyroid hormone on the urinary excretion of cyclic AMP and phosphorus in normal controls and in patients with pseudohypoparathyroidism. Each control is marked with different lines. Each patient is marked with different symbols. W: patient 1 . 0 : patient 2. A: patient 3 . x : patient 4. Parathyroid hormone was infused at 0 hours. For details, see text.
of distal epiphyseal lines was the explanation of the short metacarpal and metatarsal bones, and that the first thing observed was a decreased growth in the central parts of the epiphyseal line. Our studies do not allow a conclusion on this problem, neither of the problem of advanced skeletal maturation in PHP (16), which we also observed. From early life, patient 2 had a round face and thick-set stature, subcutaneous osteomas and calcifications. As her serum calcium and phosphorus were normal, she was classified as PPHP, although renal PTH responsiveness was not studied. She later developed hypocalcaemia and hyperphosphataemia. In retrospect she probably had PHP from early life.
491
Except for a round face and thick-set figure, characteristics so common that they are of little significance per se, patient 3 lacks all other physical characteristics of PHP, and would not have been studied further were it not for the family history. She had normal serum calcium but somewhat high phosphorus values, but as she did not respond to PTH with increased urinary cyclic AMP excretion, she was classified as having PHP. Another patient with normocalcaemia and blunted cyclic AMP response to PTH has recently been reported (4), and indicate that hypocalcaemia is secondary in PHP, and may develop during increased calcium demand, i.e. pregnancy and growth ( 11, 15). If patient 3 follows the developmental pattern of her sister (patient 2), she will probably develop hypocalcaemia and more pronounced hyperphosphataemia in time. Hypocalcaemia and hyperphosphataemia in PHP usually develops in the late part of first decade (15). The transition from normocalcaemia to hypercalcaemia in PHP is now well recognized, although the underlying mechanism is not fully understood (11, 12). The presence of hypocalcaemia or normocalcaemia is thus not sufficient for the distinction between PHP and PPHP. In all ages, the diagnosis of PHP or PPHP should not be made unless the PTH response has been studied. Until 1969 the renal PTH response was measured by its phosphaturic effect (Ellsworth-Howard test), and patients with PHP had a blunted response, whereas PPHP behaved like normals. The phosphaturic response, however, is a biochemical parameter of limited value (3, 5 , 19), as also shown by our data. Recently it has been observed that a blunted phosphaturic response to PTH in PHP Type I1 (see below) may be normalized by calcium infusion (17) or by vitamin D therapy (18). The urinary cyclic AMP response to PTH is, however, clearly demonstrable and stable and should be the parameter to be preferred in evaluating renal PTH responsiveness (5, IS, 19). Actu Pzdiatr S c a d 65
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Frame et al. (10) presented data indicating a spectrum of disorders of PHP and they suggested three main syndromes of PHP, here presented in order of decreasing frequency and characterized by ( a ) a renal and skeletal resistance to PTH, ( b ) a renal resistance and skeletal responsiveness to PTH, and ( c ) a renal responsiveness and skeletal resistance to PTH. We have not studied the skeletal responsiveness to repeated injections of PTH in our patients. However, patients 1 , 2 and 4 had high alkaline phosphatases while hypocalcaemic, and although they do not show the classical signs of osteitis fibrosa, they all are distinctly osteoporotic. We therefore believe that our patients have a renal resistance and at least a partial skeletal responsiveness to PTH. The syndrome of PHP with renal responsiveness and skeletal resistance to PTH seems rare, with only two or three documented cases (8, 13, 18). The child reported by Drezner et al. (8) had no physical characteristics of PHP, but hypocalcaemia, hyperphosphataemia, normal urinary cyclic AMP response to PTH, but no phosphaturic response. The adult reported by Rodriguez et al. (17) had similar findings, but physical characteristics of PHP. Both patients showed a skeletal resistance to PTH. Drezner et al. (8) named the condition PHP Type I1 and suggested a pathogenesis of a defect in the sequence of reactions between the cyclic AMP step and the proper renal physiological response (phosphaturia), whereas in the more common PHP, a defect in the renal PTH receptorladenyl cyclase enzyme is suggested (5). A similar pathogenesis like that suggested for PHP Type I1 could also explain the findings of hormone-sensitive adenyl cyclase in a post-mortem kidney from a patient with PHP (13). However, the blunted phosphaturic response to PTH, and the apparently normal adenyl cyclase mechanism cannot be considered sufficient for such an interpretation, Acta Pzdiatr Scand 65
as it h$s been shown that the blunted phosphaturic response of PHP Type I1 may be normalized by calcium infusions (17) and by vitamin D, therapy (18). Thus, it is possible that the syndrome of PHP Type I1 is due to a defective skeletal, but normal renal PTH receptorladenyl cyclase system, and that the blunted phosphaturic response is due to the hypocdcaemic state of these patients. The relation between PHP and PPHP is intriguing. It is well known that PHP and PPHP may occur in the same family (12), and it has been suggested that PPHP is a mild form of PHP (11). This hypothesis is difficult to understand in relation to the difference in urinary cyclic AMP response to PTH in PHP and PPHP ( 5 ) . However, it is tempting to speculate if PPHP might be considered, for some unknown reason, a normocalcaemic variant of PHP Type 11, and thus that the different syndromes of PHP and PPHP could be considered the pleiotrophic effect of a single gene, which may affect the skeletal development, the renal PTH responsiveness and/or the skeletal PTH responsiveness. Further studies are needed to clarify the distinction between these different syndromes. REFERENCES 1 . Albright, F . , Burnett, C . H . , Smith, P. H. & Parson, W.: Pseudohypoparathyroidism-an example of “Seabright-Bantam Syndrome”. Endocrinology, 30: 922, 1942. 2. Albright, F., Forbes, A . P. & Heeneman, P. H.: Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians, 65: 337, 1952. 3. Aurbach, G. D., Marcus, R., Winickoff, R. N., Epstein, E . H. & Nigra, T. P.: Urinary excretion of 3‘. 5‘-AMP in syndromes considered refractory to parathyroid hormone. Metabolism, 19: 799, 1970. 4. Balachander, V . , Pahuja, J. & Collipp, P. J . : Pseudohypoparathyroidism with normal serum calcium level. Am J Dis Child, 129: 1092, 1975. 5. Chase, L. R., Melson, G. L. & Aurbach, G. D.: Pseudohypoparathyroidism: Defective excretion of 3’, 5’-AMP in response to parathyroid hormone. J Clin Invest, 48: 1832, 1%9. 6. Christoffersen, T., Msrland, J., Osnes, J. B. & @ye, I.: Development of cyclic AMP metabolism in rat liver. Biochim Biophys Acta, 313: 338, 1973. 7. Cusmano, J. V . , Baker, D. H. & Finby, N.: Pseudohypoparathyroidism. Radiology, 67: 845, 1956.
Pseudohypoparathyroidism 8. Drezner, M., Neelon, F. A. & Lebovitz, H. E.: Pseudohypoparathyroidism Type 11: A possible
9.
10.
11.
12.
13.
14.
15.
defect in the reception of the cyclic AMP signal. N Engl J Med, 289: 1056, 1973. Elrick, H., Albright, F., Bartter, F. C . , Forbes, A. P. & Reeves, J. D.: Further studies on pseudohypoparathyroidism: Report of four new cases. Acta Endocrinol, 5: 199, 1950. Frame, B., Hanson, C. A., Frost, H. M., Block, M. & Arnstein, A. R.: Renal resistance to parathyroid hormone with osteitis fibrosa. Am J Med, 52:311, 1972. Gershberg, H. & Weseley, A. C.: Pseudohypoparathyroidism and pregnancy. J fediatr, 56: 383, 1960. Mann, J. B., Altermann, S. & Hills, A. G.: Albright’s hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Ann Intern Med, 56: 315, 1962. Marcus, R., Wilber, J. F. & Aurbach, G. D.: Parathyroid hormonesensitive adenyl cyclase from the renal cortex of a patient with pseudohypoparathyroidism. J Clin Endocrinol Metab, 33: 537, 1971. Parfitt, A. M.: Investigation of disorders of the parathyroid glands. Clin Endocrinol Metabol, 3: 451, 1974. Potts, J . T.: Pseudohypoparathyroidism. In Stanbury, J. B . , Wyngaarden, J. B. and Fredricksen,
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D. S . (eds.): The Metabolic Basis of Inherited Disease. McGraw-Hill Book co., New York 1972, p. 1305. 16. Ray, E. W. & Gardner, L. 1.: Pseudo-pseudo-hypoparathyroidism in a child. J fuediatr, 23: 520, 1959. 17. Rodriguez, H. J . , Villarreal, H., Klahr, S . & Slatopolsky, E.: Pseudohypoparathyroidism Type 11: Restoration of normal renal responsiveness to parathyroid hormone by calcium administration. J Clin Endocrinol Metab, 39: 693, 1974. 18. Suh, S. M., Fraser, D. & Kooh, S. W . : Pseudohypoparathyroidism: Responsiveness to parathyroid extract induced by vitamin D, therapy. J Clin Endocrinol Metab, 30: 609, 1970. 19. Tomlingson, S., Barling, P. M., Albano, J. D. M., Brown, B. L . & ORiordan, J. L . H.: The effect of exogenous parathyroid hormone on plasma and urinary adenosine 3’, 5’-cyclic monophosphate in man. Clin Sci Mol Med, 47: 481, 1974. Submitted June 2, 1975 Accepted Jan. 16, 1976 (E. M.) Department of Paediatrics Rikshospitalet Oslo Norway
Acta Pzdiutr Scand 65
PSEUDOHYPOPARATHYROIDISM A DifficultDiagnosis in Early Childhood E I R I K MONN, JAN BJIbRN OSNES, IVAR @YE and KARL WILHELM WEFRING From the Department of Paediatrics, ~ i k s ~ o s ~ i t a Wniversity lei, of Oslo, Department of Pharmacology, University of Oslo and Department of Paediatrics, Vestfold Sentralsykehus, Tensberg, Norwlay
ABSTRACT. Monn, E., Osnes, J. B., @ye, I. and Wefring, K. W. (Department of Paediatrics, Rikshospitalet, University of Oslo, Department of Pharmacology, University of Oslo and Department of Paediatrics, Vestfold Sentralsykehus, Tonsberg, Norway). Pseudohypoparathyroidism. A difficult diagnosis in early childhood. Acta Paediatr Scand, 65: 487, 1976.-We have studied one adult and three children with pseudohypoparathyroidism and observed that the physical character of short metacarpal bones is not evident in the first 4-5 years of life, that hypocalcaemia and hyperphasphataemia may be absent in the first years of life, but that the renal unresponsiveness to parathyroid hormone can still be demonstrated. Our data confirm earlier observation that in evaluating the renal responsiveness to parathyroid hormone, urinary cyclic AMP is a better parameter than urinary phosphorus. Thus in early childhood, it may be difficult to differentiate between a normal child, a child with pseudohypoparathyroidism and a child with pseudo-pseudohypoparathyroidism unless the renal parathyroid hormone responsiveness is studied. KEY WORDS: Pseudohypoparathyroidism, cyclic AMP, children
In 1942 Albright et al. (1) described the syndrome of pseudohypoparathyroidism (PHP) characterized by the physical characteristics of round face and short, thick-set figure, early epiphyseal closure of some metacarpal or metatarsal bones with resulting shortening of the involved fingers and toes, subcutaneous foci of ectopic calcification and calcium deposits in basal ganglia. The incidence of the different physical characteristics varies ( 1 , 15). In addition, patients with PHP had high serum phosphorus, low serum calcium and showed a blunted phosphaturic response to exogenous parathyroid hormone (PTH) (1). High endogenous serum parathyroid hormone levels have been observed before the hypocalcaemic state is corrected (14).
In 1952 Albright et al. (2) described the syndrome of pseudo-pseudohypoparathyroidism (PPHP) characterized by the four physical signs mentioned above, but with normal serum phosphorus and calcium values. Although Albright’s patient did not respond to exogenous PTH, other studies have shown that patients with PPHP do have a normal renal PTH-response ( 5 , 15). In 1969 Chase et al. demonstrated that the mechanism of action of PTH is mediated through cyclic AMP which in the kidneys causes phosphaturia through a series of unknown intermediate steps. Normal individuals and patients with PPHP or hypoparathyroidism showed a pronounced increase in urinary cyclic AMP after injection of PTH, whereas patients with PHP showed a reduced or absent Acta Pzdiatr Scand 65
488
E . Monn et al.
response ( 5 ) . The findings led to the conclusion that the metabolic defect in PHP is a partial o r total lack of the PTH-sensitive receptor/adenyl cyclase complex in renal and/or skeletal tissue. In adults the main physical and biochemical characteristics of the PHP and PPHP syndromes thus are well delineated. Few reports have appeared concerning these syndromes in young children (7, 9, 16). and to our knowledge there is no report on the urinary cyclic AMP response to PTH in children in the first decade. We have had the opportunity of following some patients with such syndromes from early life: one mother, her two daughters and one non-related girl. The purpose of this article is to describe our studies on these 4 patients. Our studies show that in early life it may be difficult to differentiate between a normal child, a child with PHP and a child with PPHP. MATERIALS AND METHODS Controls were 6 patients (age 6 weeks to 13 years) without renal or metabolic disorders, who had indwelling urinary catheters for various reasons (operations for hypospadia, 4; cerebral damage, 2). Informed consent was obtained from all patients. Chemical analyses were done by standard methods. Normal values for alkaline phosphatase: adults less than 270 I.U./l, children less than 750 I.U./l. Urinary cyclic AMP was measured by the protein-binding assay of Gilman as previously described (6). The urine samples were diluted 5-100 times in SO mM sodium acetate buffer (pH 4.0) before assaying. Serum PTH and calcitonin were measured by radio-immunoassay (Dr. Gautvik, Oslo). Normal values: calcitonin less than 0.5 nglml, PTH less than 1.3 ng/ml. The protocols for testing the urinary cyclic AMP response to hormones were as follows. Individuals were fasted from 7 p.m. the previous night. At 7 a.m. they were given 15-20 ml of water/kg perorally, and thereafter about 10 ml of water/kg/hour. Urine samples were collected hourly by spontaneous voiding or by indwelling catheter. After three control specimens were obtained, the hormone was infused.
Parathyroid hormone Parathormon (Lilly) was dissolved in 20 ml of 5 % glucose, and infused intravenously in 10 minutes in an amount of 5 I.U./kg. A maximum dose of 200 I.U. was given. After infusion, urine was collected after 30, 60 and 120 minutes. The same batch of hormone was used in all experiments. Aclu Pzdiutr Scand 65
CASE REPORTS AND RESULTS Putient 1
A woman, born 1937. She had no subjective symptoms of her disease during childhood, and passed high school with average marks. Since puberty she noticed periodically some muscular stiffness and paraesthesiae. She became pregnant in December 1964, developed right-sided cataract in April 1965 and underwent an operation for its removal. Later she developed a moderate left-sided cataract. Two days after delivery in 1965 she noticed moderate involuntary muscular contractions in both arms for a few days. After her daughter (patient 2) was taken to hospital in 1966, the patient was admitted to the medical department. Her height was 159 cm, weight 54 kg, the blood pressure was 120/80. She had a round face, short lateral fingers and some hard small nodules over the sternum and over the left wrist. A biopsy showed osteoma cutis. She had normal haemoglobin, creatinine and serum sodium, potassium and chloride. Serum calcium was 2.7 mEq/l, serum phosphorus 7.0 mg/100 ml, alkaline phosphatase 480 I.U./I. EEG showed generalized dysrhythmia. X-ray of the skeleton showed moderate generalized osteoporosis, calcifications in the basal ganglia of the brain and subcutaneously over sternum, left wrist and in the feet. All metacarpal bones were short (Fig. I ) , and lateral metatarsal bones were short. She received 70000 U. vitamin D, daily since 1966, and calcium and phosphorus values normalized. Since then she has had two normal pregnancies with delivery of a normal healthy girl in 1969 and of patient 3 in 1972. In October 1974 she was admitted to hospital for testing hormone responsiveness. Her serum calcium was 4.7 mEq/l. serum phosphorus 4.8 mgl100 ml and serum PTH 0. I2 ng/ml and serum calcitonin 0.30 ng/ml.
Patient 2
A girl, born September 1965, first child of patient I . She was delivered at term, weight 4080 g, length 53 cm. When she was 2 months old, nodules 1-2 mm in diameter were noticed subcutaneously on the trunk and lower extremities. A biopsy was taken and showed osteoma cutis. She was admitted to the paediatric department at the age of 9 months and was then 74 cm long and weighed 11.7 kg. Except for the osteomas, which later disappeared, the clinical examination was normal, including ophthalmoscopy. She was considered to have normal psychomotor development. She had normal haemoglobin, normal serum creatinine, sodium, potassium and chloride. Serum calcium 4.4 mEq/l, phosphorus 4.7 mgl100 ml, alkaline phosphatase 670 I.U./l. X-ray of the skeleton showed normal findings, including the metacarpal bones, which also appeared normal when she was 20 months old (Fig. 2). The serum calcium and phosphorus values in relation to age were normal until 61 years of age. She was then considered slightly retarded in her psychomotor development. Serum calcium was 3.8 mEq/
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Fig. 1 . X-ray of the hand of patient 1 at 28 years of age.
I , phosphorus 7.8 mg/lOO ml, alkaline phosphatase 890 l.U./I. X-ray of the skeleton now showed short lateral metacarpal bones and the skeleton appeared osteoporotic (Fig. 2). She has received 50000 U. vitamin D2 daily since. Her serum calcium and phosphorus values normalized and she appeared less retarded. In March 1974, when she was 84 years old, serum calcium was 4.4 mEq/l and phosphorus 3.8 mg/lOO ml. Examination of hormone responsiveness was carried out, and was repeated in October 1974 with similar results. Serum calcium was then 4.8 mEq/l, phosphorus 6.5 mg/ 100 ml, PTH 0.1 ng/ml and calcitonin 0.12 ng/ml. She is now in second grade of primary school and is doing well with some supportive teaching. Patient 3 A girl born September 1972, third and youngest daughter of patient 1. A normal delivery at term, length 55 cm, weight 4600 g. Except for a round face the clinical examination was normal, her serum calcium was 4.4 mEq/l and X-ray of the hands showed normal metacarpal bones (Fig. 3). Her serum calcium and phosphorus values remained normal throughout the first year, and she was admitted to the paediatric department in March 1974 for further studies. At 18 months she was slightly hypotonic, but could walk a few steps by herself. She was overweight, 14.5 kg and 76 cm long. X-ray of the skeleton did not reveal
Fig. 2 . X-rays of the hand of patient 2 at different ages. The short lateral metacarpal bones are not evident before 6 years of age. At 9 years of age the skeletal age is 11 years
anything pathological (Fig. 3). Serum calcium was 5.5 mEq/l. The renal response to PTH was measured. This test was repeated in October 1974 with similar results. She was then 24 months old, length 88 cm, weight 18.4 kg. She was considered to have slight psychomotor retardation. No osteoma could be revealed. She had normal EEG, and X-ray of the skeleton was normal (Fig. 3). Serum calcium was 3.8 mEq/l, phosphorus 6.8 mg/lOO ml, alkaline phosphatase 510 I.U./I. Serum PTH was 0.1 nglml and calcitonin 0.14 nglml. Acta Pzdiatr Scand 65
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Fig. 3. X-rays of the hand of patient 3 at different ages. No shortening of metacarpal bones is evident. At 2 years of age the skeletal age is 4 years.
Patient 4 A girl, born December 1967. She is of a healthy family, with three elder siblings. The parents and siblings all have normal serum calcium and phosphorus values, and normal X-rays of the hands. She was delivered at term after a normal pregnancy, length 45 cm, weight 2 450 g. She was admitted to the paediatric department when 5 months old due to transitory diarrhoea. The clinical examination was normal, as were serum calcium and phosphorus and X-ray of the hand (Fig. 4). She developed normally until she was 4 years old when she had convulsions of few minutes’ duration. EEG showed generalized dysrhythmia, and she was given phenytoin. She was admitted to the paediatric department in April 1972. She was 4 years 5 months old, thick-set, 21.8 kg and 100 cm. She had a round face and short lateral fingers. Ophthalmoscopy was normal. The deep tendon reflexes were brisk, and she had a positive Chvostek sign. Haemoglobin was 7995, serum calcium 2.7 mEq/l, phosphorus 9 mg/100 ml, alkaline phosphatase 1150 I.U./I. X-ray of the skeleton showed osteoporosis, subcutaneous calcium deposits in the left foot, and short lateral metacarpal bones (Fig. 4). An EEG showed moderate generalized dysrhythmia. She was given 100000 U. vitamin D, and 500 mg calcium daily, and the phenytoin was continued. She was readmitted in February 1974, when the clinical examination was negative and she was in good condition. Serum calcium was 4.8 mEq/l, phosphorus 4 mg/100 ml, alkaline phosphatase 600 I.U./I. Tests for hormone responsiveness were carried out
DISCUSSION Based on the blunted urinary cyclic AMP response to PTH, all 4 patients are classified as having PHP. Our studies show that the diagnosis of PHP is difficult in early life, and as to the diagnosis, the physical characteristics are less important than the biochemical. The pathogenesis of the former characteristics are also less understood than those of the latter. Although the incidence of the different physical characteristics i,n PHP and PPHP varies, the most classical finding is the abnormally short fourth or fifth metacarpal or metatarsal bones ( 1 , 15). The X-rays of the hand of patient 2, 3 and 4 indicate that in early life the typical shortening of the metacarpal bones is not present, but is evident at about 4 . 5 years of age. Elrick et al. (9) studied one patient and suggested that premature closure
Puruthyroid hormone responsitieness After injection of PTH, all six controls showed a rapid and distinct increase in urinary cyclic AMP, whereas the phosphaturic effect was much more variable (Fig. 5). Compared with the controls, all 4 patients showed a reduced cyclic AMP excretion. Patient I did not respond to PTH at all, whereas patient 4 had the highest response, but well below that of the controls. As to the phosphaturic response, the group of patients were more homogeneous than the controls and on the whole showed a relatively small response. Acta Pzdiutr Scund 65
Fig. 4. X-rays of the hand of patient 4 at different ages. Short metacarpal bones are not present at 5 months of age. At 5 years of age the skeletal age is 6-61 years.
Pseudohypoparathyroidism CONTROLS
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Fig. 5. Effect of parathyroid hormone on the urinary excretion of cyclic AMP and phosphorus in normal controls and in patients with pseudohypoparathyroidism. Each control is marked with different lines. Each patient is marked with different symbols. W: patient 1 . 0 : patient 2. A: patient 3 . x : patient 4. Parathyroid hormone was infused at 0 hours. For details, see text.
of distal epiphyseal lines was the explanation of the short metacarpal and metatarsal bones, and that the first thing observed was a decreased growth in the central parts of the epiphyseal line. Our studies do not allow a conclusion on this problem, neither of the problem of advanced skeletal maturation in PHP (16), which we also observed. From early life, patient 2 had a round face and thick-set stature, subcutaneous osteomas and calcifications. As her serum calcium and phosphorus were normal, she was classified as PPHP, although renal PTH responsiveness was not studied. She later developed hypocalcaemia and hyperphosphataemia. In retrospect she probably had PHP from early life.
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Except for a round face and thick-set figure, characteristics so common that they are of little significance per se, patient 3 lacks all other physical characteristics of PHP, and would not have been studied further were it not for the family history. She had normal serum calcium but somewhat high phosphorus values, but as she did not respond to PTH with increased urinary cyclic AMP excretion, she was classified as having PHP. Another patient with normocalcaemia and blunted cyclic AMP response to PTH has recently been reported (4), and indicate that hypocalcaemia is secondary in PHP, and may develop during increased calcium demand, i.e. pregnancy and growth ( 11, 15). If patient 3 follows the developmental pattern of her sister (patient 2), she will probably develop hypocalcaemia and more pronounced hyperphosphataemia in time. Hypocalcaemia and hyperphosphataemia in PHP usually develops in the late part of first decade (15). The transition from normocalcaemia to hypercalcaemia in PHP is now well recognized, although the underlying mechanism is not fully understood (11, 12). The presence of hypocalcaemia or normocalcaemia is thus not sufficient for the distinction between PHP and PPHP. In all ages, the diagnosis of PHP or PPHP should not be made unless the PTH response has been studied. Until 1969 the renal PTH response was measured by its phosphaturic effect (Ellsworth-Howard test), and patients with PHP had a blunted response, whereas PPHP behaved like normals. The phosphaturic response, however, is a biochemical parameter of limited value (3, 5 , 19), as also shown by our data. Recently it has been observed that a blunted phosphaturic response to PTH in PHP Type I1 (see below) may be normalized by calcium infusion (17) or by vitamin D therapy (18). The urinary cyclic AMP response to PTH is, however, clearly demonstrable and stable and should be the parameter to be preferred in evaluating renal PTH responsiveness (5, IS, 19). Actu Pzdiatr S c a d 65
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Frame et al. (10) presented data indicating a spectrum of disorders of PHP and they suggested three main syndromes of PHP, here presented in order of decreasing frequency and characterized by ( a ) a renal and skeletal resistance to PTH, ( b ) a renal resistance and skeletal responsiveness to PTH, and ( c ) a renal responsiveness and skeletal resistance to PTH. We have not studied the skeletal responsiveness to repeated injections of PTH in our patients. However, patients 1 , 2 and 4 had high alkaline phosphatases while hypocalcaemic, and although they do not show the classical signs of osteitis fibrosa, they all are distinctly osteoporotic. We therefore believe that our patients have a renal resistance and at least a partial skeletal responsiveness to PTH. The syndrome of PHP with renal responsiveness and skeletal resistance to PTH seems rare, with only two or three documented cases (8, 13, 18). The child reported by Drezner et al. (8) had no physical characteristics of PHP, but hypocalcaemia, hyperphosphataemia, normal urinary cyclic AMP response to PTH, but no phosphaturic response. The adult reported by Rodriguez et al. (17) had similar findings, but physical characteristics of PHP. Both patients showed a skeletal resistance to PTH. Drezner et al. (8) named the condition PHP Type I1 and suggested a pathogenesis of a defect in the sequence of reactions between the cyclic AMP step and the proper renal physiological response (phosphaturia), whereas in the more common PHP, a defect in the renal PTH receptorladenyl cyclase enzyme is suggested (5). A similar pathogenesis like that suggested for PHP Type I1 could also explain the findings of hormone-sensitive adenyl cyclase in a post-mortem kidney from a patient with PHP (13). However, the blunted phosphaturic response to PTH, and the apparently normal adenyl cyclase mechanism cannot be considered sufficient for such an interpretation, Acta Pzdiatr Scand 65
as it h$s been shown that the blunted phosphaturic response of PHP Type I1 may be normalized by calcium infusions (17) and by vitamin D, therapy (18). Thus, it is possible that the syndrome of PHP Type I1 is due to a defective skeletal, but normal renal PTH receptorladenyl cyclase system, and that the blunted phosphaturic response is due to the hypocdcaemic state of these patients. The relation between PHP and PPHP is intriguing. It is well known that PHP and PPHP may occur in the same family (12), and it has been suggested that PPHP is a mild form of PHP (11). This hypothesis is difficult to understand in relation to the difference in urinary cyclic AMP response to PTH in PHP and PPHP ( 5 ) . However, it is tempting to speculate if PPHP might be considered, for some unknown reason, a normocalcaemic variant of PHP Type 11, and thus that the different syndromes of PHP and PPHP could be considered the pleiotrophic effect of a single gene, which may affect the skeletal development, the renal PTH responsiveness and/or the skeletal PTH responsiveness. Further studies are needed to clarify the distinction between these different syndromes. REFERENCES 1 . Albright, F . , Burnett, C . H . , Smith, P. H. & Parson, W.: Pseudohypoparathyroidism-an example of “Seabright-Bantam Syndrome”. Endocrinology, 30: 922, 1942. 2. Albright, F., Forbes, A . P. & Heeneman, P. H.: Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians, 65: 337, 1952. 3. Aurbach, G. D., Marcus, R., Winickoff, R. N., Epstein, E . H. & Nigra, T. P.: Urinary excretion of 3‘. 5‘-AMP in syndromes considered refractory to parathyroid hormone. Metabolism, 19: 799, 1970. 4. Balachander, V . , Pahuja, J. & Collipp, P. J . : Pseudohypoparathyroidism with normal serum calcium level. Am J Dis Child, 129: 1092, 1975. 5. Chase, L. R., Melson, G. L. & Aurbach, G. D.: Pseudohypoparathyroidism: Defective excretion of 3’, 5’-AMP in response to parathyroid hormone. J Clin Invest, 48: 1832, 1%9. 6. Christoffersen, T., Msrland, J., Osnes, J. B. & @ye, I.: Development of cyclic AMP metabolism in rat liver. Biochim Biophys Acta, 313: 338, 1973. 7. Cusmano, J. V . , Baker, D. H. & Finby, N.: Pseudohypoparathyroidism. Radiology, 67: 845, 1956.
Pseudohypoparathyroidism 8. Drezner, M., Neelon, F. A. & Lebovitz, H. E.: Pseudohypoparathyroidism Type 11: A possible
9.
10.
11.
12.
13.
14.
15.
defect in the reception of the cyclic AMP signal. N Engl J Med, 289: 1056, 1973. Elrick, H., Albright, F., Bartter, F. C . , Forbes, A. P. & Reeves, J. D.: Further studies on pseudohypoparathyroidism: Report of four new cases. Acta Endocrinol, 5: 199, 1950. Frame, B., Hanson, C. A., Frost, H. M., Block, M. & Arnstein, A. R.: Renal resistance to parathyroid hormone with osteitis fibrosa. Am J Med, 52:311, 1972. Gershberg, H. & Weseley, A. C.: Pseudohypoparathyroidism and pregnancy. J fediatr, 56: 383, 1960. Mann, J. B., Altermann, S. & Hills, A. G.: Albright’s hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Ann Intern Med, 56: 315, 1962. Marcus, R., Wilber, J. F. & Aurbach, G. D.: Parathyroid hormonesensitive adenyl cyclase from the renal cortex of a patient with pseudohypoparathyroidism. J Clin Endocrinol Metab, 33: 537, 1971. Parfitt, A. M.: Investigation of disorders of the parathyroid glands. Clin Endocrinol Metabol, 3: 451, 1974. Potts, J . T.: Pseudohypoparathyroidism. In Stanbury, J. B . , Wyngaarden, J. B. and Fredricksen,
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D. S . (eds.): The Metabolic Basis of Inherited Disease. McGraw-Hill Book co., New York 1972, p. 1305. 16. Ray, E. W. & Gardner, L. 1.: Pseudo-pseudo-hypoparathyroidism in a child. J fuediatr, 23: 520, 1959. 17. Rodriguez, H. J . , Villarreal, H., Klahr, S . & Slatopolsky, E.: Pseudohypoparathyroidism Type 11: Restoration of normal renal responsiveness to parathyroid hormone by calcium administration. J Clin Endocrinol Metab, 39: 693, 1974. 18. Suh, S. M., Fraser, D. & Kooh, S. W . : Pseudohypoparathyroidism: Responsiveness to parathyroid extract induced by vitamin D, therapy. J Clin Endocrinol Metab, 30: 609, 1970. 19. Tomlingson, S., Barling, P. M., Albano, J. D. M., Brown, B. L . & ORiordan, J. L . H.: The effect of exogenous parathyroid hormone on plasma and urinary adenosine 3’, 5’-cyclic monophosphate in man. Clin Sci Mol Med, 47: 481, 1974. Submitted June 2, 1975 Accepted Jan. 16, 1976 (E. M.) Department of Paediatrics Rikshospitalet Oslo Norway
Acta Pzdiutr Scand 65
