Hypoparathyroidism and pseudohypoparathyroidism in childhood

9 Hypoparathyroidism and Pseudohypoparathyroidism in Childhood DENIS DANEMAN SANG WHAY KOOH DONALD FRASER

The parathyroid glands arise as endodermal derivatives from the third and fourth branchial pouches. The superior glands come from the fourth branchial cleft and attach to the posterior aspect of the thyroid capsule, while the inferior ones, from the third pouch, lie below the lower pole of the thyroid. However, other positions of the parathyroids, particularly in the anterior mediastinum, are not uncommon. Parathyroid hormone (PTH) is the secretory product of the chief cells, being synthesized in the cells as a large molecule, preproparathyroid hormone. After two cleavage steps pTH, with a molecular weight of 9500, is secreted into the circulation where it is further cleaved into active and inactive fragments (Habener et al, 1976). The smaller of these fragments, containing 34 amino acids and starting at the amino terminal end, possesses the full physiological activity of PTH. These specific cleavage steps may serve as points of metabolic control regulating both the amount of biologically active hormone available for secretion and the concentration of circulating active peptides. The concentration of calcium ion in the fluid perfusing the parathyroid glands constitutes the major controlling factor in determining the rate of PTH secretion (Rasmussen, 1971). A decrease in ionized calcium stimulates both synthesis and secretion of PTH, while an increase inhibits both processes. In addition to calcium ion concentration, PTH secretion may also be controlled by the concentration of 1,25-dihydroxyvitamin D (Rasmussen and Feinblatt, 1971; DeLuca, 1980; Fraser, 1980). The biological action of PTH is mediated at a cellular level by 3'5' (cyclic) adenosine monophosphate (cAMP) (Chase and Aurbach, 1967). This mechanism applies to many other peptide hormones, including calcitonin, and the biogenic amines. Although many aspects of this action remain to be elucidated, the following summarizes the currently accepted mode of action of cAMP-mediated hormones. Most hormones that act at the cell surface interact with this system to stimulate the production of cAMP. The Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 11, No. 1, March 1982.

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D. DANEMAN, S. W. KOOHAND D. FRASER

hormone is recognized by and bound to its specific membrane-bound protein receptors which usually have high affinity, but limited capacity, for the hormone. The hormone-receptor complex in turn acts on a coupling protein (N- or G-protein), a newly recognized component linking the receptor to adenylate cyclase. The N-protein itself is inactive unless it is bound to guanosine triphosphate (GTP) (Pfeuffer, 1977; Rodbell, 1980). This binding is facilitated by the interaction between the hormone--receptor complex on the one hand and N-protein on the other. GTP-bound N-protein is then able to stimulate adenylate cyclase activity, which catalyses the conversion of adenosine triphosphate (ATP) to cAMP. This reaction chain is schematically represented in Figure 1. The means by which cAMP mediates the spectrum of hormonal effects is uncertain, but phosphorylating enzymes (protein kinases) are certainly involved (Nimmo and Cohen, 1972). Specificity of hormone action resides in the receptor protein. The other components of the chain are common to all hormonal processes mediated by cAMP. PTH has five major effects which either directly or indirectly impact upon every process involved in formation and resorption of the skeleton. These are briefly:

P ~ ~GT A P T cAMP Figure 1. Postulatedmechanismof cAMP-mediatedPTH response. 1. Renal phosphate excretion: PTH simultaneously reduces resorption of sodium, calcium, phosphate and bicarbonate in the proximal renal tubule. The effect on sodium is not of major significance, but the net result is a substantial phosphaturia accompanied by increased bicarbonate excretion (Hellman, Au and Bartter, 1965; Agus et al, 1971). 2. Bone resorption: PTH accelerates bone breakdown. This is the most well-known action of the hormone, but it forms only part of an extremely complex bone response with anabolic as well as catabolic elements (Parsons, 1979). 3. Renal calcium retention: calcium reabsorption is reduced by PTH acting on the proximal tubule. However, resorption by the distal tubule is markedly enhanced and this is the predominant effect (Nordin and Peacock, 1969).

HYPOPARATHYRO1DISM AND PSEUDOHYPOPARATHYROIDISM

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4. Intestinal calcium absorption: P T H has an indirect effect on calcium

absorption in the intestine by mediating changes in the rate of renal conversion of 25-hydroxy- to la,25-dihydroxyvitamin D (1,25-(OH)2D) (De Luca, 1980; Fraser, 1980). This effect is slow, but nevertheless sensitive and specific. 5. B o n e f o r m a t i o n : this remains a controversial subject, though recent literature strongly supports its significance (Parsons, 1979). C L A S S I F I C A T I O N OF H Y P O P A R A T H Y R O I D I S M IN N E O N A T E S AND C H I L D R E N Deficient parathyroid function in childhood can be divided as follows: first, conditions that are associated with failure of appropriate secretion o f P T H in response to the usual stimuli (hypoparathyroidism), and, secondly, Conditions associated with defective end-organ responsiveness to P T H (pseudohypoparathyroidism). The incidence of permanent hypoparathyroidism and pseudohypoparathyroidism is low. The experience over a 14-year period (1962 to 1976) in the metabolic clinic of the Hospital for Sick Children, Toronto is summarized in Table 1. There are specific age-related conditions, particularly in the neonatal period, to be considered. Table 2 lists the classification and c o m m o n clinical features of the conditions discussed below. Table 1. Incidence of permanent hypoparathyroidism and pseudohypoparathyroidism at the

Hospital for Sick Children, Toronto (1962-1976)

A. Permanent hypoparathyroidism 1. Isolated (a) neonatal onset (b) childhood onset 2. Associated with other endocrine deficiencies and autoimmune disease 3. DiGeorge syndrome (complete and incomplete) 4. Post-thyroidectomy hypoparathyroidism 5. Secondary to thalassaemia major Total

4 8 9 5 5 2 33

B. Pseudohypoparathyroidism 1. Type I -- with AHO a - - without AHO 2. Type II

6 4 1

Total

11

aAHO Albright's hereditary osteodystrophy Neonatal

Hypocaicaemia

This is the most prevalent type of parathyroid disorder encountered in paediatrics. To understand its pathophysiology, a short s u m m a r y of perinatal calcium and phosphate homeostasis is required. At term, the bones o f the infant skeleton are well mineralized. To accomplish this a large part of the infant's skeletal calcium is transferred to the fetus across the placenta during the last trimester of pregnancy. The placenta serves as an active calcium ' p u m p ' during this phase; both total

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and ionized calcium concentrations in the fetal plasma are approximately 10 per cent higher than those in maternal plasma. At delivery the fetus needs to begin acquiring calcium via its own gastrointestinal tract. In the normal full-term infant, plasma calcium concentrations decrease somewhat during the first one to three days after birth, reaching values as low as 1.75 to 2.1 mmol/1 (7.0 to 8.5 mg/dl). The nadir depends partly on the particular feeding regimen employed. The level then slowly rises to normal by four to five days of age. This transition is not usually associated with symptoms of hypocalcaemia. To explain these changes, it is postulated that fetal hypercalcaemia suppresses fetal PTH and stimulates calcitonin secretion. Experimental data suggests that neither PTH nor calcitonin is able to cross the placenta. Relative hypoparathyroidism and hypercalcitoninism favour mineralization of the fetal skeleton. At delivery, the supply of calcium via the placenta is shut off and the suppressed parathyroid glands cause temporary hypocalcaemia. In the mature neonate, this serves as a trigger for synthesis and secretion of PTH and suppression of calcitonin and thereby the reestablishment of normal calcium homeostasis. Symptomatic hypocalcaemia results if these homeostatic adjustments are delayed. Plasma inorganic phosphate is higher in full-term infants than in childhood and may rise to 3.1 mmol/1 (10.0 mg/dl) or above. It then decreases gradually throughout childhood. Factors contributing to high plasma inorganic phosphate levels in early infancy include the high phosphorus content in cow's milk, low neonatal glomerular filtration rate and relatively high tubular reabsorption of phosphate (TRP). The latter is attributable to the low PTH secretion, but transient unresponsiveness of the renal tubules to the hormone has also been claimed. Transient neonatal hypocalcaemia This can be subdivided into two major groups: (1) early-onset hypocalcaemia beginning in the first 48 hours after birth before feedings have begun, and (2) late-onset hypocalcaemia beginning usually at the end of the first week of life in infants fed with formulas containing high phosphate concentrations. Significant hypocalcaemia (plasma calcium < 1.9 mmol/1 (< 7.5 mg/dl) in the term infant; < 1.75 retool/1 (< 7.0 mg/dl) in the preterm) occurs in approximately one per cent of term infants. The incidence is significantly higher in preterm infants, infants of diabetic mothers, and infants with birth asphyxia, brain injury or some other perinatal complication (Roberts, Cohen and Forfar, 1973; Rosli and Fanconi, 1973). Many remain asymptomatic, but when symptoms are present the condition is synonymous with tetany of the newborn. Frequent clinical signs and symptoms include jitteriness, twitching of extremities, eyes and facial muscles, apnoeic spells, loose bowel movement and true convulsions. Several factors may be implicated in the pathogenesis of hypocalcaemia in these infants. An exaggeration of the 'physiological' transient hypoparathyroidism described above is probably operative to a degree in all these neonates, but the exact aetiology often cannot be pin-pointed. Refractori-

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217

ness to the calcium-raising effects of PTH due to end-organ immaturity has been proposed as another contributing factor. Excessive secretion of calcitonin, or at least an imbalance between calcitonin and PTH, may be a precipitating factor in the early-onset variety. The high phosphate load from various causes including the use of cow's milk formula, anoxic brain damage and acute renal failure may be important, particularly in the lateonset cases (Gardner, 1952; Lealman et al, 1976).

Congenital permanent hypoparathyroidism in the neonate Two types of congenital permanent hypoparathyroidism may be present at birth and in the neonatal period: first, hypoparathyroidism may be isolated (i.e., no associated abnormalities) and, secondly, it may present as part of the DiGeorge syndrome.

Isolated hypoparathyroidism. This is a rare condition and in the neonate is initially indistinguishable clinically and biochemically from the transient varieties described above. The diagnosis of permanent idiopathic hypoparathyroidism becomes more likely if hypocalcaemia persists beyond one month of age, and is virtually certain if hypocalcaemia is still present after six months, the oldest age at which recovery from neonatal hypocalcaemia has been reported. The presenting features are the same as those described for transient neonatal hypocalcaemia. The plasma calcium is usually below 1.8 mmol/1 (< 7.0 mg/dl) and ionized calcium is proportionately reduced. Plasma inorganic phosphate is usually above 2.4 mmol/1 (7.5 mg/dl). Plasma PTH levels are undetectable. The presumed cause of this condition is defective parathyroid development. However, since these children rarely die, few opportunities have arisen to study glandular histology. This type of hypoparathyroidism is always isolated and is usually sporadic. However, a sex-linked recessive form and one with dominant transmission have also been reported.

DiGeorge (III and IV pharyngeal pouch) syndrome. Defective development of those structures which derive embryologically from the III and IV pharyngeal pouches and branchial arches give rise to a host of congenital problems involving mainly the parathyroids, thymus, aortic arch, heart, lower jaw and ears (DiGeorge, 1968). The DiGeorge syndrome refers to the association of absent parathyroid glands and thymus with congenital heart disease involving the aortic arch. Hypocalcaemia is present, and susceptibility to monilial and viral infections results from the lack of normal T cell function. Other features may include micrognathia, high or cleft palate and abnormalities of either the external or inner ear. Previously most newborns with this syndrome succumbed during the first few weeks of life. However, it appears that many of the infants do not have complete absence of parathyroids and thymus. Thus if they survive early life both hypocalcaemia and immunological incompetence may gradually improve and may resolve completely by six to nine months. Such patients are considered to have partial DiGeorge syndrome.

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D. DANEMAN, S. W. KOOH AND D. FRASER

Transient neonatal hypoparathyroidism secondary to maternal hyperparathyroidism This is a very rare cause of transient neonatal hypoparathyroidism. The signs, symptoms and laboratory values are indistinguishable from other forms of neonatal hypocalcaemia. Thus the diagnosis depends on concomitant investigation of the mother. The onset usually occurs three to 14 days after birth. Symptoms may be precipitated by changing the feeding from breast to cow's milk, even several weeks after birth. The cause of the disorder is fetal PTH suppression caused by maternal, and hence fetal, hypercalcaemia. Occasional instances of hypoparathyroidism persisting beyond infancy suggest that maternal hyperparathyroidism may permanently affect fetal parathyroid gland development. In principle, it should be standard practice to investigate the mother of every hypocalcaemic newborn. In one case of which we are aware, the failure to do this in the mother until after the birth of her second hypocalcaemic infant resulted in a three-year delay in recognition and treatment of the mother's hyperparathyroidism. Neonatal hypocalcaemia due to hypomagnesaemia A well-established relationship exists between magnesium and calcium homeostasis (Suh et al, 1973; David and Anast, 1974). There is a rare inborn error o f intestinal absorption of magnesium. Hypomagnesaemia (plasma Mg < 0.25 mmol/1 (< 0.5 mEq/1; < 0.6 mg/dl)) develops between two and three weeks of age, with a marked secondary hypocalcaemia. The latter is corrected within two to three days by correction of the low magnesium levels. Magnesium deficiency may lead to hypocalcaemia by either of the following mechanisms: (1) functional hypoparathyroidism, due to impaired PTH synthesis and/or release (Anast et al, 1972); and (2) end-organ (bone) refractoriness to the effects of PTH (Suh et al, 1973; David and Anast, 1974). Evidence exists to support both mechanisms, though the authors favour the first as being more important. In this disorder, hypomagnesaemia is treated initially by intramuscular or intravenous MgSO4, 0:5 to 0.75 mmol/kg body weight/day in two to three divided doses. This is followed by long-term supplement of magnesium salts in sufficient dosage to maintain a normal plasma magnesium. Control of hypomagnesaemia immediately rectifies calcium homeostasis. Lesser degrees of hypomagnesaemia (plasma levels 0.45 to 0.65 mmol/1; (12 to 18 mg Mg)/kg are not uncommon in the neonatal period. It is our opinion that this degree of hypomagnesaemia does not cause hypocalcaemia by itself. However, when mild hypomagnesaemia and neonatal hypocalcaemia coexist in the same patient, both should be treated. In addition, plasma magnesium levels should be measured routinely in all hypocalcaemic neonates. Differential diagnosis in the newborn period The clinical manifestations of neonatal hypocalcaemia are virtually indistinguishable from those of several other common unrelated neonatal

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conditions. Of particular note are hypoglycaemia and brain injury. Aminoacidopathies may also cause neonatal convulsions. Thus it is important to rule out other causes of twitching and convulsions before making the provisional diagnosis of neonatal tetany.

Hypoparathyroidism Developing after the Newborn Period Idiopathic hypoparathyroidism can develop at any age. However, symptoms of hypocalcaemia most often appear between two and 10 years of age. The onset is usually fairly abrupt with the development of carpopedal spasms, painful cramps in the extremities or abdomen, paraesthesia in the circumoral regions, fingers and toes, and, occasionally, laryngospasm. Quite often convulsions are the presenting feature. The clinical and EEG findings may be indistinguishable from those due to an idiopathic seizure disorder. Failure to measure plasma calcium may, therefore, delay the diagnosis of hypoparathyroidism by several years. Trousseau's and Chvostek's signs, which are unreliable in the newborn, may help in diagnosis in the older child. Hyperventilation readily precipitates tetany. In addition, a frequent finding in children whose symptoms begin in childhood is severe enamel hypoplasia (Nikiforuk and Fraser, 1981 (Figure 2). The presence of this sign indicates that the disturbance of calcium homeostasis had its onset prior to 2 years of age, the age by which enamel formation of the permanent incisors is complete. Long-standing hypocalcaemia may also cause mental disorientation, increased intracranial pressure and papilloedema (pseudotumour cerebri).

Figure 2. Severeenamel hypoplasiain a boy with long-standinghypoparathyroidism.

220

D. DANEMAN, S. W. KOOH AND D. FRASER

If hypocalcaemia is overlooked, the cerebral signs may lead to the mistaken diagnosis of intracranial neoplasia. This process is slowly reversible after the restoration of normocalcaemia. Skeletal radiographs are usually normal, but generalized or localized osteosclerosis has been reported. Hypocalcaemia can also eventually cause cataracts. Deposition of calcium in the basal ganglia has been described as a late manifestation of hypoparathyroidism. In our series of paediatric patients, we have frequently observed intracranial calcification in pseudohypoparathyroidism, rarely in hypoparathyroidism. A number of types of hypoparathyroidism can be distinguished after the neonatal period: I. Idiopathic isolated (simple) hypoparathyroidism; 2. Hypoparathyroidism associated with other endocrine deficiencies and autoimmune disease; and 3. Post-thyroidectomy hypoparathyroidism.

Idiopathic isolated hypoparathyroidism In this condition, the clinical and biochemical features are attributable solely to deficiency of PTH. Other endocrine functions are normal, candidiasis does not occur and growth is normal (Forbes, 1956; Harrison, 1956). Simple hypoparathyroidism usually occurs sporadically, though an autosomal dominant pattern of inheritance has been reported. In most cases the pathogenesis is unknown, but agenesis, partial or complete atrophy, and inflammatory damage of the parathyroids are possible mechanisms. Haemochromatosis, as occurs for example in thalassaemia major, is another cause of parathyroid destruction, albeit relatively uncommon (Gertner et al, 1979). Impaired parathyroid reserve is common in patients with thalassaemia major and has been suggested as a marker of significant iron overload. The diagnosis of isolated hypoparathyroidism cannot be made with any certainty in childhood, since children who first appear to have this disorder often develop additional endocrine or immunological abnormalities later on. The syndrome described below then emerges as the correct diagnosis. Hypoparathyroidism associated with other endocrine deficiencies and autoimmune disease Hypoparathyroidism may occur in association with a variety of other endocrine deficiency states and manifestations of immunological incompetence. The most common associated deficiency is hypoadrenalism (Addison's disease) but others may also occur (diabetes mellitus, ovarian dysgenesis, hypothyroidism) either singly or in combination. Chronic mucocutaneous candidiasis is another frequent sign of immune deficiency disease. Others include alopecia, vitiligo, corneal keratitis, hepatic damage and a decreased resistance to infection. A number of different classifications exist. MEDAC refers to multiple endocrine deficiencies, autoimmune disease and candidiasis; HAM refers to

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hypoparathyroidism, Addison's disease and moniliasis. The latter has also been referred to as autoimmune polyglandular syndrome type I (Neufeld, MacLaren and Blizzard, 1980). These latter authors reviewed 65 patients from the literature, plus 41 gathered from members of the Lawson Wilkins Pediatric Endocrine Society. The results of their review show a pattern most consistent with an autosomal recessive disease, but with a female predominance. Onset is usually during childhood. Insulin-dependent diabetes is rare, but chronic hepatitis is relatively common. A striking uniformity is that presentation occurs with chronic mucocutaneous candidiasis appearing most often, followed first by hypoparathyroidism and then by Addison's disease. All patients with this disorder should be screened regularly for the appearance of additional abnormalities. In addition, healthy sibs should be screened regularly for at least the first decade of life. It is felt that the various lesions of this syndrome arise from an underlying deficit in cell-mediated immunity, especially in regard to thymus-derived (T) lymphocyte function. For example, circulating immunoglobulin A (IgA) levels have often been found to be low and suppressor T lymphocyte function defective; a defective cell-mediated immunity to candida is also frequent (Arulanatham, Owyers and Genel, 1979; Neufeld, MacLaren and Blizzard, 1980). Each abnormality requires specific treatment. Hypocalcaemia and hyperphosphataemia usually respond well to vitamin D therapy. The control of the hypoparathyroidism, however, becomes more difficult when Addison's disease is also present since the plasma calcium-raising effect of vitamin D is somewhat offset by the adrenocortical hormones. In fact, the unexpected development of hypercalcaemia in a well-stabilized vitamin D-treated patient may be the 'tip-off' that adrenal insufficiency is developing. The candidiasis is especially difficult to treat and may cause serious debility.

Post-thyroidectomy hypoparathyroidism Damage to the parathyroid glands is a well-established risk of neck surgery, especially during total or subtotal thyroidectomy. Even when performed by an experienced surgeon, permanent parathyroid deficiency occurs in about five per cent of subtotal thyroidectomies and is significantly more common after total thyroidectomy for malignant thyroid disease. Transient hypoparathyroidism is far more common and may occur in as many as twothirds of all patients. Hypoparathyroidism is usually caused by an interference with the blood supply of the glands and is rarely due to complete ablation of the parathyroid tissue. Clinical experience suggests that those children developing severe tetany within 12 hours postoperatively, and those with symptomatic hypocalcaemia persisting beyond 10 days, are likely to require long-term vitamin D therapy. However, even these children may eventually recover sufficient parathyroid function to allow withdrawal of supportive treatment, but they may still have diminished parathyroid reserve. Symptomatic hypocalcaemia in the early postoperative period is treated for the first two to three days with intravenous calcium gluconate (vide

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D. DANEMAN, S. W. KOOH AND D. FRASER

infra). Thereafter, oral calcium supplements are used. If this does not control hypocalcaemia, vitamin D is added. Because of the often transient nature of the condition, therapy should be withdrawn cautiously after a short period. If therapy is required beyond three months, permanent hypoparathyroidism is usually present. Non-surgical damage to the parathyroid glands can occur as a result of massive doses of external irradiation (Eipe et al, 1968). However, the parathyroids are relatively radiation-resistant so definite hypoparathyroidism following treatment for thyroid disease is exceptionally rare (Sagel et al, 1972). Occasional cases of hypoparathyroidism have also been recorded as a result of extensive metastatic deposition in the glands.

Pseudohypoparathyroidism (PHP) Type I and II and Pseudopseudohypoparathyroidism (PPHP) P H P type I is a syndrome characterized by hypocalcaemia and hyperphosphataemia due to end-organ refractoriness to P T H (Albright et al, 1942). Associated somatic and mental abnormalities are frequently present. Of diagnostic importance is the failure of urinary cAMP excretion to increase significantly in response to P T H administration. It is this defect in urinary cAMP response to exogenous P T H that distinguishes P H P from hypoparathyroidism. The defect in cAMP response is present at birth, yet plasma calcium and phosphate concentrations remain normal for years. Symptomatic hypocalcaemia has not been reported prior to three years of age. Immunoreactive P T H is present in the plasma, usually reaching supranormal levels. P P H P is a condition with the somatic and mental abnormalities of P H P , but lacking in any abnormalities in ~calcium and phosphate homeostasis, with normal levels of circulating P T H and normal end-organ sensitivity to PTH. Albright's classical description of P H P emphasized the somatic and mental features of the syndrome (Albright et al, 1942; Elrick et al, 1950; Albright et al, 1952). However, it is now recognized that the condition often occurs without the somatic findings and with normal intellectual development. In recognition of Albright's original contributions, it has become customary to refer to the typical somatic and mental features as Albright's hereditary osteodystrophy (AHO); hence: P H P type I with AHO, and P H P type I without AHO. The features of A H O include shortening of metacarpal and metatarsal bones due to premature epiphyseal fusion. This process occasionally involves the phalanges as well as the metacarpals. The fourth metacarpal is often conspicuously short so that a dimple appears at its distal end when a fist is made. A round face, obesity and short stature are also common features (Figure 3). Cutaneous and subcutaneous plaques of calcium may be present near joints as well as on the abdomen and elsewhere. Such plaques have not been observed in hypoparathyroidism. Basal ganglia calcification is also very common in P H P . Again, in our experience it does not occur in children with hypoparathyroidism. Enamel hypoplasia, which is commonly

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found in childhood hypoparathyroidism (vide supra), was absent in most of our children with PHP. This we presume is due to the relatively later onset of hypocalcaemia in PHP. Apart from the changes described in the metacarpals, skeletal radiographs are normal in most patients with PHP; in the others, subperiosteal erosions, evidence of secondary hyperparathyroidism, may be found. The intellect is usually, but not always, retarded. The degree of AHO varies from patient to patient. In some the features are quite pathognomonic; in others, they are not definite enough to establish the diagnosis. In our series of 11 children with PH P type I, four had no features of AHO (Table 1). These individuals cannot be distinguished from hypoparathyroidism without performing a parathyroid hormone response test and measuring the plasma PTH concentration. A significant proportion of patients with P H P will be misdiagnosed as having hypoparathyroidism unless these tests are carried out. Recent observations suggest that both diabetes mellitus and mild hypothyroidism are considerably more common in PHP than would be expected on the basis of a random occurrence (Marx, Hershman and Aurbach, 1971), The generally accepted mechanism has been that PHP type I is due to impaired PTH-stimulated cAMP synthesis in those cells controlling calcium--phosphate homeostasis. This hypothesis is based on the observation of Aurbach and associates that there is little or no increase in urinary cAMP excretion in response to intravenously administered bovine P TH extract. In normal subjects administration of a similar dose immediately causes a striking increase in the excretion of cAMP (Chase, Melson and Aurbach, 1969). Several postulates have been proposed to explain the above response to PTH, but none fits all the observations. Recent studies of the hormone-receptor--adenylate cyclase system in PH P have demonstrated a marked reduction of the coupling protein activity known as N-protein or G-protein in the plasma membranes of red blood cells and cultured skin fibroblasts (Farfel et al, 1980; Drezner, Neelon and Lebovitz, 1973). This defect was observed in the majority of patients with P H P type I with AHO, but not in those without AHO or those with PH P type II. N-protein deficiency in target cells would explain impaired responsiveness to PTH. Since the same N-protein is required for cAMP generation by a multitude of hormones, deficiency of this protein might also be expected to affect the response to other cAMP-mediated hormones. Consistent with this theory are the findings that some patients are resistant to exogenous antidiuretic hormone (ADH), glucagon and gonadotrophin administration, and have abnormal release of thyroid-stimulating hormone (TSH) and prolactin following thyrotrophin-releasing hormone (TRH) administration (Marx, Hershman and Aurbach, 1971; Carbon, Brickman and Botazzo, 1977; Werder et al, 1978; Wolfsdorf et al, 1978). However, the actual correlation of N-protein activity with responses to these cAMP-mediated hormones has not yet been reported in individual patients. PT H resistance in patients with normal N-protein activity remains unexplained. Considerable evidence has been assembled to suggest that PH P type I and

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P P H P are variable expressions o f the same genetic defect, but the reason for the variations in expression of both the physical and biochemical abnormalities remains obscure (Mann, Alterman and Hills, 1962; Lee et al, 1968). Both can occur in a single family, and patients with P P H P can produce children with P H P . Patients with P H P have a permanent disturbance of calcium--phosphate homeostasis; in our experience, they do not subsequently convert to cases of P P H P . However, degrees of P H P do exist and, on rare occasions, individuals with A H O and impaired urinary cAMP excretion to exogenous P T H may be normocalcaemic and normophosphataemic. The ratio of females to males is approximately 2:1. Most evidence supports an X-linked dominant inheritance, but a sex-influenced autosomal dominant inheritance has also been proposed (Mann, Alterman and Hills, 1962). P H P Type II is a distinct but very rare form of P H P in which exogenous P T H elicits the same blunted phosphaturic and calcaemic responses which characterize type 1 disease, but in which there is a normal increase in urinary cAMP excretion. This condition is presumed to represent an intracellular defect beyond the cAMP-generation step in the reaction chain mediated by P T H . A H O is not present in P H P type II. The mode of inheritance is unknown (Lee et al, 1968; Rodriguez et al, 1974; Farfel et al, 1980). Therapy in P H P is with large doses of vitamin D or one of its metabolites. The biochemical abnormalities are readily corrected, but the somatic and mental abnormalities remain unchanged. No therapy is required for patients with P P H P , since calcium homeostasis is normal. Similarly, none is needed in normocalcaemic P H P with AHO.

Differentiation of Hypoparathyroidism and Pseudohypoparathyroidism It is imperative to establish early on whether a particular patient has hypoparathyroidism or pseudohypoparathyroidism because of the genetic implications and frequently poor outlook for physical and intellectual development in the latter condition. Pertinent features of the different conditions are shown in Table 3. Particularly in cases where somatic features of P H P are absent or equivocal, it is essential to employ biochemical criteria to make the differentiation. The two tests o f importance are (1) measurement o f immunoreactive P T H levels and (2) the parathyroid hormone response test. It is best to perform these tests prior to the initiation of therapy, since vitamin D may considerably alter some of the responses (Kind et al, 1973). The parathyroid hormone response test employed by the authors (Kind et al, 1973) evaluates three actions of P T H : (i) the ability to increase urinary cAMP excretion, (ii) the decreased renal reabsorption of phosphate and (iii) the plasma calcium-raising action. The first two are tested by administration o f a single-intravenous dose of P T H , the third by repeated intramuscular injections. Measurement of urinary cAMP excretion is the most important aspect of the test. In untreated hypoparathyroidism, plasma P T H levels are low or undetectable; i.v. P T H administration causes an immediate and marked

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D. DANEMAN, S. W. KOOH AND D. FRASER

Table 3. Differential diagnosis of hypoparathyroidism (HP), pseudohypoparathyroidism

(PHP) types I and H and pseudopseudohypoparathyroidism (PPHP) HP

Age of onset of hypocalcaemia Family history

any age

Somatic features (AHO) Intracranial calcification Enamel hypoplasia

absent absent frequent, signifies early onset present with autoimmune polyglandular syndrome

Addison's disease, candidiasis, other autoimmune disease Plasma Ca 2+ Pi

alkaline phosphatase PTH

PTH response test urinary cAMP phosphaturia hypercalcaemia Skeletal x-rays periosteal erosions brachydactyly

PHP I

usually

PPHP

absent

$ ? N O-low N N N

usually > 5 yrs

> 5 yrs

rare

P H P II

x-linked dominant often present frequent rare

x-linked dominant always present absent absent

absent not known not known

absent

absent

absent

{ " N/$ N/"

N N N N

$ I N 1

O/Slight

N

blunted blunted

N N

m

~_/--

m

+/-

m

not known

N

blunted blunted m

+

-

increase in urinary cAMP excretion and a considerable reduction in renal reabsorption of phosphate; i.m. injections lead to hypercalcaemia in one to two days. In untreated PHP, on the other hand, plasma PTH levels are normal or elevated; i.v. PTH causes very little or no increase of cAMP excretion and the phosphaturic response is blunted, but not completely absent. With repeated i.m. injections, plasma calcium increases only slightly, reaching a plateau in 48 hours. Vitamin D therapy enhances the phosphaturic and plasma calciumraising effects of PTH in both HP and PHP. In treated PHP, circulating PTH levels decline. These signs become unreliable for differentiation once therapy has been instituted. Thus, in the treated patient PTH-stimulated cAMP excretion is the only reliable differentiation between hypo- and pseudohypoparathyroidism. TREATMENT Two aspects of therapy require attention in hypoparathyroidism. First, the feature of utmost urgency is symptomatic hypocalcaemia; convulsions, tetany, laryngeal stridor and cardiac arrhythmia require intravenous calcium administration. Secondly, the long-term management of hypocalcaemia and hyperphosphataemia must be considered. Although in the newborn and in postthyroidectomy, the hypoparathyroidism may be a transient phenomenon, vitamin D therapy should be introduced once it is evident the hypoparathyroidism is a long-standing problem.

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Treatment of symptomatic hypocalcaemia If symptoms are present, the major objective is to raise the plasma calcium to safe limits until spontaneous recovery or response to vitamin D therapy has occurred. In infancy, symptomatic hypocalcaemia may lead to cerebral damage and sudden cardiac death. Thus initial therapy should be intravenous calcium gluconate given by continuous infusion to avoid undesirable fluctuations in the plasma concentration of calcium. Calcium gluconate should only be given intravenously because of the danger of calcium deposition and tissue necrosis if administered intramuscularly or subcutaneously. A suitable starting dose is 0.1 mmol (0.2 mEq or 4 mg) of elemental calcium/kg body weight/hour. Calcium gluconate for injection is usually marketed as a 10 per cent solution, which should be diluted to two per cent before use. The elemental calcium content is nine per cent by weight. The rate of infusion should be adjusted every three to four hours, depending on the serum calcium level, and the infusion continued for as long as necessary to prevent recurrence. Correction of the hypocalcaemia stops tetany and muscle spasms at once, though convulsions may persist for several days, requiring anticonvulsant therapy. If the infant is not being breast fed, a low phosphorus formula should be employed. Oral calcium supplement providing 100 mg/kg/day of elemental calcium is added in three to four divided doses. Standard vitamin D prophylaxis (400 IU/day) should be given. In the neonate, the disturbance is frequently transient, allowing discontinuation of intravenous therapy after four to five days and oral calcium shortly thereafter. In those in whom hypocalcaemia persists for longer than about two weeks, vitamin D, or preferably faster acting 1,25-dihydroxyvitamin D 3 (1,25-(OH)2D3) or la,OHD3, should be employed. In older children, if prominent symptoms of hypocalcaemia are present at diagnosis, calcium therapy may be employed as described above. If symptoms are mild, oral calcium supplements may be sufficient until vitamin D therapy takes effect. Vitamin D and related compounds With the exception of infancy and postthyroidectomy, hypoparathyroidism and PHP are permanent conditions requiring long-term therapy. The definitive therapy for these conditions is with long-term vitamin D or a related compound, which act by virtue of their ability to increase intestinal calcium absorption and mobilize calcium from bone. Vitamin D is the cheapest of the agents available and is, in our opinion, as effective as dihydrotachysterol (DHT) for long-term therapy. The required dose of vitamin D to restore normocalcaemia and normophosphataemia in hypoparathyroidism far exceeds physiological requirements. In our experience, the maintenance dose in all types of hypoparathyroidism averages 2000 IU (50/ag)/kg/day (Kind et al, 1977) but sensitivity to the vitamin varies somewhat from individual to individual. This requirement is similar in PHP, though later on the dose can often be reduced somewhat.

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In all conditions requiring vitamin D therapy, there is a similar method of obtaining optimal vitamin D dosage. Treatment is initiated with 2000 I U / k g / d a y by mouth as a high-potency preparation, several of which are available on the market. We prefer the liquid form of the vitamin since it has the major advantage of allowing precise dose adjustment. The medication may be given directly into the child's mouth via a tuberculin syringe. Plasma calcium should be measured frequently during the first one to two weeks and then at four to six weeks since it takes this time to reach full drug effect. This is presumably due to the fact that the vitamin is dispersed to many storage depots. Clinical evidence of hypo- or hypercalcaemia is sought at each clinic visit. The aim of therapy is to maintain a plasma calcium level of 2.15 to 2.35 mmol/1 (8.6 to 9.5 mg/dl). It is important to maintain plasma calcium in the lower end of the normal range to avoid hypercalcaemia which may result in serious renal lesions. If the calcium remains below the desired level, the dose of vitamin D should be increased by 15 to 20 per cent and the effect reevaluated in a further four to six weeks. In the event of hypercalcaemia, vitamin D is withheld until normocalcaemia is restored (usually five to 10 days); therapy is then reinstituted with a dose 20 per cent below that administered previously. Once a suitable dose has been established, the biochemical indices should be measured every two to three months for as long as treatment continues. Hypercalcaemia is a definite danger of excessive vitamin D dosage. We consider an elevated plasma calcium level to be the single most important indicator of vitamin D toxicity. No residual damage is demonstrable from a single short episode of mild hypercalcaemia. If vitamin D toxicity persists, however, permanent renal damage may occur. Vigorous therapy may be needed to reverse this, including discontinuation of vitamin D therapy, a low calcium diet, high liquid intake, expansion of the extracellular volume by intravenous fluids, and occasionally corticosteroid administration. Recently, synthetic 1a25-dihydroxyvitamin D 3 (1,25-(OH)2D3) and 1ahydroxyvitamin D have been used in both hypoparathyroidism and P H P (for review see Raisz, 1980). The dose of 1,25-(OH)2D 3 required for treatment is 0.025 to 0.05/ag/kg day, about a thousandth the dose of vitamin D needed to achieve the same effect. The advantages of 1,25-(OH)ED 3 are its speed of action and the rate of disappearance of its calcaemic effect when therapy is discontinued. It has not been proved to have major advantages in treating chronic hypoparathyroidism, but is particularly useful in states of transient hypoparathyroidism. 1,25-(OH)ED3 may be effective in those few patients resistant to both vitamin D and DHT. In newborns, a vitamin D metabolite is indicated if hypocalcaemia persists beyond two weeks. We prefer 1,25-(OH)2D 3 given as an oily solution by mouth in a dose of 0.10 to 0.15/ag/kg/day, reduced to 0.025 to 0.05/ag/kg/day after three to four days' therapy. Plasma calcium increases in one to two days. To avoid unnecessarily prolonged therapy, the metabolite should be discontinued after one week with careful biochemical monitoring. If hypocalcaemia returns, therapy should be reinstituted.

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Parathyroid h o r m o n e response test (Kind et al, 1973) R e n a l response to P T H . Renal phosphate handling and c A M P excretion in

the urine are assessed in response to a single i.v. injection of synthetic bovine P T H , equivalent to 8 USP U / k g , given over 15 minutes. The test is performed after a six to eight hour fast. At 07.00 h, two hours prior to starting the urine collections, the subject drinks 20 ml of w a t e r / k g to induce diuresis; subsequently water intake is matched to urine output until the test ends at 16.00 h. Plasma samples for inorganic phosphate and creatinine are collected at 09.00 h and hourly throughout the test. Urine is collected hourly for three hours, and then coincident with P T H administration, half-hourly for two periods and hourly for the three remaining hours, cAMP, phosphate and creatinine outputs are determined on each urine sample. The rate o f urinary c A M P excretion and the tubular reabsorption of phosphate are calculated for each of the eight periods. Calcaemic response to P T H . After completion of (i), synthetic P T H equivalent to 8 USP units (3.0/ag)/kg is given every eight hours by injection until hypercalcaemia (plasma calcium > 3 mmol/1; > 12 mg/dl) occurs or until plasma calcium stabilizes at a lower level. The plasma calcium is measured four hours after each dose to detect the earliest evidence of hypercalcaemia and stop the test.

SUMMARY Although relatively u n c o m m o n , the conditions o f hypoparathyroidism and pseudohypoparathyroidism in childhood provide an exciting diagnostic and therapeutic challenge. Knowledge of calcium-phosphate homeostasis has progressed rapidly over the past few years so that our understanding of the basic pathophysiological mechanisms has increased tremendously. H o w ever, further clinical and basic scientific research will, no doubt, unravel further variations o f the various disease entities described. ENDNOTE Part of this material is also published in Textbook ofPaediatrics, 2nd and 3rd Editions (Ed.) Forfar, J. O. & Arneil, G. C., pp. 1001-1014, 1978 and in press, Churchill Livingstone, Edinburgh. ACKNOWLEDGEMENT This work was supported in part by Ontario Health Research Grant PR 399. REFERENCES Agus, Z. S., Puschett, J. B., Senesky, D. et al (1971) Mode of action of parathyroid hormone on cyclic adenosine 3'5'-monophosphate on renal tubular phosphate reabsorption in the dog. Journal of Clinical Investigation, 50, 617-626. Albright, F., Burnett, C. H., Smith, P. H. et al (1942) Pseudohypoparathyroidism -- an example of 'Seabright--Bantam' syndrome. Endocrinology, 30, 922-932. Albright, F., Forbes, A. P., Henneman, P. H. et al (1952) Pseudo-pseudohypoparathyroidism. Transactions of the Association of American Physicians, 65, 337-350.

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Anast, C. S., Mohs, J. M., Kaplan, S. L. et al (1972) Evidence for parathyroid failure in magnesium deficiency. Science, 177, 606-608. Arulanatham, K., Owyers, J. M. & Genel, M. (1979) Evidence for defective immunoregulation in the syndrome of familial candidiasis endocrinopathy. New England Journal of Medicine, 300, 164-168. Carbon, H. E., Brickman, A. S. & Botazzo, G. F. (1977) Prolactin deficiency in pseudohypoparathyroidism. New England Journal of Medicine, 296, 140-144. Chase, L. R. & Aurbach, G. D. (1967) Parathyroid function and the renal excretion of 3'5' adenylic acid. Proceedings of the National Academy of Science, USA, 58, 518-525. Chase, L. R., Melson, L. & Aurbach, G. D. (1969) Pseudohypoparathyroidism: defective excretion of 3'5'-AMP in response to parathyroid hormone. Journal of Clinical Investigation, 48, 1832-1844. David, L. & Anast, C. S. (1974) Calcium metabolism in newborn infants: the interrelationship of parathyroid function and calcium, magnesium and phosphorus metabolism in normal, 'sick' and hypocalcemic newborns. Journal of Clinical Investigation, 54, 287-296. Drezner, M., Neelon, F. A. & Lebovitz, H. E. (1973) Pseudohypoparathyroidism type II - - a possible defect in the reception of the cyclic AMP signal. New England Journal of Medicine, 289, 1050-1060. DeLuca, H. F. (1980) Some new concepts emanating from a study of the metabolism and function of vitamin D. Nutrition Reviews, 38, 169-182. DiGeorge, A. M. (1968) Congenital absence of the thymus and its immunologic consequences. Concurrence with congenital hypoparathyroidism. In Birth Defects, Original Articles Series (Ed.) Bergsman, D. & Good, R. A. 4 (1), 16. Eipe, J., Johnson, S. A., Kiamko, R. T. & Bronsky, D. (1968) Hypoparathyroidism following t3~I therapy for hyperthyroidism. Archives of Internal Medicine, 121, 270-272. Elrick, H., Albright, F., Bartter, F. C. et al (1950) Further studies on pseudo-hypoparathyroidism. Report on four new cases. Acta Endocrinologica, 5, 199-225. Farfel, Z., Brickman, A. S., Kaslow, H. R. et al (1980) Defect of receptor--cyclase coupling protein in pseudohypoparathyroidism. New England Journal of Medicine, 303, 237-242. Fraser, D. R. (1980) Regulation of the metabolism of vitamin D. Physiological Reviews, 60, 551-613. Forbes, G. B. (1956) Clinical features of idiopathic hypoparathyroidism in children. Annals of the New York Academy of Science, 64, 432-455. Gardner, L. I. (1952) Tetany and parathyroid hyperplasia in the newborn infant: influence of dietary phosphate load. Pediatrics, 9, 534-543. Gertner, J. M., Broadus, A. E., Anast, C. S. et al (1979) Impaired parathyroid response to induced hypocalcemia in thalassemia major. Journal of Pediatrics, 95, 210-213. Habener, J. F., Mayer, G. P., Dee, P. C. et al (1976) Metabolism of amino- and carboxylsequence irnmunoreactive parathyroid hormone in the bovine. Evidence for peripheral clearage of hormone. Metabolism, 25, 385-395. Harrison, H. E. (1956) Idiopathic hypoparathyroidism. Pediatrics, 17, 442-448. Hellman, D., Au, W. Y. W. & Bartter, F. C. (1965) Evidence for a direct effect of parathyroid hormone on urinary acidification. American Journal of Physiology, 209, 643-650. Kind, H. P., Parkinson, D. K., Suh, S. M., Fraser, D. & Kooh, S. W. (1973) Parathyroid hormone response test and effects of vitamin D in hypoparathyroidism and pseudohypoparathyroidism. Endocrinology, 92, A146. Kind, H. P., Handysides, A., Kooh, S. W. & Fraser, D. (1977) Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism: weight-related dosages for initiation of therapy and maintenance therapy. Journal of Pediatrics, 91, 1006-1010. Lealman, G. T., Logan, R. W., Hutchison, J. H. et al (1976) Calcium, phosphorus and magnesium concentrations in plasma during first week of life and their relation to type of milk feed. Archives of Diseases in Childhood, 51, 377-384. Lee, J. B., Tashjian, A. H., Streeto, J. M. et al f1968) Familial pseudohypoparathyroidism: role of parathyroid hormone and thyrocalcitonin. New England Journal of Medicine, 279, 1179-1184. Mann, J. B., Alterman, S. & Hills, A. G. (1962) Albright's hereditary osteodystrophy comprising pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Annals of In ternal Medicine, 36, 315 -342.

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Marx, S. J., Hershman, J. M. & Aurbach, G. D. (1971) Thyroid dysfunction in pseudohypoparathyroidism. Journal of Clinical Endocrinology and Metabolism, 33, 822-828. Neufeld, M., Maclaren, N. & Blizzard, R. (1980) Autoimmune polyglandular syndromes. Pediatric Annals, 9, 43-53. Nikiforuk, G. & Fraser, D. (1979) Etiology of enamel hypoplasia and interglobular gentin: the roles of hypocalcemia and hypophosphatemia. Metabolic Bone Disease and Related Research, 2, 17-23. Nikiforuk, G. & Fraser, D. (1981) The etiology of enamel hypoplasia: a unifying concept. Journal of Pediatrics, 98, 888-893. Nimmo, H. G. & Cohen, P. (1972) Hormonal control of protein phosphorylation. In Advances in Cyclic Nucleotide Research (Ed.) Greengard, P. & Rohison, A. pp. 702-720. New York: Raven Press; Parsons, J. A. (1979) Physiology of parathyroid hormone. In Endocrinology, Volume 2, (Ed.) De Groot, L. J. et al, pp. 621-629. New York: Grune and Stratton. Pfeuffer, T. (1977) GTP-binding proteins in membranes and the control of adenylate cyclase activity. Journal of Biological Chemistry, 252, 7224-7234. Raisz, L. G. (1980) Direct effects of vitamin D and its metabolites on skeletal tissue. Clinics in Endocrinology and Metabolism, 9, 27-41. Nordin, B. E. C. & Peacock, M. (1969) Role of the kidney in regulation of plasma calcium. Lancet, ii, 1280-1283. Rasmussen, H. (1971) Ionic and hormonal control of calcium homeostasis. American Journal of Medicine, 50, 567-588. Rasmussen, H. & Feinblatt, J. (1971) The relationship between the actions of vitamin D, parathyroid hormone and calcitonin. Calcified Tissue Research, 6, 265-279. Rodbell, M. (1980) The role of hormone receptors and GTP-regulatory protein in membrane transduction. Nature, 284, 17-22. Roberts, S. A., Cohen, S. D. & Forfar, J. O. (1973) Antenatal factors associated with neonatal hypocalcaemic convulsions. Lancet, ii, 809-811. Rodriguez, H. J., Villareal, H. Jr, Klahr, S. et al (1974) Pseudohypoparathyroidism type II: restoration of normal renal responsiveness to parathyroid hormone by calcium administration. Journal of Clinical Endocrinology and Metabolism, 39, 693-701. Rosli, A. & Fanconi, A. (1973) Neonatal hypocalcemia. 'Early type' in low birth weight newborns. Helvetia Pediatrica Acta, 28, 443-457. Sagel, J., Epstein, S., ~(alk, J. & van Mieghen, W. (1972) Radioactive iodine therapy for thyrotoxicosis at Groote Schuur Hospital over a 6-year period. Postgraduate Medical Journal, 48, 308-313. Suh, S. M., Tashjian, A. H., Matsuo, N., Parkinson, D. K. & Fraser, D. (1973) Pathogenesis of hypocalcemia in primary hypomagnesemia: normal end-organ responsiveness to parathyroid hormone, impaired parathyroid gland function. Journal of Clinical Investigation, 52, 153-160. Werder, E. A., Fischer, J. A., Illig, R. et al (1978) Pseudohypoparathyroidism and idiopathic hypoparathyroidism: relationship between serum calcium and parathyroid hormone levels and urinary cyclic adenosine-3'5'-monophosphate response to parathyroid extract. Journal of Clinical Endocrinology and Metabolism, 46, 872-879. Werder, E. A., lllig, R., Bernasconi, S. et al (1975) Excessive thyrotropin response to thyrotropin releasing hormone in pseudohypoparathyroidism. Pediatric Research, 9, 12-16. Wolfsdorf, J. I., Rosenfield, R. L., Fang, V. S. et al (1978) Partial gonadotr0pin resistance in pseudohypoparathyroidism. Acta Endocrinologica, 88, 321-328.