Pseudohypoparathyroidism type 1a presenting as congenital hypothyroidism

CLINICAL AND LABORATORY OBSERVATIONS

Pseudohypoparathyroidism type l a presenting as congenital hypothyroidism Yosef Weisman, M.D., Avraham Golander, M.D., Zvi Spirer, M.D., and Zvi Farfel, M.D. Tel Aviv, Israel

PSEUDOHYPOPARATHYROID1SM TYPE 1 is an inherited metabolic disorder characterized by hypocalcemia and hyperphosphatemia, which are caused by end organ resistance to the action of PTH?. 2 Most of these patients have, in addition, the skeletal abnormalities of Albright hereditary osteodystrophy.2 The molecular basis for the resistance to P T H in most patients ( P H P - l a ) is an impairment in c A M P synthesis3 caused by deficient activity of guanine nucleotide regulatory protein of adenylate cyclase (Nprotein), 4-7 a plasma m e m b r a n e protein that couples hormone receptors to the catalytic u n i t of adenylate cyclase. 8 The localization of the defect distal to the hormone receptor implies that resistance to other hormones that act via c A M P may occur in PHP-1. Indeed, resistance to T S H , glucagon, A D H , and gonadotropins has been demonstrated in patients with PHP-1.6, 7

challenge. A thyroid scan showed a faint image of a gland of normal outline. Congenital hypothyroidism was diagnosed, and treatment with thyroxine was started. An osteotomy of the left tibial bone was performed at the age of 3 years because of bowing of the leg. Physical examination at the age of 5 years, in our clinic, revealed an obese child with round face, short fleck, brachydactyly with short metacarpal bones, and mild mental retardation (Figure). He was slightly above the 10th percentile for height and 3 SD above the mean for weight. Basal serum T4, TSH, and prolactin concentration, after stopping thyroxine treatment for 3 weeks, were 4 ~.g/ml (normal 5 to 13 ,tg/ml), 25/~U/ml (normal 20 ng/ml).

We describe a child in whom hypothyroidism was diagnosed shortly after birth; at the age of 5 years, a diagnosis of PHP-1 a was made. CASE R E P O R T This 5-year-old boy of Jewish Yemenite-lraqi extraction, with congenital hypothyroidism, was referred to the Pediatric Endocrinology Clinic of our hospital for follow-up. He was born at term after an uncomplicated first pregnancy. Birth weight was 2.94 kg. The infant was discharged from hospital 4 days after birth, with a serum bilirubin concentration of 12 mg/dl. At 10 days of age, he was admitted to another hospital because of jaundice, hypothermia, edema, and hypoglycemia. It was then noticed that he had macroglossia and an umbilical hernia; he did not have a goiter. Laboratory studies showed low serum T4 (3.5 tzg/dl) and slightly elevated TSH (25 ~u/ml) levels. The 131Iuptake at 24 hours was 13.5% (normal >20%), and did not change with perchlorate From the Department of Pediatrics and the Bone Disease Unit, Tel Aviv Medical Center, and the Clinical Pharmacology Unit and the Department of Medicine, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Saekler School of Medicine. Submitted for publication Dec. 3, 1984; accepted Feb, 20, 1985. Reprint requests: Yosef Weisman, M.D., Bone Disease Unit, lchilov Hospital, 6 Weizmann St., Tel Aviv 64239, Israel.

ADH AHO cAMP PHP PTH T4 TRH TSH

Antidiuretic hormone Albright hereditary osteodystrophy Cyclic adenosine 3 ' 5 '-monophosphate Pseudohypoparathyroidism Parathyroid hormone Thyroxine Thyrotropin releasing hormone Thyroid stimulating hormone

Serum calcium concentration was 7.8 to 8.4 mg/dl, phosphorus 6.3 to 6.8 mg/dl, alkaline phosphatase 238 mU/ml, and serum PTH (RIA kit; Sorin, Fleures, Belgium) 7.0 mlU/ml (normal 2.0 to 5.0 mlU/ml). We also tested the end organ response to exogenous PTH. Two hundred units of parathyroid extract (Parathorm; Hormon Chemie, GmbH, Munich) were given intravenously over 15 minutes. The phosphate/creatinine ratio was 0.86 and 1.12 in two basal 1-hour urine samples; after PTH administration, the ratio was 1.18 and 1.84 in two 1-hour urine samples. Similarly, urinary cAMP excretion was 2.3 and 2.4 nmol/ml in the two basal urine samples, and 4.2 and 3.4 nmol/ml during the two 1-hour periods after PTH administration. The blunted responses of urinary cAMP and phosphate excretion to PTH infusion are typical in patients with PHP-1 and demonstrate the end organ resistance to PTH. N-protein activity in extracts of red blood cell membranes was measured by the ability to The Journal of P E D I A T R | C S Vol. 107, No. 3, September 1985

413

4 14

Clinical and laboratory observations

Figure. Six-year-old boy with pseudohypoparathyroidism. Note round facies, obesity, short stature, short neck, and brachydactyly.

complement the N-protein deficiency of $49 cyc murine lymphoma cell membranes in vitro as described previously. 4 The Nprotein activity of the patient's red blood cells was 50% of that obtained in l0 normal control subjects. DISCUSSION Patients with PHP-1 often have additional endocrine abnormalities. These abnormalities are consistent with resistance to other hormones that act via the c A M P system, such as T S H , A D H , glucagon, and gonadotropins. 6,7 These endocrine dysfunctions are probably the results of a generalized defect in the activity of guanine nucleotide binding regulatory protein (N or G protein), which functionally couples the hormone receptor to the catalytic unit of adenylate eyclase. 6-~ Hypothyroidism is the commonest of these additional endocrine abnormalities in patients with PHP-1. In one study, clinically significant hypothyroidism requiring replacement therapy was found in 15 of 26 patients with PHP-1.4, ~2Levine et al. 7 reported an exagerrated serum T S H response to T R H in such patients. In all cases so far reported, hypothyroidism was found after pseudohypoparathyroidism had been estab-

The Journal of Pediatrics September 1985

lished as the primary diagnosis. In our patient, hypothyroidism was diagnosed shortly after birth; only when he was 5 years of age did the appearance of features of A H O raise the possibility of P H P - l a as being the primary disease. This delay in diagnosis resulted frdm the following factors. First, hypocalcemia in our patient was mild and asymptomatic, and features of A H O were not identified until a few years after birth. Second, some of the clinical features, such as overweight, short stature, round face, and mental retardation, are common to both A H O and hypothyroidism. And third, the child had mild hypothyroidism as a manifestation of the generalized defect in hormonesensitive adenylate cyclase. It is possible, therefore, that in some infants with hypothyroidism, P H P - I is the basic disease. We suggest that the diagnosis of P H P - 1 should be considered in children with hypothyroidism, especially during infancy, when the features of A H O are not pronounced. Hypothyroidism may occur in patients with PHP-1 without A H O . 6 Finally, there was no increase in serum prolactin concentration after intravenous administration of T R H in our patient, whereas the T S H response was exaggerated. This pattern of impaired prolactin response and increased T S H secretion has been reported in both P H P - l a and P H P - l b (PHP-1 with normal N protein activity). However, Levine et al. 7 did not observe an impaired prolactin response to T R H in PHP; the reason for this discrepancy is not clear. REFERENCES 1. Albright R, Burnett CH, Smith PH, Parson W: Pseudohypoparathyroidism: an example of Seabright-Bantam syndrome. Report of three cases. Endocrinology 1942;30:922 2. Drezner MK, Neelon FA: Pseudhypoparathyroidism. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown US, eds: The metabolic basis of inherited disease. New York: McGraw-Hill, 1983; pp 1508-1528 3. Chase LR, Melson GL, Aurbach GD: Pseudoparathyroidism: defective excretion of 3,5-AMP in response to parathyroid hormone. J Clin Invest 1969;48:1832 4. Farfel Z, Brickman AS, Kaslow HR, Brothers VM, Bourne H R: Defect of receptor-cyclase coupling protein in pseudoparathyroidism. N Engl J Med 1980;303:237 5. Levine MA, Downs RW, Singer M, Marx S J, Aurbach GD, Spiegel AM: Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem Biophys Res Commun 1980; 94:1319 6. Farfel Z, Bourne HR: Pseudohypoparathyroidism: mutation affecting adenylate cyclase. Mineral Electrolyte Metab 1982;8:227 7. Levine MA, Downs RW, Moses AM, et al: Resistance to multiple hormones in patients with pseudohypoparathyroidism: association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983;74:545 8. Gilman AG: Guanine nucleotide binding regulatory proteins and dual control of adenylate cyelase. J Clin Invest 1984;73:1 9. Bourne HR, Kaslow HR, Brickman AS, Farfel Z: Fibrobtast

Volume 107 Number 3

defect in pseudohypoparathyroidism type I: reduced activity of receptor cyclase coupling protein. J Clin Endocrinol Metab 1981;53:636 10. Farfel Z, Bourne HR: Deficient activity of receptor cyclase coupling protein in platelets of patients with pseudohypoparathyroidism. J Clin Endocrinol Metab 1980;51:1202 11. Downs RW, Levine MA, Drezner NK, Burch WM, Spiegel

Clinical and laboratory observations

4 15

AM: Deficient adenylate cyclase regulatory proteins in renal membranes fi'om a patient with pseudohypoparathyroidism. J Clin Invest I983;71:231 12. Farfel Z, Brothers VM, Brickman AS, Conte F, Neer R, Bourne HR: Pseudohypoparathyroidism: inheritance of deficient receptor cyclase coupling activity. Proc Natl Acad Sci USA 1981;78:3098

Physiologic testosterone or estradiol induction of puberty increases plasma somatomedin- C Robert L. Rosenfield, M.D., and Richard Furlanetto, M.D., Ph.D. Chicago, Illinois, and Philadelphia, Pennsylvania

THE PLASMA somatomedin-C concentration increases above adult values during puberty, ~'2 a change correlated with rising sex hormone concentrations5 We report the results of studies designed to test the hypothesis that pubertal amounts of sex hormones bring about this change, and if so to determine whether this is a direct effect or whether it is mediated by growth hormone.

METHODS Six sexually infantile, GH-intact children were given testosterone (group 1) (Table). One patient had anorchia, one Kallman syndrome, one Turner syndrome (given the lowest testosterone dose for only 6 months as part of a study of this as possible anabolic therapy), and three had profoundly delayed puberty with G n R H test results consistent with hypogonadotropinism. Five teenagers with Turner syndrome were given estradiol (group 2). Four teenagers with G H deficiency and hypogonadotropinism (group 3) were studied while receiving hormone replacement treatment, which included hGH 0.1 U/kg thrice weekly and testosterone. They were 16.4 _+ 1.0 (SEM) years of age, with bone age of 13.7 --2-0.21 years; control

From the Department of Pediatrics, University of Chicago Pritzker School of Medicine and Wyler Children's Hospital, Chicago; and the University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia. Supported in part by Grants HD-06308 and RR-305 from the Public Health Service and by Grant BC-386 fi'om ACS. Preliminary data presented at the meeting of the Society for Pediatric Research, May 4, 1983 (Pediatr Res 17:171A, 1983). Submitted for publication Dec. 10, 1984; accepted Jan. 29, 1985. Reprint requests: Robert L. Rosenfield, M.D., Wyler Children's Hospital, 584l S. Maryland, Chicago, IL 60637.

samples had been obtained in two 6 months prior, just before the initiation of testosterone therapy. Testosterone cypionate 37 to 100 mg/m~/mo was given by intramuscular injection monthly to patients in groups 1 and 3 to initiate puberty. 3 Estradiol cypionate 1.1 to 1.4 m g / m 2 / m o was given similarly to patients in group 2. 4 GH-deficient patients received hGH (courtesy National Hormone and Pituitary Program) intramuscularly 15 to 18 hours before blood sampling. Growth, pubertal development, and bone age were monitored as previously reported? Blood specimens were obtained within 3 months before instituting therapy and 1 week after steroid injections; in four of the patients with Turner syndrome, control plasma specimens were also obtained 1.1 _+ 0.3 (range 0.5 to 1.9) years earlier. Informed consent was obtained. GH GnRH Sm-C

Growth hormone Gonadotropin releasing hormone Somatomedin-C

I I

I

Plasma was separated promptly and stored at - 2 0 ~ C until assayed. Plasma testosterone, estradiol, and Sm-C were measured by radioimmunoassay as previously reported. ~Sm-C results are expressed in terms of a pooled adult plasma standard (Ortho unassayed control; Ortho Laboratories, Raritan, N.J.) arbitrarily defined as containing 1.0 U S m - C / m l . Results were analyzed by t test, paired for comparisons within a treatment group or using the Cochran modification for unequal variance when unpaired; all P values are two-tailed.

RESULTS Without sex steroid therapy, plasma Sm-C did not change significantly over the control period (2.0 + 0.4 vs 2.1 _+ 0.5 U / m l , n = 4).