Robert A. Richman

Psychosocial aspects of constitutional short stature: Social competence, behavior problems, self-esteem, and family functioning

To determine the psychosocial effects of short stature, we administered a battery of psychologic tests to 24 children (ages 6 to 12 years) with constitutional short stature. Their results were compared to those of a group of 23 healthy children with normal stature matched for age, IQ, sex, and socioeconomic status. The short children had significantly higher scores on parental ratings of behavioral difficulties, especially somatic complaints, social withdrawal, and schizoidal tendencies. There were also indications of impaired self-concept as expressed by feelings of unpopularity and dissatisfaction. Parental responses suggested a tendency to set less clear limits on behavior, but not necessarily toward overprotectiveness. Parents of short children also gave responses indicating poorer communication and cooperation among family members. In contrast to recent studies of growth hormone-deficient children, in which no maladjustment surfaced, these results indicate that children with constitutional delay have characteristic behavioral difficulties.

Adverse effects of large doses ofmedroxyprogesterone (MPA) in idiopathic isosexual precocity

Medroxyprogesterone (MPA) is a progestin with no clinically detectable estrogenic and androgenic properties used in the treatment of sexual precocity. This report presents the results of administering large intramuscular doses of MPA (200 to 300 mg every 7 to 10 days for periods ranging from 5 to 40 months) in 3 girls and 1 boy with rapidly progressing idiopathic sexual precocity (e.g., breast enlargement, penile enlargement, pubic hair growth). Urinary steroids were measured by bioassay, standard modification of the double isotope derivative method, and other standard methods. The MPA regimen suppressed the signs and symptoms of precocious puberty. The 3 girls did not have further menstrual flow, breast tissue regressed, uterine size decreased, and vaginal cornification diminished, although not to prepubertal levels. A marked decrease in frequency of erections, no further penile enlargement, and only minimal progression of sexual hair were observed in the boy (the testis continued to enlarge, however). Excessive weight gain, rapid rate of linear growth and skeletal maturation were observed in the children during treatment, as was blood pressure elevation. The effectiveness of MPA appears to be mediated by the suppression of pituitary gonadotropin secretion. However, there was no consistent reduction of urinary gonadotropin levels, and suppression of gonadal stimulation was incomplete. Evidence of drug toxicity precludes further administration of high dosages of MPA even for research purposes.

SUBTLE SPEECH AND MOTOR DEFICITS OF CHILDREN WITH CONGENITAL ‘ HYPOTHYROID TREATED EARLY

This study surveyed the development and functioning of a group of 16 children with congenital hypothyroidism who had been followed closely since treatment was instituted at an average age of 15‐6 days. This group of early‐treated young children had no deficits in cognitive or adaptive functioning. Some isolated motor deficits were found, although results of the Finger‐tapping and Marching subtests of the Reitan‐Indiana battery did not replicate the New England Congenital Hypothyroid Collaborative (1985) finding of impaired performance. Speech deficits were documented in some. Congenitally hypothyroid children with delayed neonatal bone‐age performed more poorly on most measures than those whose bone‐age had been normal at birth.

411 IDENTIFYING THE ACADEMIC AND EMOTIONAL DIFFICULTIES ASSOCIATED WITH SHORT STATURE

To determine if children with growth retardation are at greater risk for academic and emotional problems than those of normal stature, we studied twenty-five children of normal intelligence with constitutional short stature or growth hormone deficiency. On the Child Behavior Checklist, 44% of these children scored in the 90th percentile or higher on the overall index of behavioral difficulty, a level typical of children referred for mental health services. Our patients had specific elevations on indices of somatic complaints, schizoidal tendencies, obsessive-compulsive traits and depression. They also had a disproportionate incidence of excessive clowning (45%), being teased (65%), unhappiness (48%), and underachievement (41%). Another striking finding was that the children had a high prevalence of grade retention, 28% having repeated at least one grade, in spite of having normal intelligence (mean full scale IQ=105.3, S.D. 14.9). Furthermore, 30% of the subjects had a verbal IQ that was 20 or more points higher than the performance score, a discrepancy occurring in only 10% of the population. In conclusion, short children seem to be at increased risk for developing academic and emotional difficulties. To better define the development problems unique to these children, we are now administering an extensive battery of intelligence, achievement, and personality tests to our patients and a control group matched for age, sex and socioeconomic class.

Alteration of the complement system in children with acquired thyroid disease

Abstract The complement system was studied in detail in 23 children with acquired thyroid disease of various etiologies. Seventeen patients had elevated titers of antithyroglobulin and/or antimicrosomal antibodies; 16 had complement abnormalities. Five of 6 patients with thyromegaly, but without circulating antibodies, also had alterations in serum complement. Of the 21 children with complement abnormalities, 13 had alterations in the classical pathway consisting of decreased serum levels of C4 or C2. Serum levels of C1 and the ability of these sera to lyse an antibody-coated target cell or consume C3–C9 with a preformed immune precipitate were normal. Alternative pathway abnormalities were also present in 8 of these 13 patients while isolated alternative pathway changes were found in another eight patients. Alternative pathway abnormalities were varied and consisted of depressed serum levels of factor B, properdin, and/or properdin convertase. In addition, various sera failed to support the lysis of rabbit erythrocytes or C3–C9 consumption with zymosan and/or cobra venom factor. Analysis of multiple specimens from 10 patients over a period of one year revealed the persistence of the original complement abnormalities. Complement changes were independent of the diagnostic classification of the thyroid disease, the presence or type of antithyroid antibody, abnormalities in thyroid function, or the response to therapy. These data indicate a diffuse alteration of the complement system in most children with acquired thyroid disease. Whether this alteration reflects the involvement of complement in the pathogenesis of these disorders remains unclear.

Abnormal osmoreceptors in Kallman's syndrome (KS)

We have previously described high set osmotic threshold (OT) for vasopressin release and deficient thirst in a patient with KS (ESPE-meeting 1980). In the present study the OT was evaluated by an isovolemic infusion of 5% NaCl in 7 patients with KS. The OT was defined at the plasma osmolality (Posm) at which the free water clearance (CH2O) abruptly fell. The OT was abnormally high in 5 patients, 291-296mOsm/kg. It was normal in one, 287mOsm/kg, and abnormally low in one patient, 270mOsm/kg. These values are compared to the OT in 73 normal volunteers previously reported (A.M.M & M.M), 287.3 ± 0.9(SD) mOsm/kg. The 5 patients with high set OT denied thirst at Posms as high as 296-316mOsm/kg. Normal response of volume regulation of vasopressin release was demonstrated by an appropriate fall in CH2O during water deprivation. Normal response of baroreceptors was shown by a fall in CH2O and a rise in plasma ADH during infusion of the hypotensive agent trimethaphan in 2 patients. It is concluded that the hypothalamic involvement in KS include deficient thirst sensation and abnormal setting of the osmoreceptors, that can be at an abnormal high or low setting.

88 DESMOPRESSIN THERAPY FOR ENURESIS

To determine the effectiveness of desmopressin (DDAVP, a vasopressin analogue) for treating enuresis, we performed a double-blind crossover study at three medical centers. Subjects (N=43) ranged from 6 to 16 years old, had normal renal function and denied polyuria, polydipsia and daytime incontinence. The study encompassed four consecutive two-week periods: pre-treatment, treatment with placebo or DDAVP (40 mcg intranasally at 8 PM), crossover treatment, and post-treatment. DDAVP did not produce adverse side effects or significantly alter blood pressure, body weight, serum osmolality or urine osmolality. The results were as follows:Thirteen of 43 children responded to DDAVP (number of wet nights <6). In 6 of the responders, the drug effect persisted into the next study period. Only 2 of 24 children responded to placebo during the first treatment period. In conclusion, DDAVP appears safe for treating enuresis. A childs response to the drug can be determined by a two-week therapeutic trial.

Kallman's syndrom with high set osmotic threshold (OT) and deficient thirst

A patient with Kallmans syndrom is presented, who had deficient thirst mechanism and high set OT for vasopressin secretion. Random determinations of plasma osmolality (Posm) revealed high values of 296-307 mOsm/kg. The OT defined by the isovolemic infusion of hypertonic saline, was 296mOsm/kg. This was significantly higher than the OT of 7 normal controls, 286.6±0.9 (M±SD). He had intact volume receptors, as shown by an appropriate fall of free water clearance during dehydration, from -0.3 to -1.25/min. His pressor receptors were shown to be intact by a normal response to the hypotensive agent trimethaphane with a fall of free water clearance from 10 to 1 ml/min. and a rise of plasma ADH from < 1 to 26uU/ml. Indifference to thirst was expressed at plasma osmolality as high as 301mOsm/kg. It is suggested that deficient thirst and high set OT are additional manifestations of the hypothalamic involvement of Kallmans syndrom.

335 DEHYDRATION STUDIES AND RESPONSES TO CLOFIBRATE IN PEDIATRIC PATIENTS WITH DIABETES INSIPIDUS

Some children with central diabetes insipidus (DI) may lelease ADH under certain conditions. We have studied 10 patients with central DI ranging in age from 3 to 18 years. Their evaluation included a dehydration test and a trial of clofibrate therapy.During the dehydration test, hourly plasma and urine osmolalities (Posm & Uosm) were measured. When there was a plateau in Uosm, the patients received aq. Pitressin. Greater than a 9% rise in Uosm one hour later confirmed the diagnosis of DI. Four patients had a Uosm higher than their Posm revealing releasable ADH. This occurred with marked thirst associated with an elevatec Posm. When the Posm exceeded 290 mOsm/1, the relationship of Uosm to Posm was always subnormal in our patients when compared to values obtained in 127 normal subjects. By comparing simultaneous Uosm and Posm values, the diagnosis of DI can be strongly suspected; and, the diagnosis will not be missed even in patients with DI who can release ADH when moderately dehydrated.The 10 patients received clofibrate (500 mg q6h) for 3 to 7 days. Eight patients concentrated their urine 50 to 400% higher than previous levels during random hydration periods. These increases in Uosm were associated with decreases in daily urine volumes. Because Posm measurements during the trial of clofibrate were the same or even lower than during random conditions, we attributed this finding also to the presence of releasable ADH in most pediatric patients with central DI.

336 UTILIZATION OF THE ALTERNATIVE PATHWAY OF COMPLEMENT IN PATIENTS WITH THYROID DISEASE: PRESUMPTIVE EVIDENCE AGAINST A ROLE FOR ANTIBODY

Complement studies were performed on 21 patients, 2 months to 16 years of age, with various types of thyroid disease. Circulating antithyroglobulin or antimicrosomal antibodies were present in 12/21 (titers > 1:40). All sera were quantitated for C4 (classical pathway); factor B, properdin and properdin convertase (alternative pathway); C3 and C3-C9 activity (both path-ways). In addition, functional assays were done by determining the extent of complement activation by an immune complex (classical pathway) or by zymosan, cobra venom factor, or rabbit erythrocytes (alternative pathway). Abnormalities were found in 16 patients, 11/12 with antithyroid antibodies and 5/9 without detectible antibodies. All but one of the abnormalities occurred in the alternative pathway. These consisted primarily of low serum levels (> 3 SD below the mean for age) of factor B and properdin or ineffective function with CoF. Such abnormalities suggest in vivo utilization of this pathway. No association, however, exists between the titers of antibody and any abnormality. Since C3 is deposited on the thyroid gland in many of these disorders, it would appear that it is the alternative pathway which is responsible for that deposition. Further, since antibody is not usually associated with alternative pathway activity, its role in that process is open to question.