Virginia V. Weldon

Growth hormone-dependent growth failure

Growth failure may be associated with low serum somatomedin concentrations despite normal to increased concentrations of serum growth hormone. We have recognized five patients who responded to GH administration with an increase in serum Sm and an acceleration in skeletal growth, and have characterized the circulating GH in an homologous human GH radioreceptor assay employing the IM-9 lymphocyte as a source of human GH receptor. These five prepubertal children, who had a mean height 7.8 SD below the mean for age, had a mean RIA-GH of 34.2 +/- 3.5 ng/ml in response to stimulation, a basal Sm activity by hypophysectomized rat cartilage bioassay of less than 0.3 IU/ml, and a mean peak Sm of 0.9 +/- 0.1 IU/ml in response to 48 hours of GH therapy. During a one-year trial of GH therapy, four of these children significantly increased their growth velocity as compared to their growth rate before GH therapy. These children had a mean RIA-GH/RRA-GH ratio of 2.f. The fifth patient had a low RIA-GH/RRA-GH ratio and had no increase in growth rate. These studies suggest that growth in certain growth retarded children may be dependent on exogenous GH, even though they are not GH deficient by standard criteria.

Cerebral Edema Complicating Therapy for Diabetic Ketoacidosis

Four cases of cerebral edema associated with therapy for diabetic ketoacidosis are reported. One patient had an inappropriate ADH-like syndrome at the time of onset of clinical symptoms of cerebral edema; he survived. The remaining patients had hyponatremia at or near the time of onset of clinical symptoms of cerebral edema, and they subsequently died. The literature is reviewed and some aspects of therapy, which might be casually related to cerebral edema observed in association with therapy of diabetic ketoacidosis, are discussed.

Evaluation of growth hormone release in children using arginine and L-dopa in combination*

L-Dopa in a dose ranging from 125-500 mg and arginine monochloride in a dose of 0.5 gm/kg were given simultaneously to 56 children with short stature (height less than third percentile). Sixteen of these children were subsequently diagnosed as having growth hormone deficiency. The diagnosis of hyposomatotropism was based on clinical findings and on responses to the combination test and to arginine and L-dopa administered as separate tests. All of the remaining 40 children had a normal GH response of greater than 6 ng/ml to the combination test. However, in this group, nine children were identified who responded to the combination test but who failed to respond to arginine and L-dopa in individual tests. The data suggest that a positive response to arginine and L-dopa in combination in children, who do not respond to the usual provocative tests when administered individually, may fail to identify children with partial GH deficiency who would benefit from treatment. The integrated stimulated GH response in the 31 children in whom a normal GH response to all three tests occurred suggests that the effects of L-dopa and arginine are additive.

Comparison of Predicted and Adult Heights in Short Boys: Effect of Androgen Therapy

Summary: We evaluated the accuracy of height predictions based on the tables of Bayley and Pinneau (2) in 43 boys with short stature. Sixteen boys were treated with androgens and 27 received no treatment. In 17 boys whose bone ages were within normal limits, and who received no treatment, the mean ± SE predicted height of 164.9 ± 1.5 cm was not significantly different from the mean adult height (166.5 ± 1. 5 cm). The predicted height exceeded the actual adult height by more than 5.1 cm in only one instance [5.1 cm is the degree of accuracy reported by Bayley and Pinneau (2)]. In 10 boys, whose bone ages were severely delayed (more than 2 SD below their chronologic age) and also were not treated, predicted height overestimated adult height by more than 5.1 cm in five of them. This difference was statistically significant (P < 0.05).In five boys with normal bone ages, androgen therapy had no significant effect on either predicted height (168.1 ± 4.1 before, 166.8 ± 4.4 cm after) or actual adult height (166.5 ± 4.1 cm). The 11 boys with severely delayed bone ages had a significant increase in predicted height during androgen therapy (165.4 ± 1.5 to 169.8 ± 1.7 cm, P < 0.01), but actual adult height (162.4 ± 2. 4 cm) was not significantly greater than pretreatment predicted height. Further, the number of boys whose predicted height exceeded their adult height by 5.1 cm was not significantly different in treated (4/11) or untreated (5/10) boys.The Bayley-Pinneau method of predicting adult height markedly overestimates adult height in about one-half of boys who have a bone age delay of more than 2 SD. Short-term therapy with androgens does not alter this outcome.

Outcome in Children with Normal Growth Following Removal of a Craniopharyngioma

Ten children who had normal or excessive growth rates following surgical removal of a craniopharyngioma have been followed. Final adult heights for three were more than 2.5 standard deviations below the mean adult height for sex. Nine of the 10 children showed a deceleration in growth rate that occurred 1.5–6 years following surgery. The deceleration in linear growth did not appear to correlate with changes in weight gain, somatomedin-C, or the integrated insulin response to an oral glucose load. These results suggest that the mechanisms whereby some children with growth hormone deficiency have normal growth rates following neurosurgic procedures are complex. The authors recommend that these children have continued follow-up so that growth hormone therapy may be instituted when appropriate.

Pseudohermaphroditism with testes and a 46, XX karyotype

A 14 4/12-year-old white girl, evaluated for progressive virilization and clitormegaly, was found to have the unusual combination of a 46, XX karyotype, well-developed Mullerian structures, and dysgenetic testes with Leydig cell hyperplasia. Although there have been previous case reports of 46, XX males, in all of these patients development of the Mullerian ducts had been suppressed. When contemporary classifications of human disorders of sexual differentation were reviewed, no report of a similar patient was found. We speculate that the genotype and phenotype in our patient correspond to the genetic intersexuality of the hornless goat, thereby raising the possibility that the human autosome may play a role in the control of sexual development.

Somatomedin C response to growth hormone in psychosocial growth retardation.

Three children with psychosocial growth retardation increased their serum somatomedin C levels from 0.20 +/- .02 to 0.81 +/- 0.2 U/ml in response to exogenous growth hormone. The pattern of somatomedin C response to growth hormone was no different from that seen in 11 prepubertal children with growth hormone deficiency who received growth hormone according to the same acute treatment regimen. This result suggests that the poor growth response of children with psychosocial growth retardation to exogenous growth hormone is not due to an inability to synthesize somatomedin C, and that it may represent a degree of resistance to the actions of somatomedin C.

280 TOPICAL TESTOSTERONE THERAPY FOR MICROPHALLUS IN MALE CHILDREN WITH HYPOPITUITARISM

Previous reports have documented the presence of microphallus in boys with hypopituitarism and have indicated the beneficial effects on phallic growth of systemic testosterone (T). Phallic growth probably depends on adequate tissue levels of dihydro-testosterone (DHT) with T being converted to DHT in the target tissue. Growth hormone (GH) may play a permissive role. We have studied the results of short-term (3 wks), topical application of 5% T in 4 boys with this syndrome.All patients were receiving GH at the time of T therapy. No acceleration of linear growth and no advance in osseous maturation occurred during or after treatment.We conclude that local T for this brief period is a safe, effective, and simple means of stimulating phallic growth. Whether the effect is due to local tissue levels of elevated blood concentration of T remains to be demonstrated.

308 DWARFISM DUE TO IMMUNOREACTIVE BUT BIOLOGICALLY INACTIVE GROWTH HORMONE

In the syndrome of familial dwarfism with high plasma immunoreactive growth hormone (GH)(Laron Syndrome), elevated levels of GH are associated with low levels of plasma somatomedin that do not increase following administration of GH. These patients do not respond to treatment with GH.The two subjects of this report were three-year-old boys with dwarfism (height ages 1 3/12 and 1 6/12 years) and delayed bone ages (1 3/12 and 1 9/12 years). Both had normal GH response after stimulation associated with undetectable levels of somatomedin. However, unlike patients with Laron Syndrome, the two patients generated normal levels of somatomedin after intra-muscular administration of GH. Treatment with GH (2 IU every other day) brought a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment, to 16 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 11.0 cm/year while on treatment.The two cases represent a new syndrome of dwarfism due to biologically inactive, immunoreactive GH. If erroneously diagnosed as having Laron Syndrome, these patients may be denied the benefit of treatment.