Response to growth hormone treatment and final height after cranial or craniospinal irradiation

Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n = 27) and the other with normal GH secretion (n = 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n = 10) and -1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6 +/- 0.3 yr in girls and 11.0 +/- 0.3 yr in boys) and bone age (9.6 +/- 0.4 yr in girls and 12.6 +/- 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.     

Human growth hormone therapy of non-growth hormone deficient children

With biosynthetically derived human growth hormone (hGH) available in large quantities, attempts will be made to promote growth in short children who do not fulfill the 'classical' criteria for growth hormone deficiency (GHD). By these criteria, GHD is excluded if hGH levels to pharmacological stimuli exceed a definite level. Several studies have shown that a variety of short children, who are not growth hormone deficient by these criteria, will demonstrate an increased growth rate with hGH treatment. A subpopulation of children with clinical features of GHD, delayed bone age and low somatomedin levels, have low levels of spontaneously secreted growth hormone or 'bioinactive' growth hormone. These children increase their growth rates to substitution doses of hGH. In other children whose growth disorder is not likely to be caused by a disorder in the growth hormone-somatomedin axis, growth increments are occasionally seen on higher hGH doses. Future long-term studies--carefully considering the ethics of such approaches--will have to evaluate the relationships between hGH dose and both metabolic and growth responses and side effects in children with short stature in order to define more specifically further target groups of short children who will benefit from hGH therapy.     

Response to Growth Hormone Treatment and Final Height after Cranial or Craniospinal Irradiation

ABSTRACT. Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n=27) and the other with normal GH secretion (n= 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n=10) and - 1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6±0.3 yr in girls and 11.0± 0.3 yr in boys) and bone age (9.6 ± 0.4 yr in girls and 12.6 ± 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.     

Who is Treated with Growth Hormone Today?

ABSTRACT. The present demographic data from the Kabi International Growth Study (KIGS) database are summarized. Of the 2580 patients included, 85% have growth hormone deficiency (GHD) and 15% have other causes of growth failure. Idiopathic GHD is present in 78.5% of the patients, the remaining 21.5% have organic GHD. Isolated GHD is common in idiopathic GHD whereas multiple pituitary hormone deficiencies occur in at least 50% of the organic GHD patients. A preponderance of boys is observed in most groups of patients. Median chronological age (CA) at start of treatment is 10 years and median duration of therapy is 2.3 years. However, a wide range is observed. In most cases growth retardation is severe. In most patients with GHD height SDS for chronological age at start of therapy is at or below -3. The median difference between idiopathic and organic GHD is 1 SDS. Most patients have 6 or 7 injections of growth hormone (GH) per week. The median total weekly dose is approximately 0.5 IU/kg/week, but it is lower in older patients. It is concluded that steadily increasing numbers of patients with idiopathic and organic GHD are being treated with human GH (hGH). In addition, many patients with other growth disorders not necessarily associated with GHD receive hGH therapy. Chronological age at start of treatment still appears to be (too) high in most patients and growth retardation severe. The frequency of hGH injections has been increased to nearly daily administration. However, the total weekly dose appears to be low, especially in the older patients. It is hoped that KIGS will contribute to improving the efficacy of treatment and hence the quality of life for all patients with growth disorders.     

Occurrence of acute megakaryoblastic leukemia in a patient with idiopathic growth hormone deficiency

We describe a case of a 15 year old boy who developed acute megakaryoblastic leukemia (AMKL) while receiving treatment with human growth hormone (hGH) for idiopathic growth hormone deficiency (GHD). He was diagnosed as having idiopathic GHD and given hGH from December 1991. The examination of his peripheral blood showed mild pancytopenia 2 months before the start of the hGH therapy. Since January 1992, paleness of the skin, general fatigue and fervescence progressed gradually. In February 1992, because of the occurrence of acute leukemia, administration of hGH was discontinued. Judging from the results of surface marker analysis of the blast cells, the patient was diagnosed as having AMKL. He was treated with chemotherapy for acute non-lymphoblastic leukemia from March 1992. A complete remission was obtained after 4 weeks of treatment. The chemotherapy was completed in July 1993. He remains in complete remission 26 months after diagnosis. This case suggests the importance of hematological examination and, when there is any abnormality which is not caused by GHD, such as pancytopenia, more detailed medical examinations (for example bone marrow examination) are necessary.     

Screening for growth hormone deficiency using urinary growth hormone measurement

The diagnostic approach in growth hormone deficiency (GHD) is complicated. Two or more provocative tests are essential for definitive diagnosis of GHD. However, such testing cannot be carried out routinely on all subjects with short stature because of the need for hospitalization and blood sampling. A simple screening method for GHD would be of great value. Human growth hormone (hGH) levels were measured in the early morning urine of 192 children aged 7–15 years with height 2.0 s.d. below the mean for their ages. Sixty-eight subjects were selected because they showed a urinary hGH level < 10 ng/g creatinine. They were further examined in terms of bone age and plasma insulin-like growth factor (IGF-I) levels. In 30 subjects, the ratio of bone age: chronological age was < 0.8 and/or plasma IGF-I level was < 0.7 U/mL. Finally 24 of these subjects were examined with provocative tests and other endocrinological tests. Eleven subjects proved to have poor growth hormone secretion and one subject was diagnosed as having Turner syndrome. In conclusion, 11 patients with GHD were diagnosed from 192 children with short stature using urinary hGH measurement as the first screening method. These findings suggests that urinary hGH measurement could be a useful and simple method for detecting GHD.     

Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1–29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5–29.3 ng/ml). Continuous s.c. administration of GHRH of 4–6 g/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m² daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.Abbreviations GH growth hormone - GHD growth hormone deficiency - GHRH growth hormone releasing hormone - hGH human growth hormone - rhGH recombinant human growth hormone - SM C/IGF I somatomedin C/insulin-like growth factor I On the occasion of the 85th birthday of Prof. Dr.Dr.h.c. mult. Adolf Butenandt     

Prediction of growth response in prepubertal children treated with growth hormone for idiopathic growth hormone deficiency

Several multiple regression models have been developed to predict the first-year growth response to human growth hormone (hGH) in children with growth hormone deficiency (GHD). It was the aim of this study to analyse the significance of various growth parameters for a height prediction model. Data from 148 prepubertal children with idiopathic GHD were evaluated. The prediction model was developed by means of univariate and stepwise linear regression analysis and an “all possible” regression approach using Mallow's C(p) statistics. Six out of eight selected variables had a significant influence on the first-year growth rate. The most important parameter was the difference between target height SDS and height SDS at the start of therapy (THSDS - HSDSC0), accounting for 23.95% and 25.74% of the variability. No other single variable or combination of variables was more informative than the variable THSDS - HSDSC0 alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS - HSDSC0) + 6.8 cm/y ± 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSC0. This equation was validated in a small group of 18 GHD patients demonstrating a predicted vs. observed first-year growth rate of 9.4 ± 1.1 vs. 9.5 ± 2.6 cm/y. We conclude that the difference between THSDS and height SDS at the start of therapy is an important predictor of the first-year growth response in children treated with hGH for idiopathic GHD. Unlike in previous studies, additional parameters did not increase predictability.     

Growth hormone deficiency in Dubowitz syndrome

Severe short stature as a result of intra-uterine growth retardation is one of the characteristics of Dubowitz syndrome. There have been few reports elaborating growth hormone secretory status in this syndrome. A child with Dubowitz syndrome, who was found to have complete growth hormone (GH) deficiency and who responded to growth hormone therapy, is described. This appears to be the first documentation of GH deficiency in this syndrome.     

Growth and endocrine disorders secondary to cranial irradiation

External cranial radiation for the treatment of malignant diseases has become a frequent cause of growth hormone deficiency (GHD). The timing of occurrence and the frequency of GHD were related to the hypothalamic-pituitary radiation dose. Frequency varied from 50% in leukemia (2400 cGy) to 75% in face and neck tumors or medulloblastoma (2500-4500 cGy) and up to 100% in optic glioma (greater than 4500 cGy). The significantly more severe growth deficit in patients with GHD given higher radiation doses suggests different levels of residual GH secretion according to radiation dosage. The minimum harmful radiation dose is probably close to 1800-2000 cGy. Our data show that stimulation tests remain a useful means of defining GHD and predicting growth. A fair agreement between GH secretion and growth was found in most cases, regardless of the radiation dose. The only exception was a group of leukemic children (2400 cGy) who achieved normal prepubertal growth despite a low GH response. The 24-h spontaneous plasma GH profiles and IGF-I measurements may add information if growth is retarded despite a normal GH response. We showed that growth retardation occurring after some schedules of total body irradiation was not due to GH deficiency but rather to radiation-induced skeletal lesions. Early or true precocious puberty, generally associated with GHD, was another cause of height loss. As the role of GH deficiency in the final height reduction was demonstrated in all groups of patients after cranial radiation, we suggest that hGH therapy should be considered in any child with proven GH deficiency and significant growth retardation after such radiation.     

Biosynthetic growth hormone therapy in children with growth hormone deficiency: Experience at AIIMS,New Delhi

A total of 20 previously untreated children with growth hormone deficiency (GHD) were treated for one year with biosynthetic human growth hormone (hGH). The mean chronologic age was 9.43±3.52 years with a height age of 5.02 years, and bone age 9.43±3.52 (TW2-RUS) 6.42 years. The mean pretreatment growth velocity was 2.43±0.90 cm/year. Of these 14 children had complete GHD (peak GH levels less than 5 ng/ml) and 6 had partial GHD. They were treated with recombinant GH in a dose of 0.5 IU/kg/week divided into 6–7 injections per week subcutaneously at night. The mean growth velocity increased to 8.88±2.10 cm/yr at the end of 6 months and 8.00±2.21 cm/yr at 12 months. The actual gain ranged from 6–11 cm in a year. There were no local adverse reactions. One child developed vitiligo of the face and another transient hyperglycemia.     

Single incisor syndrome and growth hormone deficiency

The syndrome of single incisor belongs to the group of midline malformations and is characterized by a single incisor in the patient's maxilla. A growth hormone deficiency (GHD) can be associated. We report about two of our patients with this syndrome. A GHD was diagnosed at the age of 11.0 and 7.6 years, respectively, although a single incisor had already been present during their first dentition. The first patient was treated with HGH to a chronological age of 18.6 years (final height 168 cm), the second patient is still on therapy. The growth of children with craniofacial dysmorphic features must be controlled closely in order to diagnose a GHD in time.     

Diagnostic value of pituitary MRI in differentiation of children with normal growth hormone secretion, isolated growth hormone deficiency and multiple pituitary hormone deficiency

Pituitary height, volume and morphology were investigated by MRI in patients aged 3.5-24.9 years with growth hormone deficiency (GHD) in relation to birth history and hormonal findings. Three groups with comparable age, sex and pubertal stage were studied: group I (n=42)--patients with isolated growth hormone deficiency (IGHD); group II (n=22)-- patients with multiple pituitary hormone deficiency (MPHD); and group III (n=30)--healthy controls. Pituitary height and volume differed significantly between the three groups, with the smallest in group II and largest in group III (p <0.001 for both). Both variables correlated significantly with peak GH value in the patient groups (p <0.001). The specificity of pituitary dysmorphology in the determination of GHD was 100% and its sensitivity in differentiation of IGHD and MPHD was 95%. Ectopic neurohypophysis was present in 75% of breech births and 27% of head-presenting patients (p <0.01). This study emphasizes the differential diagnostic value of pituitary MRI and its contribution to the understanding of the pathogenesis and prognosis in GHD.     

Growth hormone deficiency in a patient with lysinuric protein intolerance

Introduction Lysinuric protein intolerance (LPI; MIM 222700) is a rare, autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes the light chain of the cationic amino acids (CAA) transporter y+. The clinical presentation of LPI includes gastrointestinal symptoms, failure to thrive, episodes of coma, hepatosplenomegaly and osteporosis. However, other findings have also been reported, and these suggest a multisystem involvement.Discussion We report a girl with confirmed LPI who presented with severe short stature that was unresponsive to adequate LPI treatment. The girl was found to have a classic growth hormone deficiency (GHD) and responded well to growth hormone (GH) replacement therapy.Conclusion While it is not known whether the mechanisms involved in the GHD of our patient are related to LPI, this case suggests that GH/IGF-I axis should be investigated in LPI children with persistent growth failure.     

The educational, vocational, and marital status of growth hormone-deficient adults treated with growth hormone during childhood

The goal of growth hormone therapy in childhood is to increase stature, thereby facilitating normal psychosocial development. To determine the social outcome of patients with growth hormone deficiency (GHD), we interviewed 116 adults with GHD across Canada, including 86 men and 30 women 18 to 38 years of age who were treated with growth hormone during childhood. The education of the 96 patients who had completed their formal education was similar to their siblings and to the general population. Of the patients in the labor force, 35.4% were unemployed; the unemployment rates for those patients less than 25 years of age and those 25 years of age or older were 45% and 23%, respectively, compared with national rates of 21.2% and 9.4% for the same age groups, respectively. Of the 90 patients with GHD who were not attending school, 70 lived with their parents or relatives. Only 15 patients were married; one was divorced. The percentage of patients with GHD who were married was less than 30% of the expected age-adjusted rate. No difference in the rate of employment or marriage was found between the patients with idiopathic isolated GHD and organic hypopituitarism. In summary, the achievements of patients with GHD seem to be normal in the education system, but the rate of employment and marriage are much lower than expected. This poor outcome was unrelated to the response to growth hormone therapy and emphasizes the need to develop strategies that lead to more satisfactory psychosocial integration of patients with GHD in adult life.     

Growth hormone treatment in a child with Williams-Beuren syndrome: a case report

Growth retardation is a consistent finding in Williams-Beuren syndrome. The cause of short stature in this syndrome is unknown. Endocrine studies have failed to reveal abnormalities in the growth hormone – insulin-like growth factor I axis. We report a boy with confirmed Williams-Beuren syndrome, who was found to have classical growth hormone deficiency and responded well to growth hormone therapy. Conclusion Although growth hormone deficiency is not likely to be a common cause of short stature in Williams-Beuren syndrome, we nevertheless recommend evaluation of the growth hormone – insulin-like growth factor I axis in all cases. Received: 14 February 1998 / Accepted in revised form: 4 April 1998     

Evaluation of growth hormone secretion after completion of therapy

BACKGROUND: Growth hormone (GH) reserve in young adults previously diagnosed as having GH insufficiency, who were treated with human (h)GH replacement in childhood needs confirmation in adulthood. METHODS: Nine patients (seven males, two females; two empty cella, one hypoplasia of the hypophysis and six with idiopathic GH deficiency) diagnosed as having GH insufficiency by the insulin tolerance test (ITT) and dopamine stimulation test in childhood (mean age 12.8+/-2.6 years) were retested at completion of linear growth (mean age 21.0+/-3.0 years), 4.6+/-1.6 years after discontinuation of hGH therapy. RESULTS: At the initial diagnosis, seven had complete and two had partial GH deficiency. At diagnosis, the mean peak GH response to ITT and dopamine was 4.8+/-4.08 and 3.4+/-2.9 mU/L, respectively. At retesting, the mean GH response to ITT and dopamine stimulation was 3.5+/-2.5 and 3.3+/-3.1 mU/L, respectively (P=0.91 and 0.96, respectively). During hGH therapy, mean height velocity increased from 3.5+/-1.9 cm/year at diagnosis to 9.9+/-3.64 cm/year during the first year (P=0.002). One of nine children diagnosed as having GH insufficiency who was treated with hGH replacement had normal growth hormone secretion at completion of linear growth. CONCLUSIONS: All GH-insufficient children should be retested after completion of their hGH treatment and linear growth to identify those who are truly GH insufficient and who may benefit from GH therapy in adulthood.     

Growth hormone secretion following administration of growth hormone releasing hormone in constitutional short stature and idiopathic growth hormone deficiency

A stimulation test using 1 microgram growth-hormone-releasing factor (GRF 1-29 X NH2)/kg bodyweight was performed in children with familial short stature and in children with constitutional delay of growth and development. The GH secretion induced by this means was not different in these groups, but there was a difference in the response between normal children and children with idiopathic growth hormone deficiency (GHD). GH secretion after GRF administration was significantly lower in the GHD group than in the other groups. However, 6 of 24 patients with GHD responded to the test with a normal increase in GH (greater than 10 ng/ml), and 11 with an intermediate response (2-10 ng/ml). Thus, the test does not differentiate individual patients with defective growth hormone secretion from normal short children.     

Confirming the diagnosis of growth hormone deficiency (GHD) and transitioning the care of patients with childhood-onset GHD

Growth hormone deficiency (GHD) diagnosed in childhood may persist into adult life. After attainment of final height, retesting of the patient's growth hormone-insulin-like growth factor (GH-IGF) axis using the adult GHD diagnostic criteria should be performed after an appropriate interval of 1-3 months off GH therapy. At the time of retesting, other pituitary hormones and serum IGF-I levels should also be measured. The opportunity should be taken to assess body composition, bone mineral density, and fasting lipid and insulin levels. Patients with severe, long-standing, multiple pituitary hormone deficiency, genetic defects, or severe organic GHD can be excluded from GH retesting. When the diagnosis of adult GHD is established, continuation of GH therapy can be recommended unless there is a known risk of diabetes mellitus or malignancy. The patient's transition to GH replacement in adulthood should be arranged as a close collaboration between the pediatric and adult endocrinologists, who should discuss the reinitiation of treatment with the patient.     

Growth in a case of Russell-Silver syndrome treated for hypopituitarism

The growth characteristics of Russell-Silver syndrome (RSS) include dwarfism of prenatal onset, moderate retardation of bone age and normal postnatal height velocity. We describe a case of hypopituitarism in a girl with typical RSS who suffered from a severe trauma at birth. Signs of hypopituitarism appeared during childhood. Before substitutive treatment, a short course of human growth hormone (hGH) induced a moderate rise in plasma IGF-I levels which was within the range observed in other pituitary dwarfs. Under replacement therapy, catch-up growth was similar to what is observed in other growth hormone deficient children. However, bone age matured much faster than chronological age. This observation appears to be a particular feature of RSS, possibly enhanced by hGH therapy. An improvement of adult height beyond the final height usually observed in RSS children without endocrine disturbances should therefore not be expected from hGH therapy. Growth hormone deficiency and RSS do not appear to be causally related. However, in each child with RSS, a particular attention should be given to a decreased height velocity, a severely delayed bone age as well as a history of major perinatal problems. Should one of these factors be found, a careful evaluation of the hypothalamo-pituitary axis ought to be performed with, accordingly, an appropriate substitutive therapy.