Phenotypic heterogeneity in familial isolated growth hormone deficiency type I-A

We studied an Argentinian family of Spanish ancestry in which the parents are of normal height and three of their four children have isolated GH deficiency type I-A. Restriction endonuclease analysis of DNA isolated from leukocytes was done using 32P-labeled human GH (hGH) cDNA sequences as a probe. The three siblings were homozygous, while their parents and the remaining sibling were heterozygous for a deletion of about 7.5 kilobases DNA, which included the normal hGH gene. The phenotype of the affected subjects differed in several respects. There was variation between the homozygotes in birth length and height before hGH treatment and growth responses during long term hGH treatment. Furthermore, heterozygotes in this family had normal height despite their diminished hGH responses to provocative tests.     

Serum luteinizing hormone and follicle-stimulating hormone and the response to luteinizing hormone-releasing factor in children and adolescents with isolated growth hormone deficiency

Serum concentrations of LH and FSH were measured in 95 patients (62 males and 33 females) with presumed isolated GH deficiency [chronological age range, 5-17 yr; bone age (BA) range, 2-15.5 yr] before and after the iv administration of 100 micrograms LRF. The results were compared to those of patients of similar skeletal maturity, derived from a population of 136 children (79 males and 57 females) with constitutional short stature. Mean serum LH concentrations were similar in the GH-deficient and control patients of either sex within the age ranges studied. Mean basal FSH concentrations in males with GH deficiency were similar to the controls between BA 2 to less than 10 yr and more than 12 to 15.5 yr. The mean peak, peak minus basal, and integrated responses of LH concentrations after the iv administration of LRF were not significantly different in patients with GH deficiency from the responses in normal short children of similar ages. After LRF administration, GH-deficient males of BA between 2 and less than 10 yr had diminished FSH responses. The mean peak concentration was 1.9 +/- 0.2 ng/ml in GH-deficient males (n = 34) and 2.8 +/- 0.3 ng/ml (less than 0.05) in control males (n = 45). GH-deficient males of BA between 10-12 yr had slightly elevated mean peak and total integrated FSH concentrations; in GH-deficient patients (n = 15), these values were 2.7 +/- 0.2 ng/ml and 2.1 +/- 0.2 ng X min ml-1, respectively; and in controls (n = 18), they were 1.8 +/- 0.2 ng/ml (P less than 0.05) and 1.5 +/- 0.2 ng X min ml-1 (P less than 0.05). In the BA range from 4-8 yr, the mean peak response to LRF was diminished in GH-deficient females (n = 24; 4.0 +/- 0.4 ng/ml) compared to that in control females (n = 18; 6.0 +/- 0.9 ng/ml; P less than 0.05). In the BA range from more than 8 to 13 yr, the corresponding mean peak FSH concentration in GH-deficient females (n = 9) was 3.2 +/- 0.3 ng/ml; in control females (n = 39), it was 4.9 +/- 0.4 ng/ml (P less than 0.05). This study fails to confirm previous reports that LRF-evoked LH release is diminished in patients with isolated GH deficiency compared to that in normal short children of similar skeletal maturity. Small differences in group mean FSH concentrations were noted, but these findings are of limited clinical importance because an extensive degree of overlap of individual FSH concentrations was found in all comparisons between GH-deficient patients and normal children.     

Human pituitary growth hormone (hGH) therapy in growth hormone deficiency

This review has attempted to answer a number of questions regarding human growth hormone therapy in growth hormone deficiency. I believe that the available data support several conclusions which form a suggested current approach to the clinical use of hGH. While these conclusions are derived from data obtained using pituitary growth hormone, it is likely that they are applicable to growth hormone manufactured by recombinant DNA technology, as well. Treatment should be begun as early as the diagnosis can be made in anticipation of a better initial and long-term response in younger patients. Growth hormone should be administered on the basis of body weight in an initial dose of 0.06-0.10 unit/kg 3 times a week. Growth hormone may be administered either intramuscularly or subcutaneously. Therapy should be continuous whenever possible. Treatment should be given until there is no further response which generally will reflect closure of the epiphyses. Associated hormone deficiencies should be adequately treated, and patients should be periodically evaluated for the development of additional deficiencies. Concomitant therapy is not indicated unless deficiencies are clearly demonstrated. Thyroid replacement should be at full dosage, while glucocorticoid replacement should probably not exceed 10-15 mg/m2 x day. Gonadal steroids should be used at the bone age when puberty is expected, and hGH should be continued during pubertal development. There is no general indication for giving anabolic/androgenic steroid in combination with hGH in prepubertal patients. If a waning effect of therapy is observed, the dose of hGH should be incrementally increased, and/or the addition of anabolic/androgenic steroid therapy should be considered. While most reports have focused on the effect of hGH on linear growth, changes in weight, bone age, body proportions, and body composition have also been observed. The effect on bone age is variable, but there is greater enhancement of linear growth than of epiphyseal development in the majority of treated patients. Bone age must be monitored during hGH administration whether or not anabolic/androgenic steroids are used concurrently. Growth hormone administration is remarkably free of side effects. However, neutralizing antibodies to hGH may develop and they should be sought in patients in whom an unexplained decrease in response is observed. Certainly the available incomplete data allow for different conclusions. The expanding supply of hGH should lead to a more systematic evaluation and provide more definite answers to the questions which this review has considered.     

Combined treatment with growth hormone and gonadotropin-releasing hormone analogues in children with isolated growth hormone deficiency.

In subjects with an isolated GH deficiency the inhibition of puberty by GnRH-analogue administration may be attempted to delay the onset, or to prolong the duration, of pubertal maturation in order to improve final height. We report our experience on the matter in 10 subjects (6M, 4F) suffering from isolated GH deficiency with a chronological age ranging from 6.5 to 10.6 years at diagnosis. After a period of 1-5.1 years of GH treatment, GnRH-analogues (long-acting D-Trp-6-GnRH) were added to GH for 12 months, when six subjects were still prepubertal and four in early puberty. During combined therapy, a regression in pubertal development was shown in three out of four children in early puberty, while serum testosterone or estradiol decreased. Height velocity decreased (from 5.23 +/- 1.49 (mean +/- SD) to 4.12 +/- 0.67 cm/year; p < 0.02), whereas height SD scores for bone age increased (from -0.75 +/- 0.42 to -0.47 +/- 0.55; p < 0.02). During the year of combined therapy, bone age increased only 0.57 +/- 0.27 years. The values for predicted height (TW2 and Bayley-Pinneau method) after combined treatment were also higher than those after treatment with GH alone (p < 0.02 and p < 0.001, respectively). Our preliminary data showed that the addition of GnRH-analogues to GH in subjects with isolated GH deficiency reduces the effect of GH on height velocity, but determines an improvement in statural prognosis, although a proper answer will not be obtained until final height has been achieved.     

Dose dependence of growth response to human growth hormone in growth hormone deficiency.

A trial of the relative effect on growth of 20 IU/week and 10 IU/week of human growth hormone has been made in 38 patients with "isolated" growth hormone deficiency over 1 year of treatment, 18 patients over 2 years and 10 over 3 years, and in 17 patients with surgically treated craniopharyngiomata over 1 year. The velocity of height growth in the first year of treatment, compared with a full year of pre-treatment control, was 1.3 times as great in both groups of patients on the larger dose as it was in those on the smaller one. Second-degree equations fitted to the treatment catch-up curve gave estimates of 1.7 cm more height gained on the larger dose by the end of the first year, 2.7 cm by the end of the second, and 3.4 cm by the end of the third. Adjusting treatment increment by covariance for bone age at the beginning of treatment, pre-treatment velocity, and body surface area did not alter these mean differences. Bone age velocity during treatment was the same in both treatment groups (mean 1.09 "years"/year in the first year); thus we anticipate a gain in final adult height of the order of 10 cm from employing the larger dose. The decrease in skin folds occurring on treatment, however, was no different with the larger than with the smaller dose. This reinforces previous observations that the short-term metabolic and longer-term auxologic effects of hGH are not necessarily related.     

Evaluation of adult idiopathic growth hormone deficiency with other pituitary hormones deficiency

The type and percentage of multiple pituitary hormone deficiency (MPHD) were studied in 42 patients with idiopathic growth hormone deficiency (IGHD). It was found that the development of secondary sexual characteristics was poor or absent in 39 patients (93%) with gonadotropin deficiency (GnD). Mean serum testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the 39 patients were significantly less than those of normal adult males (P less than 0.01). Mean testicular volume in 36 patients with GnD was significantly less than that in 3 with normal T level. We also found that 24-hour urinary free cortisol level (24 hour UFC) was low in 24 (57.1%) of 42 patients, but it is important that none had obvious symptoms of hypoadrenocorticism such as hypoglycemia, hypotension etc and received adrenal-corticosteroid treatment. 22 (52.4%) of the 42 patients suffered from hypothyroidism, with serum thyroxine (T4) level lower than normal but thyrotrophin (TSH) within normal range. 6 patients with hypothyroidism had moderate symptoms such as cold intolerance, constipation, rough and dry skin, slowing down both mentally and physically. 17 patients have treated with thyroxine. From the results mentioned above, 14 of the 41 patients with MPHD had pan-pituitary hormones (LH, FSH, TSH, ACTH) deficiency, only one had isolated growth hormone deficiency. Among all the patients, 23 underwent breech delivery and 11 patients had birth asphyxia. We therefore conclude that: (1) most of the IGHD cases are complicated with other pituitary hormone deficiency; (2) most of the IGHD cases have with MPHD; (3) Breech delivery and birth asphyxia were important etiological factors of IGHD.     

Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II).

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.     

Outcome of growth hormone therapy in children with growth hormone deficiency showing an inadequate response to growth hormone-releasing hormone

Saizen (recombinant growth hormone [GH]), 0.2 mg/(kg x wk), was given in an open-label fashion for an average of 51 mo to 27 children with presumed idiopathic GH deficiency who had withdrawn from a trial of Geref (recombinant GH-releasing hormone [GHRH] 1-29) because of inadequate height velocity (HV) (25 children), the onset of puberty (1 child), or injection site reactions (1 child). Measurements were made every 3-12 mo of a number of auxologic variables, including HV, height standard deviation score, and bone age. The children in the study showed excellent responses to Saizen. Moreover, first-year growth during Saizen therapy was inversely correlated with the GH response to provocative GHRH testing carried out 6 and 12 mo after the initiation of Geref treatment. These findings indicate that GH is effective in accelerating growth in GH-deficient children who do not show or maintain a satisfactory response to treatment with GHRH. In addition, they suggest that the initial response to GH therapy used in this way can be predicted by means of provoc-ative testing.     

Effects of exogenous growth hormone pretreatment on the pituitary growth hormone response to growth hormone-releasing hormone alone or in combination with pyridostigmine in type I diabetic patients.

We evaluated the effects of iv pretreatment with exogenous GH on the GH response to GHRH either alone or in combination with pyridostigmine in 14 Type I diabetic patients and 6 normal subjects. All the subjects received an iv bolus injection of biosynthetic human GH, 2 IU; 2 h later they received either a. pyridostigmine, 120 mg orally, or b. placebo, 2 tablets orally, followed 1 h later by iv injection of GHRH(1-29) NH2, 100 micrograms. In normal subjects the median GH peak after GH+ GHRH was 1.8, range 1.2-6.9 micrograms/l. Pyridostigmine enhanced the GH response to GHRH in all subjects. The median GH peak after pyridostigmine + GH + GHRH was 32.7, range 19.8-42.1 micrograms/l (p less than 0.001 vs GHRH alone). Seven diabetic subjects had median GH peaks after GH + GHRH greater than 6.9 micrograms/l (the maximum GH peak after GH + GHRH in normal subjects) (group A: median GH peak 35.7, range 21.7-55 micrograms/l). The other diabetic subjects had GH peak lower than 6.9 micrograms/l (group B: median GH peak 4.4, range 2.1-6.5 micrograms/l). Pyridostigmine significantly increased the GH response to GHRH in group B patients (median GH peak 29.3, range 15.7-93.4 micrograms/l, p less than 0.001 vs GH + GHRH alone), but not in group A patients (median GH peak 39.9, range 21.9-64.9 micrograms/l). Group A diabetic patients were younger and had higher HbA1c and blood glucose levels than group B patients. In those diabetic patients with an exaggerated GH response to GH + GHRH, pyridostigmine failed to cause the increase in GH secretion observed in diabetic and control subjects with no responses to GH + GHRH.(ABSTRACT TRUNCATED AT 250 WORDS)     

A new and accurate prediction model for growth response to growth hormone treatment in children with growth hormone deficiency

OBJECTIVE: To identify parameters which predict individual growth response to recombinant human GH (rhGH) therapy and to combine these parameters in a prediction model. DESIGN: Fifty-eight prepubertal patients with GH deficiency (17 females) participated in this prospective multicenter trial with 1 year of follow-up. METHODS: Auxological measurements, parameters of GH status and markers of bone metabolism were measured at baseline and at 1, 3 and 6 months after the start of rhGH treatment. Correlations with height velocity during the first 12 months of treatment (HV+12) were calculated. Prediction models were derived by multiple regression analysis. RESULTS: The model which best predicted HV+12 combined the following parameters: pretreatment bone age retardation as a fraction of chronological age, pretreatment serum levels of IGF-I, urinary levels of deoxypyridinoline (a marker of bone resorption) after 1 month of treatment and height velocity after 3 months of treatment. This model explained 89% of the variation in HV+12 with a standard deviation of the residuals of 0.93 cm/year. Defining successful rhGH therapy as a doubling of pretreatment height velocity, the model had a specificity of 90% and a sensitivity of 100% in predicting therapeutic success. CONCLUSIONS: This model is an accurate and practicable tool to predict growth response in GH-deficient children. It may help to optimize rhGH therapy by individual dose adjustment and contribute to improved overall outcomes.     

Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies

CONTEXT: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. OBJECTIVES: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. DESIGN AND SETTING: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. PATIENTS AND METHODS: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 microg/liter after an insulin tolerance test or peak GH levels less than 5 microg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. RESULTS: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. CONCLUSIONS: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.     

Two siblings with isolated GH deficiency due to loss-of-function mutation in the GHRHR gene: successful treatment with growth hormone despite late admission and severe growth retardation

Patients with growth hormone releasing hormone receptor (GHRHR) mutations exhibit pronounced dwarfism and are phenotypically and biochemically indistinguishable from other forms of isolated growth hormone deficiency (IGHD). We presented here two siblings with clinical findings of IGHD due to a nonsense mutation in the GHRHR gene who reached their target height in spite of late GH treatment. Two female siblings were admitted to our clinic with severe short stature at the age of 13.8 (patient 1) and 14.8 years (patient 2). On admission, height in patient 1 was 107 cm (-8.6 SD) and 117 cm (-6.7 SD) in patient 2. Bone age was delayed in both patients (6 years and 9 years). Clinical and biochemical analyses revealed a diagnosis of complete IGHD (peak GH levels on stimulation test was 0.06 ng/mL in patient 1 and 0.16 ng/mL in patient 2). Patients were given recombinant human GH treatment. Genetic analysis of the GH and GHRHR genes revealed that both patientscarried the GHRHR gene mutation p.Glu72X (c.214 G>T) in exon 3 in homozygous (or hemizygous) state. After seven years of GH treatment, the patients reached a final height appropriate for their target height. Final height was 151 cm (-1.5 SD) in patient 1 and 153 cm (-1.2 SD) in patient 2. In conclusion, genetic analysis is indicated in IGHD patients with severe growth failure and a positive family history. In spite of the very late diagnosis in these two patients who presented with severe growth deficit due to homozygous loss-of-function mutations in GHRHR, their final heights reached the target height.     

The association between growth response to growth hormone and baseline body composition of children with growth hormone deficiency

ObjectiveWe wanted to examine the relationship between initial growth response to recombinant human Growth Hormone (rhGH) treatment and body composition in children with growth hormone deficiency (GHD).Design and methodsForty-two patients (21 boys and 21 girls) aged between 5.7–15.5 years (mean age: 10.8 ± 2.6 years) with isolated GHD. The auxological and laboratory data (GH and IGF-I levels) and results of bioelectrical impedance analyses were evaluated. Children with GHD were followed up for 12 months and categorized according to growth response to rhGH into good and poor responders (change in height of > 0.7 SDS or < 0.7 SDS over one year respectively). Mean doses of rhGH per kg of fat free mass (FFM) were calculated.ResultsForty-eight percent of patients showed a good growth response to rhGH therapy. At study entry, mean age, height SDS, weight SDS, serum IGF-1 SDS, IGFBP-3 SDS, growth velocity prior to rhGH therapy, GH after clonidine and l-dopa were similar in the two groups. At baseline, BMI SDS and waist–hip ratio were significantly higher in good responders (p = 0.02 and p = 0.006, respectively). Good responders had lower percentages of FFM (73.4 ± 8.9 vs. 83.1 ± 5.9) and total body water (TBW) (56.5 ± 5.3 vs. 63.1 ± 4.4), compared to poor responders (p < 0.05). There were significant correlations between changes in height SDS over one year and baseline body composition in children with GHD on rhGH treatment (r = ? 0.617 for percentage of FFM, r = ? 0.629 for percentage of TBW, p < 0.001). A correlation between BMI SDS, waist–hip ratio, mean rhGH dose per FFM and growth response was observed only in prepubertal subjects.ConclusionBaseline body composition data in children with GHD can be used to predict the growth response to rhGH treatment. A management strategy that involves titrating rhGH dose according to FFM as a means of optimizing the growth response to intervention requires further study.     

Reduced longevity in untreated patients with isolated growth hormone deficiency

Increased longevity of hypopituitary dwarf mice and GH- resistant knockout mice appears to be in contrast with observations made in clinical practice. In humans, on one hand hypopituitarism and GH deficiency (GHD) are believed to constitute risk factors for cardiovascular disease and, therefore, early death. But on the other hand, patients with a PROP-1 gene mutation, presenting with a combined pituitary-derived hormonal deficiency, can survive to a very advanced age, apparently longer than normal individuals in the same population. The aim of this study was to analyze the impact of untreated GHD on life span. Hereditary dwarfism was recognized in 11 subjects. Genetic analysis revealed an underlying 6.7-kb spanning deletion of genomic DNA encompassing the GH-1 gene causing isolated GHD. These patients (five males and six females) were never treated for their hormonal deficiency and thus provide a unique opportunity to compare their life span and cause of death directly with their unaffected brothers and sisters (11 males and 14 females) as well as with the normal population (100 males and females). Although the cause of death did not vary between the two groups, median life span in the GH-deficient group was significantly shorter than that of unaffected brothers and sisters [males, 56 vs. 75 yr (P < 0.0001); females, 46 vs. 80 yr (P < 0.0001)]. Therefore, with the wealth of information regarding the beneficial effects of GH replacement and the dramatic findings of this study, GH treatment in adult patients suffering from either childhood- or adult-onset GHD is crucially important.