Adherence in children with growth hormone deficiency treated with r-hGH and the easypod™ device.

PURPOSE: Poor adherence to recombinant human growth hormone (r-hGH) therapy is associated with reduced growth velocity in children with growth hormone deficiency (GHD). This twelve-month observational study was to assess adherence in r-hGH patients treated with the easypod™, an electronic, fully automated injection device designed to track the time, date and dose administered. METHODS: Ninety-seven prepubertal patients receiving r-hGH therapy were included in the study from ten Italian clinical sites and 88 completed the study. To avoid possible confounding effects, only GHD patients (79/88; 89.7 % of the overall study population) were considered in the final analysis. The primary endpoint-adherence to treatment-was calculated as the proportion of injections correctly administered during the observational period out of the expected total number of injections. The relevant information, tracked by the easypod™, was collected at months 6 (V1) and 12 (V2) after baseline (V0). At study termination, adherence data were partially available from 16 patients and fully available from 53 patients. As secondary endpoints, serum IGF-1 levels, fasting serum glucose and insulin levels and key anthropometric characteristics (height, waist circumference and BMI) were also determined. RESULTS: The easypod™ data showed that 56.7 % of the patients were considered to be fully (≥92 %) adherent to their treatment throughout the period V0-V2. Treatment improved stature, significantly increased IGF-1 and produced a non-significant increase in blood glucose and insulin levels. CONCLUSIONS: The injection-recording system and other characteristics of easypod™ could enhance the ability of physicians to monitor adherence to r-hGH treatment.

Long-term auxological and pubertal outcome of patients with hereditary insulin-like growth factor-I deficiency (Laron and growth hormone-gene deletion syndrome) treated with recombinant human insulin-like growth factor-I.

BACKGROUND: GH-IGF-I axis is mainly involved in the complex process of somatic growth but emerging evidence suggests that it also influences hypothalamic-pituitary-gonadal (HPG) function. SUBJECTS: We report some data regarding long-term auxological and pubertal outcome of five female patients with hereditary forms of GH-IGF-I deficiency (Laron and GH-gene deletion syndrome) and a mean age of 23.4±5.3 yr (range 19-32). METHODS: All the patients received recombinant human IGF-I (rhIGF-I, Pharmacia and Upjohn, Stockholm, Sweden, and rhIGF-I, Genentech, San Francisco, CA, USA) from a mean age of 8.6 yr (range 3.2-14.2) up to the final height. RESULTS: Final height was very disappointing (≤ -5.0 SD scores) and lower than target height in all the patients. Pubertal onset was delayed in most of them but menarche occurred spontaneously in all the patients. Median age at menarche was 15.1 yr. Menstrual cycles were regular for several years. Median duration of gynecological follow- up was 8.3 yr with the longest span of 17.2 yr. CONCLUSION: We can assert that GH-IGF-I axis has an essential role in promoting linear growth in humans and its physiological action cannot be replaced by pharmacological treatment in most patients with hereditary forms of IGF-I insufficiency as demonstrated by their subnormal final height. Our clinical observations can also support an essential role of IGF-I in genitalia growth but not in the function of HPG axis as demonstrated by the maintenance of regular menstrual cycles in the presence of subnormal levels of IGF-I after treatment discontinuation.

Epidemiology of SHOX deficiency.

Deletion of short stature homeobox-containing (SHOX) gene, in the pseudoautosomal region (PAR1) of X and Y chromosomes, is an important cause of short stature. Homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia, while SHOX haploinsufficiency cause a wide spectrum of short stature phenotypes, including patients with Turner syndrome, Leri Weill dyschondrosteosis (LWD), and idiopathic short stature (ISS). In Turner syndrome, haploinsufficiency of SHOX gene, as well as short stature, are present in 100%; nevertheless, SHOX deficiency accounts for only two-thirds of Turner patients' short stature. In LWD the prevalence of SHOX gene anomalies varies from 56% to 100%. This wide range might be due to different factors such as selection criteria of patients, sample size, and method used for screening SHOX mutations. The real challenge is to establish the prevalence of SHOX deficiency in ISS children given that published studies have reported this association with a very broad frequency range varying from 1.5% to 15%. An important variable in these studies is represented by the method used for screening SHOX mutations and sometimes by differences in patient selection. Short stature is present by definition in 3 out of 100 subjects; if we consider a frequency of SHOX defects of 3% among ISS, we should expect a population prevalence of 1 in 1000. This prevalence would be higher than that of GH deficiency (1:3,500) and of Turner syndrome (1:2,500 females), suggesting that SHOX deficiency could be one of the most frequent monogenetic causes of short stature.

GH secretion in a cohort of children with pseudohypoparathyroidism type Ia.

Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by Albright's hereditary osteodistrophy (AHO) and resistance to hormones that act via the alpha subunit of the Gs protein (Gsalpha) protein, ie PTH, TSH, FSH/LH, and, as recently described in limited series, GHRH. However, the current lack of data on GHRH secretion, obesity and short stature included in the AHO phenotype hampers interpretation of GH secretory status and its effects on these subjects. We evaluated GH secretion after GHRH plus arginine (Arg) stimulus, IGF-I levels and anthropometric features in an exclusively pediatric population of 10 PHP-Ia subjects. Of our PHP-Ia children, 5 out of 10 (50%) showed impaired GH responsiveness to the provocative test, with a lower prevalence than the 75-100% previously reported. A negative correlation (p=0.024) was found between GH secretion and body mass index (BMI), whereas no correlation emerged between GH and IGF-I values (p=0.948). Height and growth velocity did not significantly differ between GH-deficient and GH-sufficient subjects. In the 5 GH-deficient patients, GHRH resistance could arguably be responsible for hormonal impairment; however, 3 of them were obese, showing normal stature and IGF-I levels: the increased BMI in these subjects could influence GH secretion and its effects. In conclusion, GH deficiency is frequent among PHP-Ia children and its prevalence is variable, two factors indicating that GH secretory testing should be part of the routine management of this patient group. It could be argued that GHRH resistance is the pathogenetic mechanism in most patients, but further studies on GHRH secretion are needed to define which values can be considered as raised. Lastly, because BMI has been indicated as a major determinant of evoked adult GH response to provocative testing, GH levels related to increased BMI also in childhood could be helpful in defining GH assessment in obese or overweight PHP-Ia children.

Assessment of serum IGF-I concentrations in the diagnosis of isolated childhood-onset GH deficiency: a proposal of the Italian Society for Pediatric Endocrinology and Diabetes (SIEDP/ISPED).

The diagnosis of GH deficiency (GHD) is based on the measurement of peak GH responses to pharmacological stimuli. Pharmacological stimuli, however, lack precision, accuracy, are not reproducible, are invasive, non-physiological and some may even be hazardous. Furthermore, different GH commercial assays used to measure GH in serum yield results that may differ considerably. In contrast to GH, IGF-I can be measured on a single, randomly-obtained blood sample. A review of the available data indicates that IGF-I measurement in the diagnosis of childhood-onset isolated GHD has a specificity of up to 100%, with a sensitivity ranging from about 70 to 90%. We suggest an algorithm in which circulating levels of IGF-I together with the evaluation of auxological data, such as growth rate and growth, may be used to assess the likelihood of GHD in pre-pubertal children.

Final height in short polytransfused thalassemia major patients treated with recombinant growth hormone.

We measured the final height (FH) of 25 short polytransfused thalassemia major (Th) patients (18 males) with a reduced GH reserve treated for 3.3 +/- 1.2 yr with recombinant GH (rhGH), 0.2 mg/kg/week sc. At baseline, all patients were clinically prepubertal; their chronological (CA) and bone ages (BA) were 13.6 +/- 2.0 and 11.4 +/- 1.6 yr, respectively. In 9 out of 18 males and 5 out of 7 females, the onset of puberty occurred spontaneously during the treatment. At the end of the rhGH administration, the height of the enrolled children was not significantly increased when calculated for CA (HxCA), while it was significantly decreased (p=0.004) when calculated for BA (HxBA); the BA increase (3.29 +/- 1.65 yr) was significantly higher (p<0.001) than the height age increase (2.16 +/- 0.98 yr). The FHxCA showed a significant increase (p=0.001) compared to both baseline and the end of therapy, while the FHxBA was significantly decreased (p<0.001) compared with the corresponding value at baseline. At the end of therapy, both HxCA and HxBA resulted positively related to the BA at baseline (r=0.50 and 0.42, p=0.012 and 0.034, respectively). FH was positively correlated with CA (r=0.63, p=0.001), BA (r=0.68, p<0.001) and HxBA (r=0.59, p=0.002) evaluated at baseline, and with both HxCA and HxBA (r=0.82 and 0.74, respectively, p<0.001), evaluated at the end of treatment. A negative correlation was found between FH and the length of treatment (r=-0.56, p=0.004). Our data seem to exclude that prolonged rhGH therapy could improve FH in Th patients; on the contrary, a negative effect may be hypothesized.

[Calcium-phosphate metabolism and bone markers in two patients with Noonan's syndrome treated with growth hormone]. / Metabolismo calcio-fosforico e markers ossei in due pazienti con Sindrome di Noonan trattati con ormone della crescita.

AIM: To evaluate the possible effects of recombinant growth hormone (rhGH) therapy on mineral homeostasis and bone turnover, the authors studied calcium-phosphate metabolism parameters, including some bone markers, in 2 prepubertal subjects with Noonan's syndrome (NS). METHODS: Two prepubertal males suffering from NS, short stature (-3.9 and -5.4 SDS respectively) and low growth velocity (3.9 and 3.3 cm/year), were treated with rhGH (0.85 U/kg/week) for 1 year. Serum levels of total calcium (Ca), inorganic phosphate (P), magnesium (Mg), parathyroid hormone (PTH), calcitonin (CT), 25OH vitamin D, 1.25(OH)(2)D, osteocalcin (BGP), type I procollagen carboxy-terminal propeptide (PICP) and its telopeptide (ICTP) were measured. RESULTS: The baseline values were in the normal range; during the treatment no remarkable difference in the values of every one parameters was detected in the 2 patients studied. In one of them, who responded to GH treatment with significantly improved growth velocity, serum levels of the BGP increased during the first semester, and then progressively declined; conversely, serum levels of the ICTP remained stable during the first 6 months of GH-therapy, whereas increased in the following 6 months. CONCLUSION: The results suggest that in Noonan's syndrome patients responding to GH-therapy, a stimulation of bone turnover, with ensuing increase of height velocity, takes place, at least during the first year of GH-therapy. The authors underline the necessity of confirming their results on a larger group of patients with Noonan's syndrome.

[Psychological findings in children with short stature]. / Aspetti psicologici in bambini con bassa statura.

AIM: The aim of this study is to evaluate the psychological findings in patients with short stature. METHODS: We studied 19 subjects, 13 males and 6 females, with age range 7-14 years. We evaluated heigth, growth velocity, bone age, target height and growth hormone secretion after provocative stimuli. Psychological evaluation included: Kovacs Scale, Children's Depression Inventory (CDI), Anxiety Scale (Busnelli-Dall'Aglio-Farina); drawing of the human figure (Goodenough Test); Raven Test for neuropsychological performances (P.M. 38 and 47). Statistical analysis was performed using Mann-Whitney U-test. RESULTS: We diagnosed familial short stature (FSS) in 7 patients and growth hormone deficit (GHD) in 12. No statistical difference was found in the anxiety and depression tests, although the score was higher in GHD patients. The human figure drawing and the interview revealed low self-esteem, sense of inadequacy, dependence from parents, social inhibition in all patients. These characteristics were more evident in patients with GHD. Neuropsycho-logical evaluation by Raven test showed normal score in all patients, however subjects with FSS exhibited a higher score than with GHD (p<0.05). CONCLUSIONS: Our data suggest a negative influence of short stature on the affective field of children with short stature; GHD patients exhibited lower neuropsychological performances and more psychological problems than patients with FSS.

Growth and puberty in thalassemia major.

Present transfusional regimen protocols increase the life expectancy of patients with beta-thalassemia major, but cause a progressive iron overload that can be prevented or limited only by appropriate iron chelation. Siderosis is responsible for the clinical complications of the disease. Short stature and hypogonadism are extremely frequent in patients with thalassemia. Many factors are responsible for short stature in patients with thalassemia, the most important of which are dysfunction of the GH-IGF-I axis and desferoxamine (DFX)-induced bone dysplasia. Hypogonadism is the most frequent endocrine complication, mostly due to gonadotrophins deficiency secondary to iron overload. Sex steroid treatment for induction of puberty and/or maintenance of sexual characteristics is necessary. Both short stature and hypogonadism are present in a significant percentage of bone marrow transplanted patients with thalassemia. Factors responsible for short stature are previous iron overload, liver impairment, DFX treatment, and toxicity of chemotherapeutic agents. In some patients absence of pubertal development is due to gonadotropin insufficiency, probably secondary to previous iron overload; other patients exhibit hypergonadotrophic hypogonadism due to the toxic effect of chemotherapeutic agents on the gonads. Both groups need hormonal replacement therapy. These data support the need for vigilant follow-up of patients with thalassemia before and after transplantation, in order to treat endocrine dysfunctions at the appropriate age.

Syndrome of renal, genital and feet malformations.

We report a 2 months old girl affected by renal hypoplasia, genital abnormalities, syndactyly and a pattern of minor anomalies. Although the pattern of malformations overlaps the Townwes-Brock syndrome and that reported by Green et al in 1996, differential diagnosis was made with other several syndromes including acral and renal anomalies.

Recombinant growth hormone treatment in short patients with thalassemia major: results after 24 and 36 months.

Treatment with recombinant growth hormone (rhGH), 0.6 IU/kg/week s.c., previously successfully conducted for one year, was continued in 15 (Group A) and 8 (Group B) short thalassemia major patients with reduced GH reserve, for two and three years, respectively. In Group A, height for chronological age (Ht SDSCA) increased significantly (p = 0.021) from the start of treatment, but the positive effect was only apparent because of the concomitant slight worsening of height for bone age (Ht SDSBA). Median deltaHt SDSCA/deltaHt SDSBA was <1.0 with respect to both the start (0.87) and the end of the first year of rhGH therapy (0.89). IGF-I levels increased significantly (p = 0.043) compared with values both at the start and at the end of the first year of rhGH therapy. In Group B neither Ht SDSCA nor Ht SDSBA differed statistically from starting values, the former having a positive trend and the latter a negative one. Median deltaHt SDSCA/deltaHt SDSBA was 0.92 with respect to the start, and 0.94 with respect to the end of the second year. IGF-I levels increased significantly (p = 0.043) with respect to starting values. Our data show that the encouraging results described from the first year of rhGH treatment did not persist during the second and third years, and we conclude that this is because increase in bone age with continued treatment is equal to, or slightly greater than the height age increase. We propose that patients with thalassemia major with short stature should receive rhGH treatment for only one year, and that more prolonged treatment should be reserved for selected adolescents who have psychological problems due to shortness; for these patients growth acceleration could represent the main goal, even if this leads to a substantially unchanged or slightly decreased final height.

Management of puberty for optimal auxological results in beta-thalassaemia major.

Short stature is present in a significant percentage of patients affected by beta-thalassaemia major. Growth failure of patients with thalassaemia is multifactorial. The most important contribution is attributed to the toxic effect of desferrioxamine and to endocrine disorders, due to iron overload. The commonest endocrine complication is hypogonadism. The growth pattern of patients with thalassaemia is characterized by normal growth during childhood, a deceleration of growth velocity around age 9-10 years, and a reduced pubertal growth spurt. In addition, reduced growth of the trunk is often present. Short stature and short trunk are more evident at pubertal age. Hypogonadism is usually considered responsible for the pubertal growth failure, as well as the aggravation of body disproportion at pubertal age. However, data suggest that pubertal height gain and final height are reduced in both patients with spontaneous puberty and patients with induced puberty. It is concluded that several aspects of peripubertal growth in patients with thalassaemia remain to be clarified.

Unresolved problems in optimal therapy of pubertal disorders in oncological and bone marrow transplanted patients.

Specialised clinics for the long-term follow-up of survivors from childhood cancer have developed over recent years. The problems encountered among patients who received multiple chemotherapy and radiotherapy can be challenging and require high expertise and close collaboration among different professionals (e.g. oncologists, endocrinologists, radiotherapists, psychologists). Endocrine disorders are often seen, particularly among those who received cranial radiotherapy or gonadotoxic chemotherapy; puberty can be affected and the spectrum of disorders may range from precocious or accelerated puberty to delayed, arrested or even absent pubertal development. Growth impairment can be multifactorial and growth hormone deficiency is an important but probably not the only factor involved. Many questions remain about the optimal management of this group of young patients. In the consensus guidelines that follow the overview an attempt is made to help optimise patients' growth and puberty by suggesting practical clinical approaches to some of the most challenging issues.

[Bone metabolism markers in thalassemia]. / Markers del metabolismo osseo nella talassemia.

The A.A. performed a screening on 113 patients affected by beta-thalassemia major ranging in age between 2 and 40 years, randomized among those which come to the Microcitemic Center of our Institute, and in a control group. In everybody, serum levels of calcium, phosphate, parathyroid hormone (PTH), calcitonin and 25-OH vitamin D were measured. Average serum levels of PTH were significantly (P < 0.001) lower in patients than controls and 12.4% of them were clearly under normal range, especially in the group above 16 years of age. Also serum levels of 25-OH vitamin D were lower in thalassemic subjects than in controls, because of the presence of 32 patients with values under normal limit. Our results are in agreement with current literature that underline the increasing incidence of endocrine complications in thalassemic patients which undergo to high transfusion regimens, owing to the increase of emosiderosis due to the low compliance to iron chelation therapy. Controversial is the pathogenesis of the absence of hypocalcemia in many patients with hypoparathyroidism and the determinism of the deficit of vitamin D.

[Calcium phosphate metabolism in thalassemia]. / Metabolismo calciofosforico nella talassemia.

The AA. performed a screening test on 113 patients affected by beta thalassemia major ranging between 2 and 40 years of age, randomized among those who come to the Microcitemic Center of our Institute, and on a control group. In all of them serum levels of calcium, phosphate, parathyroid hormone (PTH), calcitonin and 25-OH vitamin D were measured. Average serum levels of PTH were significantly (P < 0.001) lower in our patients than in control group and 12.4% of the former were clearly under normal range, especially in the group over 16 years of age. Also serum levels of 25-OH vitamin D were lower in thalassemic patients than in controls, because of the presence of 32 patients with average values under normal limit. Our results are in agreement with current literature and underline the increasing incidence of endocrine complications in thalassemic patients who undergo high transfusion regimens, because of to the increase of hemosiderosis due to the low compliance to iron chelation therapy. Controversial is the pathogenesis of the absence of hypocalcemia in many patients with hypoparathyroidism and the cause of the deficit of vitamin D.

Celiac disease and Turner syndrome.

BACKGROUND: Short stature is one of the features of Turner syndrome and a form of presentation of monosymptomatic celiac disease. METHODS: The recognition of celiac disease in two antiendomysium antibody-positive Turner syndrome girls who did not respond to growth hormone treatment led us to perform as a screening for celiac disease IgA and IgG antigliadin antibodies and antiendomysium antibodies determination in other 35 Turner syndrome patients. Intestinal biopsy was proposed to the antiendomysium antibodies-positive girls; in the former, subtotal villous atrophy was found; in the latter, one parent's consent for intestinal biopsy was not obtained. RESULTS: The prevalence of celiac disease in Turner syndrome patients observed in the present study (8.1 if we consider 3 villous atrophy, 10.8 if we consider 4 antiendomysium antibody-positive) is quite high and seems to indicate that the association of these two disorders could not be coincidental. As to the clinical picture, celiac disease appeared atypical in one case, typical in another one and as a silent form in the third case. Of the 3 cases with villous atrophy on gluten-free diet growth hormone therapy was not effective in two girls, who were older than 16 years, while in the younger patient, detected by the screening, a significant increment of height velocity and height Standard Deviation Score for Chronological Age according to Turner references was observed. CONCLUSIONS: This study suggests that celiac disease can be associated with Turner syndrome and even responsible for a failure of growth hormone therapy. Therefore we propose to perform in Turner syndrome patients antiendomysium antibody determination as a screening followed by intestinal biopsy in positive cases. This would be advisable at least before starting growth hormone treatment.

Hyporesponsiveness to intradermal administration of hepatitis B vaccine in insulin dependent diabetes mellitus.

The immune response to intradermal or intramuscular hepatitis B vaccine in 18 children with insulin dependent diabetes mellitus (IDDM) compared with 24 healthy children was studied. Patients were divided into responders, hyporesponders, and non-responders according to their antihepatitis B serum concentrations after hepatitis B vaccination. We also studied HLA class II antigen distribution and did delayed type hypersensitivity (DTH) tests on children with IDDM and controls. No difference in the immune response (antihepatitis B surface antigen antibody titres) was found with intramuscular administration, whereas with intradermal administration a statistically lower immune response (p < 0.001) was observed in children with IDDM v controls. This hyporesponsiveness cannot be attributed to HLA class II antigen distribution because their frequency was the same in both groups of children with IDDM. It is suggested that the poor immune response to intradermal hepatitis B vaccine may be due to impaired macrophage activity resulting in failure of antigen presentation, which may be of importance in the immune dysfunction in children with IDDM. This hypothesis is suggested by a significantly lower score on a DTH test to a battery of antigens in the IDDM group when compared with controls. It is therefore suggested that when the hepatitis B vaccination is offered to children with IDDM it may be preferable to give it intramuscularly.

Short stature and body proportion in thalassaemia.

Short stature and short trunk have been reported in thalassaemic patients. We report a study on stature and body proportions in 476 patients (2-36 years old) with beta-thalassaemia major, followed in 12 Italian centres. Auxological data (standing height, sitting height, subischial leg length, target height), haematological data (age at first transfusion, age at start of desferrioxamine [DFX] chelation, mean dose of DFX, ferritin values) and information regarding the presence of endocrine disorders and of bone lesions, were collected and analysed according to the age of the patients, in order to investigate the natural history of the disproportion and the role of siderosis, DFX toxicity and endocrine disorders. Our data indicate that about 18% of thalassaemic patients exhibit short stature; disproportion between the upper and lower body segments is present in 14%; however, a short trunk despite normal stature is present in another 40% of patients. This is due to a spinal growth impairment which starts in infancy and progressively aggravates. We think that a short trunk is peculiar to the disease itself; however, other factors such as hypogonadism, siderosis, or DFX-induced bone dysplasia are probably involved in aggravating the body disproportion in these patients.

Short-term therapy with recombinant growth hormone in polytransfused thalassaemia major patients with growth deficiency.

Growth failure is commonly described in polytransfused thalassaemia major patients (Th) with or without growth hormone (GH) releasing hormone-GH axis impairment. We have investigated the efficacy of short-term recombinant GH (rhGH) therapy (Saizen [Serono] 0.1 IU/kg/day 6 evenings/week administered s.c. for 12 months) on growth and predicted final height in 28 (19M, 9F) regularly transfused Th with growth deficiency (aged 14.8 +/- 2.0 yr) on long term desferrioxamine s.c. therapy. All Th had no evidence of congestive heart failure, hypothyroidism or impaired glucose tolerance; in all patients the GH peak (evaluated during both insulin and clonidine test) was < or = 20 mIU/l; hypergonadotropic hypogonadism was excluded in Th with delayed puberty. At the start of therapy height age (HA)/bone age (BA) ratio was 0.92 +/- 0.12. Bone age delay was positively correlated to chronological age (CA), serum ferritin levels (mean of the last three years), the age at the start of chelation therapy, growth velocity calculated for CA during the last year; a positive correlation was also found between circulating IGF-I levels and age at the start of chelation therapy. After 1 year on rhGH therapy there was a significant increase of height calculated for CA (not for BA), of growth velocity calculated for both CA and BA and of circulating IGF-I levels; the HA variation/BA variation ratio was 1.85 +/- 1.71, without any significant difference between predicted final height at the start (-1.08 +/- 1.28 SDS) and at the end of rhGH therapy (-0.88 +/- 1.13). The variation of height calculated for CA was positively correlated to both CA and growth velocity during the last year before rhGH therapy (calculated for CA) and negatively to the height at the start (calculated for CA). There were no side effects and haematological parameters did not show significant changes. In conclusion, our data, obtained in a relatively large group of Th, confirm the emerging results of short-term (12 months) rhGH therapy on growth, as shown by the increase of both growth velocity and height calculated for CA. With regard to final height, although the mean variation of HA/variation of BA ratio was 1.85, no significant increase of the predicted final height was found between the start and the end of rhGH therapy. We are evaluating the effect of long-term rhGH therapy on growth in these patients.