Orthopedic complications related to growth hormone therapy in a pediatric population.

Since the introduction of recombinant growth hormone, its use has diversified and multiplied. Growth hormone is now the recommended therapy for a growing indication to all forms of short stature because of its direct and indirect role on bone growth. Hereby, we discuss the orthopedic complications associated with growth hormone treatment in pediatric patients. These complications include carpal tunnel syndrome, Legg-Calve-Perthes' disease, scoliosis, and slipped capital femoral epiphysis. Their incidence rates recorded in several growth hormone therapy-related pharmacovigilance studies will be summarized in this study with focused discussion on their occurrence in the pediatric and adolescent age groups. The pathogenesis of these complications is also reviewed.

Long-term safety of recombinant human growth hormone in turner syndrome.

CONTEXT: Turner syndrome (TS) affects more than 50,000 girls and women in the United States. The National Cooperative Growth Study (NCGS) has collected efficacy and safety data for 5220 TS children treated with recombinant human GH (rhGH) during the last 20 yr. OBJECTIVES: Our objective was to determine frequencies of specific targeted adverse events (AEs) and additional AEs of interest in TS patients. Corresponding safety data in non-TS patients or normal populations were compared for selected AEs. METHODS: Patients may be enrolled at rhGH initiation and followed until discontinuation. Investigators submit AE reports describing any event that is potentially rhGH related or is a targeted event. RESULTS: The Genentech Drug Safety department received 442 AE reports for TS NCGS patients as of June 30, 2006, including 117 serious AEs. Seven deaths occurred; five resulted from aortic dissections/ruptures. The incidence of certain events known to be associated with rhGH (targeted events), including intracranial hypertension, slipped capital femoral epiphysis, scoliosis, and pancreatitis, was increased compared with other non-TS patients in NCGS. There were 10 new-onset malignancies that occurred, including six in patients without known risk factors. Type 1 diabetes also appeared to be increased compared with other NCGS groups. CONCLUSIONS: Children with TS who were treated with rhGH exhibit an increased underlying risk for selected AEs associated with rhGH and for type 1 diabetes, which is likely unrelated to rhGH. The aortic dissection/rupture incidence reflects the higher baseline risk for these events in TS, was consistent with current epidemiological data in smaller TS populations, and is likely unrelated to rhGH. It is not known whether the reported malignancies represent an inherently increased risk in TS patients. Twenty years of experience in 5220 patients indicates no new rhGH-related safety signals in the TS population. The NCGS and similar registries, although focused on the years during rhGH treatment, may also be a window into the natural history of TS in childhood.

Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database.

BACKGROUND: Several uncommon adverse effects may be related to growth hormone (GH) treatment. Three potential side effects, headache, idiopathic intracranial hypertension (IIH) and slipped capital femoral epiphysis (SCFE), will be discussed. Data from 57,968 children in the KIGS (Pfizer International Growth Study database) were analyzed to determine the effects of recombinant human GH (Genotropin) on these side effects. The diagnostic groups were idiopathic GH deficiency (IGHD) (n = 27,690), congenital GHD (CGHD) (n = 2,547), craniopharyngioma (n = 1,155), cranial tumours (n = 2,203), Turner syndrome (TS) (n = 6,092), idiopathic short stature (ISS) (n = 5,286), small for gestational age (SGA) (n = 2,973), chronic renal insufficiency (CRI) (n = 1,753) and Prader-Willi syndrome (PWS) (n = 1,368). RESULTS: Total incidence (per 100,000 treatment years) of headache was 793.5 (n = 569). The incidence was significantly higher in the groups of patients with craniopharyngiomas, CGHD and cranial tumours than in the other diagnostic groups (p < 0.05 for all). IIH occurred in 41 children resulting in a total incidence (per 100,000 treatment years) of 27.7. The incidence (per 100,000 treatment years) was significantly lower in patients with IGHD (12.2) than in those with TS (56.4) (p = 0.0004), CGHD (54.5) (p = 0.0064), PWS (68.3) (p = 0.0263) and CRI (147.8) (p < 0.001). No cases of IIH were reported in the ISS group of patients. The median duration from onset of GH therapy to IIH ranged from 0.01 to 1.3 years in various diagnostic groups. SCFE was observed in a total of 52 children resulting in a total incidence (per 100,000 treatment years) of 73.4. The incidence (per 100,000 treatment years) was significantly lower in patients with IGHD (18.3) and in those children with ISS (14.5) than in the TS (84.5), cranial tumours (86.1) and craniopharyngioma groups (120.5) (p < 0.05 for all). No cases of SCFE were reported in the SGA and PWS groups. The median duration from onset of GH therapy to SCFE ranged from 0.4 to 2.5 years. CONCLUSIONS: The incidences of IIH and SCFE in this analysis are lower than the values reported in previous KIGS analyses and comparable to other databases. Patients with TS, organic GHD, PWS and CRI seem to be more prone to these side effects.

Monozygotic twins with Turner syndrome develop slipped capital femoral epiphysis on growth hormone therapy.

Monozygotic twins with Turner syndrome have rarely been reported. An increased incidence of slipped capital femoral epiphysis has been associated with growth hormone therapy, as well as with Turner syndrome, but has never been described in twins with Turner syndrome. We report the first case of monozygotic twins with Turner syndrome with a 46,Xi(Xq) karyotype, both of whom developed slipped capital femoral epiphysis during growth hormone therapy. This report adds to existing reports of monozygotic twins with Turner syndrome and contributes to recognition of the potential clinical course in such patients. In addition, the association between slipped capital femoral epiphysis, growth hormone therapy, and Turner syndrome is emphasized.

Orthopaedic concerns in children with growth hormone therapy.

Growth hormone (GH) therapy is widely used in children; it may have various severe orthopaedic complications. Slipped capital femoral epiphysis, Legg-Calvé-Perthes disease, scoliosis and carpal tunnel syndrome may occur with GH treatment. Before beginning GH therapy, it is important to take into account all the risk factors of the individual patient, as some conditions could contraindicate GH treatment. During GH treatment, close monitoring with both clinical and radiographic examination is mandatory. The paediatric orthopaedic surgeon will frequently be asked about the management of these complications and about the necessity for treatment arrest. The authors review the orthopaedic complications which the orthopaedic surgeon may encounter in patients treated with GH.

Atypical slipped capital femoral epiphysis after radiotherapy and chemotherapy.

Atypical slipped capital femoral epiphysis after radiotherapy and chemotherapy is uncommon. Only 32 cases have been reported in the literature. Because patients may have slippage at atypical ages, we report two cases of slipped capital femoral epiphysis in children and review the 32 cases previously reported to heighten clinicians' awareness of this condition in patients who have received radiation and chemotherapy for pelvic tumors. The controversy over prophylactic pinning of the uninvolved hip in radiotherapy-associated slipped capital femoral epiphysis is unresolved. It may be justifiable to fix the nonslipped epiphysis if possible prodromal signs of abnormal radiographic findings are detected. Because radiotherapy and chemotherapy were used in the two children reported, it is not possible to state whether one or both forms of treatment were responsible for the atypical slipped capital femoral epiphysis.

Bone diseases in children receiving growth hormone.

The authors report two cases of bone disorders in children with short stature, with confirmed growth hormone (GH) deficiency treated by GH supplementation. The first patient, aged 15 years, developed avascular necrosis of the femoral head and scoliosis. The second one, aged 17 years, had avascular necrosis of the femoral capital epiphysis on one side and acute slipped capital femoral epiphysis (SCFE) on the other side. All these complications were diagnosed while they were receiving GH-therapy. The exact aetiology and the role of GH in the pathogenesis of these conditions are still unknown.

Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease.

OBJECTIVE: Recombinant human growth hormone (rhGH) has been used to improve the growth retardation associated with chronic renal insufficiency (CRI) and end-stage renal disease. We determined the incidence of one of four targeted adverse events (AEs): malignancy, slipped capital femoral epiphysis (SCFE), avascular necrosis (AN), and intracranial hypertension (ICH). STUDY DESIGN: During a 6.5-year period, we prospectively assessed patients enrolled in the CRI, dialysis, and transplant registries of the North American Renal Transplant Cooperative Study. The availability of an untreated control population facilitated determining whether or not there was the association between the AE and rhGH treatment. RESULTS: Of the targeted AE, the only significant relation with rhGH treatment was the presence of ICH in patients with CRI; however, in all 3 instances, ICH occurred 2, 50, and 1131 days after discontinuation of rhGH. Considering that the mechanism of ICH in rhGH-treated patients is thought to be increased CSF production, rhGH probably had no role in the development of ICH in at least 2 of the 3 patients with CRI. A number of nontargeted AE were identified that have been associated with rhGH treatment in patients without renal disease. The incidence of glucose intolerance, pancreatitis, progressive deterioration of renal function, acute allograft rejection, and fluid retention were not more frequent in those receiving rhGH treatment compared with the control population. CONCLUSIONS: This report validates the importance of a control population in ascribing AE to any therapeutic intervention. Previously identified AE associated with rhGH treatment are infrequent in patients with CRI and end-stage renal disease.

Can GnRH-agonist treatment cause slipped capital femoral epiphysis?

Slipped capital femoral epiphysis (SCFE) mainly occurs in pubertal children and is associated with delayed skeletal maturation, obesity, high growth velocity and tall stature. Furthermore, SCFE often coincides with endocrine disorders. This is the first report of a possible relationship between SCFE and GnRH agonist treatment: four patients developed SCFE during or shortly after treatment with GnRH agonists was stopped. We compared the clinical aspects of these patients with patients described in the literature who developed SCFE. Puberty started at the age of 3.3, 9.6, 0.0 and 5.6 years respectively. One patient developed sequential SCFE of both hips. SCFE occurred at the age of 11.9 (patient 1), 12.7 (patient 2), 14.3 (patient 2), 11.3 (patient 3) and 11.3 (patient 4) years. Of the five incidences of SCFE, one occurred during GnRH agonist treatment and four shortly after treatment was stopped. None of our patients met the typical criteria seen in SCFE and no 'regular' characteristics of patients with SCFE could be designated. Probably the hormonal changes during and shortly after treatment with GnRH agonists make the epiphysis more prone to slip. Considering our observations and by reviewing the literature, GnRH agonist treatment might present a risk factor for the occurrence of SCFE.

[Rôle of growth hormone therapy in the genesis of slipped capital femoral epiphysis]. / Rôle du traitement par hormone de croissance dans la genèse de l'épiphysiolyse fémorale supérieure.

The authors report two cases of children treated with growth hormone who had a secondary slipped capital femoral epiphysis. Endocrine disease, radiotherapy are some well-known etiological factors reported in literature, but growth hormone influence is still discussed. This hormone could have an indirect incidence on this pathology because of its effects on growth cartilage. The increased number of treatment with growth hormone is certainly a risk factor for slipped capital femoral epiphysis. Regular checking from "France Hypophyse" allows an early diagnosis of epiphysis and surgical fixation can be made immediately. Systematic controlateral side fixation it still discussed but allowed to continue the treatment with the same posology.

Adverse events during growth hormone therapy.

The aim of this study was to ascertain the frequency of adverse events occuring during GH therapy in Australia and New Zealand since 1988. Data for children receiving GH has been collected prospectively on a national database, OZGROW, after informed consent has been given. Adverse events were coded by clinicians and have been analysed in relation to the nature of the event and the underlying diagnosis. There were 2922 subjects analysed, representing 9004 years of GH therapy. 151 subjects reported a total of 210 adverse events giving an overall frequency of 2.3% adverse events/patient treated year. Events that were probably related to GH therapy included peripheral oedema, injection site problems and increased frequency of kyphoscoliosis and slipped epiphysis in some groups. Adverse events were more frequent in growth hormone deficient children who had previously been treated for leukaemia, 8.1%, and in children previously treated for craniopharyngioma, 5.6%. A lower frequency was found for those with a diagnosis of idiopathic short stature, 1.6%, and familial short stature, 0.9%. Kyphoscoliosis was more frequently seen in Turner's syndrome, and slipped epiphyses in adolescent individuals with growth hormone deficiency, especially following treatment for leukaemia. There were no de novo tumours reported but the frequencies of recurrence/patient year for leukaemia, solid cranial tumours and craniopharyngioma were 1.1%, 2.2% and 3.8% respectively. A low frequency of adverse events has been reported on the OZGROW database but subsets of patients may be at increased risk of musculoskeletal abnormalities during GH therapy. The frequency of tumour recurrence during therapy is not different from known rates of recurrence in individuals not treated with GH.

Slipped capital femoral epiphysis during treatment with recombinant human growth hormone for Turner syndrome.

Recombinant human growth hormone has recently been used to treat the short stature of Turner syndrome. However, this therapy may induce slipped capital femoral epiphysis, since the epiphyseal plate widens and becomes weak through either growth hormone or hypogonadism. This report shows that a slipped capital femoral epiphysis occurred during this treatment for an 11-year-old girl who was suffering from Turner syndrome. Thus, these patients who are being treated with growth hormone should be carefully observed.

[Acceleration of epiphyseolysis capitis femoris lenta as a complication of growth hormone therapy in hypophyseal insufficiency]. / Beschleunigung einer Epiphyseolysis Capitis Femoris Lenta als Komplikation einer Wachstumshormontherapie bei Hypophyseninsuffizienz.

Slipped capital femoral epiphysis is a rare complication of growth hormone therapy. We report on a young man with pituitary insufficiency, diagnosed and treated with growth hormone at the age of 14 9/12. The patient withdrew from treatment after 6 months of growth hormone therapy without significant catch-up growth or complications. At the age of 21 8/12 years slipping of the left femoral capital epiphysis became apparent 2 1/2 months after treatment with growth hormone had been resumed in combination with low dose testosterone. Young adult patients with unfused epiphyses undergoing growth hormone substitution should be informed that pain in the lower extremities during therapy may be an important sign of a complication of growth hormone therapy. In this age group, patients complaining of pain in the limb should alert the physician to the possibility that a slipped capital femoral epiphysis may be present.

[Hormonal treatment of hypophyseal dwarfism, a cause of epiphyseolisthesis capitis femoris? (author's transl)]. / Die hormonelle Behandlung des hypophysären Minderwuchses, eine Ursache des Epiphysenabrutsches?

Two cases of hypophyseal proportional dwarfism which were treated by hormones are reported. After the treatment had been finished the epiphyseal cartilage remained persistent over a long period. Moreover, in both patients an epiphyseolisthesis capitis femoris occurred in their third decennium. A causal nexus is discussed.

[Ultrastructural studies on an animal model of epiphyseolysis. Cells and matrix in the proximal growth plate of the rat tibia after administration of DL-serine(3,4,5-trihydroxybenzyl)-hydrazide] (author's transl) / Ultrastrukturelle Untersuchungen an einem Epiphyseolysemodell

After administration of DL-serine-(2,3,4-trihydroxybenzyl-)hydrazide, the growth plate of rat tibia, and most of all the zone of hypertrophic cartilage, is much widened. Numerous chondrocytes become necrotic, and their columnar arrangement disappears. There is no zone vascular invasion. Spontaneous epiphyseolyses occur frequently, The ergastoplasm is damaged most; it is dilated and forms giant and/or collapsed cisternae. At a later stage it is reduced to a few vesicles. It is assumed that the chondrocytic synthesis and secretion are disturbed. The loss of cytoplasmic processes also confirms this. In the cartilage matrix there are broad collagen fibres of an axial periodicity of 650 A, which are atypical of hyaline cartilage. Possible pathogenetic mechanisms of the distrubed fibrillogenesis are discussed in conncetion with the epiphyseolysis.