Michaela Marx

Radiation therapy of optico–hypothalamic gliomas (OHG) – radiographic response, vision and late toxicity

BACKGROUND Management strategies for optic pathway gliomas include observation, surgery, irradiation, chemotherapy and a combination of these modalities. It has been the policy of our University Hospital to consider radiation as the standard treatment for progressive optic pathway gliomas. This report describes the clinical presentation, treatment patterns and outcome with special emphasis on the long term functional status of patients with optico-hypothalamic gliomas (OHG). PATIENTS AND METHODS Between 1975 and 1997, 25 patients with OHG were treated by radiation therapy (RT) following surgery or biopsy. All patients received a local RT with a 0.5-1 cm margin around the lesions as depicted on CT or MRI scans. Age adjusted radiation doses ranged from 45 to 60 Gy with a single fraction size of 1.6-2 Gy. Endpoints of the study were: radiographic response, survival, progression-free survival and time to endocrinologic toxicity as well as the visual function during follow-up. The median follow-up time was 9 years (range, 1.5-23 years). RESULTS A partial response was noted in six (24%) of the patients, 13 (52%) patients had a stable tumour throughout the observation period and six (24%) patients had a tumour progression. Overall survival and progression-free survival rates were 94 and 69% at 10 years, respectively. A significant influence on progression-free survival was noted for age at diagnosis (P=0.04) and total dose (P=0.05). Nine out of 13 (69%) patients aged below 10 years compared with 3/12 (25%) patients aged above 10 years experienced hypothalamic-pituitary deficiency (P=0.008) during follow-up. As for visual acuity, nine patients had an improvement, another 13 patients a stable situation and three patients a measurable deterioration. Visual field deficits improved in three, remained unchanged in 16 patients and worsened in only one patient. CONCLUSION Postoperative RT with a total dose above 45 Gy should be considered as standard treatment in OHG with documented progression. Close radiographic monitoring and lifelong yearly evaluation for the need of possible hormone replacement are strongly recommended.

Endokrinologische Funktionsstörungen nach Hirntumortherapie im Kindesalter

Hintergrund: Fortschritte in der Therapie maligner Hirntumoren im Kindesalter haben in den letzten Jahrzehnten zu einer deutlichen Verbesserung der Überlebensraten geführt. Daher kommt dem Erkennen therapiebedingter Spätfolgen zunehmend eine Bedeutung zu. Neben Zweittumoren, kognitiven und intellektuellen Einbußen spielen hormonelle Folgestörungen eine bedeutende Rolle. Methode: Eigene Erfahrungen und Literaturrecherche. Ergebnisse: In der Regel kommt es als erstes und am häufigsten zu Störungen der Wachstumshormonsekretion. Störungen der spontanen Wachstumshormonsekretion wurden bereits nach konventionell fraktionierter Schädelbestrahlung mit 18 Gy beobachtet. Mit einiger Latenz können auch Störungen der anderen hypothalamo-hypophysären Achsen bis hin zum Panhypopituitarismus auftreten. Die Pubertät kann verfrüht oder verspätet beginnen oder ganz ausbleiben. Insbesondere bei Mädchen kommt es nach Hirntumortherapie gehäuft zur frühen und im Ablauf beschleunigten Pubertätsentwicklung, die durch eine akzelerierte Knochenreifung zu einer weiteren Verminderung der Endgröße führt. Hypothalamo-hypophysär bedingte Störungen der Schilddrüsenfunktion und der Nebennierenrindenfunktion sind seltener und werden in der Regel erst nach hypothalamo-hypophysären Strahlendosen von über 40 Gy beobachtet. Schlußfolgerung:Überlebende eines Hirntumors im Kindesalter müssen als Langzeitüberlebende betrachtet werden, bei denen bereits kurz nach Ende der Tumortherapie die ersten der therapiebedingten Spätfolgen auftreten. Um für den individuellen Patienten eine maximale Lebensqualität zu erreichen, ist eine langfristige Betreuung mit enger Kooperation der verschiedenen beteiligten Fachdisziplinen unabdingbar.Background: Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role. Method: Own data and literature review. Results: Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy. Conclusion: Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.

Pubertas praecox vera bei einem indischen Mädchen nach Adoption durch deutsche Eltern

ZusammenfassungDie Abhängigkeit der zeitlichen Pubertätsentwicklung von nutritiven Faktoren ist bekannt. In der Literatur zeigt sich bei Mädchen, die aus Entwicklungsländern in hochindustrialisierte Länder adoptiert wurden, eine erhöhte Inzidenz der Pubertas praecox vera. Wir berichten über ein indisches Mädchen, das mit 5 Jahren aus einem südindischen Waisenhaus von deutschen Eltern adoptiert wurde und mit 6 Jahren eine Pubertas praecox vera zeigte. Unter Therapie mit dem GnRH-Analogon Leuprorelinazetat konnte die Progredienz der Pubertät aufgehalten werden. Diskussion: Als Ursache für die erhöhte Inzidenz der vorzeitigen Pubertätsentwicklung bei Kindern nach Adoption aus Entwicklungsländern kommen neben genetischen und psychosozialen Faktoren die verbesserten Ernährungsbedingungen in Betracht, die in einer zeitlich begrenzten kritischen Phase der hypothalamischen Reifung zu einer vorzeitigen Aktivierung des hypothalamischen GnRH-Pulsgenerators führen können. Über welche Mechanismen die verstärkte Stoffwechselaktivität auf die hypothalamische Reifung Einfluß nimmt und ob einzelne Neurotransmitter oder Substanzen wie Leptin als primäre Signale wirken, ist bislang noch nicht bekannt.SummaryThe correlation between nutritional status and the timing of puberty is well known. Literature shows an increased incidence of central precocious puberty in children after adoption from developing countries with poor socioeconomic standard. We report the case of an Indian girl that has been adopted by German parents at the age of five years. At the age of six she showed a central precocious puberty, the progression of which could be stopped by a therapy with the GnRH-analogue Leuprorelin-acetate. Discussion: Apart from genetic and psychosocial reasons the influence of improved nutritional conditions, that are able to lead to a premature activation of the hypothalamic GnRH-pulse-generator during a critical phase of hypothalamic maturation, have to be taken into account to explain this observation. Exact mechanisms of how hypothalamic maturation is influenced by the increased metabolic ability and the role of single neurotransmitters or substances like leptin, are unknown upto now.

Effects of Puberty on Bone Age Maturation in a Girl After Medulloblastoma Therapy

BACKGROUND Craniospinal radiotherapy for malignant brain tumors can result in a variety of neuroendocrine disturbances, among which are the development of growth hormone deficiency and early puberty, which can markedly reduce adult height. METHODS The authors report the case of a girl who received craniospinal radiotherapy for a medulloblastoma at the age of 3.4 years. At 9.1 years, growth hormone therapy was started, and spontaneous onset of puberty (Tanner stage B2) occurred at age 10.3 years. Interval until menarche was short, at only 0.9 years. RESULTS Although chronologic age at appearance of Tanner stages was within the normal range, the patient showed a rapid acceleration in skeletal maturation, resulting in adult short stature. CONCLUSION Bone age seems to be a more precise parameter for biologic maturation in some patients after craniospinal irradiation than is clinical assessment of pubertal stages. Thus, if progression of bone age and decreasing final height predictions are noted, puberty should be stopped with gonadotropin-releasing hormone analogs, even if pubertal development seems to be adequate for chronologic age, because this increases the remaining time for growth hormone treatment.

A Boy Presenting with Familial Short Stature - Diagnosis Gitelman Syndrome

Patients with Gitelman syndrome are usually diagnosed by chance or present with muscular weakness, constipation, or tetanies due to hypokalemia and hypomagnesemia. We present a short statured boy with a clear history of familial short stature, normal growth and a final height prognosis within the target height range. However, routine laboratory studies led to the diagnosis of Gitelman syndrome. If a baseline laboratory analysis had not been performed, this diagnosis would have been missed.

Short-term adverse effects of testosterone used for priming in prepubertal boys before growth hormone stimulation test

Abstract Background: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. Methods: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. Results: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. Conclusions: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.

Adrenal crisis in a 14-year-old boy 12 years after hematopoietic stem cell transplantation

Summary We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison’s disease along with autoimmune thyroid disease and/or type 1 diabetes. Learning points: Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period. Primary adrenal insufficiency after HSCT is absolutely rare. The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2.

Sequentialer Arginin-Insulin-Test (SAIT) Eine sinnvolle Alternative zum isolierten Insulintoleranztest und Arginintest?

ZusammenfassungFragestellung: Es wurde eine retrospektive Analyse zur Beurteilung des sequentialen Arginin-Insulin-Tests (SAIT) in der Diagnostik eines Wachstumshormon(GH)-Mangels durchgeführt. Patienten und Methode: 29 kleinwüchsige Kinder (4,1–16,1 Jahre) waren mit dem SAIT getestet worden, 20 (5,2–19,3 Jahre) hatten einen Insulintoleranztest und am nächsten Tag einen Arginintest erhalten. Ergebnisse: SAIT-Gruppe: Bei 5 Kindern fand sich ein GH-Mangel. 5 Patienten hattenkeinen GH-Anstieg nach Arginin, erreichten aber GH-Werte von im Mittel 13,3 ng/ml nach Insulin. Kinder, die schon nach Arginin GH-Werte >10 ng/ml hatten, zeigten nach Insulingabe keinen weiteren Anstieg. Bei 13/29 Patienten mußte der Test wegenstarker hypoglykämischer Nebenwirkungen abgebrochen werden. In der Gruppe mit isolierten Insulintoleranz- bzw. Arginintests zeigten 12/20 Kinder einen normalen GH-Anstieg >10 ng/ml. 8/20 Patienten wiesen einen GH-Mangel uf. Schlußfolgerung: Nach normalem GH- Anstieg auf Arginin ist die insulin-induzierte Hypoglykämie im SAIT nicht in der Lage,einen 2. GH-Peak auszulösen. Sie verhindert lediglich den physiologischen GH-Abfall und scheint daher nicht sinnvoll. Zusätzlich isteine hochdosierte Insulingabe nach Arginininfusion mit einer höheren Nebenwirkungsrate beladen.SummaryBackground: Retrospective analysis toassess the value of the sequential arginine-insulin-test (SAIT) in the diagnosis of growth hormone deficiency (GHD). Patients and methods: 29 short statured children (4.1–16.1 years) were tested with the SAIT, 20 (5.2–19.3 years) received aninsulin tolerance test and on the following day an arginine test. Results: SAIT-group: GHD was diagnosed in 5 patients. After arginine there was no GHincrease in 5 children, but after insulin they reached maximal GH concentrations of13.3 ng/ml (mean). In children with GH values >10 ng/ml after arginine we found no further GH peak after insulin. The test had to be interrupted in 13 patients because ofhypoglycemic side effects. In the group with isolated insulin tolerance or arginine tests, respectively, 12 children had normal GH peaks >10 ng/ml and 8 were found to have GHD. Conclusion: After a normal GH response to arginine, insulin induced hypoglycemia in the SAIT is not able to stimulate a further GH peak. It just prevents the physiologic GHdecrease and therefore seems to make no sense. Additionally, a high dose insulin injection after arginine infusion causes more side effects.