No correlation between androgen receptor CAG and GGN repeat length and the degree of genital virilization in females with 21-hydroxylase deficiency.

CONTEXT: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Case report: Kasabach-Merritt syndrome: a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha.

We describe the successful treatment of a neonate with Kasabach-Merritt syndrome who received local irradiation and interferon alpha therapy after failure of corticosteroid treatment. A male neonate, born after an uneventful pregnancy, had a huge haemangioma involving the upper right cervical region as well as severe thrombocytopenia. He was treated with corticosteroids, interferon alpha and radiotherapy. Prednisolone therapy (5 mg kg(-1) day(-1)) was started at 41 days of age. No therapeutic effect was observed after 2 weeks. At this time the tumour size had increased dramatically, platelet counts had decreased progressively and coagulation abnormalities had developed. Because corticosteroid therapy had been ineffective and the child was in a life-threatening condition, irradiation was delivered up to a total dose of 9.5 Gy in five fractions. Simultaneously, prednisolone therapy was slowly decreased and interferon alpha therapy (3 million U m(-2) day(-1)) was started and continued for 6 weeks. After irradiation with 9.5 Gy and beginning interferon alpha therapy, the tumour decreased in size and coagulation parameters normalized within 4 weeks. 6 months later, platelet counts and coagulation parameters were still normal. The tumour had further decreased in size. No acute severe side effects were observed. Radiation therapy combined with interferon alpha treatment is an alternative treatment modality when high dose corticoid steroid therapy has been ineffective in patients with Kasabach-Merritt syndrome, despite the risks of growth delay and secondary malignancy. In children showing no response to corticosteroids, radiotherapy and/or interferon alpha should be considered in Kasabach-Merritt syndrome.

Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.

OBJECTIVE: In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. DESIGN AND PATIENTS: Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. RESULTS: The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. CONCLUSIONS: Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

Long-term results of growth hormone therapy in Turner syndrome.

Short stature is one of the main features of Turner syndrome. Today, most patients are treated with growth hormone (GH) to improve adult height. We have reviewed the literature reporting adult height in patients with Turner syndrome treated with GH alone or in combination with oxandrolone. The reported adult heights as well as the height gain over projected or predicted height are still preliminary and vary considerably among studies. There is some evidence that the age of onset of therapy, dose of GH, duration of GH therapy, target height, time of estrogen substitution, or concurrent treatment with oxandrolone affect adult height. The reported height gains over projected height range from -0.20 to +16.0 cm (median: 5.1 cm) in patients treated with GH and from +0.68 cm to +10.3 (median: 6.40 cm) in patients treated with GH and oxandrolone. Thus, the presently available data are extremely varied and need further detailed analysis after all ongoing clinical trials have published the final results of all patients included in the study.

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-HSDSCO), 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-HSDSCO alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS-HSDSCO) + 6.8 cm/y +/- 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSCO. 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.

The effects of etoposide on testicular function in boys treated for Hodgkin's disease.

BACKGROUND: Testicular dysfunction with elevated follicle-stimulating hormone (FSH) levels (indicating oligospermia and/or azoospermia) is a major late sequelae after treatment for Hodgkin's disease (HD) with high cumulative doses of procarbazine, cyclophosphamide, or chlorambucil. Etoposide is a newer antineoplastic agent that is effective in the treatment of HD. However, little is known regarding its testicular toxicity, especially in the pediatric age group. METHODS: The authors evaluated testicular function in 46 young adults in first continuous complete remission after stage-dependent treatment for HD with the vincristine, etoposide, prednisone, and doxorubicin (OEPA) or OEPA/cyclophosphamide, vincristine, procarbazine, and prednisone [COPP] chemotherapy regimens and involved field irradiation, excluding patients with ilioinguinal radiotherapy. Pubertal development was documented and a standardized intravenous gonadotropin-releasing hormone test was performed measuring testosterone and basal and stimulated levels of FSH and luteinizing hormone (LH). RESULTS: Testicular volumes, Tanner stages of pubic hair, and genital development were found to be appropriate or slightly delayed for the patients' chronologic age. All 27 patients had normal basal levels of FSH and LH after treatment of Ann Arbor Stage I-IIA HD with 2 courses of OEPA. Stimulated FSH and LH levels were found to be elevated only in rare patients, thus indicating normal endocrine function and spermatogenesis. However, basal and stimulated FSH levels were outside the +2 standard deviation range in 37.5% and 83.3% of patients receiving 2 cycles of OEPA and 2 cycles of COPP chemotherapy, and in 36.4% and 66.7% of patients receiving 2 cycles of OEPA and 4 cycles of COPP chemotherapy, demonstrating a high risk of oligospermia or azoospermia with these regimens. Basal LH levels essentially were normal, whereas stimulated LH levels frequently were elevated. CONCLUSIONS: Testicular function was found to be normal in patients with Stage I-IIA HD when etoposide was used in combination with vincristine, prednisone, and doxorubicin (2 cycles of OEPA). Additional chemotherapy with cyclophosphamide and procarbazine (2 cycles of OEPA and 2 or 4 cycles of COPP) negatively affected spermatogenesis and possibly Leydig cell function in a considerable number of patients. This major gonadotoxic effect most likely is due to procarbazine, although an additional effect of etoposide and cyclophosphamide cannot be excluded.

Long-term effects on testicular function of high-dose testosterone treatment for excessively tall stature.

High-dose testosterone treatment is applied during puberty to reduce the predicted adult height in excessively tall boys. To date it has remained unclear whether this therapy produces any long-term effects on reproductive functions of the patients. To clarify this question, we performed a follow-up study in 47 tall men, determining seminal and hormonal parameters 10.6 +/- 2.5 years (mean +/- SD) after cessation of therapy. The tall men treated were compared with 123 normal men attending the Institute of Reproductive Medicine as volunteers for various clinical studies. Clinical examination revealed a significantly higher prevalence of varicoceles and history of maldescended testes in the testosterone-treated tall men compared with the controls. Semen analysis revealed significantly lower progressive motility in the tall men compared with the normal men (49.2 +/- 13.4 vs. 54.3 +/- 12.8%). A nonsignificant tendency towards lower sperm concentration (43.8 +/- 35.4 vs. 57.8 +/- 45.6 mL/mL), lower total sperm count (184.4 +/- 158.0 vs. 225.4 +/- 277.5 mL/ejaculate), and reduced normal sperm morphology (27.6 +/- 12.5 vs. 30.9 +/- 13.1%) was evident in the testosterone-treated tall men. Although there was no difference in testicular volume and FSH between the groups, testosterone was lower in the testosterone-treated tall men (19.9 +/- 7.4 vs. 23.9 +/- 7.0 nmol/L). Statistical analysis of the subgroups of testosterone-treated tall men and control men without varicocele and cryptorchidism revealed no differences in any ejaculate parameter. The small difference in semen variables may be explained by a higher prevalence of varicocele and maldescended testes in the testosterone-treated tall men.

Final height in children with growth hormone deficiency.

Forty-six patients (28 boys, 18 girls) were treated with growth hormone (GH) for short stature. Twenty-eight patients had total growth hormone deficiency (GHD), 12 partial GHD and 6 patients had short stature without GHD. Brain tumours were the cause of GHD in 8 patients and multiple pituitary hormone deficiency was present in 9 children. All patients received GH with subcutaneous injections only, 6-7 times/week. Mean final height for all patients was -1.11 SDS and was similar in boys (-1.09 SDS) and girls (-1.13 SDS). Target height SDS was -0.80 SDS in 42 patients, comparing favourably with a final height SDS of -1.05. Similar results were obtained in all patient sub-groups. Height velocity during the last year of therapy was between 2.1 and 9.9 cm/year in 34 patients and below 2 cm in 12 patients. As further growth is to be expected, target height will probably be reached by most patients.

Hodgkin's disease in children: combined modality treatment for stages IA, IB, and IIA. Results in 356 patients of the German/Austrian Pediatric Study Group.

UNLABELLED: 356 children below 16 yrs of age with CS/PS IA, IB, and IIA were treated in the studies HD-78, HD-82, HD-85, HD-87, and OEPA-pilot 87 between June 1978 and Sept 1990. All patients received combined modality treatment (CMT) with 2 courses of chemotherapy (CT). In HD-78 and HD-82, the MOPP-derived drug combination OPPA (ADR instead of mechlorethamine) was applied. Extended-field radiotherapy (RT) was given in HD-78 using 36-40 Gy to involved-fields (IF) and 36-40 Gy vs. 18-20 Gy to adjacent fields. In HD-82 only IF-RT was applied using 35 Gy. When gonadotoxic effects of procarbazine (PC) in boys was detected in follow-up examinations, this drug was eliminated in studies HD-85 and HD-87 (OPA). Dosages of IF-RT were 35 Gy in HD-85 and 30 Gy in HD-87. With HD-87 a simultaneous pilot study was initiated to test the new combination OEPA (E = etoposide) together with 25 Gy IF-RT. RESULTS: (May 1993): Rates for event-free survival and survival are HD-78 (73 patients): 0.90 and 0.97 at 10 yrs; HD-82 (100 patients): 0.98 and 1.0 at 10 yrs; HD-85 (53 patients): 0.85 and 0.98 at 8 yrs; HD-87 (104 patients): 0.85 and 0.99 at 6 yrs; OEPA-pilot (26 patients): 0.96 and 0.96 at 5 yrs. No secondary leukemias, MDS, or solid tumors were observed in 14-yr observation time. After 2 OPPA, elevated FSH levels indicating impaired spermatogenesis were found in 29% of male patients. In contrast, after 2 OPA (without PC) only normal FSH levels were observed. In female patients, no gonadal dysfunction was found. Subclinical hypothyroidism was seen only after RT doses of > 30 Gy to the neck. Cardiomyopathies were not observed. CONCLUSION: 2 OPPA plus IF-RT using < 30 Gy can presently be considered optimal therapy for girls with localized HD. 2 OEPA plus 25 Gy IF-RT are being evaluated for boys in a phase III study (HD-90). In summary, there are good reasons to use CMT in early stages of HD in children, provided a highly effective CT of short duration and low long-term toxicity with low-dose IFI is applied.

Treatment of children with Hodgkin's disease--results of the German Pediatric Oncology Group.

Six hundred sixty-seven children under age 16 were enrolled in 4 consecutive studies in West Germany between 1978 and 1990. These trials were mainly designed to reduce the long-term sequelae of high dose extended-field irradiation as well as the late effects of chemotherapy, in the context of combined modality treatment for all stages. Treatment concepts and results of studies HD-82, HD-85 and HD-87 are presented here. Patients with stages IA/B and IIA were treated with 2 cycles of OPPA (HD-82, n = 100) or OPA without procarbazine (HD-85, n = 53; HD-87, n = 104), followed by involved field irradiation (IFI) using 35 Gy (HD-82, HD-85) or 30 Gy (HD-87). Kaplan-Meier estimates (KME) for event-free survival (survival) at 4.5 years are 99% (100%) in HD-82, 85% (98%) in HD-85 and 88% (100%) in HD-87. Thus, 2 x OPPA is a highly effective chemotherapy eradicating occult microfoci in the non-irradiated adjacent fields, whereas 2 x OPA is less efficacious. Reduction of the radiation dose to 30 Gy (IFI) within the combined modality concept does not affect treatment outcome. About 30% of the boys treated with 2 x OPPA, but none of the girls and none of the boys treated without procarbazine (PC) showed elevated FSH-levels indicating gonadal dysfunction. No secondary leukemias and preleukemias were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Testicular function after OPA/COMP chemotherapy without procarbazine in boys with Hodgkin's disease. Results in 25 patients of the DAL-HD-85 study]. / Testikuläre Funktion nach OPA/COMP-Chemotherapie ohne Procarbazin bei Jungen mit Morbus Hodgkin. Ergebnisse bei 25 Patienten der Studie DAL-HD-85.

Gonadal function was evaluated in 25 boys treated for Hodgkin's disease according to the DAL-HD-85 protocol with OPA- or OPA/COMP-chemotherapy (vincristine-prednisone-adriamycine/cyclophosphamide-vincristine-m ethotrexate- prednisone). All boys were in first continuous complete remission for 6 to 45 months at chronological ages varying from 14.0 to 18.9 years. Testosterone, basal and GnRH-stimulated LH- and FSH-levels were measured. Gonadal function was normal in 16 patients treated with 2 cycles of OPA-chemotherapy in Hodgkin stages I-IIA. 9 patients were treated with 2 OPA- and 2 or 4 COMP-cycles of chemotherapy and had received mean cyclophosphamide doses ranging from 2004 to 3722 mg/m2. Again, no major testicular damage was noted, though some patients had increased stimulated LH-levels possibly indicating compensated Leydig cell-insufficiency. Our results demonstrate, that testicular function is not severely affected when patients are treated for Hodgkin's disease without procarbazine even if cyclophosphamide is given in cumulative doses below 3800 mg/m2. The previously documented severe testicular damage in boys treated according to the DAL-studies HD-78 and HD-82 is thus a result of the gonadotoxic action of procarbazine.