Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement.

OBJECTIVE: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). DESIGN: Combined cross-sectional and retrospective clinical study. METHODS: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. RESULTS: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. CONCLUSIONS: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

[Medical care of young women with Turner syndrome in Germany]. / Medizinische Betreuung von jungen Frauen mit Ullrich-Turner-Syndrom in Deutschland.

BACKGROUND: Many recommendations for medical care for women with Turner syndrome (TS) have been published in the past. There are no studies that analyse the care situation of the women in Germany until now. METHODS: The study was performed in 2015 based on a questionnaire that was completed by TS women (aged ≥ 18 years; median: 25 years). The questionnaire was devised by a French team and used with their permission. All women had received growth hormone treatment during childhood. The women were identified and addressed in writing through eleven cooperating centers and the support group. In all, 130 questionnaires were evaluated. RESULTS: 79 of the 130 women (61 %) stated that they had health problems. 38 % of the women were under medical care by only one physician and 42 % by two physicians. The gynecologist was mentioned most often (by 80.3 %), followed by the family physician (53.8 %). ENT was mentioned as a problem system by 35 %, but only 3 % of the women attended an ENT physician. The question as to whether at least one of the following examinations (measurements of blood pressure, blood sugar, blood fats, liver function and/or thyroid hormones, echocardiographic and/or audiogram examination) had been performed during a period of 4 years was answered as follows: blood pressure (85 %), blood sugar (47 %), blood fats (41 %), liver function (46 %), thyroid hormones (44 %), echocardiography (57 %) and audiogram (35 %). A comprehensive examination was performed in 9.8 % of the women. 103 women (80.5 %) received sexual hormone replacement therapy. 76 women were on further drugs; thyroid hormones (44 %) and antihypertensive drugs (11 %) were stated most often. CONCLUSIONS: This is the first study which analyses the current situation of medical care of TS women in Germany. Our data show that medical care of young adult TS women is not optimal. The study cannot clarify the reasons. Due to the numerous and different comorbidities, the medical care of TS women is complex and should therefore be provided multidisciplinarily by different specialists under the direction of one physician.

A New Model of Adult Height Prediction Validated in Boys with Constitutional Delay of Growth and Puberty.

BACKGROUND: For children with retarded bone ages such as in constitutional delay of growth and puberty (CDGP) there are no specific methods to predict adult height based on bone age. Widely used methods such as Bayley-Pinneau (BP) tend to overestimate adult height in CDGP. OBJECTIVE: We aimed to develop a specific adult height prediction model for teenage boys with retarded bone ages >1 year. METHODS: Based on the adult heights of 68 males (median age 22.5 years) a new height prediction model was calculated based on 105 height measurements and bone age determinations at a median age of 14.0 years. The new model was adapted for the degree of bone age retardation and validated in an independent cohort of 32 boys with CDGP. RESULTS: The BP method overestimated adult height (median +1.2 cm; p = 0.282), especially in boys with a bone age retardation ≥2 years (median +1.6 cm; p = 0.027). In the validation study, there was no significant difference between adult height and predicted adult height based on the new model (p = 0.196), while the BP model led to a significant overestimation of predicted adult height (median +4.1 cm; p = 0.009). CONCLUSIONS: The new model to predict adult height in boys with CDGP provides novel indices for height predictions in bone ages >13 years and is adapted to different degrees of bone age retardation. The new prediction model has a good predictive capability and overcomes some of the shortcomings of the BP model.

[Life Situation of Young women with Turner Syndrome: Results of a Questionnaire-based Study in Germany]. / Lebenssituation von jungen Frauen mit Ullrich-Turner-Syndrom nach dem Ende der Wachstumshormontherapie: Ergebnisse einer Umfrage in Deutschland.

INTRODUCTION: Psychosocial problems such as anxious personality, low self-esteem, late separation from home and/or late sexual experience have been described in girls and women with Turner syndrome (TS). METHODS: The study was performed in 2015 based on a questionnaire that was sent out to 779 women with TS aged 25 years (median). The questionnaire was devised by a French team and used with their permission. In all, 130 questionnaires (16.7 %) could be evaluated. The questions from the individual topics were not always completely answered. RESULTS: (mean ± SD).: 116 women (89.9 %) were not married; 52 women (40 %) lived in their parents' home. 47.6 % had a high-school/technical diploma or university degree. 60 women (46 %) had a job; 51 women (39 %) had not completed vocational training. Puberty was induced at the age of 14.2 ± 2.1 years in 78 % of the women. 80 % of the women received hormone replacement therapy at the time of the questionnaire survey. 66 of 93 women (71 %) found that the disease had a negative influence on emotional life. "Love life and sexual relationship" was the topic mentioned most frequently by 44 women (66.6 %). 116 women answered questions on sexuality. Here, 77 % had the first French kiss at the age of 16.4 ± 3.6 years and 62.4 % had sexual intercourse for the first time at the age of 19.0 ±â€Š3.4 years. 81 % of the women stated that they had a partner relationship for more than 6 months (94 women had a male partner and 5 had a female partner). The question as to the wish to have children was answered in the affirmative by 89 of 124 women (71.8 %); 38.2 % desired spontaneous pregnancy and 44.9 % had considered in vitro fertilization or adoption. DISCUSSION: The women's answers show that care needs to be improved. There are deficits in the topics of family, emotional life, relationships, sexuality, fertility and pregnancy. Therefore, the medical team should also include psychologists and social workers.

Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients.

Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80-90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.

Sodium Chloride Supplementation Is Not Routinely Performed in the Majority of German and Austrian Infants with Classic Salt-Wasting Congenital Adrenal Hyperplasia and Has No Effect on Linear Growth and Hydrocortisone or Fludrocortisone Dose.

INTRODUCTION: Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous. OBJECTIVE: To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database. RESULTS: Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999-2004 to 37.5% in children born 2011-2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life. CONCLUSION: In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis.

Effects of growth hormone treatment on adult height in severely short children with X-linked hypophosphatemic rickets.

BACKGROUND: We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients. METHODS: We carried out a follow-up analysis of a randomized controlled open-label GH study in short prepubertal children with XLH on phosphate and active vitamin D treatment. The changes in SD scores (SDS) of height, sitting height, leg and arm length, and sitting height index (i.e., the ratio between sitting height and height) were analyzed in 11 out of 16 patients followed-up until adult height. RESULTS: At baseline, XLH patients showed disproportionately short stature with reduced standardized height (-3.2 ± 0.6), sitting height (-1.7 ± 0.6), leg (-3.7 ± 0.7) and arm (-2.5 ± 0.8) length, and markedly elevated sitting height index (3.3 ± 0.6; each p < 0.01 versus healthy children). In GH-treated patients, adult height, sitting height, leg length, and arm length exceeded baseline values by 0.7 SDS, 1.7 SDS, 0.7 SDS, and 1.2 SDS respectively, although this was only significant for sitting height. In controls, no significant changes in linear body dimensions were noted. Adult height did not statistically differ between groups (-2.4 ± 0.7 vs -3.3 ± 1.2, p = 0.082). GH did not exaggerate body disproportion. CONCLUSIONS: Growth hormone treatment did not significantly increase adult height in this group of short children with XLH, which may be at least partly due to the small number of patients included in our study.

Assessment of Primary Cancer Incidence in Growth Hormone-Treated Children: Comparison of a Multinational Prospective Observational Study with Population Databases.

BACKGROUND/AIMS: Although results of the majority of clinical studies have shown no association between growth hormone (GH) treatment in childhood and risk of primary cancer, concerns remain regarding the potential influence of GH therapy on neoplastic cell growth. This study evaluated the incidence of primary malignancies in a large observational study of paediatric GH treatment. METHODS: Primary cancer incidence was assessed in a cohort of 19,054 GH-treated children without a reported prestudy history of malignancy in the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). The standardised incidence ratio (SIR) for primary cancer in GH-treated children was determined by comparing cancer incidence in the GeNeSIS study population with incidence rates for country-, age-, and sex-matched cohorts of the general population. RESULTS: During a mean follow-up of 3.4 years in GeNeSIS (64,705 person-years), 13 incident potential primary cancers were identified in GH-treated patients. The SIR (95% confidence interval) for all observed cancers was 1.02 (0.54-1.75), and the crude incidence was 20.1 (10.7-34.4) cases per 100,000 person-years. CONCLUSION: Acknowledging the relatively short follow-up in our study, GH-treated children without a history of previous malignancy did not have a higher risk of all-site primary cancer during the study when compared to general-population cancer registries.

Blood Pressure in a Large Cohort of Children and Adolescents With Classic Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency.

BACKGROUND: Data on blood pressure (BP) in children and adolescents with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are conflicting in the literature. PATIENTS AND METHODS: BP data of n = 716 children and adolescents (aged 3-18 years) from a national CAH database were analyzed. BP data were adjusted for height and compared to contemporary national reference data. A systolic and diastolic BP above the 95th centile was defined as hypertensive. RESULTS: Overall prevalence of hypertension was 12.5%. Prevalence of hypertension was higher in younger children than in adolescents (18.5% vs. 4.9%). Until 8 years of age, fludrocortisone dose/m(2)/day correlated significantly with BP in regression analysis (P < 0.0001). BP correlated significantly with body mass index standard deviation score (BMI-SDS) (P < 0.0001), but not with hydrocortisone dose. In patients with salt-wasting CAH, BMI-SDS and BP were significantly higher compared to patients with simple virilising CAH, P < 0.01. CONCLUSION: Especially young CAH children seem to be at risk for-most likely transient-hypertension, since the prevalence of hypertension decreases with age. In children up to 8 years of age, the used fludrocortisone dose is a significant risk factor for hypertension. Therefore we recommend accurate measurement of BP and careful fludrocortisone dosing in children with CAH.

Secondary Malignancies Following Treatment for Hodgkin's Lymphoma in Childhood and Adolescence.

BACKGROUND: About 155 persons under age 18 develop Hodgkin's lymphoma (HL) in Germany every year. More than 90% survive at least 20 years. They may, however, suffer from late sequelae of treatment, including secondary malignant neoplasia (SMN). METHODS: 2548 patients from the German, Austrian, and Swiss pediatric Hodgkin's lymphoma studies that were conducted over the period 1978-2002 were asked every 2-3 years about possible late sequelae of treatment, either directly or through their physicians. The documented cases of SMN were analyzed for cumulative incidence, standardized incidence rates (SIR), and absolute excess risk (AER). RESULTS: 147 cases of SMN were diagnosed in 138 of the 2548 patients, including 47 cases of thyroid cancer, 37 of breast cancer, and 15 of hematopoietic neoplasia. The cumulative incidence of SMN at 20, 25, and 30 years was 7% , 11.2% , and 18.7% , respectively. These percentages are rather low compared to other international studies. For all types of SMN, the SIR was 9.1 and the AER was 16.8. Among the 123 patients with secondary solid tumors, 105 (85% ) had a tumor in the irradiated region. CONCLUSION: Survivors of pediatric HL must be informed about the risk of late sequelae of treatment for HL, including SMN in the irradiated region, and that they will need regular follow-up examinations. In the future, radiotherapy for children and adolescents should be further reduced or entirely avoided.

Parenthood in adult female survivors treated for Hodgkin's lymphoma during childhood and adolescence: a prospective, longitudinal study.

BACKGROUND: Little is known about parenthood in women who were treated for Hodgkin's lymphoma during childhood and adolescence. We aimed to assess the frequency of parenthood in female survivors of Hodgkin's lymphoma younger than 18 years at diagnosis, and to compare it with that in a female population control group. METHODS: In this prospective, longitudinal study, our cohort consisted of 590 female patients younger than 18 years at diagnosis who participated in one of five Hodgkin's lymphoma treatment studies between June 19, 1978, and July 12, 1995. Women who had been followed up for 5 years or longer, were in continuous complete remission, and had no second malignancy or Hodgkin's lymphoma relapse before parenthood were included in our parenthood analysis. Parenthood was defined as the delivery of a liveborn child. Frequency of parenthood was compared with that in the German female population aged 16-49 years, using data from the 2012 Mikrozensus population survey. We assessed parenthood by estimating cumulative incidences and hazard ratios (HRs) with associated variables. FINDINGS: 467 of 590 patients in our cohort had long-term follow-up (median 20·4 years [IQR 16·3-24·8]) and were in continuous complete remission. 228 (49%) of 467 patients had 406 children (median of 1·78 children per mother, range 1-7). Cumulative incidences of parenthood were 67% (95% CI 64-75) at 27·7 years of follow-up (the longest number of years that a patient was followed up before she had her first child) and 69% (61-74) at 39·8 years of age (the oldest age of a patient before she had her first child). The incidence of parenthood did not differ between our cohort and the female German population for any age group up to 49 years, except for the 66 women aged 40-44 years at the time of last information, who had a significantly lower frequency of parenthood compared with the general population (40 [61%] of 66 vs 2,208,000 [78%] of 2,847,000; p=0·001). Procarbazine in cumulative doses up to 11,400 mg/m(2), cyclophosphamide in cumulative doses up to 6000 mg/m(2), alkylating agent dose scores of 1-5, therapy group based on disease stage at diagnosis, abdominal and supradiaphragmatic radiation, and age at treatment had no significant or only minor effects on parenthood. Parenthood was significantly reduced in survivors receiving pelvic radiation compared with those who received abdominal and supradiaphragmatic radiation (HR 0·76, 95% CI 0·61-0·95; p=0·01). INTERPRETATION: The results of this study document an overall favourable prognosis for parenthood in female survivors of Hodgkin's lymphoma. They will assist counselling of female survivors about their positive potential for future parenthood. FUNDING: Deutsche Kinderkrebsstiftung, Jens-Brunken-Stiftung für Leukämie und Lymphomforschung, and Kinderkrebshilfe Münster.

Breast cancer in young women after treatment for Hodgkin's disease during childhood or adolescence--an observational study with up to 33-year follow-up.

BACKGROUND: The treatment of Hodgkin's disease (HD; also called Hodgkin's lymphoma) in children and adolescents with radiotherapy and chemotherapy leads to high survival rates but has a number of late effects. The most serious one is the development of a secondary malignant tumor, usually in the field that was irradiated. In women, breast cancer can arise in this way. METHOD: Data on the occurrence of secondary breast cancer (sBC) were collected from 590 women who were treated in five consecutive pediatric HD treatment studies in the years 1978-1995 and then re-evaluated in a late follow-up study after a median interval of 17.8 years (maximum, 33.7 years). Information was obtained from 1999 onward by written inquiry to the participants and their treating physicians. The cumulative incidence of sBC was calculated by the Gooley method. RESULTS: By July 2012, sBC had been diagnosed in 26 of 590 female HD patients; the breast cancer was in the irradiated field in 25 of these 26 patients. Their age at the time of treatment for HD was 9.9 to 16.2 years (the pubertal phase), and sBC was discovered with a median latency of 20.7 years after HD treatment (shortest latency, 14.3 years) and at a median age of 35.3 years (youngest age, 26.8 years). The radiation dose to the supradiaphragmatic fields ranged from 20 to 45 Gy. The cumulative incidence for sBC 30 years after treatment for HD was 19% (95% confidence interval, 12% to 29%). For women aged 25 to 45 in this series, the frequency of breast cancer was 24 times as high as in the corresponding normal population. CONCLUSION: Women who were treated for HD in childhood or adolescence have an increased risk of developing breast cancer as young adults. The risk is associated with prior radiotherapy and with the age at which it was administered (the pubertal phase). Because of these findings, a structured breast cancer screening project for this high-risk group has been initiated in collaboration with the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).

Quality of life in long-term survivors following treatment for Hodgkin's disease during childhood and adolescence in the German multicentre studies between 1978 and 2002.

PURPOSE: The purpose of this study was to cross-sectionally assess quality of life (QoL) in survivors of childhood Hodgkin's disease (HD) in a cohort treated for HD in the successive German-Austrian therapy studies HD-78, HD-82, HD-85, HD-87, HD-90, HD-95, respectively, in accordance with the HD-Interval-Treatment recommendation between 1978 and 2002. PATIENTS AND METHODS: Data from QoL questionnaires were provided by 1,202 (66 %) of 1,819 invited survivors. These included the EORTC QLQ-C30 and socio-demographic variables. Data of a homogenous sub-sample (n = 725) defined by age (21-41 years) and event- free-survival (no progress, relapse or secondary malignancies) were compared to an age-adjusted German reference sample (n = 659). RESULTS: While the global and physical QoL scores were comparable to those of the general population, survivors' mean scores were more than 10 points lower on the EORTC QLQ-C30 scales "Emotional" and "Social Functioning". On the symptom scales, higher mean scores, exceeding 10 points, were obtained for the scales "Fatigue" and "Sleep". In general, there was a gender effect showing lower functioning and higher symptom levels in women, most prominently in the group of young women (21-25 years). The results within the group of HD survivors could not be associated with the time since treatment, the age of HD survivors at diagnosis or the extent of therapy burden. CONCLUSION: Clinicians engaged in follow-up care should be sensitive to aspects of fatigue and related (emotional) symptoms in HD childhood cancer survivors and encourage their patients to seek further support if needed.

Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction.

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.

Growth hormone treatment adherence in prepubertal and pubertal children with different growth disorders.

BACKGROUND/AIMS: Treatment of children with growth disorders with recombinant human growth hormone is necessary for improved outcomes, including final height. METHODS: Adherence data from the Observational Study Saizen®-online, recorded with the easypod™ device collected between October 2009 and May 2011, were analyzed in pediatric patients receiving recombinant human growth hormone treatment for a variety of growth disorders. RESULTS: Data from 75 children (46 boys, 29 girls) with different growth disorders were analyzed over a period of 343 ± 201 (SD) days. Boys and girls showed similar mean ± SD adherence rates of 90.5 ± 3.1% and 92.2 ± 10.7%, respectively. Pubertal children (n = 41) had a significantly lower adherence rate (89.1 ± 13.7%) than prepubertal children (n = 29) (96.5 ± 3.9%; p < 0.005). There were nonsignificant differences in adherence rates according to diagnosis: growth hormone deficiency (n = 48) 91.4 ± 11.0%, small for gestational age (n = 18) 91.1 ± 15.3%, Turner syndrome (n = 6) 86.0 ± 14.5%, and chronic renal failure (n = 3) 99.3 ± 1.0%, although the latter two groups were small. CONCLUSION: Our data indicate that only a small number of pediatric patients using the easypod device had poor adherence to treatment. Further reliable adherence data are required to identify factors affecting long-term adherence in this population.

Multiplex ligation-dependent probe amplification analysis of the NR0B1(DAX1) locus enables explanation of phenotypic differences in patients with X-linked congenital adrenal hypoplasia.

BACKGROUND/AIM: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadic hypogonadism. It is caused by deletions or point mutations of the NR0B1 gene, on Xp21. AHC can be associated with glycerol kinase deficiency, Duchenne muscular dystrophy and mental retardation (MR), as part of a contiguous gene deletion syndrome. A synthetic probe set for multiplex ligation-dependent probe amplification analysis was developed to confirm and characterize NR0B1 deletions in patients with AHC and to correlate their genotypes with their divergent phenotypes. RESULTS: In 2 patients, isolated AHC was confirmed, while a patient at risk for metabolic crisis was revealed as the deletion extends to the GK gene. A deletion extending to IL1RAPL1 was confirmed in both patients showing MR. Thus, a good genotype-phenotype correlation was confirmed. CONCLUSIONS: Multiplex ligation-dependent probe amplification analysis is a valuable tool to detect NR0B1 and contiguous gene deletions in patients with AHC. It is especially helpful for IL1RAPL1 deletion detection as no clinical markers for MR are available. Furthermore, multiplex ligation-dependent probe amplification has the advantage to identify female carriers that, depending on the deletion extension, have a high risk of giving birth to children with MR, AHC, glycerol kinase deficiency and Duchenne muscular dystrophy.

Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets.

Children with X-linked hypophosphatemic rickets (XLH) are prone to severe stunting. A multicenter mixed-longitudinal study was conducted to assess age-related stature, sitting height, arm and leg length in XLH patients on continuous treatment with phosphate and calcitriol. Mean standard deviation scores (SDS) for all body dimensions were markedly reduced and differed significantly among each other at the initial and subsequent evaluations (baseline: stature -2.48 SDS; sitting height -0.99 SDS; arm length -1.81 SDS; leg length -2.90 SDS; each p<0.001). A strong association between stature and leg length (r (2)=0.87, p<0.001) was noted. Leg length SDS decreased progressively during childhood (2-9 years) and adolescence (12-15 years; each p<0.001). Sitting height SDS increased significantly during late childhood, indicating uncoupled growth of the legs and trunk and resulting in an ever increasing sitting height index (i.e. ratio of sitting height to stature; age 2 years 2.0 SDS; age 10 years 3.3 SDS; p<0.001) that was associated with the degree of stunting (r (2)=0.314, p<0.001). Mean serum phosphate levels were positively associated with stature and leg length, but negatively with sitting height index. Based on these results, we can conclude that growth of the legs and trunk is uncoupled in XLH and related to serum phosphate levels.

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies.

BACKGROUND: To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD). METHODS: The study cohort comprised 1,132 survivors of HD who received treatment before 18 years of age in consecutive trials between 1978 and 1995. They had maintained remission without secondary malignancy for 3.1-29.4 years. The cumulative doxorubicin dose was uniformly 160 mg/m(2), the mediastinal radiation dose (MedRD) was 36, 30, 25, 20, or 0 Gy. Follow-up questionnaires complemented by additional contacts served to collect information on late effects from patients and physicians. A central expert panel reviewed all reported cardiac abnormalities. RESULTS: By October 2008, cardiac diseases (CD) had been diagnosed in 50 of 1,132 patients aged 15.0-41.7 (median 32.2) years. The interval since HD therapy was 3.0-28.2 (median 19.5) years. Valvular defects were diagnosed most frequently, followed by coronary artery diseases, cardiomyopathies, conduction disorders, and pericardial abnormalities. The cumulative incidence of CD after 25 years was highest in the MedRD-36 group (21%) decreasing to 10%, 6%, 5%, and 3% in the lower MedRD groups (P < 0.001). Multivariate Cox analysis of several putative risk factors showed MedRD to be the only significant variable predicting for CD-free survival (P = 0.0025). CONCLUSIONS: Our results indicate that lower MedRDs are less cardiotoxic. Consequently, reduction of cardiac late effects may be expected with the lower radiation doses used in current HD protocols. Longer follow-up is needed to confirm the present results.

Disorders of pubertal development.

BACKGROUND: Puberty is an extremely important phase in the physical and psychosocial development of the adolescent. METHODS: Selective literature review. RESULTS: The diagnosis of abnormal puberty requires thorough knowledge of normal pubertal development and of the variations of normal puberty as well as its pathology. Variations of normal pubertal development can be expected, by definition, to occur at a frequency of roughly 3%. A detailed history is the first step in the diagnostic evaluation of a normal variant or an abnormal puberty. Further evaluation includes laboratory testing (estradiol, testosterone, and the results of a GnRH test, among others) and imaging studies (x-ray of the left hand and wrist, ultrasonography of the gonads, magnetic resonance imaging). Treatment is directed at both the acute and the long-term consequences of precocious, markedly delayed, or absent pubertal development. CONCLUSIONS: Disorders of pubertal development should be recognized early, correctly diagnosed by a pediatric endocrinologist, and appropriately treated.