S. L. S. Drop

Children Born Small for Gestational Age: Do They Catch Up?

ABSTRACT: Postnatal growth of 724 (423 premature, 301 full-term) small for gestational age infants (SGA. birth length less than the third length percemile (P3) for gestational age) was studied for the first 2 y of lile. The study group consisted of all SGA infants who had been admitted over a period of 8 y at the Departments of Neonatology of three University Hospitals in The Netherlands with exclusion of infants with well defined causes for growth retardation, such as chromosomal disorders, syndromes, severe malformations, or complications during the neonatal period or later on. The aim of the study was to describe postnatal growth of SGA infants and to find predictive factors for catch-up growth ≥P3 during the first 2 y of life. The majority (around 85%) of the healthy SGA infants showed catch-up growth to a height ≥P3 during the first 2 y of life. The percentage of premature SGA infants with catch-up growth ≥P3 at 2 y of age (82.5%) was not significantly different from that of full-term SGA infants (87.5%). Birth length SDS was more sensitive than birth weight SDS in predicting catch-up ≥P3 in premature SGA infants. In contrast, birth weight SDS was the best predictor for catch-up >P3 in full-term SGA infants. Gestational age, multiple birth, and sex were not significantly associated with catch-up in height ≥P3. For children with a length still below P3 at 3 or 6 mo of age, the actual length SDS at that age appeared positively associated with catch-up ≥P3. In SGA premature infants there was also a positive association between the weight gain during the first 6 mo and the catch-up growth ≥P3. SGA children with short stature (height <P3) at 2 y of age need further investigation.

Final Height and Its Predictive Factors after Renal Transplantation in Childhood

ABSTRACT: A retrospective study is reported assessing final height (FH) and its predictive factors in 52 patients (31 male, 21 female) who underwent renal transplantation (RTx) before the age of 15 y. They received prednisone daily or on alternate days as well as azathioprine. The study period covered 20 y. FH remained below the third height percentile [height standard deviation score for chronologic age (hSDSCA) < −1.88] for most of these patients (77% males, 71% females). Median (range) FH was 165.0 (143.0–176.8) cm in males and 153.0 (135.0–168.4) cm in females. Median difference between FH and target height was 15.0 and 15.4 cm for males and females, respectively. For both sexes, the median hSDSCA was already below −1.88 at the start of the first hemodialysis, after which it decreased significantly until the first RTx. After RTx, there was no significant improvement of hSDSCA. The predictive factors for FH were determined by evaluating various factors simultaneously in a multiple regression analysis. This analysis provided a regression equation for predicting FH. A higher hSDSCA at the time of the first RTx and alternate-day versus daily prednisone therapy both had a significantly positive influence on FH, whereas a longer duration of reduced GFR (<50 mL/min/1.73 m2) had a significantly negative effect on FH. Other factors such as age or bone age at first RTx, primary renal disease, duration of initial dialysis, repeat RTx, and the cumulative dose of prednisone did not influence FH significantly. In conclusion, 71–77% of patients that received their first renal transplant before the age of 15 ended up with severely short adult stature. Optimization of the hSDSCA at first RTx appears very important. Long-term administration of prednisone on alternate days would then result in optimal FH, particularly if the GFR remains above 50 mL/min/1.73 m2.

Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism

CONTEXT Gonadectomy is avoided whenever possible in boys with 45,X/46,XY. However, no clinical markers are currently available to guide clinicians in predicting gonadal tumor risk or hormone production. OBJECTIVE The objective of the study was to test the hypothesis that gonadal histology and risk for development of a malignant germ cell tumor are reflected by the clinical presentation of a 45,X/46,XY individual. DESIGN The design of the study was the correlation of clinical data [external masculinization score (EMS), pubertal outcome] with pathology data (gonadal phenotype, tumor risk). SETTING This was a multicenter study involving two multidisciplinary disorder of sex development teams. PATIENTS Patients included genetically proven 45,X/46,XY (and variants) cases, of whom at least one gonadal biopsy or gonadectomy specimen was available, together with clinical details. INTERVENTIONS Patients (n = 48) were divided into three groups, based on the EMS. Gonadal histology and tumor risk were assessed on paraffin-embedded samples (n = 87) by morphology and immunohistochemistry on the basis of established criteria. MAIN OUTCOME MEASURES Gonadal differentiation and tumor risk in the three clinical groups were measured. Clinical outcome in patients with at least one preserved gonad was also measured. RESULTS Tumor risk in the three groups was significantly related to the gonadal differentiation pattern (P < 0.001). In boys, hormone production was sufficient and was not predicted by the EMS. CONCLUSIONS The EMS reflects gonadal differentiation and tumor risk in patients with 45,X/46,XY. In boys, testosterone production is often sufficient, but strict follow-up is warranted because of malignancy risk, which appears inversely related to EMS. In girls, tumor risk is limited but gonads are not functional, making gonadectomy the most reasonable option.

Long-Term Effects of Treatment for Acute Lymphoblastic Leukemia with and without Cranial Irradiation on Growth and Puberty: A Comparative Study

ABSTRACT: We investigated the comparative effect on long-term growth of CNS prophylactic treatment for acute lymphoblastic leukemia (ALL) with either 25-Gy cranial irradiation or moderate-dose i.v. methotrexate. In 80 children with complete continuous first remission, data on growth and pubertal development were investigated up to 11 y from ALL diagnosis. Forty patients had 25-Gy cranial irradiation, 16 of them with high-risk factors and 24 without. Another 40 non-high-risk ALL patients had moderate-dose methotrexate. Chemotherapy lasted 31/4 y for high-risk ALL patients and 21/4 y for those not at high risk. Pubertal development and final height were assessed separately for girls diagnosed before or after age 7 and for boys before or after age 9. All patients had a similar decline in height SD score during the first 6 mo of treatment, which persisted in irradiated children only. The nonirra-diated group had no further decline. Catch-up growth only started when chemotherapy ended for irradiated and non-irradiated patients alike. Five y after cessation of treatment, changes in height SD score for nonirradiated children remained within the range for healthy children against a significant decline in height SD scores for irradiated children. Pubertal development in irradiated girls diagnosed before age 7 was within normal range, but their final height was disappointing due to a blunted growth spurt. In contrast, irradiated girls diagnosed later had a delayed onset of puberty but satisfactory final height. Comparable results were found in boys. In summary, 25-Gy cranial irradiation in the treatment of ALL causes long-term growth retardation, whereas moderate-dose i.v. methotrexate seems to have only a temporary effect on growth.

Leydig cell hypoplasia: Cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene

background Defective male sex differentiation in patients with hypoplasia of Leydig cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH.

Final Height after Gonadotrophin Releasing Hormone Agonist Treatment for Central Precocious Puberty: The Dutch Experience

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p < 0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment started < 6 years of age, height gain was significantly higher than when started > 8 years of age. Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

Androgen Insensitivity Syndrome (AIS): Emotional Reactions of Parents and Adult Patients to the Clinical Diagnosis of AIS and Its Confirmation by Androgen Receptor Gene Mutation Analysis

The emotional reactions of parents and adult patients on disclosure of the clinical diagnosis of androgen insensitivity syndrome (AIS) and its later confirmation by gene mutation analysis were assessed. A semistructured interview and three questionnaires were used. Parents came from 18 different families with a total of 20 children (15 complete AIS, 5 partial AIS), 19 raised as girls, 1 as a boy. Ten adult women with complete AIS came from six families. The short-term reaction upon the clinical diagnosis was in the majority of both parents and adult patients associated with shock, grief, anger, and shame and in the mothers and adult patients with guilt. Emotional reactions were more long-lasting in mothers and adult patients than in fathers. The confirmation by DNA analysis did not alter the actual feelings of both parents. Adolescents with AIS should be informed completely – but in a step-by-step way – about their condition, since adult patients indicated that they had suffered from being not at all or misinformed about AIS in their adolescence.

Auxological and Biochemical Evaluation of Pubertal Suppression with the GnRH Agonist Leuprolide Acetate in Early and Precocious Puberty

We studied the auxological effects of treatment with the GnRH agonist leuprolide acetate (Lucrin®) at 3.75 mg/ 28 days in 38 children with early or precocious puberty. We present our newly developed scoring system, the Puberty Suppression Score (PSS), in which clinical and biochemical parameters determine whether suppression was effective. Leuprolide acetate suppressed pubertal development in the majority of cases. During treatment there was a significant correlation between the number of times that PSS was >0 and gain in predicted adult height (PAH) compared to initial prediction at the start of treatment. After 6 months of treatment, ineffective suppression measured by PSS was associated with the magnitude of gain in PAH. We conclude that a leuprolide acetate dosage of 3.75 mg every 28 days effectively suppresses puberty. PSS is helpful in monitoring the suppressive capacity of a GnRH agonist. We recommend to start with leuprolide acetate at 3.75 mg/28 days and to increase the injection frequency or dose in case PSS is >0 after 6 months of treatment.

Growth after Renal Transplantation in Prepubertal Children: Impact of Various Treatment Modalities

ABSTRACT: A retrospective study evaluated posttrans-plant growth of 70 prepubertal children during the first 2 y after renal transplantation (RTx). Immunosuppressive treatment consisted of prednisone administered either daily or on alternate days in combination with either azathioprine or cyclosporin A. The increment in height standard deviation score for chronologic age during the first 2 y after RTx was less than 0.5 SD for 70% of the study population. The predictive factors for posttransplant growth were determined by evaluating several factors and treatment modalities singly and simultaneously in a multiple regression analysis. Patients with the most severe growth retardation at RTx appeared to have the most pronounced growth spurt after RTx, but even they never had complete catchup growth, and 2 y after RTx they were still shorter than those with less severe growth retardation at RTx. Alternate-day instead of daily prednisone administration had a significantly positive influence, whereas a high cumulative dose of prednisone, azathioprine instead of cyclosporin A therapy, and a persistently reduced GFR (GFR < 50 mL/ min/1.73 m2) had a significantly negative influence on catch-up growth during the 2 y after RTx. Other factors, such as gender, chronologic and bone age at RTx, primary renal disease, duration of initial dialysis, repeat RTx, and target height SD score for chronologic age, whether evaluated singly or simultaneously with other significant factors, appeared to have no significant influence on post-RTx growth. Thus, 70% of the prepubertal children do not experience appreciable catch-up growth during the first 2 y after RTx. Optimization of pretransplant height appears very important. Immunosuppressive treatment with cyclosporin therapy in combination with a minimal dose of alternate-day prednisone would then result in optimal post-transplant growth, particularly if the GFR remains above 50 mL/min/1.73 m2).

Fertility and Ovarian Function in High-Dose Estrogen-Treated Tall Women

BACKGROUND/OBJECTIVE High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence. METHODS This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22-47 yr served as controls. RESULTS Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44, 95% CI 1.76-6.73). Moreover, fecundity was notably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased. CONCLUSION High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility.