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.

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.

Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation.

CONTEXT: The Lhx3 LIM-homeodomain transcription factor gene is required for development of the pituitary and motoneurons in mice. Human LHX3 gene mutations have been reported in five subjects with a phenotype consisting of GH, prolactin, TSH, LH, and FSH deficiency; abnormal pituitary morphology; and limited neck rotation. OBJECTIVE: The objective of the study was to determine the frequency and nature of LHX3 mutations in patients with isolated GH deficiency or combined pituitary hormone deficiency (CPHD) and characterize the molecular consequences of mutations. DESIGN: The LHX3 sequence was determined. The biochemical properties of aberrant LHX3 proteins resulting from observed mutations were characterized using reporter gene and DNA binding experiments. PATIENTS: The study included 366 patients with isolated GH deficiency or CPHD. RESULTS: In seven patients with CPHD from four consanguineous pedigrees, four novel, recessive mutations were identified: a deletion of the entire gene (del/del), mutations causing truncated proteins (E173ter, W224ter), and a mutation causing a substitution in the homeodomain (A210V). The mutations were associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. Whereas subjects with del/del, E173ter, and A210V mutations had limited neck rotation, patients with the W224ter mutation did not. CONCLUSIONS: LHX3 mutations are a rare cause of CPHD involving deficiencies for GH, prolactin, TSH, and LH/FSH in all patients. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed, and limited neck rotation is not a universal feature of patients with LHX3 mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.

Long-term carbimazole treatment of neonatal nonautoimmune hyperthyroidism due to a new activating TSH receptor gene mutation (Ala428Val).

BACKGROUND: Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin receptor gene. Antithyroid treatment failed to control hyperthyroidism in most cases, so that primary thyroid ablation or 131I therapy is advocated as the preferred treatment of choice. PATIENT/METHODS: We describe a case of neonatal nonautoimmune hyperthyroidism treated with carbimazole. Molecular analysis revealed a new heterozygous point mutation (A428V) in the TSH receptor (TSHR) gene. RESULT: Antithyroid treatment was successful in controlling hyperthyroidism for the first 5.9 years of age. CONCLUSION: We conclude that carbimazole therapy is effective in treating nonautoimmune hyperthyroidism. It may be an alternative to thyroidectomy or radioiodine treatment.

Intrauterine therapy of goitrous hypothyroidism in a boy with a new compound heterozygous mutation (Y453D and C800R) in the thyroid peroxidase gene. A long-term follow-up.

We report the results of intrauterine L-thyroxine therapy, and the long-term follow-up in a fetus who presented at 32 weeks' gestation with goitrous hypothyroidism, hyperextension of the neck, and polyhydramnios. Spontaneous delivery was possible and hypothyroidism improved. Molecular analysis revealed a new compound heterozygous mutation (Y453D/C800R) in the TPO gene.

Ovarian function following pelvic irradiation in prepubertal and pubertal girls and young adult women.

PURPOSE: To analyze the effect of pelvic radiotherapy on ovarian function in prepubertal and pubertal girls and young adult women. PATIENTS AND METHODS: In a retrospective monoinstitutional analysis, patients < 30 years of age at diagnosis were included who had been irradiated between 1979 and 1998. The main tumor types were Hodgkin's disease (38%), Ewing's sarcoma (20%) and nephroblastoma (11%). Patients were classified into three groups according to the position of the ovary in relation to the radiation portals. Group 1 was defined by direct irradiation of both ovaries. Group 2 patients were included with both ovaries potentially located in the radiation portals. In group 3, at least one ovary was not directly irradiated. The median follow-up was 128 months. RESULTS: 16 of 55 analyzed patients were categorized in group 1. In ten of these patients, hormone status was evaluable. The ovarian doses were >/= 15 Gy. Except for one patient treated with 15 Gy all developed hormone failure. Eight of 14 patients of group 2 were evaluable. Seven of these patients developed ovarian failure. 19 of 24 patients in group 3 were evaluable. Nine of these patients developed ovarian failure. The observed difference in the rate of ovarian failure between the groups is statistically significant (p = 0.045). CONCLUSION: All patients receiving > 15 Gy to the ovaries developed hormone failure. In one case of a patient receiving an ovarian dose of 15 Gy, hormone failure was not found. In case of pelvic irradiation excluding at least one ovary, approximately half of the patients developed ovarian dysfunction, probably also due to the effects of polychemotherapy.