Sperm DNA damage measured by sperm chromatin structure assay in men with a history of undescended testes.

The aim of this study was to compare sperm DNA damage between men with a history of congenital undescended testis (UDT) and men with a history of acquired UDT. A long-term follow-up study of men with previous UDT was performed. Fifty men with congenital UDT who had undergone orchiopexy at childhood age, 49 men with acquired UDT after a 'wait-and-see'-protocol (e.g. awaiting spontaneous descent until puberty and perform an orchiopexy in case of non-decent), and 22 healthy proven fertile men were included. The DNA fragmentation index (DFI) using sperm chromatin structure assay (SCSA) was used to express the level of sperm DNA damage. Decreased fertility potential was considered if DFI was above 30%. Sperm DNA damage was not statistically different between cases of congenital and acquired UDT. DFI was significantly more often >30% in the complete group of men with congenital UDT (9/50; 18%) and in the subgroup with bilateral congenital UDT (3/7; 43%) in comparison with the controls (none) (p-value 0.049 and 0.01, respectively). Age at orchiopexy in congenital UDT had no statistical effect on DNA damage. In men with acquired UDT, DFI did not statistically differ between those having undergone orchiopexy and those experiencing spontaneous descent. This study supports the hypothesis that UDT is a spectrum representing both congenital UDT and acquired UDT. Sperm DNA damage at adult age is not influenced by age at orchiopexy in congenital UDT cases and by orchiopexy or spontaneous descent in acquired UDT cases.

Scrotal ultrasound findings in previously congenital and acquired unilateral undescended testes and their contralateral normally descended testis.

The aim of this study was to report on different anomalies found by physical examination and scrotal ultrasound in men with previously unilateral congenital undescended testes (UDT; N = 50), acquired UDT (N = 49), their contralateral normally descended testis (CNDT) and control testes (N = 53). Acquired UDT significantly more often had a testicular volume being <15 mL than congenital UDT (88% vs. 68%). In the congenital group, significant differences were found between UDT and CNDT for soft consistency (UDT 36% vs. CNDT 14%), epididymal diameter (UDT 7.6 mm vs. CNDT 8.9 mm), testicular volume (UDT 9.8 mL vs. CNDT 13.8 mL), and inhomogeneous parenchyma (UDT 38% vs. CNDT 14%). In the acquired group, significant differences were found between UDT and CNDT for epididymal diameter (UDT 7.5 mm vs. CNDT 8 mm), testicular volume (UDT 9.3 mL vs. CNDT 14.1 mL), testicular volume <15 mL (UDT 88% vs. CNDT 59%), and inhomogeneous parenchyma (UDT 27% vs. CNDT 6%). The following parameters of congenital UDT, acquired UDT, congenital CNDT, and/or acquired CNDT significantly differed compared with controls: soft testicular consistency (congenital UDT 36%, acquired UDT 20%, congenital CNDT 14%, acquired CNDT 12% vs. controls 0%), epididymal diameter (congenital UDT 7.6 mm, acquired UDT 7.5 mm, acquired CNDT 8 mm vs. controls 9.2 mm), testicular volume (congenital UDT 9.8 mL, acquired UDT 9.3 mL, congenital CNDT 13.8 mL, acquired CNDT 14.1 mL vs. control testes 15.8 mL), testicular volume <15 mL (congenital UDT 68%, acquired UDT 88%, congenital CNDT 66% vs. controls 43%), inhomogeneous parenchyma (congenital UDT 38%, acquired UDT 27%, congenital CNDT 14% vs. controls 0%), and testicular microlithiasis (congenital CNDT 24% vs. control testes 8%). Few differences between congenital and acquired unilateral UDT and congenital and acquired CNDT support the hypothesis of a spectrum of maldescended testes containing congenital and acquired UDT instead of them being two different entities. The CNDT also has anomalies albeit less severe than the UDT, indicating that in unilateral UDT both testes are affected.

Acquired undescended testes and fertility potential: is orchiopexy at diagnosis better than awaiting spontaneous descent?

The aim of this study was to evaluate testicular function in men with previous acquired undescended testis (UDT) in whom orchiopexy was performed at diagnosis compared with a similar group of men in whom spontaneous descent was awaited until puberty. Secondly, we examined the influence of age at orchiopexy on fertility parameters in adult life. A total of 169 men of the 'orchiopexy at diagnosis' group and 207 men of the 'wait and see' protocol group were invited for participation. All participants underwent an andrological evaluation, including medical history, physical examination, scrotal ultrasound, determination of reproductive hormones, and semen analysis. Results were compared for men in whom orchiopexy was performed at diagnoses with men in whom spontaneous descent was awaited until puberty followed by orchiopexy in case of non-descent. In the 'orchiopexy at diagnosis' group, 63 men of whom 14 with bilateral UDT, and in the 'wait and see' protocol group, 65 men of whom 15 with bilateral UDT were included. For unilateral UDT Inhibin B was found to be significantly lower and median progressive motility was higher in men with orchiopexy at diagnosis. For bilateral UDT, semen concentration and progressive motility showed a trend toward a favorable outcome for orchiopexy at diagnosis. Age at orchiopexy being under or above 10 years of age had no significant influence on the fertility potential. The outcome of physical examination, scrotal ultrasound, endocrine function, and semen analysis indicates a compromised fertility potential in men with previous acquired UDT. None of the protocols proved to be superior. For bilateral UDT, a trend toward favorable outcome of orchiopexy at diagnosis was seen. Furthermore, age at orchiopexy did not have an influence on fertility parameters. Therefore, in our opinion a 'conservative policy' is warranted for unilateral UDT, especially because over 50% of acquired UDT descend spontaneously.

Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.

Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use.

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3­4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03­0.05 mg/kg/day starting from the age of 8­10 years onward scan be considered.

Fertility potential in men with a history of congenital undescended testes: a long-term follow-up study.

Men with a history of congenital undescended testes (UDT) have an increased risk of fertility problems. Despite no definitive proof, current guidelines recommend early surgical intervention because this may have a positive effect on future fertility potential by preventing degenerative changes of the testes in early life. Also surgical intervention facilitates observability of the testes in view of possible malignancy. We evaluated testicular function in adult men with previous UDT treated at different ages before puberty. A long-term follow-up study of men with previous UDT was performed. Andrological evaluation included medical history taking, physical examination, scrotal ultrasound, determination of reproductive hormones, and semen analysis. Findings were compared with those of a control group of men with normal testicular descent. The influence of age at orchiopexy on future fertility parameters was evaluated in a multivariate regression analysis. 62 men were included of whom seven had had bilateral UDT. Twenty-four patients had had their orchiopexy before the age of 24 months of whom eight men had it before 12 months of age. Forty-eight men had had unsuccessful luteinizing-hormone-releasing-hormone (LHRH) nasal spray treatment during childhood, whereas 14 of 24 men operated before 24 months of age had not received LHRH treatment before orchiopexy. Fertility potential in men with a history of UDT is compromised in comparison with controls. We could not detect any influence of age at orchiopexy on fertility parameters. However, the number of patients operated before the age of 12 months is limited. This study does not support the assumption that early orchiopexy results in better fertility potential.

Long-term endocrine side effects of childhood Hodgkin's lymphoma treatment: a review.

BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gained interest. Childhood Hodgkin's lymphoma has been treated successfully for decades now. We provide an overview of the literature on long-term endocrine side effects, such as gonadal dysfunction and growth retardation, as a result of childhood Hodgkin's lymphoma treatment. METHODS A comprehensive search of the Pubmed database was performed. RESULTS We identified 16 studies (10 studies: 298 male survivors and 6 studies: 230 female survivors) about gonadal dysfunction. In survivors treated with alkylating agents or pelvic radiotherapy, severe gonadal damage is described. Recovery was rarely described. Seven studies (481 survivors) about bone mineral density (BMD) and growth were identified. The effects on BMD appear to be small. Data on growth are scarce, but show that radiotherapy in a dose of >30 Gy including the spine, especially in pre-pubertal children, results in reduced height. We included 10 studies (4012 survivors) about thyroid complications. Hypothyroidism is the most common thyroid disorder after radiotherapy. There is also a significant incidence in thyroid carcinoma after low-dose radiation. In survivors treated with chemotherapy only, hypothyroidism and thyroid cancer have not been reported. CONCLUSIONS The severity of endocrine toxicity after childhood Hodgkin's lymphoma depends on the type of treatment. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy. The knowledge obtained in specific follow-up programmes for paediatric cancer survivors will help to find the optimal balance between curability and long-term side effects.

Surgical findings in acquired undescended testis: an explanation for pubertal descent or non-descent?

AIM: Surgical findings were studied to find an explanation for the phenomenon that some acquired undescended testes (UDT) descend spontaneously whereas others need orchiopexy. METHODS: In patients with acquired UDT spontaneous descent was awaited until at least Tanner stage P2G2. Orchiopexy was performed when a stable scrotal position had not been achieved by the end of follow-up. RESULTS: Orchiopexy was needed in 57 of 132 cases (43%). In cases requiring orchiopexy, the difference in testis volume compared to the contralateral healthy testis was significantly larger than for spontaneously descended testes. 41 (72%) undescended testes were found in the superficial inguinal pouch; 16 (28%) at the external annulus. 26 of the 41 testes in the superficial inguinal pouch position (63%) could be manipulated preoperatively into a non-stable scrotal position; 15 could only reach the scrotal entrance prior to surgery. None of the 16 testes located at the external annulus could reach a scrotal position. Inguinal exploration in most cases revealed a fibrous string or a partially open processus vaginalis. CONCLUSION: The mobility of acquired UDT located within the external annulus is limited. It is mainly the fibrous string and the partially open processus vaginalis that prevent normal elongation of the spermatic cord with growth. These testes are unlikely to descend spontaneously. Acquired UDT lying in the superficial inguinal pouch can often be pushed down well below the scrotal entrance. We speculate that under normal hormonal stimulation at puberty, some of these growing testes may overcome the strength of the fibrous string in the spermatic cord and descend again spontaneously.

Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: a prospective study.

BACKGROUND: This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment. PATIENTS AND METHODS: We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C) and methionine synthase reductase (MTRR 66A > G) single nucleotide polymorphisms (SNPs) on total body BMD (BMD(TB)) and lumbar spine BMD (BMD(LS)) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients ≥ 4 years (n = 68). RESULTS: Carriers of the MTHFR 677 T-allele showed a lower baseline BMD(TB) than non-carriers (-0.38 SDS vs. +0.55 SDS, p = 0.01) and BMD(TB) remained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMD(TB) (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMD(TB) compared with non-carriers. Combining these two SNPs, patients carrying ≥ 2 risk alleles had a significantly lower BMD(TB) (-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A > C had higher homocysteine levels, this SNP was not related to BMD(TB). BMD(LS) of carriers was similar to non-carriers of the investigated SNPs. CONCLUSIONS: The MTHFR 677C>T SNP and the MTRR 66A >G SNP were identified as determinants of impaired BMD(TB) in childhood ALL patients.

Should blood gas analysis be part of the diagnostic workup of short children? Auxological data and blood gas analysis in children with renal tubular acidosis.

BACKGROUND: Renal tubular acidosis (RTA) is a rare cause of growth failure, therefore it is uncertain whether routine screening with blood gas analysis of short infants and children is cost-effective. OBJECTIVE: To investigate the clinical, growth and laboratory parameters in children with RTA to estimate the possible value of laboratory screening for this disorder in infants and children referred for short stature according to a recent guideline. METHOD: Retrospective chart analysis of 30 children diagnosed between 1978 and 2005 in The Netherlands and 3 centers in Belgium. RESULTS: The current guideline for short stature detected 33% of children with RTA. Assuming a pre-test probability of RTA of 0.6 per 100,000 births, the likelihood ratio of poor growth was 58 and 17 below and above 3 years, respectively. Sensitivity was 17/30 and 12/24 for a -2.0 SDS cutoff for weight and body mass index, respectively. In infants and toddlers diagnosed before 3 years of age, the mean weight loss was 1.5 SD, and 0.8 SDS in older children. In short children >3 years RTA was extremely rare, always associated with clinical symptoms, and rarely detected by blood gas analysis. CONCLUSION: According to our data a decreasing weight SDS for age is a sufficient indication to perform blood gas analysis in children <3 years of age, particularly in the presence of additional clinical features, whereas it can be omitted in short children >3 years of age.

High-dose GH treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height.

OBJECTIVE: To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS). DESIGN AND METHODS: Forty children with no signs of puberty, age at start 4-8 years (girls) or 4-10 years (boys), height SDS <-2.0 SDS, and birth length >-2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m(2) per day (equivalent to 75 microg/kg per day at start and 64 microg/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (S.D.) age of 20.4 (2.3) years. RESULTS: GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2-5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (-1.3 (0.8) SDS versus -2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3-12 years, AH was -2.1 (0.7) and -1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain. CONCLUSION: High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls.

A randomized trial investigating an exercise program to prevent reduction of bone mineral density and impairment of motor performance during treatment for childhood acute lymphoblastic leukemia.

BACKGROUND: Reduced bone mineral density (BMD), altered body composition, impaired motor performance and passive ankle dorsiflexion are side effects of acute lymphoblastic leukemia (ALL) treatment. We performed a randomized study investigating whether an exercise program could prevent these side effects. PROCEDURE: At diagnosis we randomized 51 ALL patients (median age: 5.4 years) into a group receiving a 2-year exercise program or a control group receiving standard care. BMD of total body (BMD(TB)), lumbar spine (BMD(LS)) and body composition were measured using dual energy X-ray absorptiometry, motor performance with Bayley Scales of Infant Development or Movement-ABC, and passive ankle dorsiflexion with a goniometer. The investigator was blinded to the randomization. RESULTS: Body fat increased equally during treatment in both groups. One year after cessation of therapy more rapid decline of excessive body fat was observed in the intervention group than in the controls (P = 0.01). Lean body mass, BMD(TB) and BMD(LS) of both groups decreased equally during treatment and increased equally thereafter. Both groups showed a similar decrease in passive ankle dorsiflexion and motor performance during treatment. Adherence to the intervention program varied considerably. Adherence to intervention: 11% of children exercised daily, 37% > once a week, 16% once weekly, 36% < once a week. CONCLUSIONS: The exercise program was not more beneficial than standard care in preventing reduction in BMD, motor performance and passive ankle dorsiflexion than standard care, most likely due to unsatisfactory compliance. Increased BMI and body fat in the intervention group normalized faster after cessation of chemotherapy.

Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels.

BACKGROUND: Besides short stature, gonadal dysgenesis leading to a lack of oestrogen is one of the main characteristics of Turner syndrome (TS). In most TS girls, puberty is induced with exogenous oestrogens. OBJECTIVE: To describe the pubertal development and uterine dimensions achieved by low-dose 17beta-oestradiol (17beta-E2) orally started at an appropriate age. Additionally, to determine whether serum hormone levels aid evaluation of pubertal progression. DESIGN: In 56 TS girls, we prospectively studied pubertal stage, serum E2, LH, FSH, SHBG and oestrone (E1), starting oestrogen treatment with a low-dose 17beta-E2 (5 microg/kg/day) during GH treatment at mean (SD) age 12.7 (0.7) years. Hormone levels were measured at start, 3 months after start and after increasing 17beta-E2 dosage. Uterine dimensions were measured in 39 TS women at age 19.9 (2.2) years. RESULTS: Although breast and pubic hair development were similar to that in normal Dutch girls up to Tanner stage B5 and P5, respectively, breast development was 2 years later. Before oestrogen therapy, E2 levels were comparable to those in prepubertal girls. With a 17beta-E2 dose of 5 microg/kg/day, these levels increased significantly, becoming comparable to normal late pubertal or adult concentrations, whereas SHBG levels were unchanged. At the adult 17beta-E2 dose, SHBG had increased significantly. Uterus shape was juvenile in four (10.2%), cylindrical in four and mature-adult shaped in 31 (79.5%) of TS patients. CONCLUSIONS: During GH treatment in TS girls, normal breast development up to B5 can be mimicked, with just a 2-year delay. In a clinical setting, serum hormone levels provide no additional information for evaluating pubertal progression. After age-appropriate pubertal induction, uterine dimensions in women aged nearly 20 years were subnormal. It remains unclear whether this was related to E2 dosage, timing or duration, or factors related to TS.

Developing evidence-based guidelines for referral for short stature.

OBJECTIVE: To establish evidence-based guidelines for growth monitoring on a population basis. STUDY DESIGN: Several auxological referral criteria were formulated and applied to longitudinal growth data from four different patient groups, as well as three samples from the general population. RESULTS: Almost 30% of pathology can be detected by height standard deviation score (HSDS) below -3 or at least two observations of HSDS below -2.5 at a low false-positive rate (<1%) in 0-3-year-old infants. For 3-10-year olds, a rule concerning distance to target height of >2 SD in combination with HSDS <-2.0 has the best predictive value. In combination with a rule on severe short stature (<-2.5 SDS) and a minor contribution from a rule on "height deflection", 85.7% of children with Turner syndrome and 76.5% of children who are short because of various disorders are detected at a false-positive rate of 1.5-2%. CONCLUSIONS: The proposed guidelines for growth monitoring show high sensitivity at an acceptably low false-positive rate in 3-10-year-old children. Distance to target height is the most important criterion. Below the age of 3 years, the sensitivity is considerably lower. The resulting algorithm appears to be suitable for industrialised countries, but requires further testing in other populations.

Further evidence for spontaneous descent of acquired undescended testes.

PURPOSE: It is still controversial whether acquired undescended testis can best be managed by orchiopexy or by the wait and see method. We prospectively evaluated spontaneous descent of acquired undescended testes and possible predictive factors in prepubertal boys. MATERIALS AND METHODS: From 1982 to 2004 spontaneous descent was awaited until at least Tanner stage P2G2 in 109 boys with a total of 83 unilateral and 52 bilateral acquired undescended testes. Annually we established testis position and size. After Tanner stage P2G2 orchiopexy was done for all testes in an unstable scrotal position. RESULTS: Two boys (3 acquired undescended testes) were excluded from analysis. Of 132 acquired undescended testes 75 descended spontaneously (57%, 95% CI 48-65), including 40 of 75 (57%) in early puberty or before puberty and 32 of 75 (43%) in mid puberty. Orchiopexy was performed in 57 of 132 acquired undescended testes (43%). Acquired undescended testes showed an increasing chance of descending spontaneously with increasing age (p trend = 0.002). In 63 of 82 unilateral undescended testes we were able to compare testis volume at the onset of puberty with that of the healthy contralateral side. Of 17 testes that needed orchiopexy 12 (71%) had a volume that was more than 1 ml smaller than the healthy testis. This was noted in only 18 of 46 spontaneously descended acquired undescended testes (39%, p = 0.053). Other factors, such as the most caudal testicular position at referral or the frequency of confirmed descended testicular position before referral, were not predictive of spontaneous descent. CONCLUSIONS: A conservative wait and see approach to acquired undescended testis until puberty could prevent more than half of the boys from undergoing orchiopexy and it does not seem detrimental in terms of testicular volume.

Growth hormone treatment in children with rheumatic disease, corticosteroid induced growth retardation, and osteopenia.

BACKGROUND: In children with severe rheumatic disease (RD), treatment with corticosteroids (CS) is frequently needed and growth retardation and osteopenia may develop. A beneficial effect of human growth hormone (hGH) has been reported but mostly in trials without a control group. AIMS: To study the effect of hGH on growth, bone mineral density (BMD), and body composition, taking the disease activity and CS use into account. METHODS: Randomised controlled trial on 17 prepubertal RD patients with growth retardation and/or decreased BMD. The hGH group (n = 10) received treatment with hGH 4 IU/m2/day (approximately 0.045 mg/kg/day) during two years. The controls (n = 7) received no GH treatment. RESULTS: During the two year study period the disease activity, and use of CS and methotrexate (MTX) did not differ between the groups. There was a significant mean increase in height standard deviation score (HSDS) in the hGH group (0.42+/-0.16 SDS) and a non-significant decrease in the controls (-0.18+/-0.11 SDS). Change in BMD did not differ significantly between the groups, although the increase in BMD for lumbar spine within the hGH group was significant. Lean body mass improved significantly in the hGH group compared to controls (0.64+/-0.19 SDS versus -0.20+/-0.17 SDS), while the decrease in percentage fat was not significant. CONCLUSIONS: There was a significant effect of hGH on growth and lean body mass, but a longer duration of treatment might be necessary to evaluate the effect of hGH on BMD.

Growth monitoring and diagnostic work-up of short stature: an international inventorization.

BACKGROUND/AIMS: Growth monitoring is almost universally performed, but few data are available on which referral criteria and diagnostic work-up are used worldwide for children with short stature. METHODS: A short questionnaire, containing questions on auxological screening and on diagnostic criteria for short stature, was sent to all members of the European Society of Paediatric Endocrinology (ESPE) and to several pediatric endocrinologists outside Europe. RESULTS: Responses were received from 36 countries. In 27 (75%) a child health care program existed and in 14 (39%) there was a protocol for referral of children with growth retardation. Height for age was mostly used as a referral criterion. Sixteen countries (45%) reported having a guideline in secondary health care for diagnostic work-up. Although all countries agreed on having biochemical, radiological and/or genetic tests in the diagnostic work-up, there was a wide variety of recommended tests. CONCLUSIONS: There is little consensus on referral criteria and diagnostic work-up of children with short stature among industrialized countries. There is a need to establish evidence-based guidelines.

Vitamin D receptor gene polymorphism predicts height and bone size, rather than bone density in children and young adults.

Peak bone mass is considered to be under strong genetic control. We studied the association among anthropometry, bone density and vitamin D receptor (VDR) genotype in an ethnically homogeneous group of 148 Caucasian children and young adults. Bone density was measured by dual energy X-ray absorptiometry (DXA) and VDR genotype was determined by a direct haplotyping procedure of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms. A second DXA measurement was made after approximately 4 years. Results are expressed as age- and sex-adjusted standard deviation scores (SDS). Previously, the collagen IA1 Sp1 polymorphism was studied in this population. We found VDR genotype to be associated with a 0.4 SDS increased height per allele copy of haplotype '3' (P = 0.04) and a 0.4 SDS increased width of the lumbar vertebral body in the haplotype '3' allele carriers (P = 0.05). We observed a trend towards a 0.3 SDS decreased bone mineral apparent density of lumbar spine (BMAD) per copy of haplotype '3' allele (P = 0.10). In contrast, no association with areal bone mineral density (BMD) was observed. In the follow-up analyses, no differences in height or bone gain among the VDR genotypes were demonstrated. By combining the risk alleles of VDR and collagen IA1 Sp1 genotype, an additive genotype effect on height (P = 0.006) and vertebral body width (P = 0.001) was found. In this exploratory study we found VDR genotype to be associated with frame size and BMAD. The VDR genotype effects on stature and bone size seem to neutralize the effect on areal BMD.

Collagen Ialpha1 polymorphism is associated with bone characteristics in Caucasian children and young adults.

A large proportion of the variation in bone mass can be explained by genetic factors. We analyzed the G to T substitution in the Sp1 binding site in the first intron of the collagen type Ialpha1 (COLIA1) gene in relation to bone mass. The genotypes GG, GT, and TT were determined in 148 Caucasian children and young adults. We performed dual energy X-ray absorptiometry twice (mean follow-up time 4.4 years), and speed of sound (SOS) was assessed by tibial ultrasonometry at follow-up. Genotype distribution was 104 (70%) GG, 40 (27%) GT and 4 (3%) TT. Carriers of the T-allele had a 0.5 SDS (standard deviation score) decreased bone mineral content (BMC) of total body (P = 0.001), and a 0.4 SDS decreased bone mineral density (BMD) for both lumbar spine (P = 0.04) and total body (P = 0.05). The genotype effect on BMD and BMC decreased after adjustment for height or body mass index. When we calculated apparent BMD, these differences diminished to 0.1 SDS and were no longer significant. T-allele carriers had shorter stature (0.4 SDS; P = 0.04) and smaller bones (0.5 SDS lower width of the lumbar vertebral body; P = 0.01). The T-allele was also associated with lower SOS (P = 0.03), independent of BMD and BMC, and lower lean body mass. Similar associations were found at follow-up. The change in BMD and BMC SDS between the first and second measurement did not differ between the GG and GT&TT group. In conclusion, the COLIA1 polymorphism in children and young adults is associated with several bone characteristics. However, at least a part of the COLIA1 effect on bone mass may be related to differences in frame size.