Pediatric Langerhans cell histiocytosis: the impact of mutational profile on clinical progression and late sequelae.

Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of BRAF and MAP2K1, but data on the impact of genetic features on progression and long-term sequelae are sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in BRAFV600 and MAP2K1 exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed BRAFV600E, one case a BRAFV600D and eleven (30%) a MAP2K1 mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either BRAFV600 or MAP2K1 mutation. Patients with BRAFV600 mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (p = 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-BRAFV600/MAP2K1 mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (n = 3) were positive for BRAFV600E. Infants below 2 years more frequently had BRAFV600 mutations (p = 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.

Improved immune recovery after transplantation of TCRαß/CD19-depleted allografts from haploidentical donors in pediatric patients.

Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αß T- and B-cell-depleted allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαß and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/µL, >200 CD19+ cells/µL and >200 CD56+ cells/µL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/µL), for CD3+4+ at day +30 (58 vs 11 cells/µL) and for CD56+ at day +14 (622 vs 27 cells/µL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.

Antifungal prophylaxis with posaconazole vs. fluconazole or itraconazole in pediatric patients with neutropenia.

Pediatric patients with hemato-oncological malignancies and neutropenia resulting from chemotherapy have a high risk of acquiring invasive fungal infections. Oral antifungal prophylaxis with azoles, such as fluconazole or itraconazole, is preferentially used in pediatric patients after chemotherapy. During this retrospective analysis, posaconazole was administered based on favorable results from studies in adult patients with neutropenia and after allogeneic hematopoietic stem cell transplantation. Retrospectively, safety, feasibility, and initial data on the efficacy of posaconazole were compared to fluconazole and itraconazole in pediatric and adolescent patients during neutropenia. Ninety-three pediatric patients with hemato-oncological malignancies with a median age of 12 years (range 9 months to 17.7 years) that had prolonged neutropenia (>5 days) after chemotherapy or due to their underlying disease, and who received fluconazole, itraconazole, or posaconazole as antifungal prophylaxis, were analyzed in this retrospective single-center survey. The incidence of invasive fungal infections in pediatric patients was low under each of the azoles. One case of proven aspergillosis occurred in each group. In addition, there were a few cases of possible invasive fungal infection under fluconazole (n = 1) and itraconazole (n = 2). However, no such cases were observed under posaconazole. The rates of potentially clinical drug-related adverse events were higher in the fluconazole (n = 4) and itraconazole (n = 5) groups compared to patients receiving posaconazole (n = 3). Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in pediatric patients. Defining dose recommendations in these patients requires larger studies.

Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD.

Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a significant impact on the patients' health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT.

Children with relapsed or refractory nephroblastoma: favorable long-term survival after high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center. PROCEDURE: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients. RESULTS: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each). CONCLUSION: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.

Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation.

Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4%) and three in the voriconazole group (6%). The percentage of patients with adverse events potentially related to clinical drugs were 14% in the voriconazole group, 12% in the itraconazole group, and 8% in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.

Short children with low birth weight born either small for gestational age or average for gestational age show similar growth response and changes in insulin-like growth factor-1 to growth hormone treatment during the first prepubertal year.

BACKGROUND/AIMS: Growth hormone (GH) is an accepted treatment for short children born small for gestational age (SGA). The aim of this analysis was to compare the growth response to GH in children with low birth weight born SGA or appropriate for gestational age (AGA). METHODS: This retrospective observational study is from one center. Of all the children with a birth weight <2,500 g treated, 50 were primarily diagnosed as having growth hormone deficiency ([A] SGA, n = 26; [B] AGA, n = 24) and 138 were originally diagnosed SGA or AGA (reclassified: [C] SGA, n = 102; [D] AGA, n = 36). RESULTS: [Median; A, B, C, D]: at an age of 4.9, 5.2, 5.8, 5.8 years, a height of -2.9, -2.4, -2.8, -2.9 SDS and a GH dose of 27, 28, 41, 39 µg/kg/day, the children grew 0.9, 0.9, 0.8, 0.9 SDS in height, respectively. Insulin-like growth factor-1 (IGF-1) at GH start was, respectively, -2.1, -2.2, -0.4, -0.9 SDS and rose to (delta IGF-1) 1.8, 2.0, 1.7, 1.5 SDS during the first year on GH. All differences were not significant. CONCLUSIONS: We show for the first time that short stature children with low birth weight born AGA experience the same increase in height and IGFs to GH treatment as those born SGA irrespective of actual GH secretory status.

Fertility preservation in girls and adolescents before chemotherapy and radiation - review of the literature.

There has been a significant improvement in survival rates over the last decade as a result of advances in the treatment of cancer in children. One of the consequences of chemotherapy may be damage to the ovarian function, which can lead to loss of fertility. Methods of fertility protection have been developed for adult women as a result of advances in reproductive medicine, which make the option of becoming pregnant after surviving cancer realistic. However, only some of the methods can be used in prepubescent girls and adolescents. In addition, a higher number of miscarriages and premature births have been found in women who underwent pelvic radiotherapy during childhood or adolescence and the children were more commonly growth retarded. The effects of cancer treatment on the ovarian function and later fertility should be discussed at the start of treatment.

Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes.

AIMS/HYPOTHESIS: The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. METHODS: ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. RESULTS: All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. CONCLUSIONS/INTERPRETATION: In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.

The course of neonatal cholestasis in congenital combined pituitary hormone deficiency.

BACKGROUND: Neonatal cholestatic hepatitis is frequently associated with congenital combined pituitary hormone deficiency (CCPHD). Data on the course of this hepatopathy are scarce. AIM: We retrospectively analyzed the data of all CCPHD infants with cholestasis who presented at the University Children's Hospital, Tuebingen. RESULTS: All infants (n = 9; 2 females) presented with early and prolonged jaundice, failure to thrive and recurrent hypoglycemia. All males had micropenis and 3/7 cryptorchidism. Median age at diagnosis was 1.4 months. Cholestasis began at a median age of 13 days (range 5-31) and resolved at 88 days (54-174). Maximum direct bilirubin level was 6.9 mg/dl (2.4-11.6). Peaks of ALP (median 721 U/l), ALT (148 U/l) and AST (195 U/l) occurred 2-4 weeks later, while GGT levels were elevated in only two infants (167 U/l). Functional liver parameters were always normal. Liver biopsies (n = 4) showed canalicular cholestasis and mild portal eosinophilic infiltration. TEBIDA radioisotope excretion into the intestinal tract was blocked. Substitution with Lthyroxine, hydrocortisone and growth hormone seemed to accelerate the cure from cholestasis. Liver function at follow-up (median 4 yr) stayed normal. CONCLUSION: Cholestasis in CCPHD follows the course described here, frequently with normal GGT levels.

Can we identify adolescents at high risk for nephropathy before the development of microalbuminuria?

AIMS: To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria. METHODS: Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS; n = 554, median duration of follow-up 10 years; range 3.0-16.7) with assessment of albumin/creatinine ratios in three early morning urine samples collected annually. An albumin excretion phenotype was derived from longitudinal data, for each individual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia. RESULTS: The albumin excretion phenotype showed reasonable correlation between age 11-15 years and age 16-18 years in both cohorts, indicative of good 'tracking'. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11-15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA(1c) > 9% at aged 11-15 years. CONCLUSIONS: Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA(1c), it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.

Late effects after stem cell transplantation (SCT) in children--growth and hormones.

Stem cell transplantation (SCT) has established itself as a very successful therapy in often otherwise unbeatable disorders. In a subset of children and adolescents there are, however, late effects, often as a combination of the underlying disorder, its primary treatment and subsequent SCT. In children and adolescents, disorders of growth and the endocrine system have been observed to occur frequently. The assurance of normal growth, puberty, fertility and thyroid function--including the prevention of secondary malignancies--is of utmost importance for the overall success of treatment and the maintenance of quality of life. This, however, requires a systematic and structured follow-up programme for patients after SCT. Patients and their families need to be made familiar with this concept early and physicians need to understand that such a system must be implemented as part of a comprehensive care.

Cortical bone density is normal in prepubertal children with growth hormone (GH) deficiency, but initially decreases during GH replacement due to early bone remodeling.

Dual energy x-ray absorptiometry (DEXA) has revealed that GH- deficient adults gain in bone mineral density during GH therapy. Measurements of volumetric bone density (grams per cubic centimeter vs. grams per square centimeter) and structure, however, are achieved through peripheral quantitative computed tomography (pQCT). In 45 prepubertal GH-deficient children, we studied pQCT measurements before the start and for 12 months of GH treatment. Serum alkaline phosphatase (AP), procollagen I carboxyl-terminal propeptide (PICP), and deoxypyridinoline reflected bone metabolism status. Findings at the start of GH treatment were (mean SD score): bone area, -0.44; cortical density, -0.03; cortical area, -1.32; cortical thickness, -1.41; and marrow area, +0.66. At 12 months, cortical density had fallen to -0.73 (P < 0.001), whereas cortical area and thickness, and marrow area did not change. AP, PICP, and deoxypyridinoline increased significantly within the first 3 months (increase: AP, 66.5 U/liter; PICP, 72 microg/liter; DPD, 11.4 nmol/mmol creatinine). The pQCT showed that cortical density is not reduced in GH-deficient patients. Higher bone metabolism explains the lower cortical density after GH therapy commenced. Thus, the manifestation of GH deficiency is evidently similar in children and adults, and pQCT provides important information in addition to DEXA measurements, as DEXA does not take bone structure into account.

Relevance of IGF-I, IGFBP-3, and IGFBP-2 measurements during GH treatment of GH-deficient and non-GH-deficient children and adolescents.

BACKGROUND: Little information is available on the relevance of parameters representing the insulin-like growth factor (IGF) system with regard to growth hormone (GH) treatment during childhood. In adults, high IGF-I levels were found to be associated with side effects and long-term risks. AIM/METHOD: Our aim was to monitor the serum levels of IGF-I, IGF-binding protein (IGFBP) 3, and IGFBP-2 during long-term GH treatment of 156 patients with GH deficiency (GHD) and of 153 non-GHD patients. We determined the extent to which the IGF parameters exceed the normal ranges and identified those parameters which are predictive of 1st-year growth. RESULTS: In prepubertal GHD children, the levels of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 exceeded the 95th centile of the reference values for this age group in 2.3, 0.3, and 7.9% of the cases, respectively, whereas in prepubertal non-GHD children, the same parameters exceeded the 95th reference centile in 20.1, 3.5, and 32.2%, respectively. In pubertal GHD children IGF-I, IGFBP-3, and IGF-I/IGFBP-3 levels exceeded the 95th reference centile in 11.1, 1.5, and 15.4%, respectively. In pubertal non-GHD children, these levels also exceeded the 95th centile in 26.7, 7.0, and 41.4%, respectively. In both GHD and non-GHD groups, however, some patients had IGF parameters which were below the reference values. Our analysis showed that, in both groups, in addition to maximum GH, all IGF parameters (IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio, IGFBP-2 or derivatives) significantly extend the scope of a calculated model for predicting 1st-year height velocity. CONCLUSION: For reasons of safety and optimization of GH therapy, it is essential to follow up IGF-I, IGFBP-3, and IGFBP-2 levels regularly during childhood.

X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients.

Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenital adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disorder are scarce. Here we present a detailed documentation of longitudinal data relating to three cases. We retrospectively collected clinical data on three boys (6, 14 and 14.5 years old) who we examined over a period ranging between 5 and 14 years. Mutational analysis of the DAX-1 gene was performed by means of direct sequencing of PCR products. The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially erroneously diagnosed with isolated aldosterone deficiency. Glucocorticoid deficiency was established by means of ACTH stimulation tests at 4 months, 3 and 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during infancy, as penis size was normal, the testes were descended, and serum samples contained normal testosterone levels. One boy exhibited transient hypergonadotrophism at age 9 but showed no clinical signs of puberty or an increase in serum testosterone. Onset of puberty and LHRH tests proved to be normal in his case as well as in another patient studied. In two patients, genetic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame shift and premature stops at codons 263 and 398. One boy was affected by a new nonsense mutation of codon 39 (W39X) inherited from his mother. Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitory functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first indicators of defects in the gonadal axis, although normal initiation of puberty is not rare. The definitive diagnosis was established by means of molecular analysis of the DAX-1 gene. There was no correlation between types of mutations and phenotypes. The diagnostic procedure in male children and adolescents presenting with adrenal crisis should include ACTH stimulation tests and mutational analysis of DAX-1 in the absence of another proven aetiology.

Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone.

Point mutations or complete deletions of SHOX, the short-stature homeobox-containing gene on the pseudoautosomal region of the sex chromosomes (Xp22 and Yp11.3), were recently reported in one family with idiopathic short stature and in several families with Leri-Weill syndrome (dyschondrosteosis). The missing SHOX is also thought to attribute to the growth failure in Turner syndrome. For testing the frequency of defects of SHOX in unexplained growth failure and recombinant human GH (rhGH) as a possible growth-promoting agent, we selected 68 children with idiopathic short stature. These probands had heights below -2.0 SD score for age, normal target heights, no significant bone age retardations, no endocrine abnormalities, no skeletal diseases, and no other organic diseases. No mutations were detected by single-strand conformational polymorphism analysis of the PCR-amplified SHOX. The analysis of three microsatellite DNA markers of the pseudoautosomal region, including one located on the 5' untranslated region of SHOX-exon 1, identified a 15-yr-old girl who carried a mutation in the form of a complete SHOX deletion. This girl who had a normal karyotype presented with mild mesomelic shortening of the forearms and lower legs. We treated two children with short stature on the basis of a SHOX point mutation (C674T) with rhGH at a dose of 1.0 IU/kg body weight-week in accordance with the regimen used in Turner syndrome. During the first 12 months of treatment, these two children (5.9- and 8.4-yr-old) showed an excellent growth spurt with a growth rate of 9.5 and 9.4 cm/yr, respectively. Growth of the lower extremities was weaker than in the trunk and arms. Our data suggest that short stature due to SHOX deletions is not a rare entity. Growth-promoting therapy with rhGH was effective with regard to height gain, but a tendency to disproportionate growth was apparent. In cases of unexplained growth failure, especially if associated with any mild skeletal disproportions, genetic analysis of SHOX should be considered.

Experience with growth hormone therapy in Turner syndrome in a single centre: low total height gain, no further gains after puberty onset and unchanged body proportions.

The experience gained since 1987, through observation of 85 girls with Turner syndrome under growth hormone (GH) treatment, has enabled the analysis of one of the largest cohorts. Our results show that age, karyotype and height reflect the heterogeneity of the patients examined at our growth centre. In 47 girls, followed over 4 years on GH (median dose 0.72 IU/kg/week), the median age was 9.4 years and mean height SDS was -3.55 (Prader) and -0.14 (Turner-specific), while height and other anthropometrical parameters [weight, body mass index, sitting height (SH), leg length (LL) SH/LL, head circumference, arm span] were documented and compared to normative data as well as to Turner-specific references established on the basis of a larger (n = 165) untreated cohort from Tübingen. The latter data are also documented in this article. Although there was a trend towards normalization of these parameters during the observation period, no inherent alterations in the Turner-specific anthropometric pattern occurred. In 42 girls who started GH treatment at a median age of 11.8 years, final height (bone age >15 years) was achieved at 16.7 years. The overall gain in height SDS (Turner) from start to end of GH therapy was 0.7 (+/- 0.8) SD, but 0.9 (+/- 0.6) SD from GH start to onset of puberty (spontaneous 12.2 years, induced 13.9 years) and -0.2 (+/- 0.8) from onset of puberty to end of growth. Height gain did not occur in 12 patients (29%) and a gain of > 5 cm was only observed in 16 patients (38%). Height gain correlated positively with age at puberty onset, duration, and dose of GH, and negatively with height and bone age at the time GH treatment started. Final height correlated positively with height SDS at GH start and negatively with the ratio of SH/LL (SDS). We conclude that, in the future, GH should be given at higher doses, but oestrogen substitution should be done cautiously, owing to its potentially harmful effect on growth. LL appears to determine height variation in Turner syndrome and the potential to treat short stature successfully with GH.

Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children.

The role of IGF-I and IGFBP-3 measurements in the diagnostic work-up of short children is established but remains controversial. Little information exists on the value of IGFBP-2 measurements. Based on reference data established in 388 children we have reinvestigated the issue, using data from 392 short children who underwent the same diagnostic procedures between 1987 and 1998 (GHD, n = 187; non-GHD, n = 205, including patients with ISS, n = 76; IUGR, n = 46; and TS, n = 83). In comparing IGF-I, IGFBP-3 and IGFBP-2 serum levels of GHD and ISS children with reference data, we calculated the sensitivity, specificity, efficiency and positive predictive value for the diagnosis of GHD. The overall sensitivity of the parameters was high, the rank order being as follows: IGF-I >IGFBP-3 >IGFBP-2 (75, 67 and 62%, respectively). In contrast, the specificity was relatively low: IGFBP-3 >IGFBP-2 >IGF-I (50, 50 and 32%, respectively). The efficiency and positive predictive value of parameters was in the order of 40, 60 and 70--80%, respectively. In repeated measurements, the recorded basal levels of IGF-I and IGFBP-3 showed an overall narrow range of variation. We conclude that the determination of basal IGF parameters is, together with anthropometry and imaging techniques, an indispensable tool for differentiating between GHD and ISS; and that IGFBP-2 plays an additional role in this process.

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children.

The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from -1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGFBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS.