Dieter Haffner

Effects of Two Years of Growth Hormone Treatment in Short Children with Renal Disease

The effect of 1‐2 years of growth hormone (GH) treatment (28‐30 IU/m2/week) on growth rate, bone age, renal function and metabolic parameters was studied in 61 short, slowly growing children with chronic renal disease (20 with preterminal chronic renal failure (CRF), 24 with end‐stage renal failure (ESRF) and 17 with functioning renal transplants). Height velocity (2‐year data) significantly increased in children with preterminal CRF from a baseline median of 4.1 cm/year to 9.2 cm/year after 1 year and to 6.6 cm/year after 2 years of treatment. In patients with transplants, the corresponding values were 2.6 cm/year before GH treatment and 8.6 and 7.2 cm/year after 1 and 2 years, respectively. This resulted in normalization of height in 8 of the 16 children who completed 2 years of treatment. The growth response after 1 year in children with preterminal CRF was significantly higher than that in children with ESRF. Bone maturation was in proportion to the increase in chronological age; the expected final height of the children therefore increased by approximately 8‐10 cm. In children with preterminal CRF, the decrease in glomerular filtration rate was not affected by 2 years of treatment with GH. The incidence of acute rejection in children with transplants was low; however, a slight stimulatory effect of GH could not be excluded. The major metabolic change induced by exogenous GH was an increase in serum levels of insulin in the three treatment groups, though all glucose tolerance tests remained stable over the 2‐year period.

Factors predicting the near-final height in growth hormone-treated children and adolescents with chronic kidney disease.

CONTEXTnGH therapy is an accepted measure to increase adult height in young prepubertal patients suffering from growth failure related to chronic kidney disease (CKD). The impact of GH therapy on final height (FH) in CKD patients of pubertal age is unclear.nnnOBJECTIVEnThis study set out to analyze near-FH in a cohort of GH-treated CKD patients.nnnDESIGN, SETTINGS, AND PATIENTSnOf 240 evaluable patients in the Pfizer International Growth Database (KIGS) with CKD, 39% were prepubertal and 61% were pubertal at baseline; 45% were on conservative treatment for CKD, 28% were on dialysis, and 27% were in the period after renal transplantation.nnnMAIN OUTCOME MEASURESnNear-FH, relation to pubertal stage, and factors predictive of growth response were the main outcome measures.nnnRESULTSnMean height sd scores increased continuously during GH treatment until near-FH by 1.2 and 1.6 in boys and girls, respectively. Mean near-FH differed significantly from prepubertal patients showing severely delayed puberty (-3.6), late pubertal patients (-2.9), early pubertal patients (-2.2), and prepubertal patients with normal onset of puberty (-2.0). The initial degree of stunting, degree of bone age retardation, duration of GH therapy, time spent on conservative treatment/dialysis, pubertal delay (>2 sd), gender, and age at start of GH treatment were significant predictors of growth response to GH therapy, explaining between 33 and 61% of the overall variability.nnnCONCLUSIONSnLong-term GH therapy of CKD patients in prepubertal and pubertal age results in an increased adult height, but response is diminished in patients on dialysis and/or with severely delayed puberty.

Short dialyzed children respond less to growth hormone than patients prior to dialysis

Recombinant human growth hormone (rhGH) is a new treatment modality for short children with chronic renal failure (CRF) prior to and during dialysis. It is difficult to analyze whether dialysis patients respond less to rhGH than children with CRF on conservative treatment because they are older and often in a pubertal age range. One hundred and eight patients were treated with 28–30 IU rhGH/kg per week for at least 1 year. We analyzed the growth response to rhGH in 56 prepubertal patients aged less than 10 years at the start of rhGH treatment; 38 children with a mean age of 6.5±2.4 years were on conservative treatment (CT) and 18 patients with a mean age of 6.5±2 years on dialysis treatment (D). Mean height velocity was 4.9±2.3 cm/year in children on CT and 4.6±1.8 cm/year in children on D. During the 1 st treatment year, height velocity was 9.5±3.8 cm/year in CT patients and 7.3±1.3 cm/year in D patients (P<0.05). The change in height was +1.1±0.8 standard deviation (SD) in CT patients and +0.5±0.4 SD in D patients (P<0.005). During the 2nd treatment year, the change in height was again greater in CT patients (0.5±0.4 SD vs. 0.2±0.4 SD;P<0.05). The difference in height velocity and change in height standard deviation score was also significant when a subgroup of patients was matched for sex, age, height. Height velocity and the change in height velocity during rhGH treatment were not correlated with residual renal function, the degree of anemia, or metabolic acidosis. We conclude that short children on D respond less to rhGH than short children on CT, indicating a greater insensitivity to rhGH during D treatment.

Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats

BACKGROUNDnActivation of the mTOR pathway has been implicated in the mediation of the progression of polycystic kidney disease (PKD). Whereas targeted inhibition of mTOR has been proven to be effective in various animal models of autosomal dominant PKD, its efficacy in autosomal recessive PKD (ARPKD) remains to be elucidated. We examined the effects of sirolimus in PCK rats, an orthologous animal model of human ARPKD.nnnMETHODSnWeaned PCK rats (n = 85) and SD-control rats (n = 72) received drinking water without and with sirolimus (corresponding to a daily intake of 2 mg/kg body weight) for 4, 8 and 12 weeks, respectively. The renal and hepatic functions were monitored throughout the treatment periods. Kidneys and livers were harvested and investigated with respect to progression of fibrosis, and number and size of cysts using the QWin image analysis programme. Expression of Akt, mTOR and its downstream target pS6K were assessed by immunohistochemistry.nnnRESULTSnFive out of 43 sirolimus-treated PCK rats, but none of the controls, died during the study. Sirolimus treatment resulted in slightly reduced weight gain. In PCK rats, grossly enlarged kidney and livers as well as hepatic fibrosis together with enlarged bile ducts were readily detectable. Whereas activation of Akt/mTOR signalling was hardly detectable in the kidneys of SD rats, strong signals were seen in the kidneys of PCK rats. Despite a significantly reduced relative kidney weight after 12 weeks of treatment (P < 0.05), neither fibrosis and cyst area nor renal function improved during treatment. Sirolimus-treated PCK rats showed only a minor inhibition of renal mTOR-specific phosphorylation of S6K. Male PCK rats on sirolimus presented with increased concentrations of bile acids and bilirubin compared with controls (each P < 0.05 at 12 weeks). Similar, albeit non-significant, effects were noted in female PCK rats.nnnCONCLUSIONSnSirolimus failed to attenuate progression of kidney and liver disease in PCK rats. The lack of a protective effect might be due to intrinsic or acquired rapamycin resistance in this animal model of ARPKD.

Mapping candidate regions and genes for congenital anomalies of the kidneys and urinary tract (CAKUT) by array-based comparative genomic hybridization

BACKGROUNDnCongenital anomalies of the kidneys and urinary tract (CAKUT) are frequently associated with malformations of other organs.nnnMETHODSnIn order to explore the role of DNA microimbalances in syndromal CAKUT, we applied genome-wide array-based comparative genomic hybridization (array-CGH) in 30 children with various CAKUT phenotypes and at least one additional extrarenal symptom.nnnRESULTSnIn three patients, causal imbalances were detected: In one patient with duplex kidney and vesico-ureteral reflux associated with extrarenal stigmata, a terminal 9.52xa0Mb gain in chromosomal band 2q37.1-q37.3 and a terminal 5.65xa0Mb loss in 7q36.2-q36.3 were detected, which were due to an unbalanced 2;7-translocation according to FISH analysis. A balanced 2;7-translocation was present in the unaffected mother. In another patient presenting with renal hypoplasia and proximal ureteric stenosis combined with mental retardation, macrocephaly and ear anomalies, a duplication of 2.73xa0Mb was detected in 1q21.1. The unaffected father had a 1.3xa0Mb gain in 1q21.1-q21.2 involving the distal part of the patients gain, for which benign copy number variation was described. A third patient affected by dysplastic kidney with a strongly dilated ureter and extrarenal abnormalities exhibited a de novo loss of 13.38xa0Mb in 3q23-q25.1 including the AGTR1 gene. However, no AGTR1 mutations were identified in the remaining allele of this case or in 108 patients with isolated renal dysplasia/hypoplasia.nnnCONCLUSIONSnIn this study, 10% of patients with syndromic CAKUT were shown to carry DNA microimbalances, and four chromosomal regions presumably associated with the CAKUT phenotype were identified: 1q21.1, 2q37.1-q37.3, 3q23-q25.1 and 7q36.2-q36.3.

Paediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, sclerostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase

Background Paediatric reference values for novel markers of phosphate homeostasis, bone formation and resorption and their putative relationship to growth are lacking. Methods A total of 424 healthy children, adolescents and young adults (221 males) aged 0.1–21 y, were enrolled in this cross-sectional study. Height, weight and height velocity were assessed. Plasma/serum samples for determination of C-terminal fragment of fibroblast growth factor-23 (cFGF-23), sclerostin, bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRAP5b) were available from 222, 264, 352 and 338 individuals, respectively. Calculation of cross-sectional centiles and z-scores was based on median (M), standard coefficient of variation (S) and the Box-Cox power (L) of transformation (LMS method) per age cohort. Correlations between variables as well as with growth were assessed. Results cFGF-23, BAP and TRAP5b were significantly correlated with age (each P < 0.01), with highest values during infancy and adolescence. Serum levels of BAP and TRAP5b were significantly higher in adolescent boys compared with girls (each P < 0.01). In contrast, sclerostin levels were independent of age and gender. BAP and TRAP5b were strongly correlated and both were significantly associated with cFGF-23 and sclerostin as well (each P < 0.01). cFGF-23 was positively correlated with serum phosphate and renal phosphate threshold concentration (each P < 0.01). Height, weight, body mass index and height velocity were weakly correlated with BAP and TRAP5b (each P < 0.05). Conclusions This study provides age- and gender-related centile charts and z-scores for cFGF-23, BAP, TRAP5b and sclerostin and highlights the link between phosphate homeostasis and markers of bone metabolism during growth.

Growth Hormone Treatment in Short Children with Chronic Kidney Disease

Growth hormone (GH) has been used for treatment of impaired growth in children with chronic kidney disease (CKD) for nearly 17 years. Controlled and open‐label studies have shown that GH is highly effective in improving growth velocity and adult height. The growth response is negatively correlated with age and height at start and time spent on dialysis treatment; it is positively correlated with dose and duration of treatment and the primary renal disease (renal hypodysplasia). In children with renal transplants, corticosteroid treatment is an additional factor negatively influencing spontaneous growth rates. However, GH treatment is able to compensate corticosteroid‐induced growth failure. GH treatment improved final height by 0.5–1.7 standard deviation score (SDS) in various studies, whereas the control group lost about 0.5 SDS in comparable time intervals. These variable results are explained in part by the factors mentioned above. The adverse events are comparable to those in non‐CKD children treated with GH.

Hemophagocytic lymphohistiocytosis and Kawasaki disease: Combined manifestation and differential diagnosis

Both hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) are diagnosed in patients with prolonged resistant fever by using a scoring system. Concurrent manifestation of both conditions has been reported previously. We describe an infant of 7 weeks whose condition fulfilled the criteria of HLH, but who, after clinical response to treatment, suddenly died from a myocardial infarction at 11 weeks. Post‐mortem examination revealed a previously unknown coronary arteritis typical for KD. Since it is difficult to distinguish between KD and HLH, both diseases should be considered in young children with overlapping symptoms. Repeated echocardiograms may be helpful in these cases. Pediatr Blood Cancer 2009;53:493–495.

Three-Year Growth Hormone Treatment in Short Children with X-Linked Hypophosphatemic Rickets: Effects on Linear Growth and Body Disproportion

CONTEXTnChildren with X-linked hypophosphatemic rickets (XLH) are prone to progressive disproportionate stunting despite oral phosphate and vitamin D treatment.nnnOBJECTIVEnOur objective was to analyze the effects of GH treatment on stature and lengths of linear body segments in short children with XLH.nnnDESIGN, SETTINGS, AND PATIENTSnA 3-yr randomized controlled open-label GH study in short prepubertal children with XLH (n = 16) on phosphate and calcitriol treatment was conducted. A cohort of XLH patients (n = 76) on conservative treatment served as an XLH reference population.nnnMAIN OUTCOME MEASURESnChanges in SD scores (SDS) of stature and linear body segments, i.e. sitting height, leg and arm length, and sitting height index (i.e. ratio between sitting height and stature) were the main outcome measures.nnnRESULTSnXLH patients presented at time of enrollment with significant impairments of stature (-3.3 SDS) and linear body segments compared with healthy children. Leg length (-3.8 SDS) was most impaired, whereas sitting height (-1.7 SDS) was best preserved. The markedly elevated mean sitting height index (+3.3 SDS) reflected severe body disproportion. GH resulted in a sustained increase in linear growth (stature, +1.1 SDS; sitting height, +1.3 SDS; leg length, +0.8 SDS; arm length, +1.1 SDS; each P < 0.05 vs. baseline), whereas no significant changes were observed in controls. Mean height SDS at 3 yr did not significantly differ between groups. Sitting height index remained stable in both the GH-treated patients and in study controls but increased further in the XLH-reference population.nnnCONCLUSIONSnThe 3-yr GH treatment improved linear growth without progression of body disproportion in short children with XLH.

Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis

When a known microimbalance affecting multiple genes is detected in a patient with syndromic intellectual disability, it is usually presumed causative for all observed features. Whole exome sequencing (WES) allows questioning this assumption. In this study of three families with children affected by unexplained syndromic intellectual disability, genome-wide copy number and subsequent analyses revealed a de novo maternal 1.1xa0Mb microdeletion in the 14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two inherited 22q11.21 microduplications of 2.5 or 2.8xa0Mb. In patient 1 carrying the 14q32 microdeletion, tall stature and renal malformation were unexplained by paternal UPD(14), and there was no altered DLK1 expression or unexpected methylation status. By WES and filtering with a mining tool, a novel FBN1 missense variant was found in patient 1 and his mother, who both showed clinical features of Marfan syndrome by thorough anthropometric assessment, and a novel EYA1 missense variant as a probable cause of the renal malformation in the patient. In patient 2 with the 22q11.21 microduplication syndrome, skin hypo- and hyperpigmentation and two malignancies were only partially explained. By WES, compound heterozygous BLM stop founder mutations were detected causing Bloom syndrome. In male patient 3 carrying a 22q11.21 microduplication inherited from his unaffected father, WES identified a novel missense variant in the OPHN1 X-linked intellectual disability gene inherited from the unaffected mother as a possible additional cause for developmental delay. Thus, WES seems warranted in patients carrying microdeletions or microduplications, who have unexplained clinical features or microimbalances inherited from an unaffected parent.