Different growth patterns in two siblings with Schimke immuno-osseous-dysplasia.

Schimke immuno-osseous-dysplasia (SIOD) is an autosomal recessive systemic disease due to pathogenic variants in SMARCAL1. Manifestations include nephrotic syndrome (NS), kidney failure, T-cell dysfunction, vaso-occlusive disease, and disproportionate short stature, a general feature of this disease. Here, we present a markedly different growth pattern in two brothers with SIOD sharing the same homozygous R561C missense variant. The index patient presented at the age of 11 years with NS and severely disproportionate short stature, followed by kidney failure at the age of 16, and severely reduced adult height (z-score - 8.0). In contrast, the younger brother showed normal growth until the age of 8 years. Mild proteinuria was noted at the age of 4.5, followed by NS at 9.5 years, kidney failure at 11 years, progressive disproportionate stature, and reduced adult height (z-score - 4.5). Both brothers had comparable disproportion in adulthood (sitting height index z-score - 0.88 and - 1.44, respectively).

Morphological changes and their associations with clinical parameters in children with nephropathic cystinosis and chronic kidney disease prior to kidney replacement therapy over 25 years.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated. METHODS: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016). RESULTS: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients. CONCLUSIONS: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear.

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. METHODS: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. RESULTS: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years). CONCLUSION: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities.

Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investigated linear growth, body proportion, body mass index (BMI), upper arm fat area (UFA) and biochemical parameters in 43 pediatric INC patients with CKD stages 1 to 5 and 49 age-matched CKD controls, with 193 annual measurements. INC patients showed more impaired height than CKD controls (-1.8 vs -0.7 z-score; P < .001), despite adequate cysteamine therapy, treatment for Fanconi syndrome and more frequent use of growth hormone. Only the youngest INC patients shared the same body pattern with CKD controls characterized by preferential impairment of leg length and rather preserved trunk length. In late-prepuberty, body pattern changed only in INC patients due to improved leg growth and more impaired trunk length. Mean UFA z-score in INC patients was slightly reduced in early childhood and progressively decreased thereafter reaching -0.8 z-score in adolescence, while CKD controls showed a steady increase in standardized BMI and UFA especially during adolescent age. Menarche in female INC patients was significantly delayed compared to CKD controls. Our data indicate that with age and progression of disease, pediatric INC patients undergo unique changes of body growth and fat stores that are distinct from those with CKD stemming from other causes, suggesting other factors apart from CKD to contribute to this development. Pediatric patients with infantile nephropathic cystinosis display more severe impaired linear growth than other peer CKD patients, despite of cysteamine treatment, supplementation for Fanconi syndrome, and more frequent use of growth hormone, with a distinct change of body proportions and overall lower body fat.

Growth hormone treatment in the pre-transplant period is associated with superior outcome after pediatric kidney transplantation.

BACKGROUND: Recombinant human growth hormone (rhGH) is frequently used for treatment of short stature in children with chronic kidney disease (CKD) prior to kidney transplantation (KT). To what extent this influences growth and transplant function after KT is yet unknown. METHODS: Post-transplant growth (height, sitting height, leg length) and clinical parameters of 146 CKD patients undergoing KT before the age of 8 years, from two German pediatric nephrology centers, were prospectively investigated with a mean follow-up of 5.56 years. Outcome in patients with (rhGH group) and without (non-prior rhGH group) prior rhGH treatment was assessed by the use of linear mixed-effects models. RESULTS: Patients in the rhGH group spent longer time on dialysis and less frequently underwent living related KT compared to the non-prior rhGH group but showed similar height z-scores at the time of KT. After KT, steroid exposure was lower and increments in anthropometric z-scores were significantly higher in the rhGH group compared to those in the non-prior rhGH group, although 18% of patients in the latter group were started on rhGH after KT. Non-prior rhGH treatment was associated with a faster decline in transplant function, lower hemoglobin, and higher C-reactive protein levels (CRP). After adjustment for these confounders, growth outcome did statistically differ for sitting height z-scores only. CONCLUSIONS: Treatment with rhGH prior to KT was associated with superior growth outcome in prepubertal kidney transplant recipients, which was related to better transplant function, lower CRP, less anemia, lower steroid exposure, and earlier maturation after KT. A higher resolution version of the Graphical abstract is available as Supplementary information.

Determinants of growth after kidney transplantation in prepubertal children.

BACKGROUND: Short stature is a frequent complication after pediatric kidney transplantation (KT). Whether the type of transplantation and prior treatment with recombinant human growth hormone (GH) affects post-transplant growth, is unclear. METHODS: Body height, leg length, sitting height, and sitting height index (as a measure of body proportions) were prospectively investigated in 148 prepubertal patients enrolled in the CKD Growth and Development study with a median follow-up of 5.0 years. We used linear mixed-effects models to identify predictors for body dimensions. RESULTS: Pre-transplant Z scores for height (- 2.18), sitting height (- 1.37), and leg length (- 2.30) were reduced, and sitting height index (1.59) was increased compared to healthy children, indicating disproportionate short stature. Catch-up growth in children aged less than 4 years was mainly due to stimulated trunk length, and in older children to improved leg length, resulting in normalization of body height and proportions before puberty in the majority of patients. Use of GH in the pre-transplant period, congenital CKD, birth parameters, parental height, time after KT, steroid exposure, and transplant function were significantly associated with growth outcome. Although, unadjusted growth data suggested superior post-transplant growth after (pre-emptive) living donor KT, this was no longer true after adjusting for the abovementioned confounders. CONCLUSIONS: Catch-up growth after KT is mainly due to stimulated trunk growth in young children (< 4 years) and improved leg growth in older children. Beside transplant function, steroid exposure and use of GH in the pre-transplant period are the main potentially modifiable factors associated with better growth outcome.

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.

Pubertal development in children with chronic kidney disease.

Impairment of pubertal growth and sexual maturation resulting in reduced adult height is an significant complication in children suffering from chronic kidney disease (CKD). Delayed puberty and reduced pubertal growth are most pronounced in children with pre-existing severe stunting before puberty, requiring long-term dialysis treatment, and in transplanted children with poor graft function and high glucocorticoid exposure. In pre-dialysis patients, therapeutic measures to improve pubertal growth are limited and mainly based on the preservation of renal function and the use of growth hormone treatment. In patients with end-stage CKD, early kidney transplantation with steroid withdrawal within 6 months of renal transplantation allows for normal pubertal development in the majority of patients. This review focuses on the underlying pathophysiology and strategies for improving height and development in these patients.

Kidney transplantation fails to provide adequate growth in children with chronic kidney disease born small for gestational age.

BACKGROUND: Children with chronic kidney disease are frequently born small for gestational age (SGA) and prone to disproportionately short stature. It is unclear how SGA affects growth after kidney transplantation (KTx). METHODS: Linear growth (height, sitting height, and leg length) was prospectively investigated in a cohort of 322 pediatric KTx recipients, with a mean follow-up of 4.9 years. Sitting height index (ratio of sitting height to total body height) was used to assess body proportions. Predictors of growth outcome in KTx patients with (n = 94) and without (n = 228) an SGA history were evaluated by the use of linear mixed-effects models. RESULTS: Mean z-scores for all linear body dimensions were lower in SGA compared with non-SGA patients (p < 0.001). SGA patients presented with higher target height deficit and degree of body disproportion (p < 0.001). The latter was mainly due to reduced leg growth during childhood. Pubertal trunk growth was diminished in SGA patients, and the pubertal growth spurt of legs was delayed in both groups, resulting in further impairment of adult height, which was more frequently reduced in SGA than in non-SGA patients (50 % vs 18 %, p < 0.001). Use of growth hormone treatment in the pre-transplant period, preemptive KTx, transplant function, and control of metabolic acidosis were the only potentially modifiable correlates of post-transplant growth in SGA groups. By contrast, living related KTx, steroid exposure, and degree of anemia proved to be correlates in non-SGA only. CONCLUSIONS: In children born SGA, growth outcome after KTx is significantly more impaired and affected by different clinical parameters compared with non-SGA patients.

Sex-specific age-related changes of information processing rate indicators during childhood and adolescence.

Despite the relevant findings on non-average information processing rate (IPR) indicators-intelligence relation, and on age-related changes of some of these indicators during aging, the research on sex-specific age-related changes of these indicators during childhood and adolescence are lacking. In a transversal study, 1197 school children (598 girls) aged 8-18 have been individually measured on 5 IPR indicators--two averages (mean_t, median_t) and three non-averages (min_t, max_t, sd_t). The results corroborated the expected non-linear changes of average IPR indicators in the observed developmental period, whereby the sex difference in related developmental patterns was detected: marked age-related decrement in girls ceased at the age of 12, and in boys around the age of 13-14, after which progress in both sexes gradually ceased by the age of 18 and was less pronounced in girls. Generally similar non-linear age-related decrements of non-average indicators were registered, but they showed mutual intensity differences at specific ages and sex difference in developmental patterns was detected, analogously to average indicators. Systematic sex differences in the whole observed period were obtained only in two non-average indicators: girls showed minor sd_t and boys showed minor min_t. In specific age groups, a number of sex differences were obtained that are explainable by two possible mechanisms: earlier maturation in girls and sex bias of the IPR task content. The justifiability of separate, average and non-average, IPR indicators application was corroborated by their distribution form differences, by mutual, predominantly low and medium correlations, by the different intensity of their developmental changes and by their different ability to detect sex differences. For all registered phenomena, the theoretical and/or empirical explanations were offered from the domain of sex specific intellectual, motor and neural development, and it has been shown that non-average IPR indicators do register age and sex differences, which average indicators do not manage to register.

Cystinosis-associated metabolic bone disease across ages and CKD stages 1-5D/T.

CONTEXT: The pathophysiology of cystinosis-associated metabolic bone disease is complex. OBJECTIVE: We hypothesized a disturbed interaction between osteoblasts and osteoclasts. DESIGN: Binational cross-sectional multicenter study. SETTING: Hospital clinics. PATIENTS: One hundred and three patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1-5D/T. MAIN OUTCOME MEASURES: Ten key bone markers. RESULTS: Skeletal complications occurred in two-thirds of the patients, with adults having a five-fold increased risk compared to children. Patients with CKD stages 1-3 showed reduced z-scores for serum phosphate and calcium, suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. CONCLUSIONS: Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counterregulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia may promote progressive bone loss.

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 1.1 Mb microdeletion in the 14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two inherited 22q11.21 microduplications of 2.5 or 2.8 Mb. 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.

Birth parameters and parental height predict growth outcome in children with chronic kidney disease.

BACKGROUND: We analyzed the impact of birth parameters and parental height on long-term growth outcome in children with chronic kidney disease (CKD) stage 3-5. METHODS: Linear growth was prospectively investigated in 509 children, with a mean follow-up of 4.1 years. Growth outcome was categorized in (i) poor growth (PG): height standard deviation score (SDS) during follow-up < -2.0 and/or actual or previous growth hormone (GH) treatment, and (ii) good growth (GG): height SDS ≥ -2.0 and no need for GH. A multivariate binary logistic regression model was constructed for predictors of PG outcome. RESULTS: PG was observed in 55 % of patients. The rate of pre-term and small for gestational age birth was significantly higher in children with PG compared to GG (43.2 vs. 25.6 % and 36.8 vs. 18.9 %; p < 0.001). Children with PG had significantly lower average values for gestational age, birth weight, length, and head circumference, umbilical cord pH, Apgar scores, and parental height than children with GG. Birth length, umbilical cord pH, and parental height were significant independent predictors of PG outcome (sensitivity 72.8 %, specificity 69.3 %). CONCLUSIONS: Birth parameters and parental height are independent predictors of growth outcome in children with CKD.

Growth and maturation improvement in children on renal replacement therapy over the past 20 years.

BACKGROUND: The attainment of normal growth and maturation remains a major challenge in the management of children and adolescents requiring renal replacement therapy (RRT). METHODS: We compared growth and maturation in 384 German children with RRT who were followed between 1998 and 2009 with 732 children who were enrolled in the European Dialysis and Transplant Association (EDTA) Registry from 1985 to 1988; of these children, 78 and 88 %, respectively, were transplanted. RESULTS: The data on the German patients included in the EDTA registry did not differ significantly from those of the patients from other European countries. Overall, the mean height standard deviation score (SDS) has improved over the past 20 years from -3.03 to -1.80 (p < 0.001). Until the age of 6 years, the difference in height SDS was not significant, whereas it improved significantly in adolescence (-3.40 vs. -1.52; p < 0.001). Significant improvements in the delay of the pubertal growth spurt, age at menarche, bone maturation and body mass index (BMI) were noted in the recent German group compared to the EDTA group (each p < 0.001). CONCLUSIONS: Our findings demonstrate a marked improvement of growth and maturation in paediatric patients on RRT during the past 20 years.

Effects of Burosumab Treatment on Mineral Metabolism in Children and Adolescents With X-linked Hypophosphatemia.

CONTEXT: Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking. OBJECTIVE: To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH. DESIGN: Prospective national registry. SETTING: Hospital clinics. PATIENTS: A total of 93 patients with XLH (65 children, 28 adolescents). MAIN OUTCOME MEASURES: Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. RESULTS: At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01). CONCLUSIONS: In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

Predictors of growth patterns in children with mucopolysaccharidosis I after haematopoietic stem cell transplantation.

Mucopolysaccharidosis type I (MPS I) is an autosomal-recessive metabolic disorder caused by an enzyme deficiency of lysosomal alpha-l-iduronidase (IDUA). Haematopoietic stem cell transplantation (HSCT) is the therapeutic option of choice in MPS I patients younger than 2.5 years, which has a positive impact on neurocognitive development. However, impaired growth remains a problem. In this monocentric study, 14 patients with MPS I (mean age 1.72 years, range 0.81-3.08) were monitored according to a standardised follow-up program after successful allogeneic HSCT. A detailed anthropometric program was carried out to identify growth patterns and to determine predictors of growth in these children. All patients are alive and in outpatient care (mean follow-up 8.1 years, range 0.1-16.0). Progressively lower standard deviation scores (SDS) were observed for body length (mean SDS -1.61; -4.58 - 3.29), weight (-0.56; -3.19 - 2.95), sitting height (-3.28; -7.37 - 0.26), leg length (-1.64; -3.88 - 1.49) and head circumference (0.91; -2.52 - 6.09). Already at the age of 24 months, significant disproportions were detected being associated with increasing deterioration in growth for age. Younger age at HSCT, lower counts for haemoglobin and platelets, lower potassium, higher donor-derived chimerism, higher counts for leukocytes and recruitment of a matched unrelated donor (MUD) positively correlated with body length (p ≤ 0.05). In conclusion, this study characterised predictors and aspects of growth patterns in children with MPS I after HSCT, underlining that early HSCT of MUD is essential for slowing body disproportion.

Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets.

Children with X-linked hypophosphatemic rickets (XLH) are prone to severe stunting. A multicenter mixed-longitudinal study was conducted to assess age-related stature, sitting height, arm and leg length in XLH patients on continuous treatment with phosphate and calcitriol. Mean standard deviation scores (SDS) for all body dimensions were markedly reduced and differed significantly among each other at the initial and subsequent evaluations (baseline: stature -2.48 SDS; sitting height -0.99 SDS; arm length -1.81 SDS; leg length -2.90 SDS; each p<0.001). A strong association between stature and leg length (r (2)=0.87, p<0.001) was noted. Leg length SDS decreased progressively during childhood (2-9 years) and adolescence (12-15 years; each p<0.001). Sitting height SDS increased significantly during late childhood, indicating uncoupled growth of the legs and trunk and resulting in an ever increasing sitting height index (i.e. ratio of sitting height to stature; age 2 years 2.0 SDS; age 10 years 3.3 SDS; p<0.001) that was associated with the degree of stunting (r (2)=0.314, p<0.001). Mean serum phosphate levels were positively associated with stature and leg length, but negatively with sitting height index. Based on these results, we can conclude that growth of the legs and trunk is uncoupled in XLH and related to serum phosphate levels.

Prematurity, small for gestational age and perinatal parameters in children with congenital, hereditary and acquired chronic kidney disease.

BACKGROUND: Low birth weight has been identified as a risk factor for chronic kidney disease (CKD). METHODS: We analysed perinatal parameters taken from the National Birth Certificates of 435 children with CKD stages 3-5 of different aetiology and time of onset of CKD. Diseases were classified as congenital with onset of renal disease during fetal life (n = 260; 60%), hereditary as genetically determined with onset after 3 months of life (n = 93; 21%) and acquired CKD (n = 82; 19%). RESULTS: The rates of prematurity and small for gestational age (SGA) were elevated in children with congenital (39.3% and 29.2%), hereditary (24.7% and 22.6%) and acquired CKD (15.5% and 29.3%); these compared to 8% (for both) in the normal population. Newborns with congenital CKD had a significantly lower gestational age [median 38 weeks, interquartile range (IQR) 36-40 weeks] than those with hereditary (39.9 weeks, IQR 37.5-40 weeks) or acquired CKD (40 weeks, IQR 38-40 weeks; P < 0.001). Median birth weight and length were lower in newborns with congenital than in hereditary and acquired diseases [2975 g (IQR 2460-3420 g) versus 3250 g (IQR 2740-3580 g) and 3260 g (IQR 2858-3685 g) (P < 0.01); 49 cm (IQR 47-52) versus 50 cm (IQR 48-52.8) and 51 cm (IQR 49-53) (P < 0.01)]. Head circumference was smaller (P < 0.05), and Apgar scores were lower (P < 0.005) in newborns with congenital diseases than in hereditary and acquired diseases. CONCLUSIONS: Children with congenital CKD had the highest rate of prematurity, a significantly lower birth weight, length, head circumference and Apgar score than newborns with hereditary or acquired CKD. Irrespective of the aetiology of CKD, all of the children had a significantly higher rate of SGA and prematurity than the reference population. We conclude that both SGA and prematurity predispose for advanced renal disease in childhood and that fetal kidney disease impairs fetal growth.

Bone and Mineral Metabolism in Children with Nephropathic Cystinosis Compared with other CKD Entities.

CONTEXT: Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD); however, systematic analyses are lacking. OBJECTIVE: To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across all stages of CKD. DESIGN: Cross-sectional multicenter study. SETTING: Hospital clinics. PATIENTS: Forty-nine children with NC, 80 CKD controls of the same age and CKD stage. MAIN OUTCOME MEASURES: Fibroblast growth factor 23 (FGF23), soluble Klotho, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, osteoprotegerin (OPG), biochemical parameters related to mineral metabolism, and skeletal comorbidity. RESULTS: Despite Fanconi syndrome medication, NC patients showed an 11-fold increased risk of short stature, bone deformities, and/or requirement for skeletal surgery compared with CKD controls. This was associated with a higher frequency of risk factors such as hypophosphatemia, hypocalcemia, low parathyroid hormone (PTH), metabolic acidosis, and a specific CKD stage-dependent pattern of bone marker alterations. Pretransplant NC patients in mild to moderate CKD showed a delayed increase or lacked an increase in FGF23 and sclerostin, and increased BAP, TRAP5b, and OPG concentrations compared with CKD controls. Post-transplant, BAP and OPG returned to normal, TRAP5b further increased, whereas FGF23 and PTH were less elevated compared with CKD controls and associated with higher serum phosphate. CONCLUSIONS: Patients with NC show more severe skeletal comorbidity associated with distinct CKD stage-dependent alterations of bone metabolism than CKD controls, suggesting impaired mineralization and increased bone resorption, which is only partially normalized after renal transplantation.

SMARCAL1 mutations: a cause of prepubertal idiopathic steroid-resistant nephrotic syndrome.

UNLABELLED: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal-recessive multisystem disorder with disproportionate growth failure, impaired T cell function, and steroid-resistant nephrotic syndrome. Recently, we presented the typical anthropometric features of SIOD. We now present data on two siblings who were initially classified as suffering from familial steroid-resistant nephrotic syndrome of unknown genetic origin. Apart from growth failure, no syndrome-specific symptoms were found until the age of 10 y. However, serial anthropometric examinations showed the development of a SIOD-like pattern with a decreased ratio of trunk to leg length in early adolescence. The growth pattern was significantly different from that seen in children with chronic renal failure of other origins. In prepuberty the siblings had proportionate short stature but developed disproportion only during adolescence. Molecular genetic analysis revealed compound heterozygosity for a known and a new mutation in the SMARCAL1 gene. CONCLUSION: the disease spectrum associated with SMARCAL1 mutations includes previously undescribed milder phenotypes that may be clinically overlooked, particularly before puberty. Serial anthropometric assessment can eventually identify patients with a growth pattern similar to that of SIOD. These patients should be tested for SMARCAL1 mutations to avoid overtreatment with immunosuppressive agents.