Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

Interleukin-10-1082A/G polymorphism is associated with renal parenchymal damage in congenital anomalies of the kidney and urinary tract.

AIM: The aim of the study was to investigate whether the functional IL10-1082A/G polymorphism exert a role in congenital anomalies of the kidney and urinary tract (CAKUT) in children. Also, the serum IL-10 and its association with genotype and renal parenchymal damage in CAKUT were explored. METHODS: In the current case-control study, 134 paediatric cases of CAKUT and 382 unrelated controls were included. The genotyping of IL10-1082A/G polymorphism was performed by amplification refractory mutation system-PCR and IL-10 serum level was determined by ELISA. RESULTS: Although, the genotype and allelic frequencies of IL10-1082 A/G polymorphism in cases and controls were similar (χ2 = 0.459; P = 0.79 and χ2 = 0.426; P = 0.51, respectively), significant different genotype distribution between patients with or without parenchymal damage/reduction was observed (χ2 = 6.9; P = 0.032). The GG-genotype was more frequent in cases with renal parenchymal damage/reduction compared to patients with preserved parenchyma (22% vs. 9%; OR = 2.987; 95% CI = 0.979-9.468; P = 0.031). On the contrary, the heterozygous genotype was less frequent among cases with parenchymal damage/reduction compared to cases with preserved parenchyma (39% vs. 59%; OR = 0.453; 95% CI = 0.214-0.958; P = 0.024). Additionally, the serum IL-10 was significantly higher in CAKUT patients compared to age-sex-matched controls (median 11.98; IQR: 7.14-31.6 vs. 5.92; IQR: 4.68-14.8; P = 0.0057). Among carriers of GG-genotype significantly higher IL-10 level was detected in cases with parenchymal damage/reduction, than cases with preserved parenchyma (P = 0.028). CONCLUSION: Our results suggested that the functional -1082A/G polymorphism in IL10 is associated with risk of renal parenchymal damage/reduction rather than genetic predisposition to CAKUT. Additionally, our study supposes that immunoregulatory cytokine IL-10 might have a significant role in CAKUT.

ACE serum level and I/D gene polymorphism in children with obstructive uropathies and other congenital anomalies of the kidney and urinary tract.

AIM: The aim of this study was to investigate the association of an insertion/deletion (I/D) polymorphism in angiotensin-converting enzyme (ACE) gene with serum ACE level in relation to the type and severity of malformations from congenital anomalies of the kidney and urinary tract (CAKUT) spectrum. METHODS: A group of 134 Bulgarian children with CAKUT divided into four subgroups according to the leading malformation and 109 controls were genotyped by classical polymerase chain reaction. The quantitative determination of serum ACE was performed by ELISA method. RESULTS: A significant elevation of DD-genotype was observed in high-grade hydronephrosis compared to low-grade (43% vs. 9%). The carrying of DD-genotype was associated with higher risk for severe hydronephrosis with OR = 7.5 (95% CI: 1.242÷45.278; P = 0.028). Also, elevated serum ACE concentrations in patients with high-grade compared to low-grade hydronephrosis (237.4 ± 45 ng/mL vs 180.5 ± 64 ng/mL; P = 0.0065) were found. ACE level was significantly lower in patients with unilateral renal agenesis; hypo/dysplasia and multicystic dysplastic kidney (156.6 ± 54 ng/mL) than controls (200.6 ± 56.7 ng/mL; P = 0.005) and the remaining CAKUT subgroups. CONCLUSION: The DD genotype of I/D ACE polymorphism encodes the highest serum ACE level may be an additional genetic risk factor contributing to the severe hydronephrosis in Bulgarian patients with obstructive uropathies in contrast to other investigated categories of CAKUT malformations.

[Profile of patients with genitourinary anomalies treated in a clinical genetics service in the Brazilian unified health system]. / Perfil de pacientes com anormalidades geniturinárias atendidos em serviço de genética clínica no sistema único de saúde.

OBJECTIVE: To describe the profile of patients with genitourinary abnormalities treated at a tertiary hospital genetics service. METHODS: Cross-sectional study of 1,068 medical records of patients treated between April/2008 and August/2014. A total of 115 cases suggestive of genitourinary anomalies were selected, regardless of age. A standardized clinical protocol was used, as well as karyotype, hormone levels and genitourinary ultrasound for basic evaluation. Laparoscopy, gonadal biopsy and molecular studies were performed in specific cases. Patients with genitourinary malformations were classified as genitourinary anomalies (GUA), whereas the others, as sex differentiation disorders (SDD). Chi-square, Fisher and Kruskal-Wallis tests were used for statistical analysis and comparison between groups. RESULTS: 80 subjects met the inclusion criteria, 91% with SDD and 9% with isolated/ syndromic GUA. The age was younger in the GUA group (p<0.02), but these groups did not differ regarding external and internal genitalia, as well as karyotype. Karyotype 46,XY was verified in 55% and chromosomal aberrations in 17.5% of cases. Ambiguous genitalia occurred in 45%, predominantly in 46,XX patients (p<0.006). Gonadal differentiation disorders accounted for 25% and congenital adrenal hyperplasia, for 17.5% of the sample. Consanguinity occurred in 16%, recurrence in 12%, lack of birth certificate in 20% and interrupted follow-up in 31% of cases. CONCLUSIONS: Patients with SDD predominated. Ambiguous genitalia and abnormal sexual differentiation were more frequent among infants and prepubertal individuals. Congenital adrenal hyperplasia was the most prevalent nosology. Younger patients were more common in the GUA group. Abandonment and lower frequency of birth certificate occurred in patients with ambiguous or malformed genitalia. These characteristics corroborate the literature and show the biopsychosocial impact of genitourinary anomalies.

Assessment of kidney function in children by enzymatic determination of 2- or 24-h creatinine clearance: comparison with inulin clearance.

BACKGROUND: Although renal inulin clearance (Cin) is the gold standard for evaluation of kidney function, it cannot be measured easily. Therefore, creatinine clearance (Ccr) is often used clinically to evaluate kidney function. Enzymatically measured Ccr was recently found to be much higher than Cin because of the tubular secretion of creatinine (Cr). This study compared three measures of renal clearance, inulin, 2-h Ccr, and 24-h Ccr, in children. METHODS: Kidney function was evaluated in 76 children (51 males and 25 females) aged 1 month to 18 years with chronic kidney disease (CKD) by three renal clearance methods at almost the same time. RESULTS: Correlations between each pair of three renal clearance measurements were determined. Approximate glomerular filtration rate (GFR) was equal to 62 % of 2-h Ccr or 76 % of 24-h Ccr. CONCLUSION: Cr secretion by renal tubules was approximately 50 % of the GFR. In this study, we indicate that the measurements of 2-h Ccr or 24-h Ccr do not show true GFR but we could infer approximate GFR from the values. The use of 2- or 24-h Ccr might contribute to the treatment of pediatric CKD patients.

Spectrum of penoscrotal positional anomalies in children.

BACKGROUND: The normal relationship between the scrotum and penis during fetal development is controlled by several genetic and hormonal factors, and impairment of this positional relation results in a wide spectrum of positional congenital anomalies. OBJECTIVE: This a cohort study analysing 63 cases of penoscrotal anomalies (PSAs) according to severity and other associated malformations to provide a simple classification for recognising, describing and categorizing cases that may require surgical correction. DESIGN AND SETTING: Between 2005 and 2013, 63 diverse cases of penoscrotal positional anomaly were detected and analysed based on their hormonal profile and other associated anomaly. RESULTS: A wide variety of PSAs were included in the study, 11 cases were of major PST with complete penoscrotal transposition in three, incomplete in eight, and minor degree in 45 cases, which are symmetrical (bilateral) in 29, sixteen are asymmetrical, 4 had midline scrotlisation, and 3 had wide penoscrotal distance. Associated genitourinary anomalies were detected in 29 babies. Sex hormonal assays showed no significant differences between the PSA patients and controls (P < .05), and no gross chromosomal anomalies were detected in any cases. CONCLUSION: Penoscrotal positional anomalies include the previously described penoscrotal transposition, and the variants of a central penile scrotalisation, and wide penoscrotal distance. A simple classification for these anomalies adopted herein.

Foetal serum but not urinary ß2-microglobulin correlates with histological injury to the kidney.

In a context of foetal obstructive uropathies, biochemical markers can be helpful to assess the renal function, but most studies to date have focused on their correlation with ultrasound findings and neonatal outcome. Our aim was to evaluate foetal ß2-microglobulin as an index of histological injury to the kidney. ß2-microglobulin was measured in serum and/or urine from 27 foetuses with bilateral obstructive uropathy, and compared to the findings of kidney examination following the termination of pregnancy. In serum, increased ß2-microglobulin levels correlated to a decreased number of glomeruli, a reduction in the blastema and the presence of primitive ducts reflecting renal hypoplasia and dysplasia. However, elevated ß2-microglobulin levels in the urine correlated only to a decreased number of glomeruli.

Fetal serum α-1 microglobulin for renal function assessment: comparison with ß2-microglobulin and cystatin C.

OBJECTIVE: To compare the prognostic value of fetal serum α1-microglobulin with that of ß2-microglobulin and cystatin C for postnatal renal function. METHOD: Retrospective study of α1-microglobulin, ß2-microglobulin, and cystatin C in fetal serum from 126 fetuses with congenital abnormalities of the kidney and urinary tract (73 and 53, respectively). Two groups were defined: group with normal renal function and group with renal failure. For live born infants, renal function was assessed on the basis of serum creatinine (cutoff 50 µmol/L) or glomerular filtration rate (cutoff 75 mL/min/1.73 m2) or both. In case of infant or fetal death, histological kidney lesions were considered. RESULTS: Significant differences (p < 0.001) were observed for the three markers between fetuses with good renal prognosis and those with renal failure (34.4 mg/L vs 67.6 mg/L for α1-microglobulin, respectively; 3.9 mg/L vs 7.35 mg/L, for ß2-microglobulin, respectively; and 1.67 mg/L vs 2.12 mg/L for cystatin C, respectively). Areas under receiver operator curves were used to compare the three markers, 0.96, 0.90, and 0.74 for ß2-microglobulin, α1-microglobulin, and cystatin C, respectively. CONCLUSION: Although α1-microglobulin is significantly different in fetuses with good renal prognosis and those with renal failure, overall, it is a less reliable prognostic marker than fetal serum ß2-microglobulin.

Measuring cystatin C to determine renal function in neonates.

OBJECTIVES: The incidence of acute kidney injury in neonates is high and associated with up to a 50% mortality rate. The purpose of this review was to determine the feasibility of using serum cystatin C measurements to assist clinicians in making early and accurate diagnoses of acute kidney injury in neonates. DATA SOURCE: We searched for the following seven key words within the PubMed database and the Cochrane Database of Systematic Reviews: cystatin C, neonates, newborn, preterm, premature, kidney failure, and kidney injury. STUDY SELECTION: The selected studies included neonates within their study populations and were published in English. We reviewed literature published between January 1990 and May 2012. DATA EXTRACTION: Ten studies had conducted serum cystatin C measurements in neonates. DATA SYNTHESIS: The cystatin C level in neonates is not influenced by the maternal level and is highest at birth. In most studies, cystatin C levels on day 1 of life ranged between 1 and 2 mg/L, gradually declined during the first year and then remained relatively stable thereafter. Cystatin C levels did not differ between male and female infants, and no significant gestational age-dependent differences were found. Cystatin C levels were increased in cases of sepsis, acute kidney injury, and congenital renal abnormalities. CONCLUSIONS: Cystatin C has all of the theoretical properties needed to be an ideal marker of renal function. It can be used to determine baseline renal function on day 1 and is increasingly being used to determine renal function in sick neonates. In the majority of studies, the day 1 cystatin C level ranged between 1 and 2 mg/L, which gradually declined in the first year of life. However, the number of available studies evaluating cystatin C in sick neonates is currently limited, and there are also no studies linking cystatin C levels in sick babies with short-term and long-term outcomes.

Assessment of serum cystatin C in children with congenital solitary kidney.

The aim of the study was to assess serum cystatin C level in children with a congenital solitary kidney, depending on their age and compensatory overgrowth of the kidney. The study group (I) consisted of 36 children, 3-21 years of age (median 10.8 years), with a congenital solitary kidney and no other urinary defects. The control group (C) contained 36 healthy children, 5-21 years old (median 10.9 years). Nephelometric methods were used to determine serum cystatin C level, the Jaffe method to assess creatinine concentration and the Schwartz formula to estimate glomerular filtration rate. Kidney length was measured with the patient in a supine position, and overgrowth was estimated (O%) in comparison with the respective kidney in the control group. Serum cystatin C level in group I was higher than that in the control group (P<0.05). Increased values, above 0.95 mg/l, were found in 16/36 (44%) children aged 12-21 years. Glomerular filtration rate (GFR, estimated by the Schwartz formula) and creatinine level in group I were similar to those of the control group (P>0.05). Increased kidney length was found (median 18.2%). Cystatin C concentration was positively correlated with O% (r=0.406, P<0.01) and kidney length to child height ratio (L/H) (r=0.376, P<0.05). We conclude that Increased serum cystatin C concentration in patients with a unilateral congenital solitary kidney occurs after 12 years of age and correlates with compensatory overgrowth of the kidney.

Reduced uterine and ovarian size in adolescent girls born small for gestational age.

Reduced fetal growth is known to be associated with a reduced ovarian fraction of primordial follicles, with ovarian hyperandrogenism and anovulation in late adolescence. In this study, we examined whether adolescent girls born small for gestational age also present an abnormality in uterine or ovarian size. Standardized ultrasound measurements of the internal genitalia were performed in 36 healthy post-menarcheal girls (mean age 14 y) born with a size that was either appropriate for gestational age (AGA) or small (SGA), birth weight averaging 0.1 and -3.0 SD, respectively; clinical and endocrine characteristics were documented concomitantly. Compared with AGA girls, the SGA girls had a smaller uterus (mean difference of 20%; p < 0.006) and a reduced ovarian volume (mean difference of 38%; p < 0.0002). In conclusion, the gynecological correlates of prenatal growth restriction are herewith extended to include a reduced size of the uterus and the ovaries.

Absence of antisperm surface antibodies in prepubertal boys with cryptorchidism and other anomalies of the inguinoscrotal region before and after surgery.

PURPOSE: Although the prepubertal immune system cannot recognize postmeiotic germ cell antigens, an overall 21 to 28% incidence of antisperm antibodies directed at these antigens has been reported preoperatively in prepubertal children with cryptorchidism and other inguinoscrotal anomalies. We investigated the prevalence of antisperm antibodies in these prepubertal patients before and after surgery. MATERIALS AND METHODS: We examined 82 prepubertal boys 0.6 to 13.2 years old, including 33 with unilateral cryptorchidism, 21 with inguinoscrotal anomalies and 28 who were normal. IgG, IgM and IgA antisperm antibodies were determined by the indirect Immunobead test. Serum testing was repeated 1 and 2 years postoperatively and annually for 2 more years in the normal children. Also sera from 183 infertile men 21 to 47 years old with a history of cryptorchidism and/or inguinal hernia operated on in childhood were similarly studied. RESULTS: Of the adults 70 (39%) tested IgG positive, including 12 (7%) who were also IgA positive, and all tested IgM negative. Repeat measurements were negative for all IgG, IgA and IgM isotypes in all children, patients and controls. CONCLUSIONS: We conclude that there are no antibodies to sperm surface antigens in prepubertal children with cryptorchidism and inguinoscrotal anomalies before and within 2 years after surgery. Autoimmunity against postmeiotic sperm membrane antigens is apparent in adults only.

Incidence of hypocomplementemia in elementary and junior high school children with urinary abnormalities.

Abnormalities were detected in 2669 of 326,257 elementary and junior high school children (169,856 males and 156,401 females) who were screened at school for urinary abnormalities. Serum complement (C3) level was measured in all 2669 children having urinary abnormalities (811 males, 1856 females). Three had a serum C3 level that was more than three standard deviations below the mean value. Type I membranoproliferative glomerulonephritis (MPGN) was diagnosed on histological examination in one of these three children, while the other two did not undergo renal biopsy because they had serum C3 levels of 40 and 44 mg/dL, respectively, and because their urinary abnormalities were transient. It was considered that there is not much significance in testing the serum complement in the urine screening done at school and the cost/benefit ratio is low. The results appeared to reflect the frequency of persistent hypocomplementemic MPGN in Japan in recent years.