A multidisciplinary nephrogenetic referral clinic for children and adults-diagnostic achievements and insights.

BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.

[PEDIATRIC NEPHROLOGY - CLINICAL MEDICINE, GENETIC AND REGENERATIVE MEDICINE TOGETHER].

INTRODUCTION: This special issue of the "Harefuah" journal is dedicated to pediatric nephrology. Four review articles and nine original articles will present acute and chronic clinical cases in daily nephrology medicine in order to inform the medical community about the risk of development of kidney injury and of acute and chronic renal insufficiency in children. The scientific articles will expand the knowledge on recent and future trends in research in nephrogenetics and regenerative nephrology.

Severe fetal hydronephrosis: the added value of associated congenital anomalies of the kidneys and urinary tract (CAKUT) in the prediction of postnatal outcome.

OBJECTIVE: The aim of this study was to focus on fetuses diagnosed with severe hydronephrosis and correlate prenatal sonographic characteristics with postnatal outcome. METHODS: Cases presenting prenatally with severe hydronephrosis (anterior-posterior renal pelvic diameter >15 mm) were collected retrospectively over a period of 11 years and divided into 2 groups: (1) isolated hydronephrosis and (2) those associated with congenital anomalies of the kidney and urinary tract (CAKUT). RESULTS: A total of 83 fetuses comprised the study group: 35 fetuses had isolated severe hydronephrosis and 48 had associated CAKUT. The mean anterior-posterior renal pelvic diameter was 22.6 ± 8.5 mm (range 15.0-66.0 mm). The CAKUT group was associated with a significantly increased incidence of postnatal need for surgery (17.6% vs 44.2%, P = .014), dysplastic kidney (0% vs 14%, P = .023), and total abnormal outcome (52.9% vs 86%, P = .001) in comparison with isolated severe prenatal hydronephrosis. CONCLUSIONS: Severe fetal hydronephrosis has a wide postnatal clinical spectrum, which is mainly influenced by the presence of associated sonographic CAKUT findings. These clinical data have biological relevance: a genetic or environmental defect that influences multiple renal developmental processes leads to hydronephrosis but also to concomitant malformations (CAKUT) and critically influences renal prognosis. A more selective abnormal developmental process that results in isolated enlarged pelvis even to a severe extent has less influence on renal prognosis.

Crossed ectopic kidney: prenatal diagnosis and postnatal follow-up.

OBJECTIVE: The objective of this study is to investigate prenatal diagnosis and postnatal outcome of fetuses with crossed ectopic kidney. METHOD: Cases referred for an empty renal fossa and diagnosed with crossed ectopic kidney confirmed postnatally were analyzed retrospectively over a period of 10 years. Prenatal diagnosis was established following the detection of one kidney in a normal position and a second ipsilateral kidney fed by abnormal blood vessels on Doppler flow RESULTS: Between 2005 and 2015, 185 fetuses were referred for an empty renal fossa. Crossed ectopic kidney was diagnosed in 10 of them. Associated congenital urological anomalies included two cases of double collecting system and bilateral hydronephrosis in one. Associated extra renal findings were single umbilical artery (4/10), ventricular septal defects (1/10), and persistent left superior vena cava (1/10). On postnatal follow-up, bilateral vesicoureteral reflux was diagnosed in a case who presented prenatally with bilateral hydronephrosis and two cases of mild hydronephrosis. All cases were managed conservatively. CONCLUSION: Crossed ectopic kidney should be suspected in cases presenting with an empty renal fossa and a normal positioned kidney. Thorough anatomical scan should be performed as well as periodic follow-up throughout pregnancy. Postnatal nephrological follow-up is recommended. © 2017 John Wiley & Sons, Ltd.

Renal hypodysplasia associates with a WNT4 variant that causes aberrant canonical WNT signaling.

Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/ß-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

Blood pressure in obese and overweight children and adolescents.

BACKGROUND: The prevalence of obesity in children and adolescents has increased dramatically in the last few decades. Primary hypertension, a known secondary complication among obese adults, has been considered rare in children. OBJECTIVES: To investigate the prevalence of hypertension and its relation to body mass index (BMI) in obese children aged 9-17 years in Israel. METHODS: Weight, height, BMI, and systolic and diastolic blood pressure (BP) (twice) were measured in children attending general and pediatric endocrine clinics. Obesity was defined as BMI > or = 95th percentile and overweight as BMI > or = 85th percentile. Pre-hypertension and hypertension were defined as systolic and/or diastolic BP > or = 90th percentile for age, gender and height and BP > or = 95th percentile respectively. In children with pre-hypertension or hypertension, repeated measurements were performed. RESULTS: We evaluated 264 children of whom 152 had BMI > or = 85th percentile (study group). Their mean age was 12.5 years. The prevalence of elevated BP (both pre-hypertension and hypertension) in the study group was 44.1% and 31% at the first and second measurements respectively, compared to 11.6% and 1.9% in the normal-weight group. Hypertension was documented in 17.2% of the study group at the second measurement. CONCLUSIONS: Elevated BP was diagnosed in 31% of overweight and obese children and adolescents. Increased awareness and early diagnosis and treatment are essential.

Diversity of kidney care referral pathways in national child health systems of 48 European countries.

Background: Primary, secondary and tertiary healthcare services in Europe create complex networks covering pediatric subspecialties, sociology, economics and politics. Two surveys of the European Society for Paediatric Nephrology (ESPN) in 1998 and 2017 revealed substantial disparities of kidney care among European countries. The purpose of the third ESPN survey is to further identify national differences in the conceptualization and organization of European pediatric kidney health care pathways during and outside normal working hours. Methods: In 2020, a questionnaire was sent to one leading pediatric nephrologist from 48 of 53 European countries as defined by the World Health Organization. In order to exemplify care pathways in pediatric primary care nephrology, urinary tract infection (UTI) was chosen. Steroid sensitive nephrotic syndrome (SSNS) was chosen for pediatric rare disease nephrology and acute kidney injury (AKI) was analyzed for pediatric emergency nephrology. Results: The care pathways for European children and young people with urinary tract infections were variable and differed during standard working hours and also during night-time and weekends. During daytime, UTI care pathways included six different types of care givers. There was a shift from primary care services outside standard working hours to general outpatient polyclinic and hospital services. Children with SNSS were followed up by pediatric nephrologists in hospitals in 69% of countries. Patients presenting with community acquired AKI were admitted during regular working hours to secondary or tertiary care hospitals. During nights and weekends, an immediate shift to University Children's Hospitals was observed where treatment was started by intensive care pediatricians and pediatric nephrologists. Conclusion: Gaps and fragmentation of pediatric health services may lead to the risk of delayed or inadequate referral of European children with kidney disease to pediatric nephrologists. The diversity of patient pathways outside of normal working hours was identified as one of the major weaknesses in the service chain.

Familial autosomal recessive renal tubular acidosis: importance of early diagnosis.

BACKGROUND AND AIMS: Untreated renal tubular acidosis (RTA) can result in severe complications. We reviewed the clinical features of patients with mutations in two genes causing RTA and evaluated their developmental expression assuming that timing, symptom severity and complications may be related to its occurrence. METHODS: Clinical data from 16 patients with RTA due to mutations in either ATP6V1B1 or CAII were retrospectively reviewed. Both genes' localization and expression pattern in the developing human kidney were analyzed by real-time polymerase chain reaction and immunostaining. RESULTS: RTA-presenting symptoms were non-specific. Patients with mutations in ATP6V1B1 had earlier presentation (4.9 vs. 11 months, p < 0.041) and longer time to diagnosis than patients with CAII mutations (5.8 vs. 57 months, p < 0.01). Patients with ATP6V1B1 mutations were more likely to develop chronic kidney disease than those with CAII mutations (follow-up GFR values: 89 vs. 110 ml/min/1.73 m2, respectively, p < 0.017), probably secondary to nephrocalcinosis. Both ATP6V1B1 and CAII were expressed early during human nephrogenesis, with relatively higher transcript levels of ATP6V1B1. CONCLUSIONS: There is considerable delay in establishing a diagnosis of both types of RTA, supporting the need for earlier biochemical investigation. RTA due to ATP6V1B1 mutations is associated with mild progressive loss of kidney function.

The yield of early postnatal ultrasound scan in neonates with documented antenatal hydronephrosis.

We retrospectively assessed the yield of early postnatal ultrasound scans in neonates with documented antenatal hydronephrosis. We reviewed recording data of prenatal renal ultrasound for 178 newborn infants and the results of renal ultrasound performed during the first days of life. Of 119 infants with prenatal diagnosis of mild hydronephrosis (renal pelvic diameter <10 mm), 116 (97.5%) had postnatal ultrasound results showing normal or mild hydronephrosis. Prenatal diagnosis of severe hydronephrosis (renal pelvic diameter >20 mm; 10 infants) was correlated with high incidence (90%) of moderate and severe postnatal hydronephrosis. Prenatal diagnosis of moderate hydronephrosis (renal pelvic diameter 10 to 20 mm) resulted in moderate postnatal hydronephrosis in 20% and improvement in 80% of the newborn infants. Our evidence supports the option of delaying postnatal renal ultrasound in infants with prenatal diagnosis of mild hydronephrosis (renal pelvic diameter <10 mm). This strategy can safely reduce the number of early postnatal studies and consequently significantly decrease hospitals' inpatient workload.

Truncating mutations in the chloride/proton ClC-5 antiporter gene in Seven Jewish Israeli families with Dent's 1 disease.

Dent's disease is an X-linked hereditary renal tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent's disease and to characterize the associated clinical syndromes. We studied 17 patients from 14 unrelated Israeli families with a clinical diagnosis of Dent's disease. LMWP was detected in all patients. Most of the affected individuals had hypercalciuria and nephrocalcinosis. Renal stones were found in 1 patient, and renal insufficiency developed in 2 patients. We identified six different truncating CLCN5 mutations that were segregated with the disease in 7 families: three nonsense mutations (Arg28stop, Arg467stop and Arg637stop), one deletion mutation (505delA) and two novel mutations, consisted of one deletion mutation (1493delG) and one insertion mutation (409insC). All the mutations cause premature termination of protein translation and result in a non-functional truncated protein. The clinical characteristics of patients with different mutations were, in general, similar.

A combined approach to the molecular analysis of cystinuria: from urinalysis to sequencing via genotyping.

BACKGROUND: Cystinuria is an autosomal recessive disease that is manifested by kidney stones and is caused by mutations in two genes: SLC3AI on chromosome 2p and SLC7A9 on chromosome 19q. Urinary cystine levels in obligate carriers are often, but not always, helpful in identifying the causative gene. OBJECTIVES: To characterize the clinical features and analyze the genetic basis of cystinuria in an inbred Moslem Arab Israeli family. METHODS: Family members were evaluated for urinary cystine and amino acid levels. DNA was initially analyzed with polymorphic markers close to the two genes and SLC7A9 was fully sequenced. RESULTS: Full segregation was found with the marker close to SLC7A9. Sequencing of this gene revealed a missense mutation, P482L, in the homozygous state in all three affected sibs. CONCLUSIONS: A combination of urinary cystine levels in obligate carriers, segregation analysis with polymorphic markers, and sequencing can save time and resources in the search for cystinuria mutations.

Beta1- or beta2-blockers to improve hemodynamics following endotracheal adrenaline administration.

BACKGROUND: The recommended dose for endotracheal adrenaline (0.02 mg/kg) causes a pronounced initial decrease in diastolic blood pressure which is detrimental at the initial phase of cardiopulmonary resuscitation. This effect was previously attributed to an early and preferential stimulation of the beta-adrenergic receptors causing vasodilatation unopposed by an alpha-adrenergic vasoconstriction. We hypothesized that inhibition of the beta2-adrenoreceptors is responsible for prevention of the deleterious initial decrease in blood pressure that takes place following endotracheal administration of adrenaline. METHODS: Adrenaline (0.02 mg/kg) diluted with normal saline (5 ml) was injected into the endobronchial tree of anesthetized dogs 3 min following pretreatment with the non-selective beta-blocker propranolol, selective beta1-blocker metoprolol (0.1 mg/kg, i.v.), or without pre-treatment. Heart rate, blood pressure and arterial blood gases were monitored. RESULTS: The selective beta-blocker metoprolol was almost as effective as the non-selective beta-blocker propranolol in attenuating the initial decrease in blood pressure following endotracheally administered adrenaline, a phenomenon that was previously attributed to inhibition of beta-adrenoreceptors. CONCLUSIONS: The outcome of this study might be explained by a dose-related loss of cardioselectivity of metoprolol. Further studies are warranted to refine the pharmacological means to abort the initial blood pressure-lowering effect of endotracheally administered adrenaline.

Tumor necrosis factor and clinical and metabolic courses after cardiac surgery in children.

OBJECTIVE: This study was undertaken to determine the relationship between plasma tumor necrosis factor concentrations and hemodynamic and metabolic parameters during the postoperative clinical course in children undergoing cardiac surgery. METHODS: Tumor necrosis factor levels of 10 consecutive children undergoing surgery for repair of congenital heart defects were analyzed in blood samples drawn at predetermined time points during surgery and up to 24 hours thereafter. Clinical data were collected at these times for correlation to tumor necrosis factor levels. RESULTS: All the patients survived. Tumor necrosis factor was detected in all 10 children. Tumor necrosis factor levels declined after induction of general anesthesia (201 +/- 65 pg/mL) steadily decreasing during surgery, reaching 80 +/- 50 pg/mL at 24 hours after the operation. Tumor necrosis factor levels were found to be inversely correlated with mean blood pressure values and indicators of acidosis (bicarbonate levels and base excess, P <.03). They were not correlated with the durations of cardiopulmonary bypass and aortic crossclamping. CONCLUSIONS: Tumor necrosis factor released into the circulation during and after pediatric cardiac surgery under cardiopulmonary bypass may be related to the hemodynamic and acid-base changes observed after cardiac surgery. Elucidation of the relationship between tumor necrosis factor and patient outcome in high-risk patients awaits further studies.

Tracheal epinephrine or norepinephrine preceded by beta blockade in a dog model. Can beta blockade bestow any benefits?

Tracheal epinephrine (adrenaline) has been associated with two major deletorious side effects: increased heart rate (HR) and an initial decrease of blood pressure (BP). This prospective randomized animal study compared the haemodynamic responses to tracheally administered epinephrine or norepinephrine (nor adrenaline) alone versus each after pretreatment with propranolol for ameliorating those two untoward effects associated with epinephrine administration. Five anaesthetized mongrel dogs underwent 25 experiments of tracheal epinephrine or norepinephrine (0.02 mg/kg diluted with normal saline to 5 ml total volume) with or without an I/V non-selective beta-blocker (propranolol 0.1 mg/kg) pretreatment, and served as their own controls. Tracheal epinephrine alone produced a rise in both diastolic and mean arterial BP and an increase of HR. Tracheal norepinephrine alone produced the largest increase of diastolic and mean BP but this change was associated with a significant tachycardia (from 37 to 72/m, P<0.001). While both epinephrine or norepinephrine after pretreatment with propranolol produced a significant increase in both diastolic (from 106 to 166 mmHg and from 118 to 169 mmHg, respectively) (P<0.01) and mean BP (from 122 to 183 mmHg and from 133 to 188 mmHg, respectively) (P<0.01), only propranolol-pretreated tracheal epinephrine yielded a significant decrease in HR (from 52 to 33/m, P=0.002). Pretreatment with a beta-blocker protected against the deleterious tachycardia associated with epinephrine or norepinephrine and, by doing so, may improve the myocardial oxygen supply-and-demand balance. At the same time, the pretreatment augmented the relatively mild diastolic BP increase associated with the beta-adrenergic effect of epinephrine.

A human integrin-α3 mutation confers major renal developmental defects.

The development of the mammalian kidney is a highly complex process dependent upon the interplay of various cell types, secreted morphogens, and the extra-cellular matrix (ECM). Although integrins are the most important receptors for ECM proteins and are ubiquitously expressed during kidney development, mice lacking expression of integrin α3 (Itga3) do not demonstrate a reduced number of nephrons, but mostly a disorganized GBM (glomerular basement membrane) leading to proteinuria. Thus, ITGA3 is considered mostly a passive GBM stabilizer and not an active player in nephrogenesis. Recently, mutations in the human ITGA3 were shown to cause congenital nephrotic syndrome, epidermolysis bullosa and interstitial lung disease, otherwise termed NEP syndrome (Nephrotic syndrome, Epidermolysis bullosa and Pulmonary disease). Herein, we performed histological and molecular analysis on the kidneys of a single patient from the initial cohort harboring an ITGA3 mutation, to illuminate the role of ITGA3 in human renal development. We show the patient to harbor a unique phenotype at birth, including severe unilateral renal hypodysplasia. Interrogation of global gene expression in the hypodysplastic kidney versus three controls (fetal, child and adult kidneys) revealed perturbed expression in several renal developmental pathways implicated in hypodysplasia, including the Wnt, BMP (bone morphogenetic protein) and TGF (transforming growth factor) pathways. Moreover, the affected kidney showed upregulation of early embryonic genes (e.g. OCT4 and PAX8) concomitant with downregulated kidney differentiation markers, implying a defect in proper renal differentiation. In conclusion, we show for the first time that ITGA3 is not merely a passive anchor for renal ECM proteins, as predicted by mouse models. Instead, our results may suggest it plays a central role in the interplay of cells, morphogens and ECM, required for proper nephrogenesis, thus adding ITGA3 to the list of CAKUT (congenital anomalies of the kidney and urinary tract)-causing genes.

Attention bias modification treatment augmenting effects on cognitive behavioral therapy in children with anxiety: randomized controlled trial.

OBJECTIVE: Attention bias modification treatment (ABMT) is a promising novel treatment for anxiety disorders, but clinical trials have focused largely on stand-alone formats among adults. This randomized controlled trial examined the augmenting effects of threat-based ABMT on cognitive behavioral therapy (CBT) in clinically anxious youth. METHOD: Sixty-three treatment-seeking children with anxiety disorder were randomly assigned to 1 of the following 3 treatment groups: ABMT + CBT; ABMT placebo + CBT; and CBT-alone. Participants in the 2 ABMT conditions received repeated training on dot-probe tasks either designed to shift attention away from threats (active) or designed to induce no changes in attention patterns (placebo). Primary outcome measures were frequency and severity of anxiety symptoms as determined by a clinician using a semi-structured interview. Self- and parent-rated anxiety measures and threat-related attention bias scores were also measured before and after treatment. RESULTS: Both the active and placebo ABMT groups showed greater reductions in clinician-rated anxiety symptoms than the CBT-alone group. Furthermore, only the active ABMT group showed significant reduction in self- or parent-rated anxiety symptoms. Finally, all groups showed a shift in attention patterns across the study, starting with a bias toward threat at baseline and shifting attention away from threat after treatment. CONCLUSIONS: Active and placebo ABMT might augment the clinical response to CBT for anxiety. This effect could arise from benefits associated with performing computer-based paradigms such as the dot-probe task. Given the absence of group differences in attention-bias changes during treatment, possible mechanisms and methodological issues underlying the observed findings are discussed. Clinical trial registration information-Augmenting Effects of ABMT on CBT in Anxious Children: A Randomized Clinical Trial; http://clinicaltrials.gov/; NCT01730625.

Glutaric Aciduria type I and acute renal failure - Coincidence or causality?

Glutaric Aciduria type I (GA-I) is a rare organic acidemia, caused by mutations in the GCDH gene, and characterized by encephalopathic crises with neurological sequelae. We report herein a patient with GA-I who presented with severe acute renal failure requiring dialysis, following an acute diarrheal illness. Histopathological evaluation demonstrated acute tubular necrosis, and molecular diagnosis revealed the patient to be homozygous for a previously unreported mutation, p.E64D. As renal impairment is not part of the clinical spectrum typical to GA-I, possible associations of renal failure and the underlying inborn error of metabolism are discussed, including recent advancements made in the understanding of the renal transport of glutaric acid and its derivatives during metabolic disturbance in GA-I.

Expression of SDF-1/CXCR4 in injured human kidneys.

The chemokine SDF-1alpha is involved in migration, survival, and development of multiple cells, most notably of hematopoietic stem cells (HSC) expressing its ligand CXCR4. Recently, we have shown engraftment of human HSC in the ischemically injured murine kidney, presumably mediated by SDF-1alpha. To further investigate a possible role of SDF-1alpha in the recruitment of CXCR4(+) cells in human renal disease of varying etiologies, we immunostained human biopsies of immunoglobulin (Ig)A nephropathy, minimal-change nephrotic syndrome, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, chronic pyelonephritis, and acute tubular necrosis (ATN) for SDF-1alpha, CXCR4, and CD45, a pan-hematopoietic marker. Irrespective of the diagnosis, intense SDF-1alpha immunoreactivity was localized to distal tubules and collecting ducts, whereas CXCR4 showed intense staining in both distal and proximal tubules. In addition, whereas varying degrees of CD45(+) cell infiltrates were observed in all biopsies, we found focal infiltrates of CXCR4(+) cells mostly localized to the corticomedullary junction only in ischemic ATN. This correlated with more extensive staining for SDF-1alpha in these sites. In all investigated renopathologic conditions, CD45+ leukocyte recruitment to the kidney seems not to be driven by SDF-1alpha/CXCR4 interaction. A contribution of SDF-1alpha for influx of CXCR4(+) cells in the vicinity of arcuate vessels is suggested only in human ATN.

Clinical and molecular findings in a family with the carbonic anhydrase II deficiency syndrome.

Carbonic anhydrase II (CA2) deficiency syndrome is an autosomal recessive disorder leading to osteopetrosis, renal tubular acidosis, and cerebral calcifications. Affected members of an Arab family with the CA2 deficiency syndrome carried the "Egyptian mutation" in CA2, i.e., c.191 del A, H64fsX90. One affected member, homozygote for the mutation, developed primary pulmonary hypertension. Primary pulmonary hypertension was never described before in patients with this unique syndrome. The likelihood of both occurring randomly in a single individual is very low. We therefore speculate that there might be a possibility of an etiologic link between these entities.

The early development of the fetal kidney-an in utero sonographic evaluation between 13 and 22 weeks' gestation.

OBJECTIVES: To establish a nomogram for early fetal kidney development during early gestation. METHODS: The study is a prospective, cross-sectional evaluation of 275 male and female fetuses between 13 and 22 weeks in normal singleton pregnancies. Measurements of fetal kidney length were performed by high resolution transvaginal ultrasonography between 14 and 17 weeks' gestation, and by transabdominal ultrasonography beyond 18 weeks' gestation. RESULTS: Adequate kidney length measurements were obtained in all 275 normal fetuses as well as in six fetuses with urinary tract anomalies. Kidney length as a function of gestational age was expressed by the regression equation: (square root) kidney length (mm) = -11.66 + 1.52 x gestational age (weeks). The correlation coefficient, r = 0.983 was found to be highly statistically significant (p < 0.0001). The normal mean and the 90% prediction limits were defined. Four cases with single kidney and two cases with posterior urethral valve had kidney length above the 95% upper limit. CONCLUSION: The present data offer a normal range of fetal kidney length from early stages of gestation that may allow intrauterine assessment of its development. It may also be helpful in the early prenatal diagnosis of renal abnormalities.