Bilateral upper eyelid swelling (Hoagland sign) in Epstein-Barr infectious mononucleosis: prospective experience.

BACKGROUND: The typical presentation of Epstein-Barr virus infectious mononucleosis includes fever, pharyngitis, measles-like rash, jaundice, and enlarged lymph nodes, liver, or spleen. A painless bilateral swelling of the upper eyelid, sometimes with drooping of the lateral aspect, may also occur. This sign, referred to as Hoagland sign, is not or only marginally mentioned in reviews and textbooks. METHODS: Between 2019 and 2021, two of us evaluated all subjects with a positive acute Epstein-Barr virus serology for the typical signs of mononucleosis and for the possible existence of the Hoagland sign. RESULTS: During the mentioned period, the diagnosis of mononucleosis was made in 26 (14 females and 12 males) subjects aged from 9.0 to 33 years. The initial presentation included fever in 24, enlarged cervical lymph nodes in 23, pharyngitis in 21, a palpable liver in 7, a palpable spleen in 7, jaundice in 2, and a measles-like rash in 2 cases. The Hoagland sign was noted in 14 cases. Patients with and without Hoagland sign did not significantly differ with respect to age and sex. CONCLUSIONS: The Hoagland sign is an easily identifiable clinical sign that is common and likely helpful early in the course of Epstein-Barr virus infectious mononucleosis. There is a need to expand awareness of this sign among physicians.

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Swiss consensus recommendations on urinary tract infections in children.

The kidneys and the urinary tract are a common source of infection in children of all ages, especially infants and young children. The main risk factors for sequelae after urinary tract infections (UTI) are congenital anomalies of the kidney and urinary tract (CAKUT) and bladder-bowel dysfunction. UTI should be considered in every child with fever without a source. The differentiation between upper and lower UTI is crucial for appropriate management. Method of urine collection should be based on age and risk factors. The diagnosis of UTI requires urine analysis and significant growth of a pathogen in culture. Treatment of UTI should be based on practical considerations regarding age and presentation with adjustment of the initial antimicrobial treatment according to antimicrobial sensitivity testing. All children, regardless of age, should have an ultrasound of the urinary tract performed after pyelonephritis. In general, antibiotic prophylaxis is not recommended.Conclusion: Based on recent data and in line with international guidelines, multidisciplinary Swiss consensus recommendations were developed by members of Swiss pediatric infectious diseases, nephrology, and urology societies giving the clinician clear recommendations in regard to diagnosis, type and duration of therapy, antimicrobial treatment options, indication for imaging, and antibiotic prophylaxis. What is Known: • Urinary tract infections (UTI) are a common and important clinical problem in childhood. Although children with pyelonephritis tend to present with fever, it can be difficult on clinical grounds to distinguish cystitis from pyelonephritis, particularly in young children less than 2 years of age. • Method of urine collection is based on age and risk factors. The diagnosis of UTI requires urine analysis and significant growth of a pathogen in culture. What is New: • Vesicoureteric reflux (VUR) remains a risk factor for UTI but per se is neither necessary nor sufficient for the development of renal scars. Congenital anomalies of the kidney and urinary tract (CAKUT) and bladder-bowel dysfunction play a more important role as causes of long-term sequelae. In general, antibiotic prophylaxis is not recommended. • A switch to oral antibiotics should be considered already in young infants. Indications for invasive imaging are more restrictive and reserved for patients with abnormal renal ultrasound, complicated UTI, and infections with pathogens other than E. coli.

Acute regulated expression of pendrin in human urinary exosomes.

It is well known that pendrin, an apical Cl-/HCO3-exchanger in type B intercalated cells, is modulated by chronic acid-base disturbances and electrolyte intake. To study this adaptation further at the acute level, we analyzed urinary exosomes from individuals subjected to oral acute acid, alkali, and NaCl loading. Acute oral NH4Cl loading (n = 8) elicited systemic acidemia with a drop in urinary pH and an increase in urinary NH4 excretion. Nadir urinary pH was achieved 5 h after NH4Cl loading. Exosomal pendrin abundance was dramatically decreased at 3 h after acid loading. In contrast, after acute equimolar oral NaHCO3 loading (n = 8), urinary and venous blood pH rose rapidly with a significant attenuation of urinary NH4 excretion. Alkali loading caused rapid upregulation of exosomal pendrin abundance at 1 h and normalized within 3 h of treatment. Equimolar NaCl loading (n = 6) did not alter urinary or venous blood pH or urinary NH4 excretion. However, pendrin abundance in urinary exosomes was significantly reduced at 2 h of NaCl ingestion with lowest levels observed at 4 h after treatment. In patients with inherited distal renal tubular acidosis (dRTA), pendrin abundance in urinary exosomes was greatly reduced and did not change upon oral NH4Cl loading. In summary, pendrin can be detected and quantified in human urinary exosomes by immunoblotting. Acid, alkali, and NaCl loadings cause acute changes in pendrin abundance in urinary exosomes within a few hours. Our data suggest that exosomal pendrin is a promising urinary biomarker for acute acid-base and volume status changes in humans.

Levamisole in relapsing steroid-sensitive nephrotic syndrome: where do we stand?

Many patients with steroid-sensitive nephrotic syndrome develop a relapsing course; therefore, alternative treatment may be necessary to avoid steroid toxicity. In this issue, a multicenter controlled study in relapsing steroid-sensitive nephrotic syndrome shows the effectiveness of levamisole. Time to first relapse was significantly increased compared with placebo. In addition, possible differential treatment effects were suggested for subgroups: patients with frequent relapses might have a superior response to those with steroid dependency.

Balancing competing needs in kidney transplantation: does an allocation system prioritizing children affect the renal transplant function?

Children often merit priority in access to deceased donor kidneys by organ-sharing organizations. We report the impact of the new Swiss Organ Allocation System (SOAS) introduced in 2007, offering all kidney allografts from deceased donors <60 years preferentially to children. The retrospective cohort study included all paediatric transplant patients (<20 years of age) before (n = 19) and after (n = 32) the new SOAS (from 2001 to 2014). Estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio (UPC), need for antihypertensive medication, waiting times to kidney transplantation (KTX), number of pre-emptive transplantations and rejections, and the proportion of living donor transplants were considered as outcome parameters. Patients after the new SOAS had significantly better eGFRs 2 years after KTX (Mean Difference, MD = 25.7 ml/min/1.73 m2 , P = 0.025), lower UPC ratios (Median Difference, MeD = -14.5 g/mol, P = 0.004), decreased waiting times to KTX (MeD = -97 days, P = 0.021) and a higher proportion of pre-emptive transplantations (Odds Ratio = 9.4, 95% CI = 1.1-80.3, P = 0.018), while the need for antihypertensive medication, number of rejections and living donor transplantations remained stable. The new SOAS is associated with improved short-term clinical outcomes and more rapid access to KTX. Despite lacking long-term research, the study results should encourage other policy makers to adopt the SOAS approach.

Long-term health-related quality of life and psychological adjustment in children after haemolytic-uraemic syndrome.

BACKGROUND: In children after haemolytic-uraemic syndrome (HUS), little is known about long-term health-related quality of life (HRQoL) and psychological adjustment as defined by behavioural problems, depressive symptoms and post-traumatic stress symptoms. METHODS: Sixty-two paediatric patients with a history of HUS were included in this study. Medical data of the acute HUS episode were retrieved retrospectively from hospital records. Data on the clinical course at study investigation were assessed by clinical examination and laboratory evaluation. HRQoL and psychological adjustment data were measured by standardised, parent- and self-reported questionnaires. RESULTS: Haemolytic-uraemic syndrome was diagnosed at a mean of 6.5 years before the initiation of the study (standard deviation 2.9, range 0.1-15.7) years. Among the preschool children, parents reported that their child was less lively and energetic (HRQoL emotional dimension), while no increased behavioural problems were reported. In the school-age children, self- and proxy-reported HRQoL was well within or even above the norms, while increased total behavioural problems were found. The school-age children reported no increased depression scores. Also none of the children met the criteria for full or partial HUS-associated posttraumatic stress disorder. CONCLUSIONS: Healthcare providers should be particularly alert to behavioural problems in school-age children with a history of HUS and to lower HRQoL in preschool children.

Health-related quality of life and mental health in parents of children with hemolytic uremic syndrome.

BACKGROUND: Little is known about health-related quality of life (HRQoL) and mental health of parents having children with a history of hemolytic uremic syndrome (HUS). METHODS: This study included 63 mothers and 58 fathers of a cohort of 63 HUS-affected children. At assessment, the mean time since a child experienced an acute episode of HUS was 6.4 years. Parental HRQoL, mental health and posttraumatic stress disorder (PTSD) were assessed with standardized self-report questionnaires. Medical data were extracted from patients' hospital records. RESULTS: The HRQoL and mental health of both the mothers and fathers were not impaired compared to normative data. However, a shorter time since a child's acute HUS episode was a significant predictor of lower HRQoL among the mothers, while no such effect was found among the fathers. Two fathers (3%), but no mothers, met the criteria for a diagnosis of HUS-related full PTSD; one father (2%) and four mothers (6%) met the criteria for a diagnosis of HUS-related partial PTSD. CONCLUSIONS: Our study shows that most parents of our study sample were doing well in terms of HRQoL and mental health, although a small number met the criteria for full or partial PTSD diagnosis due to their child's HUS. We therefore recommend that healthcare providers pay special attention to parents regarding PTSD symptoms during the clinical follow-up of a HUS-affected child since some parents may benefit from psychological support.

Outcome after prenatal diagnosis of congenital anomalies of the kidney and urinary tract.

UNLABELLED: Congenital anomalies of the kidney and urinary tract are common findings on fetal ultrasound. The aim of this prospective observational study was to describe outcome and risk factors in 115 patients born 1995-2001. All prenatally diagnosed children were stratified into low- and high-risk group and followed postnatally clinically and by imaging at defined endpoints. Risk factors were evaluated using odds ratios. Neonatal diagnosis included pelvi-ureteric junction obstruction (n = 33), vesicoureteral reflux (n = 27), solitary mild pelvic dilatation (postnatal anteroposterior diameter 5-10 mm; n = 25), and further diagnosis as primary obstructive megaureter, unilateral multicystic dysplastic kidney, renal dysplasia and posterior urethral valves. In 38 children with prenatal isolated hydronephrosis, ultrasound normalized at median age of 1.2 years (range 0.1-9). Surgery was performed in 34 children at median age of 0.4 years (0.1-10.8). Persistent renal anomalies without surgery were present in 43 children and followed in 36 for median time of 16 years (12.2-18). Oligohydramnios and postnatal bilateral anomalies were significantly associated with surgery and impaired renal function. CONCLUSION: The majority of children had a favourable postnatal outcome, in particular children with prenatally low risk, i.e. isolated uni- or bilateral hydronephrosis. Oligohydramnios and postnatal bilateral anomalies were risk factors for non-favourable outcome. WHAT IS KNOWN: • In congenital anomalies of the kidney and urinary tract significantly poorer outcome is known in patients with bilateral renal hypoplasia or solitary kidney associated with posterior urethral valves. • Other factors as proteinuria and vesicoureteral reflux were associated with a higher risk of progression to chronic renal failure in these patients. What is New: • Unlike other studies giving us above-mentioned information, we included all patients with any kind of prenatally diagnosed congenital anomalies of the kidney and urinary tract. Our study shows long-term follow up (median 16 years, range 12.2-18 years), especially in patients not needing surgery, but with persistent anomalies. • During postnatal long-term follow up (median 2.2 years, range 0.1-18 years) one third each showed normalization, need of surgery or persistence of anomalies without need of surgery. Our study revealed a good prognosis in the majority of these children, in particular with prenatally low risk, i.e. isolated uni- or bilateral hydronephrosis, and revealed oligohydramnios and postnatal bilateral anomalies as risk factors for a non-favourable outcome, defined as need of surgery, persistent anomalies with impaired renal function, end stage renal failure or death.

Standardized multilevel transition program: Does it affect renal transplant outcome?

The transfer of renal transplant patients from pediatric to adult care is a crucial step with a high risk of subsequent graft loss. Therefore, the transition should be a thoroughly planned, well-designed and multidisciplinary process focused on the individual patient. Our pediatric nephrology department introduced a structured step-by-step transition program supported by a multidisciplinary team of health professionals. The purpose of our study was to determine the effects of the transition program on eGFR and number of ARs in comparison to a group without a transition program at one and three yr after transfer. We conducted a single-center retrospective cohort study of renal transplant patients prior to and after the introduction of the transition program. Multiple regression analysis revealed a significantly lower decline of eGFR in the group with transition program (-11.3 ± 44 mL/min/1.73 m(2) ) compared to the group without transition program (-28.4 ± 33 mL/min/1.73 m(2) ) at three yr after transfer. The number of AR episodes significantly decreased from 34.6% in the group without transition program to 9.1% in the group with transition program. The standardized multilevel transition program seems to have significant positive effects on eGFR and number of AR episodes in renal transplant patients.

Neurodevelopmental long-term outcome in children after hemolytic uremic syndrome.

BACKGROUND: To investigate the long-term neurodevelopmental outcome in children after hemolytic uremic syndrome (HUS) and to compare outcome dependent on central nervous system (CNS) involvement during HUS. METHODS: A single-center retrospective cohort of 47 children was examined at a median age of 10.6 (range 6-16.9) years and a median follow-up of 7.8 (range 0.4-15.3) years after having had HUS. Intellectual performance was assessed with the German version of the Wechsler Intelligence Scale 4th version and neuromotor performance with the Zurich Neuromotor Assessment (ZNA). The occurrence of neurological symptoms during the acute phase of HUS was evaluated retrospectively. RESULTS: Mean IQ of the whole study population fell within the normal range (median full scale IQ 104, range 54-127). Neuromotor performance was significantly poorer in the domains "adaptive fine," "gross motor," "static balance" (all p < 0.05) and "associated movements" (p < 0.001); only the "pure motor" domain was within the normal reference range. Neurological findings occurred in 16/47 patients (34 %) during acute HUS. Neurodevelopmental outcome was not significantly different between children with or without CNS involvement. CONCLUSIONS: Our follow-up of children after HUS showed a favorable cognitive outcome. However, neuromotor outcome was impaired in all study participants. Neurological impairment during acute HUS was not predictive of outcome.

Successful long-term outcome after renal transplantation in a patient with atypical haemolytic uremic syndrome with combined membrane cofactor protein CD46 and complement factor I mutations.

BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is often associated with a high risk of disease recurrence and subsequent graft loss after isolated renal transplantation. Evidence-based recommendations for a mutation-based management after renal transplantation in aHUS caused by a combined mutation with complement factor I (CFI) and membrane cofactor protein CD46 (MCP) are limited. CASE-DIAGNOSIS/TREATMENT: We describe a 9-year-old boy with a first manifestation of aHUS at the age of 9 months carrying combined heterozygous mutations in the CFI and MCP genes. At the age of 5 years, he underwent isolated cadaveric renal transplantation. Fresh frozen plasma was administered during and after transplantation, tapered and finally stopped after 3 years. CONCLUSIONS: During the 5-year follow-up after transplantation there have been no signs of aHUS recurrence and graft function has remained good. The combination of heterozygous MCP and CFI mutations with aHUS might have a positive impact on the post-transplant course, possibly predicting a lower risk of aHUS recurrence after an isolated cadaveric renal transplantation.

Vaccine Hesitancy in Central Switzerland: Identifying and Characterizing Undervaccinated Children in a Pediatric Emergency Department.

Vaccinations play an important role in the prevention of potentially fatal diseases. Vaccine hesitancy has become an important problem both in the public discourse and for public health. We aimed to identify and characterize this potentially unvaccinated or incompletely vaccinated group of children presenting to the pediatric emergency department (PED) of the tertiary children's hospital in central Switzerland, a region that has anecdotally been claimed as a hotspot for vaccine hesitancy. All patients presenting to the PED (N = 20,247) between September 2018 and September 2019 were screened for their vaccination status and categorized as incomplete, unvaccinated, or fully vaccinated in a retrospective cohort study. Some 2.6% (n = 526) visits to the PED were not or incompletely vaccinated according to age, or their vaccination status was unknown. Most of the children in the cohort were not critically ill, and the minority had to be hospitalized. Undervaccinated patients were overrepresented in rural areas. Of all cohort visits, 18 (3.4%) patients received opportunistic vaccination in the PED. No cases of vaccine-preventable diseases were observed. In summary, incompletely vaccinated and unvaccinated status was less frequent than initially expected. The PED may play a role in increasing vaccination coverage by providing opportunistic vaccinations.

Pediatric Trauma and Trauma Team Activation in a Swiss Pediatric Emergency Department: An Observational Cohort Study.

BACKGROUND: Trauma is one of the most common causes of death in childhood, but data on severely injured Swiss children are absent from existing national registries. Our aim was to analyze trauma activations and the profiles of critically injured children at a tertiary, non-academic Swiss pediatric emergency department (PED). In the absence of a national pediatric trauma database, this information may help to guide the design of infrastructure, processes within organizations, training, and policies. METHODS: A retrospective analysis of pediatric trauma patients in a prospective resuscitation database over a 2-year period. Critically injured trauma patients under the age of 16 years were included. Patients were described with established triage and injury severity scales. Statistical evaluation included logistic regression analysis. RESULTS: A total of 82 patients matched one or more of the study inclusion criteria. The most frequent age group was 12-15 years, and 27% were female. Trauma team activation (TTA) occurred with 49 patients (59.8%). Falls were the most frequent mechanism of injury, both overall and for major trauma. Road-traffic-related injuries had the highest relative risk of major trauma. In the multivariate analysis, patients receiving medicalized transport were more likely to trigger a TTA, but there was no association between TTA and age, gender, or Injury Severity Score (ISS). Nineteen patients (23.2%) sustained major trauma with an ISS > 15. Injuries of Abbreviated Injury Scale severity 3 or greater were most frequent to the head, followed by abdomen, chest, and extremities. The overall mortality rate in the cohort was 2.4%. Conclusions: Major trauma presentations only comprise a small proportion of the total patient load in the PED, and trauma team activation does not correlate with injury severity. Low exposure to high-acuity patients highlights the importance of deliberate learning and simulation for all professionals in the PED. Our findings indicate that high priority should be given to training in the management of severely injured children in the PED. The leading major trauma mechanisms were preventable, which should prompt further efforts in injury prevention.

Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium.

Introduction: Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. Methods: In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses. Results: The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P < 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. Conclusion: In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.

Boy with autosomal recessive polycystic kidney and autosomal dominant polycystic liver disease.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) shows a great phenotypic variability between patients, ranging from perinatal demise to mildly affected adults. Autosomal dominant polycystic liver disease (PCLD) does not manifest in childhood. CASE-DIAGNOSIS/TREATMENT: A boy was reported with the co-occurrence of ARPKD and PCLD. He presented at the age of 16 days with pyelonephritis and urosepsis. Subsequent investigations showed enlarged kidneys and hyperechogenic renal medulla and liver parenchyma. Genetic analysis revealed compound heterozygous mutations in the PKHD1 gene (p.Arg496X and p.Ser1862Leu). After his mother was diagnosed with PCLD, the finding of a liver cyst on ultrasound prompted analysis of the PRKCSH gene, revealing a missense mutation (p.Arg139His). At the most recent follow-up at 13 years of age, the patient's course and clinical examination was uneventful with normal renal and liver function without evidence of portal hypertension. CONCLUSIONS: The patient with ARPKD and PCLD has so far demonstrated a benign clinical outcome, consistent with the great phenotypic variability of ARPKD and, apart from the liver cyst, asymptomatic manifestation of PCLD in childhood. However, close long-term follow-up is mandatory.

Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.

BACKGROUND: Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised. METHODS: In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing. RESULTS: For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found. CONCLUSIONS: The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC.

Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.

Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Wnt signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Wnt signaling.

Recurrence of membranoproliferative glomerulonephritis after renal transplantation in Denys-Drash.

Denys-Drash syndrome (DDS) consists of the triad of nephropathy, male pseudohermaphroditism, and Wilms tumor caused by mutations within exons 8 or 9 of the Wilms tumor suppressor gene 1. Early onset nephrotic syndrome progresses to end-stage renal failure. The characteristic histological lesion is diffuse mesangial sclerosis. Here, we report on a boy with DDS who presented early with diffuse mesangial sclerosis, but subsequently also developed immune complex glomerulonephritis with a membranoproliferative pattern (MPGN-pattern GN) in his native kidneys. Four years after renal transplantation, immune complex glomerulonephritis with an MPGN pattern recurred in the renal graft resulting in proteinuria and progressive renal insufficiency.