Very early and severe presentation of Triple A syndrome - case report and review of the literature.

Triple A syndrome (TAS), also known as Allgrove syndrome (OMIM#231550), is a rare, autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenal insufficiency. Additional neurological features may be present in two-thirds of patients, involving central, peripheral, and autonomic nervous system manifestations. TAS is caused by genetic alterations in the AAAS gene on chromosome 12q13, which encodes the nuclear pore complex protein termed ALADIN (ALacrima, Achalasia, aDrenal Insufficiency, and Neurologic disorder). ALADIN plays a crucial role in nucleocytoplasmic transport of specific proteins, including the transport of DNA repair proteins. TAS exhibits significant phenotypic variability in terms of symptom onset, frequency, and severity, often presenting with a progressive clinical course indicative of an underlying degenerative process. In this study, we report the case of an infant with exceptionally early and severe manifestations of triple A syndrome, with a review of the literature. Our patient exhibited the complete classical triad of TAS at six months of age, being among the youngest reported cases of the syndrome. The clinical course was complicated by severe involvement of the autonomic nervous system, neurogenic bladder, and recurrent urinary tract infections. Subsequently, the patient developed acute pancreatitis, leading to multiorgan dysfunction and a fatal outcome at 25 months of age. This case underscores the potential for atypical disease presentations and the need for clinical awareness in diagnosing and managing patients with TAS.

Reverse Phenotyping after Whole-Exome Sequencing in Children with Developmental Delay/Intellectual Disability-An Exception or a Necessity?

This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics.

Renal involvement in primary Sjogren syndrome of childhood: case report and literature review.

Renal tubular acidosis (RTA) is common in adults with primary Sjogren syndrome (pSS) but to date this condition has only been identified in 12 pediatric cases of pSS. Here we present the case of a 13-year-old, otherwise asymptomatic girl in whom the search for the etiology of incidentally found nephrocalcinosis led to diagnosis of distal RTA and nephrogenic diabetes insipidus secondary to SS-associated tubulointerstitial nephritis. Immunosupressive treatment and alkali/electrolyte supplementation resulted in stable renal function over the 6-year follow-up. A review of the literature focuses on two aspects of pSS: (1) the difficulties in diagnosing pSS in childhood and (2) clinical-pathological features, treatment and outcome of renal tubulointerstitial disease in childhood pSS. SS should be considered in older children, particularly females with otherwise unexplained RTA. A careful search for other renal dysfunctions is necessary, and renal biopsy may be of value in assessing the extent of renal damage and the need for immunomodulatory therapy.

Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): a single-center experience.

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

Epidemiology of chronic kidney disease in children in Serbia.

BACKGROUND: The epidemiological information from well-defined populations regarding childhood chronic kidney disease (CKD), particularly those concerning non-terminal stages, are scanty. The epidemiology of CKD in children is often based on renal replacement therapy (RRT) data, which means that a considerable number of children in earlier stages of CKD are missed as they will reach end-stage renal disease (ESRD) in adulthood. Here, we report the basic epidemiological data on childhood CKD in Serbia, gathered over the 10-year period of activity of the Serbian Pediatric Registry of Chronic Kidney Disease. METHODS: Since 2000-09, data on incidence, prevalence, aetiology, treatment modalities and outcome of children aged 0-18 years, with CKD Stages 2-4 and CKD Stage 5, were collected by reporting index cases from paediatric centres. RESULTS: Three hundred and thirty-six children were registered (211 boys, 125 girls, male/female ratio 1.7). The median age at registration was 9.0 years [interquartile range (IQR) 3-13]. Median follow-up was 4.0 years (IQR, 1-9). The median glomerular filtration rate (GFR) at the time of the registration was 39.6 mL/min/1.73m(2) (IQR, 13.8-65.4). Median annual incidence of CKD 2-5 stages was 14.3 per million age-related population (p.m.a.r.p.), while those of CKD 2-4 or CKD 5 were 9.1 and 5.7 p.m.a.r.p., respectively. The median prevalence of CKD 2-5 was 96.1 p.m.a.r.p., 52.8 p.m.a.r.p. in CKD 2-4 and 62.2 p.m.a.r.p. in CKD 5. The main causes of CKD were congenital anomalies of kidney and urinary tract and hereditary nephropathies. Kidney survival was the worst in children with glomerular diseases and in those with advanced CKD. Haemodialysis was the most common first modality of RRT. Mortality rate was 4.5%, mainly due to cardiovascular and infectious complications. CONCLUSIONS: Epidemiology of paediatric CKD in Serbia is similar to that reported from developed European countries. The knowledge of the epidemiology of earlier stages of CKD is essential for both institution of renoprotective therapy and planning of RRT, a fact of paramount importance in countries with limited resources.

Kawasaki-like disease and acute myocarditis in the SARS-CoV-2 pandemic - reports of three adolescents.

The novel coronavirus disease (COVID-19) may induce multisystem inflammatory syndrome (MIS) in children, which may be associated with Kawasaki-like disease and cardiac injury. In this study, we presented three male adolescents with MIS and myocardial injury admitted to the hospital during the peak of COVID-19 pandemic. All of the three patients had a history of fever, gastrointestinal symptoms, polymorph rash, non-exudative  onjunctivitis, and signs of acute myocarditis (AM). One of them had renal failure. Previously, they did not have an acute infection. Upon admission, they were hypotensive and tachycardic. A nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on reverse transcription-polymerase chain reaction (PCR) assay was negative, but neutralizing viral antibodies were positive. In combination with blood tests,  lectrocardiogram, echocardiography, and computerized tomography, a MIS associated with acute myocarditis with mild to moderate systolic dysfunction and dilated coronary arteries were diagnosed. Two of three patients had shock syndrome andrequired inotropic support. All patients were treated with intravenous imunoglobulins (Ig). The second patient had a fever up to 102.2°F (39°C) 3 days after intravenous Ig. Further, he was treated according to protocols for refractory Kawasaki disease, with an intravenous methylprednisolone pulse therapy and aspirin. After a few hours, he became afebrile and the clinical signs disappeared. The favorable short-term outcome may reflect early recognition and adequate therapy; however, the long-term outcomes are currently unknown.

Evaluation of carotid intima media thickness in children with idiopathic nephrotic syndrome.

AIM: Aim of the study was to determine if carotid intima media thickness in children with idiopathic nephrotic syndrome is greater than in healthy subjects, and to assess whether carotid intima media thickness in children with nephrotic syndrome is associated with clinical (including disease duration, cumulative dose of steroids, number of relapses) and biochemical parameters. METHODS: A cross-sectional study included 40 patients with nephrotic syndrome (mean age 11.7±4.7 years). Steroid dependent nephrotic syndrome was established in 32 patients (80%), while 8 (20%) had steroid resistant nephrotic syndrome. Control group consisted of 20 age and gender matched healthy children. Blood pressure based on 24-h ambulatory blood pressure monitoring (ABPM), carotid intima media thickness, fasting glucose, insulin, HbA1c, lipid concentrations were measured in all children. RESULTS: A significant difference was detected in carotid intima media thickness values (P=0.036). Children with nephrotic syndrome had significantly greater carotid intima media thickness compared with healthy children (0.42±0.06 and 0.38±0.03mm). Carotid intima-media thickness was positively associated with duration of nephrotic syndrome (r=0.45; P=0.004), body mass index (r=0.48; P=0.002), daytime systolic blood pressure (r=0.46; P=0.003) and night-time systolic blood pressure (r=0.52; P=0.001). Multiple linear regression showed that duration of nephrotic syndrome was the only independent predictor of carotid intima media thickness in children with nephrotic syndrome (R2=0.244; ß=0.327; P=0.037). CONCLUSION: The findings of the present study suggest subclinical vascular damage in patients with nephrotic syndrome. Duration of nephrotic syndrome was the only independent predictor of carotid intima media thickness.

Transient type 1 pseudo-hypoaldosteronism: report on an eight-patient series and literature review.

Eight boys aged 2-12 weeks with urinary tract malformations (UTMs) exhibited features of transient type 1 pseudo-hypoaldosteronism (TPHA1) in the course of urinary tract infection (UTI). Hyponatremia (120.9+/-5.8 mmol/l), hyperkalemia (6.9+/-0.9 mmol/l), metabolic acidosis (plasma bicarbonate 11+/-1.4 mmol/l), and a rise in serum creatinine levels (145+/-101 micromol/l) were associated with high urinary sodium (Na) and low potassium (K) excretion. Tubular resistance to aldosterone was indicated by high plasma aldosterone concentrations (170.4+/-100.5 ng/dl), high levels of the plasma aldosterone to potassium ratio (25.2+/-15.6), and diminished urinary K/Na values (0.31+/-0.19). With appropriate therapy, serum electrolytes, creatinine, and acid-base balance normalized within 2 weeks. A Medline search revealed another 85 cases of TPHA1 reported to date. All of the 93 patients were less than 7 months of age and 90% were less than 3 months of age, 90.3% suffered from UTM, with associated UTI in 89% of them, 11% had UTMin the absence of UTI, and 9.7% showed isolated UTI. These findings indicate that early infancy is the main contributing factor for TPHA1 to occur and that UTI and UTMare additional factors, with at least one being required for its development.

Congenital thrombocytopenia with nephritis - The first case of MYH9 related disorder in Serbia.

INTRODUCTION: The group of autosomal dominant disorders - Epstein syndrome, Sebastian syndrome, Fechthner syndrome and May-Hegglin anomaly - are characterised by thrombocytopenia with giant platelets, inclusion bodies in granulocytes and variable levels of deafness, disturbances of vision and renal function impairment. A common genetic background of these disorders are mutations in MYH9 gene, coding for the nonmuscle myosin heavy chain IIA. Differential diagnosis is important for the adequate treatment strategy. The aim of this case report was to present a patient with MYH9 disorder in Serbia. CASE REPORT: A 16-year-old boy was referred to our hospital with the diagnosis of resistant immune thrombocytopenia for splenectomy. Thrombocytopenia was incidentally discovered at the age of five. The treatment with corticosteroids on several occasions was unsuccessful. Although the platelet count was below 10 x 10(9)/L, there were no bleeding symptoms. Besides thrombocytopenia with giant platelets, on admission the patient also suffered sensorineuronal hearing loss and proteinuria. The diagnosis was confirmed with immunofluorescence and genetic analyses. CONCLUSION: Early recognition of MYH9-related diseases is essential to avoid unnecessary and potentially harmful treatments for misdiagnosed immune thrombocytopenia, and also for timely and proper therapy in attempt to delay end-stage renal failure and improve quality of life.

Growth in children with chronic kidney disease: 13 years follow up study.

BACKGROUND: Growth retardation is one of the most visible comorbid conditions of chronic kidney disease (CKD) in children. To our knowledge, published data on longitudinal follow-up of growth in pediatric patients with CKD is lacking from the region of South-East Europe. Herein we report the results from the Serbian Pediatric Registry of Chronic Kidney Disease. METHODS: The data reported in the present prospective analysis were collected between 2000 and 2012. A total of 324 children with CKD were enrolled in the registry. RESULTS: Prevalence of growth failure at registry entry was 29.3 %. Mean height standard deviation scores (HtSDS) in children with stunting and those with normal stature were -3.00 [95 % confidence interval (CI) -3.21 to -2.79] and -0.08 (95 % CI -0.22 to 0.05) (p < 0.001), respectively. Children with hereditary nephropathy had worse growth at registration (-1.51; 95 % CI -1.97 to -1.04, p = 0.008). Those with CKD stages 4 and 5 before registration had more chance to have short stature at registration than those with CKD stages 2 and 3 [odds ratio (OR) = 0.458, CI 0.268-0.782, p = 0.004]. Dialysis was an independent negative predictor for maintaining optimal stature during the follow-up period (OR = 0.324, CI = 0.199-0.529, p < 0.001), while transplantation was an independent positive predictor for improvement of small stature during follow-up (OR = 3.706, CI = 1.785-7.696, p < 0.001). CONCLUSION: Growth failure remains a significant problem in children with CKD, being worst in patients with hereditary renal disease. Growth is not improved by standard dialysis, but transplantation has a positive impact on growth in children.

[Chronic kidney disease during a 12-year period at tertiary health institution].

INTRODUCTION: Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in paediatric population. OBJECTIVE: The aim of the study was analysis of aetiology, staging and associated complications of CKD at the time of diagnosis. METHODS: Data of 97 patients (56 boys) of average age 7.8 +/- 5.8 years, referred for the first time to the Institute for Mother and Child Healthcare "Dr Vukan Cupic", Belgrade in the period 1998-2009, due to CKD, stage 2-5, were analysed. In each patient illness history was obtained, and physical examination, laboratory, X-ray and other investigations were performed according to the indications. CKD was classified according to the glomerular filtration rate into four grades: 2--mild (60-90 ml/min/1.73 m2); 3--moderate (30-60 ml/min/1.73 m2); 4--advanced (15-30 ml/ min/1.73 m2); and 5--terminal (< 15 ml/min/1.73 m2). RESULTS: The most frequent causes of CKD were congenital anomalies of the kidney and urinary tract (43.3%), followed by glomerular diseases (17.5%), hereditary kidney diseases (16.5%), metabolic diseases (7.2%) and other causes (15.5%). Mild CKD was found in 29.8%, moderate in 28.9%, advanced in 22.7%, and terminal in 18.6% children. Among patients with CKD stage 4 and 5, 75% of patients presented with acute renal failure, while 25% had earlier detected CKD (stage 1), but were not under regular follow-up. Associated complications included metabolic acidosis (63%), anaemia (60%), hypertension (42.3%), short stature (25.8%), renal osteodystrophy (13.4%) and cardiovascular diseases (7.2%). CONCLUSION: Congenital anomalies of the kidney and urinary tract are the leading cause of CKD in paediatric population. A significant proportion (41.3%) of patients had advanced and terminal CKD. In most patients CKD was diagnosed late and with associated complications.

[Transient pseudohypoaldosteronism].

INTRODUCTION: Infants with urinary tract malformations (UTM) presenting with urinary tract infection (UTI) are prone to develop transient type 1 pseudohypoaldosteronism (THPA1). OBJECTIVE: Report on patient series with characteristics of THPA1, UTM and/or UTI and suggestions for the diagnosis and therapy. METHODS: Patients underwent blood and urine electrolyte and acid-base analysis, serum aldosterosterone levels and plasma rennin activity measuring; urinalysis, urinoculture and renal ultrasound were done and medical and/or surgical therapy was instituted. RESULTS: Hyponatraemia (120.9 +/- 5.8 mmol/L), hyperkalaemia (6.9 +/- 0.9 mmol/L), metabolic acidosis (plasma bicarbonate, 11 +/- 1.4 mmol/L), and a rise in serum creatinine levels (145 +/- 101 micromol/L) were associated with inappropriately high urinary sodium (51.3 +/- 17.5 mmol/L) and low potassium (14.1 +/- 5.9 mmol/L) excretion. Elevated plasma aldosterone concentrations (170.4 +/- 100.5 ng/dL) and the very high levels of the plasma aldosterone to potassium ratio (25.2 +/- 15.6) together with diminished urinary K/Na values (0.31 +/- 0.19) indicated tubular resistance to aldosterone. After institution of appropriate medical and/or surgical therapy, serum electrolytes, creatinine, and acid-base balance were normalized. Imaging studies showed ureteropyelic or ureterovesical junction obstruction in 3 and 2 patients, respectively, posterior urethral valves in 3, and normal UT in 1 patient. According to our knowledge, this is the first report on THPA1 in the Serbian literature. CONCLUSION: Male infants with hyponatraemia, hyperkalaemia and metabolic acidosis have to have their urine examined and the renal ultrasound has to be done in order to avoid both, the underdiagnosis of THPA1 and the inappropriate medication.

Diagnostic role of initial renal cortical scintigraphy in children with the first episode of acute pyelonephritis.

OBJECTIVE: Assessment of the first febrile urinary tract infection (UTI) in children has been the subject of debate for many years. Diagnosis of acute pyelonephritis (APN) is usually based on clinical and biological data. The clinical usefulness of early Tc-99m DMSA scintigraphy remains controversial, although it may influence the type and duration of treatment. The aim of this study was to assess the role of initial cortical scintigraphy in the detection of early renal parenchymal damage in children highly suspected of having APN and to compare the scintigraphic findings with selected clinical/laboratory parameters and ultrasonography. METHODS: A prospective study was conducted in 34 infants and young children (18 boys, 16 girls), aged 1.5-36 months (mean 9.8 ± 8.7 months), hospitalized with a first episode of clinically suspected APN. Within the first 5 days after admission, Tc-99m DMSA renal scintigraphy, ultrasonography (US), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cell count (WBC) and urine analyses were performed. RESULTS: DMSA scintigraphy showed changes consistent with APN in 27/34 (79%) patients, with a mean age of 10.9 months, including 12 males (44%) and 15 (56%) females. Out of 9 febrile children with negative urine culture and supportive evidence of UTI, scintigraphy showed parenchymal involvement in 8 children (24% in the whole group, 30% in scintigraphically documented APN). There were no statistically significant correlations between the frequency or size of the initial scintigraphic abnormalities and age, sex, body temperature, CRP levels or ESR. A CRP level of >54 mg/L and a WBC of >13,300/mm³ had sensitivities of 56 and 59% and specificities of 86 and 71%, respectively. US showed changes consistent with APN in 7/34 (21%) in the whole group and in 7/27 (26%) patients with positive cortical scan (p < 0.05). CONCLUSION: Initial DMSA renal scintigraphy is a sensitive method for the early diagnosis of APN in young children and is useful in the assessment of the severity of kidney injury even in patients with negative urine culture. Clinical, biological and ultrasound parameters do not identify children with renal damage. Normal DMSA study, excluding parenchymal involvement and late sequelae, could minimize the use of scintigraphy in the follow-up and reduce the redundancy of cystography.

[Congenital nephrotic syndrome].

INTRODUCTION: Congenital nephrotic syndrome is usually presented with heavy proteinuria, hypoproteinaemia, oedema and hyperlipidaemia in a child from its birth until the age of 3 months. Aetiology of the disease is mutation in the relevant gene or it develops secondary to various infections. The most common form of congenital nephrotic syndrome is caused by mutation in gene for nephrin, the most important protein of the slit diaphragm. CASE OUTLINE: We present the patient with the clinical and laboratory signs of nephrotic syndrome expressed in the first day of life. Despite the adequate and regular substitution, antiproteinuric and antithrombotic therapy, complications occurred and the patient deceased. Genetic analysis revealed homozygous mutation in gene for nephrin (614del8ins2TT). Three years later, in the patient's mother who was in the 12th week of pregnancy at that time, biopsy of chorionic villi was performed and the foetal genetic material showed heterozygosity for the same recessive mutation which meant that the foetus had the status of a carrier. To the best of our knowledge, this is the first family in Serbia in which prenatal molecular--genetic testing for the congenital nephrotic syndrome was accomplished. CONCLUSION: We wish to stress the importance of molecular diagnosis in patients with congenital nephrotic syndrome in order to perform early prenatal diagnosis in future pregnancies.