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- Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases: Five-Year Experience of a Pediatric Tertiary Hospital in PortugalPublication . Rebelo, M; Francisco, T; Perry da Câmara, R; Pereira, A; Iraneta, A; Amorim, M; Paiva Lopes, MJ; Lopes da Silva, R; Cordeiro, AIIntroduction: Neurocutaneous syndromes (NCS) are a heterogeneous group of conditions with multiorgan involvement and diverse manifestations, evolving throughout life with significant morbidity. A multidisciplinary approach to NCS patients has been advocated, although a specific model is not yet established. The aim of this study was 1) to describe the organization of the recently created Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases (MOCND) at a Portuguese pediatric tertiary hospital; 2) to share our institutional experience focusing on the most common conditions, neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC); 3) to analyze the advantages of a multidisciplinary center and approach in NCS. Methods: Retrospective analysis of 281 patients enrolled in the MOCND over the first five years of activity (October 2016 to December 2021), reviewing genetics, family history, clinical features, complications, and therapeutic strategies for NF1 and TSC. Results: The clinic works weekly with a core team of pediatricians and pediatric neurologists supported by other specialties as needed. Of the 281 patients enrolled, 224 (79.7%) had identifiable syndromes such as NF1 (n = 105), TSC (n = 35), hypomelanosis of Ito (n = 11), Sturge-Weber syndrome (n = 5), and others. In NF1 patients, 41.0% had a positive family history, all manifested café-au-lait macules, 38.1% neurofibromas with 45.0% being large plexiform neurofibromas. Sixteen were under treatment with selumetinib. Genetic testing was performed in 82.9% of TSC patients with pathogenic variants found in TSC2 gene in 72.4% patients (82.7% if considered contiguous gene syndrome). Family history was positive in 31.4%. All TSC patients presented hypomelanotic macules and fulfilled diagnostic criteria. Fourteen patients were being treated with mTOR inhibitors. Conclusion: Offering a systematic and multidisciplinary approach to NCS patients enables timely diagnosis, promotes a structured follow-up, and encourages discussion to outline management plans for optimal care to every patient, with significant impact on the quality of life of patients and families.
- Associations of longitudinal Height and Weight with Clinical Outcomes in Pediatric Kidney Replacement Therapy: Results from the ESPN/ERA RegistryPublication . Bonthuis, M; Bakkaloglu, SA; Vidal, E; Baiko, S; Braddon, F; Errichiello, C; Francisco, T; Haffner, D; Lahoche, A; Leszczyńska, B; Masalkiene, J; Stojanovic, J; Molchanova, MS; Reusz, G; Barba, AR; Rosales, A; Tegeltija, S; Ylinen, E; Zlatanova, G; Harambat, J; Jager, KJBackground: Associations between anthropometric measures and patient outcomes in children are inconsistent and mainly based on data at kidney replacement therapy (KRT) initiation. We studied associations of height and body mass index (BMI) with access to kidney transplantation, graft failure, and death during childhood KRT. Methods: We included patients < 20 years starting KRT in 33 European countries from 1995-2019 with height and weight data recorded to the ESPN/ERA Registry. We defined short stature as height standard deviation scores (SDS) < -1.88 and tall stature as height SDS > 1.88. Underweight, overweight and obesity were calculated using age and sex-specific BMI for height-age criteria. Associations with outcomes were assessed using multivariable Cox models with time-dependent covariates. Results: We included 11,873 patients. Likelihood of transplantation was lower for short (aHR: 0.82, 95% CI: 0.78-0.86), tall (aHR: 0.65, 95% CI: 0.56-0.75), and underweight patients (aHR: 0.79, 95%CI: 0.71-0.87). Compared with normal height, patients with short and tall statures showed higher graft failure risk. All-cause mortality risk was higher in short (aHR: 2.30, 95% CI: 1.92-2.74), but not in tall stature. Underweight (aHR: 1.76, 95% CI: 1.38-2.23) and obese (aHR: 1.49, 95% CI: 1.11-1.99) patients showed higher all-cause mortality risk than normal weight subjects. Conclusions: Short and tall stature and being underweight were associated with a lower likelihood of receiving a kidney allograft. Mortality risk was higher among pediatric KRT patients with a short stature or those being underweight or obese. Our results highlight the need for careful nutritional management and multidisciplinary approach for these patients. A higher resolution version of the Graphical abstract is available as Supplementary information.
- Hypertension As an Atypical Presentation of Unilateral Ureteral ObstructionPublication . Mantas, P; Baeta Baptista, R; Santos, R; Serrão, APUreteral obstruction (ureteropelvic or ureterovesical junction obstruction) is frequently diagnosed during the workup investigation of an asymptomatic infant or child with upper urinary tract dilatation, commonly identified in a prenatal ultrasound. In older children, recurrent lumbar pain is a red flag for ureteral obstruction. Although less frequent, hypertension may be the initial and only manifestation of ureteral obstruction. The authors present two pediatric cases of unilateral ureteral obstruction with hypertension, in which the surgical treatment of the obstruction leads to blood pressure normalisation. In all pediatric age groups, a systematic investigation for secondary causes of hypertension is of paramount importance. In some cases, especially those of an obstructive nature, early surgical management can be curative, with normalization of blood pressure levels and prevention of renal injury.
- X-linked Hypophosphatemic Rickets: a New MutationPublication . Maio, P; Mano, L; Rocha, S; Baeta Baptista, R; Francisco, T; Sousa, H; Parente Freixo, J; Abranches, MPhosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient's outcome. Genetic analysis can help to establish a genotype-phenotype correlation.
- Aetiology, Course and Treatment of Acute Tubulointerstitial Nephritis in Paediatric Patients: a Cross-Sectional Web-Based SurveyPublication . Wente-Schulz, S; Aksenova, M; Awan, A; Ambarsari, CG; Becherucci, F; Emma, F; Fila, M; Francisco, T; Gokce, I; Gülhan, B; Hansen, M; Jahnukainen, T; Kallash, M; Kamperis, K; Mason, S; Mastrangelo, A; Mencarelli, F; Niwinska-Faryna, B; Riordan, M; Rus, RR; Saygili, S; Serdaroglu, E; Taner, S; Topaloglu, R; Vidal, E; Woroniecki, R; Yel, S; Zieg, J; Pape, Lackground: Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. Patients, design and setting: We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. Results: Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil. Conclusions: Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.
- Primary Hyperoxaluria type 1 – Two Case ReportsPublication . Ganhão, I; Borges, C; Amorim, M; Braga da Cruz, M; Nobre, S; Francisco, T; Cardoso, D; Abranches, MPrimary hyperoxaluria type 1 is a rare autosomal recessive inherited disease, caused by mutations in AGXT gene, with an estimated incidence of 1:100.000 live births per year in Europe. Over 50% present with end stage renal disease at diagnosis. Case reports: The first case is a 14‑year‑old boy, second child to consanguineous parents, with history of recurrent lithiasis and ureteral dilatation starting 5 years before. Urine/stone analysis revealed calcium oxalate monohydrate crystals and markedly elevated urine oxalate excretion. Genetic tests confirmed a mutation in AGXT gene, c.1151T>C, in homozygosity. Two years after, nephrocalcinosis was identified and glomerular filtration rate gradually declined. Oxalate deposition in solid organs was excluded and successful orthotopic liver transplantation was performed, with stabilization of glomerular filtration rate. The second case is a 16‑year‑old girl, with recurrent episodes of renal colic. At diagnosis, she had obstructive hydronephrosis, multiple kidney stones and an estimated glomerular filtration of 42.1mL/min/1.73m2. Metabolic study showed hypocitraturia and hyperoxaluria. With dietetic measures and irregular treatment, urine oxalate excretion remained high but renal function improved. Genetic tests confirmed the presence of two pathologic variants in AGXT gene: c.731T>C and c.1151T>C in compound heterozygous. Conclusions: Recurrent urolithiasis and nephrocalcinosis in children along with family history/consanguinity should raise the suspicion of Primary Hyperoxaluria type 1. Conservative treatment may increase renal survival. Effects of systemic oxalosis must be screened when glomerular filtration rate declines below 30‑50mL/ min/1.73m2, and sequential or combined liver and kidney transplantation should be considered.
- Portuguese Consensus Document Statement in Diagnostic and Management of Atypical Hemolytic Uremic SyndromePublication . Azevedo, A; Faria, B; Teixeira, C; Carvalho, F; Neto, G; Santos, J; Santos, MC; Oliveira, N; Fidalgo, T; Calado, JAmong thrombotic microangiopathies (TMA), the hemolytic uremic syndrome associated with dysregulation of the alternative complement pathway (aHUS) is one of the most challenging diseases a nephrologist can face. By the end of the XXth century, the complement’s role was unraveled with the discovery that mutations in the factor H coding gene were responsible for aHUS. But it was the acknowledgment that pharmacological C5-9 blockage provided a cure for aHUS that fostered the interest of the nephrology community in the genetics, pathophysiology and therapeutics of, not only of aHUS, but TMA in general. The molecular genetics of aHUS is technically demanding and, as such, in Portugal (alike many other European countries) a single laboratory emerged as a national reference center. The fact that all samples are evaluated in a single center provides a unique opportunity for data collection and a forum for discussion for all those interested in the field: immunologists, molecular geneticists, pathologists and nephrologists. The current consensus document emerged from such a discussion forum and was sponsored by the Portuguese Society of Nephrology. The goal is more to portray the Portuguese picture regarding the diagnostic approach and therapeutic options than to extensively review the state of the art of the subject. The accompanying documents that are published as supplementary data are in line with that goal. They range from the informed consent and clinical form to be sent together with the biological samples for genetic testing, to the appendix regarding the actual sampling and storing conditions. The document is also intended to set an example for future documents and independent discussion forums on other kidney diseases for which emerging diagnostic and/or therapeutic strategies are reaching clinical practice.
- Coexistence of Pheochromocytoma and Renal Artery Stenosis in a Pediatric Patient with HypertensionPublication . Serras, I; Baeta Baptista, R; Francisco, T; Casimiro, A; Lito, D; Alves, R; Abranches, MPheochromocytoma and renal artery stenosis are surgically treatable causes of hypertension. Although rare, the coexistence of pheochromocytoma and renal artery stenosis has been described in case reports. Common pathophysiological mechanisms other than extrinsic compression may be involved in this association, such as catecholamine-induced vasospasm. The early recognition of the association of pheochromocytoma with renal artery stenosis is essential for appropriate treatment planning. We present the case of a previously healthy tenyear- old boy who presented with hypertensive encephalopathy, tachycardia and diaphoresis. Hypertension was found to be secondary to a catecholamine-producing tumor associated with coexisting renal artery stenosis. Hypertension resolved a few months after successful pheochromocytoma excision, without renal artery revascularization.
- Nephrolithiasis in a Portuguese Pediatric PopulationPublication . Andrade, J; Bota, S; Francisco, T; Santos, R; Neto, G; Abranches, MIntroduction and Aims: Nephrolithiasis incidence in children has increased considerably. It is associated with substantial morbidity, recurrence and increased adulthood cardiovascular risk and chronic kidney disease. A thorough investigation is essential, as rare forms of urolithiasis have increased risk of renal failure. We aim to determine the epidemiology and outcomes of a pediatric population with nephrolithiasis presented in a nephrology unit of a tertiary centre. Methods: Retrospective study of the records of all children (<18 years) with nephrolithiasis diagnosis between 2008‑17. Clinical features, etiology, recurrence, treatment, and outcomes were evaluated and compared throughout the study period through two equal periods (2008‑12 versus 2013‑17). Results: We identified 80 cases: isolated nephrolithiasis (86%) and associated with nephrocalcinosis (14%). Mean follow‑up was 36 months (14–120). Median age at presentation was 8.6 years [3 months – 17 years]: 21% < 2 years‑old and 46% ≥ 10 years. The annual ratio of referrals for nephrolithiasis increased on average 1.2% per year [0.3‑11.8%]. Multiple etiological factors were present in 34%. A metabolic abnormality was identified in 54%: hypocitraturia (34%), hypercalcuria (24%), hyperoxaluria (15%), hyperuricosuria (15%) and cystinuria (1%), without age predominance (p=0.2). Urinary tract infection (24%) was the next most significant etiology and was more frequent below 2 years of age (p=0.001) and associated with struvite calculi (p=0.033). Median age at diagnosis was significantly lower in the study’s first half (5 vs 10 years; p=0.019) and an infectious etiology was more frequent (p=0.043). In a logistic‑regression analysis, a family history of nephrolithiasis was associated with a metabolic cause (p<0.01). Sixty‑three percent became stone free and 24% had recurrence. Discussion: Nephrolithiasis new referrals gradually increased throughout the study period. The most common etiology was metabolic, which is usually responsible for nephrolithiasis appearance and its recurrence, emphasizing the need for a complete evaluation.
- LAMA2 Gene Analysis in a Cohort of 26 Congenital Muscular Dystrophy PatientsPublication . Oliveira, J; Santos, R; Soares-Silva, I; Jorge, P; Vieira, E; Oliveira, ME; Moreira, A; Coelho, T; Ferreira, JC; Fonseca, MJ; Barbosa, C; Prats, J; Aríztegui, ML; Martins, ML; Moreno, T; Heinimann, K; Barbot, C; Pascual-Pascual, SI; Cabral, A; Fineza, I; Santos, M; Bronze-da-Rocha, ECongenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-alpha2. We describe the molecular study of 26 patients with clinical presentation, magnetic resonance imaging and/or laminin-alpha2 expression in muscle, compatible with MDC1A. The combination of full genomic sequencing and complementary DNA analysis led to the particularly high mutation detection rate of 96% (50/52 disease alleles). Besides 22 undocumented polymorphisms, 18 different mutations were identified in the course of this work, 14 of which were novel. In particular, we describe the first fully characterized gross deletion in the LAMA2 gene, encompassing exon 56 (c.7750-1713_7899-2153del), detected in 31% of the patients. The only two missense mutations detected were found in heterozygosity with nonsense or truncating mutations in the two patients with the milder clinical presentation and a partial reduction in muscle laminin-alpha2. Our results corroborate the previous few genotype/phenotype correlations in MDC1A and illustrate the importance of screening for gross rearrangements in the LAMA2 gene, which may be underestimated in the literature.
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