This Research Topic highlights high-quality case reports in Pediatric Nephrology related to advancing research in pediatric nephrology and disseminating relevant clinical information to improve the care of children with kidney disease. Our case reports aim to highlight unique cases of patients that present with an unexpected/unusual diagnosis, treatment outcome, or clinical course. Case reports provide insight into the differential diagnosis, decision making, and clinical management of unusual cases and are a valuable educational tool. This Research Topic will only accept Case Report submissions, reports must be original with the aim to significantly advance the field to be considered. All Case Reports should contain “Case Report" in the title to be considered for this Research Topic. We welcome all case reports covering aspects of Pediatric Nephrology.

Sant'Orsola-Malpighi Polyclinic

Uncovering new perspectives on pediatric nephrology through remarkable case studies.

This research topic focuses on the various causes of kidney diseases in children, and the importance of genetic counseling in providing accurate diagnosis and treatment. Highlights include: <ul> <li>Fungal infections are a common cause of hypercalcemia in pediatric kidney transplant recipients, and histoplasmosis should be considered in the differential diagnosis.</li> <li>Whole-genome sequencing was used to identify a novel deep intronic COL4A5 variant in a Chinese family with X-linked Alport Syndrome.</li> <li>Biallelic LAMA5 variants have been proven to cause steroid-resistant nephrotic syndrome in pediatric cases.</li> <li>Lesch–Nyhan disease is a rare X-linked recessive disorder caused by mutations of the HPRT1 gene.</li> <li>Classical Congenital Mesoblastic Nephroma is a rare renal tumour in children, with a good postnatal outcome.</li> </ul>

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Frontiers in Pediatrics

Pediatric Nephrology

Frontiers in Nephrology

Case Reports in Pediatric Nephrology 2022

Among all infections occurring in pediatric kidney transplant recipients, approximately 1%–5% are fungal. Most fungal infections occur in the first 6 months following kidney transplantation. We present the case of a 15-year-old boy with a history of a kidney transplant 4 years ago, who was found to have asymptomatic moderate hypercalcemia on routine laboratory testing, along with an acute deterioration of his kidney function markers. The cause of his acute kidney injury was likely related to hypercalcemia. An extensive workup for hypercalcemia revealed infection with Histoplasma capsulatum (histoplasmosis) with multiple pulmonary nodules. Hypercalcemia that was initially refractory to medical management resolved after initiating the antifungal treatment. Fungal granulomatous infections such as histoplasmosis should be considered in the differential diagnosis of hypercalcemia in an asymptomatic pediatric kidney transplant recipient.

Among all infections occurring in pediatric kidney transplant recipients, approximately 1%–5% are fungal. Most fungal infections occur in the first 6 months following kidney transplantation. We present the case of a 15-year-old boy with a history of a kidney transplant 4 years ago, who was found to have asymptomatic moderate hypercalcemia on routine laboratory testing, along with an acute deterioration of his kidney function markers. The cause of his acute kidney injury was likely related to hypercalcemia. An extensive workup for hypercalcemia revealed infection with Histoplasma capsulatum (histoplasmosis) with multiple pulmonary nodules. Hypercalcemia that was initially refractory to medical management resolved after initiating the antifungal treatment. Fungal granulomatous infections such as histoplasmosis should be considered in the differential diagnosis of hypercalcemia in an asymptomatic pediatric kidney transplant recipient.

Case report: Histoplasmosis presenting as asymptomatic hypercalcemia detected on routine laboratory testing in a pediatric kidney transplant recipient

BackgroundX-linked Alport syndrome (XLAS) is caused by pathogenic variants in COL4A5 and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities.The aim of this study was to identify gene mutations in a Chinese family with XLAS, confirm a diagnosis, and provide an accurate genetic counseling.</sec>MethodsThe proband was a 5-year-old male with microscopic hematuria and a family history of renal disease in 5 relatives.His relatives had microhematuria with or without proteinuria. His maternal uncle developed renal failure at the age of 35 years. He was evaluated by renal biopsy,whole-exome sequencing (WES) and whole-genome sequencing (WGS) for Alport syndrome. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from the skin of the proband. Then, a splicing reporter minigene assay was used to examine the effect of the variation on the splicing of the primary transcript in transfected cells.</sec>ResultsPathological examination of the kidney of the proband revealed diffuse thinning of the glomerular basement membrane, and immunofluorescence analysis indicated normal expression of the α5 chain in the basement membrane. No phenotype-associated candidate variant was detected in the proband via WES. A novel deep intronic COL4A5 variant (c.385–716G > A), which is segregated with disease in this family, was identified using WGS. In-vitro minigene assay and in-vivo RT-PCR analysis demonstrated that the variant could produce both normal and abnormal transcripts. The abnormal transcripts showed that the variant activated a cryptic splice site, introducing a 147 bp pseudoexon into the mRNA sequence and consequently generating a premature termination codon (p.G129Afs*38) and leading to frameshifting and truncation of the α5 (collagen IV) protein.</sec>ConclusionThis is the first report of the novel c.385–716G > A splicing mutation in the COL4A5 gene, which illustrates the importance of performing WGS to find additional mutations in WES-negative patients with highly suspected forms of genetic diseases. The same results obtained from the in-vitro and in-vivo splicing experiments confirm the consistency between the minigene assay and RT-PCR analysis. In addition, this study highlights the importance of functional analysis in diagnosis and genetic counseling in AS.</sec>

Background: X-linked Alport syndrome (XLAS) is caused by pathogenic variants in COL4A5 and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities.The aim of this study was to identify gene mutations in a Chinese family with XLAS, confirm a diagnosis, and provide an accurate genetic counseling.Methods: The proband was a 5-year-old male with microscopic hematuria and a family history of renal disease in 5 relatives.His relatives had microhematuria with or without proteinuria. His maternal uncle developed renal failure at the age of 35 years. He was evaluated by renal biopsy,whole-exome sequencing (WES) and whole-genome sequencing (WGS) for Alport syndrome. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from the skin of the proband. Then, a splicing reporter minigene assay was used to examine the effect of the variation on the splicing of the primary transcript in transfected cells.Results: Pathological examination of the kidney of the proband revealed diffuse thinning of the glomerular basement membrane, and immunofluorescence analysis indicated normal expression of the α5 chain in the basement membrane. No phenotype-associated candidate variant was detected in the proband via WES. A novel deep intronic COL4A5 variant (c.385–716G &gt; A), which is segregated with disease in this family, was identified using WGS. In-vitro minigene assay and in-vivo RT-PCR analysis demonstrated that the variant could produce both normal and abnormal transcripts. The abnormal transcripts showed that the variant activated a cryptic splice site, introducing a 147 bp pseudoexon into the mRNA sequence and consequently generating a premature termination codon (p.G129Afs*38) and leading to frameshifting and truncation of the α5 (collagen IV) protein.Conclusion: This is the first report of the novel c.385–716G &gt; A splicing mutation in the COL4A5 gene, which illustrates the importance of performing WGS to find additional mutations in WES-negative patients with highly suspected forms of genetic diseases. The same results obtained from the in-vitro and in-vivo splicing experiments confirm the consistency between the minigene assay and RT-PCR analysis. In addition, this study highlights the importance of functional analysis in diagnosis and genetic counseling in AS.

A deep intronic splice variant of the COL4A5 gene in a Chinese family with X-linked Alport syndrome

Single gene pathogenic mutations have been implicated in up to 30% of pediatric steroid-resistant nephrotic syndrome (SRNS) cases, mostly in infantile patients. Among them is LAMA5, which has been recently discovered and encodes the laminin α5 chain. The laminin α5β2γ1 heterotrimer is an essential component of the glomerular basement membrane and is necessary for embryogenesis and immune modulation. Biallelic LAMA5 variants have been identified in one adult and ten pediatric nephrotic syndromes (NS) patients with variable phenotypes. Biallelic truncating mutations in this gene have recently been proven to cause SRNS. Here, we present another case of infantile SRNS related to novel compound heterozygous variations of LAMA5 (c.3434G > A, p.Cys1145Tyr and c.6883C > T, p.Gln2295*), the first reported case with one missense and one nonsense allele. A 10-month-old female patient presented with eyelid edema and massive proteinuria without any extrarenal symptoms or family history. The patient was diagnosed with SRNS. Renal biopsy revealed focal segmental glomerulosclerosis with widely effaced epithelial foot processes and a “moth-eaten” appearance. She progressed to end stage kidney disease (ESKD), requiring dialysis at 31 months of age, and underwent a deceased-donor kidney transplant at 6 years of age. Four months after transplantation, she developed Ebstein-Barr Virus (EBV) infection related to post-transplantation lymphoproliferative disorder (PTLD). After chemotherapy, the patient remained healthy with adequate renal function without disease recurrence for the past 7 years. We also identified previous cases of biallelic LAMA5 variants associated with the nephrotic phenotype and analyzed the available clinical and genetic information. All reported patients had an onset of NS ranging from 3 months to 8 years, with no other syndromic features. Response to therapy and renal outcomes varied greatly; most patients exhibited steroid resistance, five progressed to ESKD, and two received kidney transplantation (KT). There was one report of PTLD. Our patient’s phenotype was markedly more severe than those with biallelic missense variants and somewhat less severe than those with two truncating variants. LAMA5 defects may also play a role in PTLD, though no conclusions can be made with such limited cases. LAMA5 should be considered a candidate gene for SRNS and should be actively tested in cases with no other genetic diagnosis.

Single gene pathogenic mutations have been implicated in up to 30% of pediatric steroid-resistant nephrotic syndrome (SRNS) cases, mostly in infantile patients. Among them is LAMA5, which has been recently discovered and encodes the laminin α5 chain. The laminin α5β2γ1 heterotrimer is an essential component of the glomerular basement membrane and is necessary for embryogenesis and immune modulation. Biallelic LAMA5 variants have been identified in one adult and ten pediatric nephrotic syndromes (NS) patients with variable phenotypes. Biallelic truncating mutations in this gene have recently been proven to cause SRNS. Here, we present another case of infantile SRNS related to novel compound heterozygous variations of LAMA5 (c.3434G &gt; A, p.Cys1145Tyr and c.6883C &gt; T, p.Gln2295*), the first reported case with one missense and one nonsense allele. A 10-month-old female patient presented with eyelid edema and massive proteinuria without any extrarenal symptoms or family history. The patient was diagnosed with SRNS. Renal biopsy revealed focal segmental glomerulosclerosis with widely effaced epithelial foot processes and a “moth-eaten” appearance. She progressed to end stage kidney disease (ESKD), requiring dialysis at 31 months of age, and underwent a deceased-donor kidney transplant at 6 years of age. Four months after transplantation, she developed Ebstein-Barr Virus (EBV) infection related to post-transplantation lymphoproliferative disorder (PTLD). After chemotherapy, the patient remained healthy with adequate renal function without disease recurrence for the past 7 years. We also identified previous cases of biallelic LAMA5 variants associated with the nephrotic phenotype and analyzed the available clinical and genetic information. All reported patients had an onset of NS ranging from 3 months to 8 years, with no other syndromic features. Response to therapy and renal outcomes varied greatly; most patients exhibited steroid resistance, five progressed to ESKD, and two received kidney transplantation (KT). There was one report of PTLD. Our patient’s phenotype was markedly more severe than those with biallelic missense variants and somewhat less severe than those with two truncating variants. LAMA5 defects may also play a role in PTLD, though no conclusions can be made with such limited cases. LAMA5 should be considered a candidate gene for SRNS and should be actively tested in cases with no other genetic diagnosis.

Case report: Genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome

Lesch–Nyhan disease (LND) is a rare X-linked recessive disease caused by pathogenic mutations of the HPRT1 gene. The typical clinical manifestations include cerebral palsy, intellectual disability, dysarthria, self-injurious behavior, and gouty arthritis in children. This report describes a Chinese boy aged 2 months and 7 days with a significantly elevated uric acid concentration accompanied by renal dysfunction and, notably, brain imaging changes. Whole-exome sequencing revealed a hemizygous mutation of HPRT1 in nucleotide 508 from cytosine to thymine (c.508C > T), resulting in a nonsense mutation (p.R170X). The incidence of LND is extremely low in China, and hyperuricemia is a common clinical manifestation. Therefore, the possibility of LND should be considered in children with increased uric acid in infancy accompanied by brain imaging changes or neurological dysfunction. Moreover, genetic testing is needed to provide adequate genetic counseling to the family, and should be conducted as early as possible in such children to avoid misdiagnosis or delayed diagnosis.

Lesch–Nyhan disease (LND) is a rare X-linked recessive disease caused by pathogenic mutations of the HPRT1 gene. The typical clinical manifestations include cerebral palsy, intellectual disability, dysarthria, self-injurious behavior, and gouty arthritis in children. This report describes a Chinese boy aged 2 months and 7 days with a significantly elevated uric acid concentration accompanied by renal dysfunction and, notably, brain imaging changes. Whole-exome sequencing revealed a hemizygous mutation of HPRT1 in nucleotide 508 from cytosine to thymine (c.508C &gt; T), resulting in a nonsense mutation (p.R170X). The incidence of LND is extremely low in China, and hyperuricemia is a common clinical manifestation. Therefore, the possibility of LND should be considered in children with increased uric acid in infancy accompanied by brain imaging changes or neurological dysfunction. Moreover, genetic testing is needed to provide adequate genetic counseling to the family, and should be conducted as early as possible in such children to avoid misdiagnosis or delayed diagnosis.

Case report: Early-onset renal failure as presenting sign of Lesch-Nyhan disease in infancy

BackgroundCongenital mesoblastic nephroma (CMN) is a rare renal tumour in children, the most common kidney tumour in the neonatal period. It can be divided into three types, classical, cellular and mixed.</sec>Case presentationA 31-year-old Chinese woman had no apparent foetal abnormality in regular prenatal care during the first and second trimesters. At 33 weeks of gestation, a solid mass in the right kidney was noted with echoes similar to liver and hypervascularity. It grew larger during late pregnancy. The infant was transferred to have a radical nephrectomy on the 9th day after birth. The postoperative histopathological result indicated classical CMN.</sec>ConclusionCMN could be detected prenatally, mainly during late pregnancy. The postnatal outcome is good.</sec>

Background: Congenital mesoblastic nephroma (CMN) is a rare renal tumour in children, the most common kidney tumour in the neonatal period. It can be divided into three types, classical, cellular and mixed.Case presentation: A 31-year-old Chinese woman had no apparent foetal abnormality in regular prenatal care during the first and second trimesters. At 33 weeks of gestation, a solid mass in the right kidney was noted with echoes similar to liver and hypervascularity. It grew larger during late pregnancy. The infant was transferred to have a radical nephrectomy on the 9th day after birth. The postoperative histopathological result indicated classical CMN.Conclusion: CMN could be detected prenatally, mainly during late pregnancy. The postnatal outcome is good.