Importance about use of high-throughput sequencing in pediatric: case report of a patient with Fanconi-Bickel syndrome.

BACKGROUND: Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male patient of 2 years 7 months old, with failure to thrive, hepatomegaly, metabolic acidosis, hypophosphatemia, hypokalemia, hyperlactatemia. RESULTS: Exome sequencing identified the homozygous pathogenic variant NM_000340.2(SLC2A2):c.1093 C > T (p.Arg365Ter), related with Fanconi-Bickel syndrome. He received treatment with bicarbonate, amlodipine, sodium citrate and citric acid solution, enalapril, alendronate and zolendronate, and nutritional management with uncooked cornstarch, resulting in an improvement of one standard deviation in weight and height. CONCLUSIONS: The importance of knowing the etiology in rare genetic disease is essential, not only to determine individual and familial recurrence risk, but also to establish the treatment and prognosis; in this sense, access to a new genomic technology in low- and middle-income countries is essential to shorten the diagnostic odyssey.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome.

BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. METHODS: Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. RESULTS: Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. CONCLUSIONS: Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI.

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.

Pattern of hereditary renal tubular disorders in Egyptian children.

BACKGROUND: Hereditary renal tubular disorders (HRTD) represent a group of genetic diseases characterized by disturbances in fluid, electrolyte, and acid-base homeostasis. There is a paucity of studies on pediatric HRTD in Egypt. In this study, we aimed to study the pattern, characteristics, and growth outcome of HRTD at an Egyptian medical center. METHODS: This study included children from one month to < 18-years of age with HRTD who were diagnosed and followed up at the Pediatric Nephrology Unit of Sohag University Hospital from January 2015 to December 2021. Data on patients` demographics, clinical features, growth profiles, and laboratory characteristics were collected. RESULTS: Fifty-eight children (57% males; 72% parental consanguinity; 60% positive family history) were diagnosed with seven HRTD types. The most commonly encountered disorders were distal renal tubular acidosis (distal renal tubular acidosis [RTA] 27 cases, 46.6%) and Bartter syndrome (16 cases 27.6%). Other identified disorders were Fanconi syndrome (6 cases with cystinosis), isolated proximal RTA (4 cases), nephrogenic diabetes insipidus (3 cases), and one case for each RTA type IV and Gitelman syndrome. The median age at diagnosis was 17 months with a variable diagnostic delay. The most common presenting features were failure to thrive (91.4%), developmental delay (79.3%), and dehydration episodes (72.4%). Most children showed marked improvement in growth parameters in response to appropriate management, except for cases with Fanconi syndrome. Last, only one case (with cystinosis) developed end-stage kidney disease. CONCLUSIONS: HRTD (most commonly distal RTA and Bartter syndrome) could be relatively common among Egyptian children, and the diagnosis seems challenging and often delayed.

Association of Familial Fanconi Syndrome with a Novel GATM Variant.

Fanconi syndrome is a disorder of the proximal renal tubule. Recently, advanced genetic analysis technology has revealed that several genes cause familial Fanconi syndrome. We identified a family with autosomal dominant Fanconi syndrome and chronic kidney disease with a novel glycine amidinotransferase (GATM) variant. Case 1 was a 57-year-old Japanese woman. Her father and two siblings had Fanconi syndrome or chronic kidney disease. She presented to our hospital at the age of 34 years with recurrent glucosuria. Her height and weight were 151 cm and 46.6 kg, respectively. Laboratory tests showed glucosuria, hypophosphatemia, hypouricemia, and normal renal function. Her serum creatinine level gradually increased over the following next two decades, and she developed end-stage renal disease. Case 2, the daughter of Case 1, was a 26-year-old woman. Her height and weight were 151 cm and 37.5 kg, respectively. Glucosuria was detected at the age of 13 years, which led to a referral to our hospital. Urinalysis showed low-molecular-weight proteinuria. She was diagnosed with Fanconi syndrome. At the age of 26 years, she had glucosuria, low-molecular-weight proteinuria, hypouricemia, and normal renal function. Genetic testing of both cases revealed a novel missense variant in GATM. The heterozygous missense variants in GATM have been reported to cause familial Fanconi syndrome, which manifests early in life and progresses to renal glomerular failure by mid-adulthood. The novel GATM variant detected in our cases was suspected to be associated with the development of Fanconi syndrome. GATM variants should be tested in patients with idiopathic Fanconi syndrome.

Combined Alport syndrome, Klinefelter syndrome and Fanconi syndrome in a Chinese boy.

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation.

Inherited Fanconi syndrome.

BACKGROUND: Fanconi-Debré-de Toni syndrome (also known as Fanconi renotubular syndrome, or FRST) profoundly increased the understanding of the functions of the proximal convoluted tubule (PCT) and provided important insights into the pathophysiology of several kidney diseases and drug toxicities. DATA SOURCES: We searched Pubmed and Scopus databases to find relevant articles about FRST. This review article focuses on the physiology of the PCT, as well as on the physiopathology of FRST in children, its diagnosis, and treatment. RESULTS: FRST encompasses a wide variety of inherited and acquired PCT alterations that lead to impairment of PCT reabsorption. In children, FRST often presents as a secondary feature of systemic disorders that impair energy supply, such as Lowe's syndrome, Dent's disease, cystinosis, hereditary fructose intolerance, galactosemia, tyrosinemia, Alport syndrome, and Wilson's disease. Although rare, congenital causes of FRST greatly impact the morbidity and mortality of patients and impose diagnostic challenges. Furthermore, its treatment is diverse and considers the ability of the clinician to identify the correct etiology of the disease. CONCLUSION: The early diagnosis and treatment of pediatric patients with FRST improve the prognosis and the quality of life.

Clinical and genetic characteristics of Tunisian children with infantile nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is an autosomal recessive disease caused by a mutation in the CTNS gene which encodes cystinosin, a lysosomal cystine transporter. The spectrum of mutations in the CTNS gene is not well defined in the North African population. Here, we investigated twelve patients with nephropathic cystinosis belonging to eight Tunisian families in order to analyze the clinical and genetic characteristics of Tunisian children with infantile nephropathic cystinosis. METHODS: Clinical data were collected retrospectively. Molecular analysis of the CTNS gene was performed by Sanger sequencing. RESULTS: We describe a new splicing mutation c.971-1G > C in the homozygous state in 6/12 patients which seems to be a founder mutation. The reported deletion of 23nt c.771_793 Del (p.Gly258Serfs*30) was detected in a homozygous state in one patient and in a heterozygous compound state with the c.971-1G > C mutation in 3/12 patients. Two of 12 patients have a deletion of exons 4 and 5 of the CTNS gene. None of our patients had the most common 57-kb deletion. CONCLUSIONS: The mutational spectrum in the Tunisian population is different from previously described populations. Thus, a molecular diagnostic strategy must be implemented in Tunisia, by targeting as a priority the common mutations described in this country. Such a strategy will allow a cost-effective diagnosis confirmation as well as early administration of treatment with oral cysteamine. A higher resolution version of the Graphical abstract is available as Supplementary information.

A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease.

Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.

Outcome of infantile nephropathic cystinosis depends on early intervention, not genotype: A multicenter sibling cohort study.

Infantile nephropathic cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease, and multiple extrarenal complications (ERCs). Cysteamine postpones the onset of end-stage kidney disease (ESKD) and reduces the incidence of ERCs; however, cysteamine is generally initiated upon establishment of the renal Fanconi syndrome (FS) and partial loss of kidney function, whereas data on long-term effects of cysteamine administered from neonatal age are lacking. An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age. None of the siblings treated from neonatal age (n = 9; age 10 ± 6 years) had reached ESKD, while 22% of their index counterparts (n = 9; age 14 ± 5 years) had commenced renal replacement therapy. Siblings treated with cysteamine from the onset of symptoms at a younger age compared with their index counterparts, reached ESKD at a significant older age (13 ± 3 vs. 10 ± 3 years, p = 0.002). In contrast, no significant difference in ERCs was observed between sibling and index patients, independently from the age at initiation of cysteamine. The CTNS genotype had no impact on the overall outcome in this cohort. In INC, presymptomatic treatment with cysteamine results in a better renal outcome in comparison to treatment initiated from the onset of symptoms. This justifies including cystinosis into newborn screening programs. SYNOPSIS: In infantile nephropathic cystinosis, presymptomatic treatment with cysteamine improves the renal outcome which justifies the inclusion of cystinosis into newborn screening programs.

Clinical Features and Genetic Sequencing of Children with Fanconi-Bickel Syndrome.

The present paper reports 10 patients (9 families) with Fanconi-Bickel syndrome managed during 2010-2021. Patients presented with polyuria, polydipsia, hepatomegaly, rickets, and stunting at a median of 5 (3, 7.3) mo; one had transient neonatal diabetes. Glucosuria, generalized aminoaciduria, ß2-microglobinuria, urinary phosphate wasting, and hypercalciuria were present in all patients; 3 patients had nephrocalcinosis. Other metabolic abnormalities included hypertriglyceridemia (n = 5/6), fasting hypoglycemia (n = 5/8), and postprandial hyperglycemia (n = 3/6). Genetic analysis showed 7 homozygous or compound heterozygous variants in SLC2A2. A pathogenic variant c.952G>A, common to 4 patients (3 families), might be a potential hotspot. At a median follow-up of 43 mo, 4 patients died at a median of 25 mo; short stature persisted in all except one patient who showed catch-up growth with uncooked corn-starch diet. The present findings suggest that the Fanconi-Bickel syndrome has a severe phenotype with an unsatisfactory outcome. A high index of suspicion for diagnosis and efforts for facilitation of dietary therapy are necessary.

Nephropathic cystinosis in Poland: a 40-year retrospective study.

INTRODUCTION: Nephropathic cystinosis (NC) is a rare, autosomal recessive disorder leading to lysosomal accumulation of cystine. It is caused by mutations in the CTNS gene encoding a cystine cotransporter cystinosin. The infantile (INC) and juvenile (JNC) forms are distinguished. The former, responsible for 95% of cases, is characterized by development of renal Fanconi syndrome, end-stage kidney disease (ESKD), and extrarenal complications. A therapy with cysteamine significantly improves outcomes. There are limited data on NC in the Central Eastern European countries. OBJECTIVES: We aimed to evaluate the prevalence, genetic background, and clinical course of NC in the Polish population. PATIENTS AND METHODS: We performed a retrospective analysis of data of all identified NC patients in Poland. RESULTS: Between 1982 and 2017, 15 patients with NC (13 ICN, 2 JCN) were identified. The most common mutations of the CTNS gene were c.18_c.21delGACT and c.681+1G>A, whereas only 2 patients carried the 57 kb deletion. The majority (11/13) of INC patients with limited access to the cysteamine therapy developed ESKD at a median age of 11 years and 9 of them received kidney transplants. Three INC patients died at a median age of 24 years. In contrast, 2 INC patients treated adequately present normal kidney function and growth at the age of 13 and 11 years. Two JNC patients presented a milder course. CONCLUSIONS: The prevalence of NC in Poland is much lower than in the Western countries and its molecular background appears to be different. The unfavorable course in the majority of INC patients was caused by a limited access to the cysteamine treatment.

Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient.

Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the liver and kidney. It is inherited as an autosomal recessive disorder caused by mutations in the SLC2A2 gene, which encodes for GLUT2. Patients with FBS have dysglycemia but the molecular mechanisms of dysglycemia are still not clearly understood. Therefore, we aimed to understand the underlying molecular mechanisms of dysglycemia in a patient with FBS. Genomic DNA was isolated from a peripheral blood sample and analyzed by whole genome and Sanger sequencing. CRISPR-Cas9 was used to introduce a mutation that mimics the patient's mutation in a human kidney cell line expressing GLUT2 (HEK293T). Mutant cells were used for molecular analysis to investigate the effects of the mutation on the expression and function of GLUT2, as well as the expression of other genes implicated in dysglycemia. The patient was found to have a homozygous nonsense mutation (c.901C>T, R301X) in the SLC2A2 gene. CRISPR-Cas9 successfully mimicked the patient's mutation in HEK293T cells. The mutant cells showed overexpression of a dysfunctional GLUT2 protein, resulting in reduced glucose release activity and enhanced intracellular glucose accumulation. In addition, other glucose transporters (SGLT1 and SGLT2 in the kidney) were found to be induced in the mutant cells. These findings suggest the last loops (loops 9-12) of GLUT2 are essential for glucose transport activity and indicate that GLUT2 dysfunction is associated with dysglycemia in FBS.

Cystinosin-deficient rats recapitulate the phenotype of nephropathic cystinosis.

The lysosomal storage disease cystinosis is caused by mutations in CTNS, encoding the cystine transporter cystinosin, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease. Preclinical testing in cystinotic rodents is required to evaluate new therapies; however, the current models are suboptimal. To solve this problem, we generated a new cystinotic rat model using CRISPR/Cas9-mediated gene editing to disrupt exon 3 of Ctns and measured various parameters over a 12-mo time course. Ctns-/- rats display hallmarks of cystinosis by 3-6 mo of age, as demonstrated by a failure to thrive, excessive thirst and urination, cystine accumulation in tissues, corneal cystine crystals, loss of LDL receptor-related protein 2 in proximal tubules, and immune cell infiltration. High levels of glucose, calcium, albumin, and protein were excreted at 6 mo of age, consistent with the onset of Fanconi syndrome, with a progressive diminution of urine urea and creatinine from 9 mo of age, indicative of chronic kidney disease. Kidney histology and immunohistochemistry showed proximal tubule atrophy and glomerular damage as well as classic "swan neck" lesions. Overall, Ctns-/- rats show a disease progression that more faithfully recapitulates nephropathic cystinosis than existing rodent models. The Ctns-/- rat provides an excellent new rodent model of nephropathic cystinosis that is ideally suited for conducting preclinical drug testing and is a powerful tool to advance cystinosis research.NEW & NOTEWORTHY Animal models of disease are essential to perform preclinical testing of new therapies before they can progress to clinical trials. The cystinosis field has been hampered by a lack of suitable animal models that fully recapitulate the disease. Here, we generated a rat model of cystinosis that closely models the human condition in a timeframe that makes them an excellent model for preclinical drug testing as well as being a powerful tool to advance research.

Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia.

OBJECTIVE: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). DESIGN: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020). METHODS: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. RESULTS: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). CONCLUSIONS: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

More than tubular dysfunction: cystinosis and kidney outcomes.

BACKGROUND: Cystinosis is a lysosomal storage disease that affects many tissues. Its prognosis depends predominantly on kidney involvement. Cystinosis has three clinical forms: nephropathic infantile, nephropathic juvenile and non-nephropathic adult. Proximal tubular dysfunction is prominent in the infantile form, whereas a combination of glomerular and tubular alterations are observed in the juvenile form. METHODS: Thirty-six children with nephropathic cystinosis were included in the study. Clinical features, molecular genetic diagnoses, and kidney outcomes of the patients were evaluated. RESULTS: Twenty-one children (58.3%) were male. The median age at diagnosis was 18.5 months. Twenty-eight patients (77.8%) had infantile nephropathic cystinosis, while eight (22.2%) had juvenile nephropathic cystinosis. An acute rapid deterioration of the kidney function with proteinuria, hypoalbuminemia, and nephrotic syndrome, was observed in 37.5% of patients with the juvenile form. The mean estimated glomerular filtration rate (eGFR) was 82.31 ± 37.45 ml/min/1.73m2 at diagnosis and 63.10 ± 54.60 ml/min/1.73m2 at the last visit (p = 0.01). Six patients (16.6%) had kidney replacement therapy (KRT) at the last visit. The median age of patients with kidney failure was 122 months. Patients with a spot urine protein/creatinine ratio < 6 mg/mg at the time of diagnosis had better kidney outcomes (p = 0.01). The most common allele was c.451A>G (32.6%). The patients with the most common mutation tended to have higher mean eGFR and lower leukocyte cystine levels than patients with other mutations. CONCLUSION: Glomerulonephritis may be a frequent finding in addition to the well-known tubular dysfunction in patients with cystinosis. Furthermore, our results highlight that the presence of severe proteinuria at the time of diagnosis is a relevant prognostic factor for kidney survival.

BCS1L mutations produce Fanconi syndrome with developmental disability.

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.

Acquired growth hormone deficiency in Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disease, resulting from mutations in the SLC2A2 gene, causing impaired glucose transporter 2 protein transporter protein function, impaired glucose and galactose utilisation, hepatorenal glycogen accumulation and organ dysfunction. Clinical features include failure to thrive, hepatomegaly, rickets, short stature and delayed puberty. Therapy includes electrolyte supplementation and uncooked cornstarch. We present a 15-year-old boy diagnosed with FBS in infancy. Growth velocity was normal on standard treatment until age 8.5 years, at which time growth failure led to a diagnosis of acquired growth hormone (GH) deficiency. Initiation of recombinant human GH (rhGH) replacement of 0.25 µg/kg/week resulted in marked improvement in growth velocity and height. While short stature is expected in FBS, growth velocity that falls below the normal range despite adequate therapy should prompt further evaluation. Our case suggests that acquired GH deficiency can arise in FBS and benefits from rhGH therapy.

Evidence for a Genotype-Phenotype Correlation in Patients with Pathogenic GLUT2 (SLC2A2) Variants.

Fanconi-Bickel syndrome (FBS) is a very rare but distinct clinical entity with the combined features of hepatic glycogen storage disease, generalized proximal renal tubular dysfunction with disproportionately severe glucosuria, and impaired galactose tolerance. Here, we report five cases (out of 93 diagnosed in our lab) with pathogenic variants on both GLUT2 (SLC2A2) alleles. They come from 3 families and presented with an exceptionally mild clinical course. This course was correlated to data from old and most recent expression and transport studies in Xenopus oocytes. GLUT2 genotype in patients 1 and 2 was p.[153_4delLI];[P417R] with the first variant exhibiting normal membrane expression and partially retained transport activity (5.8%) for 2-deoxyglucose. In patient 3, the very first GLUT2 variant ever detected (p.V197I) was found, but for the first time it was present in a patient in the homozygous state. This variant had also shown unaffected membrane expression and remarkable residual activity (8%). The genotype in patient 4, p.[153_4delLI];[(E440A)], again included the 2-amino-acid deletion with residual transporter function, and patient 5 is the first found to be homozygous for this variant. Our results provide further evidence for a genotype-phenotype correlation in patients with GLUT2 variants; non-functional variants result in the full picture of FBS while dysfunctional variants may result in milder presentations, even glucosuria only, without other typical signs of FBS.