Previous reports provided recommendations for familial renal glucosuria diagnosis without complex view on differential diagnosis of glucosuria. The aim of this review was to provide an overview of the causes of glucosuria and to create an evidence-based diagnostic approach for children with glucosuria. We searched the current literature with a focus to identify the possible etiology of glucosuria, gaining insight into the pathophysiology of glucosuria. Urinary glucose is completely reabsorbed in the proximal tubule of kidneys. It only appears in the urine if the plasma glucose concentration exceeds the renal threshold for glucose or in the case of insufficient renal glucose reabsorption. The proteins that provide glucose reabsorption are SGLT2 and SGLT1 - sodium-dependent co-transporters that transport glucose from the lumen into epithelial cells - and GLUT2 - a passive transporter providing facilitative glucose transport from epithelial cells to plasma. Renal glucose reabsorption is affected in case of acquired or inherited complex dysfunction of proximal tubule called Fanconi Syndrome or due to pathogenic variants of genes encoding glucose transporters. Prior to diagnosing any of these, diabetes mellitus must be excluded together with other conditions leading to hyperglycemia. In conclusion, glucosuria is always an abnormal finding. The review provides a simple evidence-based diagnostic approach to navigate the differential diagnosis of glucosuria.

• MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• Fanconiho syndrom diagnóza   komplikace   MeSH
• glukosa * metabolismus   MeSH
• glykosurie * diagnóza   etiologie   MeSH
• lidé MeSH
• přenašeč glukosy typ 2 metabolismus   MeSH
• proximální tubuly ledvin metabolismus   MeSH
• renální glykosurie * diagnóza   etiologie   patofyziologie   MeSH
• transportér 1 pro sodík a glukosu metabolismus   MeSH
• transportér 2 pro sodík a glukózu metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

• MeSH
• algoritmy MeSH
• dítě MeSH
• genetické testování * metody   MeSH
• lidé MeSH
• mladiství MeSH
• mutace genetika   MeSH
• nanismus genetika   diagnóza   MeSH
• pokrevní příbuzenství * MeSH
• poruchy růstu genetika   diagnóza   MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• tělesná výška genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Irák MeSH

• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• abstrakt z konference MeSH

The purpose of this study is to elucidate the genetic causes and phenotypic presentation of nonfamilial tall stature (nFTS) and to compare these findings with those of familial tall stature (FTS) from the same population that was previously studied. Children with nFTS (defined as a height > + 2 SDs with both parents' heights < + 2 SDs) underwent endocrine and anthropometric examinations and genetic testing (karyotyping, SHOX gene dosage analysis and next-generation sequencing of 786 growth-associated genes). Exome sequencing was performed in patients with negative genetic results and a height > + 3 SDs. A total of 55 children with nFTS were enrolled. The median height was + 2.8 SD (2.4-3.2 SD), and the median midparental height was + 0.7 SD (0.4-0.9 SD). Genetic causes of tall stature were identified in 6/55 (11%) children. Specifically, four children had gonosomal aneuploidy (47,XXY [2x], 47,XXX, 48,XXXX), one had a heterozygous complex rearrangement including SHOX gene duplication, and one carried a pathogenic variant in the TGFBR2 gene leading to Loeys-Dietz syndrome. A genetic cause of tall stature was significantly less common in nFTS (11%) than in our previously published cohort with FTS (32%). Conclusion: Cytogenetic abnormalities were the predominant genetic alteration identified in children with nFTS, confirming the justification of karyotype analysis in this cohort. The probability of genetic alterations was greater in children with FTS than in those with nFTS. Our findings suggest that the current guidelines for complex investigation are efficient for children with nFTS but need revision in children with FTS. What is known - what is new • Although tall stature is generally considered beneficial, it can be associated with health risks which need to be recognized in time. Tall stature without intellectual impairment is usually considered to be polygenic. • However, the cause of familial tall stature was monogenic more often than it was thought previously. • Children with non-familial and apparently non-syndromic tall stature have never been systematically investigated. • Monogenic causes of non-familial tall stature were observed in 11% of patients, including a participant with Loeys-Dietz syndrome.

• MeSH
• chromozomální aberace * MeSH
• dítě MeSH
• fenotyp MeSH
• genetické testování MeSH
• karyotypizace MeSH
• lidé MeSH
• mladiství MeSH
• poruchy růstu * genetika   MeSH
• předškolní dítě MeSH
• protein SHOX MeSH
• sekvenování exomu MeSH
• tělesná výška * genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

INTRODUCTION: Prader-Willi syndrome (PWS) is primarily caused by a paternal microdeletion of the 15q11-q13 region, maternal uniparental disomy (mUPD) or unbalanced translocations. The MKRN3 gene, located within 15q11-q13, is a master regulator of pubertal initiation. We aimed to compare variant pubertal onset and progression with recent normative data and to correlate it with abnormal MKRN3 gene status. METHODS: Age at pubarche, gonadarche, subsequent pubertal progression and bone age (BA) at gonadarche were investigated in 37 PWS patients (18 females) who already entered pubarche and/or gonadarche with median age 11.1 (95% CI: 6.4 - 18.8) years. All patients were re-tested to confirm genetic subtypes of PWS. The MKRN3 gene was analyzed using single gene sequencing. RESULTS: Out of 37 subjects, 22 had microdeletion and 15 mUPD. Regardless of genetic subtypes and MKRN3 gene status, no correlation between genotypes and the pubertal pattern was found. They initiated pubarche early - girls at 7.4 (95%CI:6.4-8.4), and boys at 9.2 (8.2-10.2) years. The subsequent progression from PH2 to PH4 (pubic hair development) was prolonged to 3.7 years in girls (1.5-5.9;p<0.05), and 2.9 in boys (2.2-3.6;p<0.001). The age at gonadarche was adequate - 10.0 years in girls (8.8-11.2), and 11.0 in boys (9.8-12.1). Progression rate of breast development from B2 to B4 was 3.9 (0.2-7.5) years in girls and of testicular volume from 4 ml to 15ml was 3.8 (0.0-8.1) years in boys. The BA at gonadarche is advanced by 0.6 ± 1.1 years (p<0.001). CONCLUSIONS: Children with PWS, regardless of the genetic subtype and/or MKRN3 status, had an early pubarche and normally timed gonadarche. Pubarche progression was slower. Advanced BA was significantly correlated with gonadarche.

• MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Praderův-Williho syndrom * genetika   patofyziologie   MeSH
• progrese nemoci MeSH
• puberta * fyziologie   genetika   MeSH
• ribonukleoproteiny genetika   MeSH
• ubikvitinligasy genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• úvodníky MeSH

• Publikační typ
• zprávy MeSH

OBJECTIVES: Subsequent to early life feeding issues, children with Prader-Willi syndrome (PWS) develop hyperphagia and severe obesity. Growth hormone (GH) therapy has been approved in PWS to improve growth, body composition, and BMI. We aimed to clarify the role of age at GH therapy onset on growth and BMI trajectories in children with PWS. METHODS: We analyzed height and BMI in 114 patients (58 boys) from REPAR - Czech national GH registry. From them, 69 started GH therapy prior to 2 y/o (age 0.8 ± 0.4 years; mean ± SD; early-onset group [EO]), and 45 later (age 7.1 ± 4.1 years; late-onset group [LO]). RESULTS: Height-SDS before therapy was similar in all (EO: -1.9 ± 1.2 [mean ± SD]; LO: -1.7 ± 1.1). After the first year of GH therapy, height-SDS in the EO group increased to -1.0 ± 1.2, in the LO group to -0.9 ± 1.1. After 5 years, height fully normalized in all (-0.1 ± 1.1 SDS). The LO children were already obese at treatment initiation (BMI-SDS: 2.9 ± 2.2), and their BMI-SDS decreased after 1 year of GH therapy by 0.9 (p=0.003). The weight in EO children was below average before GH treatment (BMI-SDS: -0.9 ± 1.2) and their BMI-SDS increased to the overweight range of 1.3 ± 2.2 (p<0.001) within the oncoming 3 years. Albeit BMI-SDS was around the obesity limit in most children after 5 years on GH therapy, the highest lifetime BMI-SDS was lower in EO (2.2 ± 2.6) than in LO (3.7 ± 2.2; p<0.001). CONCLUSIONS: GH treatment in PWS normalizes body height. After 5 years of GH therapy, BMI-SDS in EO and LO groups are similar; however, the EO group is exposed to lower maximal BMI-SDS values.

• MeSH
• dítě MeSH
• index tělesné hmotnosti MeSH
• kojenec MeSH
• lidé MeSH
• lidský růstový hormon * terapeutické užití   MeSH
• morbidní obezita * prevence a kontrola   etiologie   MeSH
• následné studie MeSH
• obezita dětí a dospívajících * prevence a kontrola   MeSH
• Praderův-Williho syndrom * farmakoterapie   komplikace   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• tělesná výška účinky léků   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

• MeSH
• deep learning * MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• genetická variace MeSH
• genetické asociační studie MeSH
• genomika metody   MeSH
• hormony štítné žlázy metabolismus   genetika   MeSH
• lidé MeSH
• mentální retardace vázaná na chromozom X genetika   metabolismus   MeSH
• mladiství MeSH
• mutace ztráty funkce MeSH
• předškolní dítě MeSH
• přenašeče monokarboxylových kyselin * genetika   metabolismus   MeSH
• stupeň závažnosti nemoci MeSH
• svalová atrofie genetika   metabolismus   patologie   MeSH
• svalová hypotonie genetika   metabolismus   MeSH
• symportéry * genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH