Adherence to PKU guidelines among patients with phenylketonuria: A cross-sectional national multicenter survey-based study in Argentina, Brazil, and Mexico.

Objective: To characterize adherence to Phenylketonuria (PKU) management practices among PKU patients treated at reference sites around Argentina, Brazil, and Mexico. Methods: This is a retrospective, observational, multicenter, and multinational survey-based study using aggregate data. From an initial list of 40 sites, 22 clinicians expressed interest in completing the survey, with 20 clinicians from 20 unique sites fulfilling all the study criteria. The Survey contained 28 questions, including respondent's clinic characteristics, clinic PKU treatment recommendations, and patient adherence to clinic recommendations. Survey was available in local languages, and the respondents were asked to consult their clinic records to complete their responses. Adherence was assessed by target blood phenylalanine (Phe), target blood testing frequency, and clinic visits. Results: A total of 1077 (out of 1377) actively managed PKU patients (seen in the clinic in the last 3 years) from 13 clinics in Brazil, six in Argentina, and one in Mexico were analyzed. Upper blood Phe target was set over 360 µMol/L in 70% of the clinics for adult patients. Around 40% of the patients >30 years old had Phe blood tests done twice a year or less, with 60% of the clinics recommending semestral visits for adults <30 years old. Twice a month was the most common frequency of visits for <1 year old. The COVID-19 pandemic was a disruptor for frequency of visits and exams. Conclusions: These results show that there is still room for improvement in terms of adherence, namely in adults and older children. More efforts must be made to educate patients and healthcare professionals about the importance of treatment adherence, accompanied by public policies that expand access to pharmacological and dietary treatment with diversity and quality to improve adherence to adequate blood Phe levels.

Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

CONSENSO ARGENTINO SOBRE LA TRANSICIÓN DE LOS CUIDADOS PEDIÁTRICOS A LOS CUIDADOS ADULTOS EN PACIENTES CON ENFERMEDADES CONGÉNITAS DEL METABOLISMO / CONSENSUS STATEMENT ON THE TRANSITION FROM PEDIATRIC CARE TO ADULT CARE IN PATIENTS WITH INBORN ERRORS OF METABOLISM IN ARGENTINA

Introducción: Los errores congénitos del metabolismo (ECM) son enfermedades producidas por trastornos genéticos que alteran la función de distintas vías metabólicas. La transición desde el sistema de atención médica pediátrica a la de adultos es un proceso clave en el desarrollo evolutivo de las personas con condiciones crónicas de salud. Los servicios de salud presentan fallas en satisfacer las necesidades de los jóvenes y sus familias. El objetivo fue definir un conjunto de herramientas y recomendaciones, adaptadas al contexto local de Argentina, para orientar al equipo de salud en el acompañamiento del proceso de transición de cuidados. Asimismo, se buscó analizar barreras y facilitadores para su implementación. Métodos: se definieron preguntas clínicas que se respondieron con la mejor evidencia científica disponible. Se elaboraron recomendaciones para jóvenes y adolescentes con diagnóstico de ECM que se encuentren en proceso de transición entre el servicio de atención pediátrico al servicio de adultos. Las recomendaciones elaboradas se consensuaron con expertos en la temática a través de un método Delphi. Resultados: se elaboraron y consensuaron 13 recomendaciones que permitirán guiar el proceso de transición de los cuidados pediátricos al de adultos en personas con ECM. Conclusiones: estas recomendaciones ayudarán al equipo de salud a mejorar la calidad de atención de estos pacientes y garantizar que ellos y sus familias tengan una experiencia adecuada durante todo el proceso de transición

Introduction: Inborn errors of metabolism (IEM) are diseases caused by genetic disorders that alter the function of different metabolic pathways. The transition from the pediatric to adult health care system is a key process in the evolutionary development of patients with chronic health conditions. Health services are failing to meet the needs of young patients and their families. The objective was to define a set of tools and recommendations, adapted to the local context of Argentina, to guide the health team in accompanying the process of transition. Likewise, it sought to analyze barriers and facilitators for its implementation. Methods: clinical questions were defined and answered with the best available scientific evidence. Recommendations were developed for young patients and adolescents diagnosed with IEM who are in the process of transitioning from the pediatric care service to the adult service. The recommendations developed were agreed with experts in the field through a Delphi method. Results: 13 recommendations were developed and agreed upon to guide the transition process from pediatric to adult care in people with IEM. Conclusions: These recommendations will help the health team improve the quality of care for these patients and ensure that they and their families have an adequate experience throughout the transition process

Galactose epimerase deficiency: lessons from the GalNet registry.

BACKGROUND: Galactose epimerase (GALE) deficiency is a rare hereditary disorder of galactose metabolism with only a few cases described in the literature. This study aims to present the data of patients with GALE deficiency from different countries included through the Galactosemia Network to further expand the existing knowledge and review the current diagnostic strategy, treatment and follow-up of this not well characterized entity. METHODS: Observational study collecting medical data from December 2014 to April 2022 of 22 not previously reported patients from 14 centers in 9 countries. Patients were classified as generalized or non-generalized based on their genotype, enzyme activities in different tissues and/or clinical picture and professional judgment of the treating physician. RESULTS: In total 6 patients were classified as generalized and 16 as non-generalized. In the generalized group, acute neonatal illness was reported in 3, cognitive and developmental delays were present in 5 and hearing problems were reported in 3. Four generalized patients were homozygous for the genetic variant NM_001008216.2:c.280G > A (p.Val94Met). In the non-generalized group, no clearly related symptoms were found. Ten novel genetic variants were reported in this study population. CONCLUSION: The phenotypic spectrum of GALE deficiency ranges from asymptomatic to severe. The generalized patients have a phenotype that is in line with the 9 described cases in the literature and prescribing dietary interventions is the cornerstone for treatment. In the non-generalized group, treatment advice is more difficult. To be able to offer proper counseling, in addition to red blood cell enzyme activity, genetic studies, transferrin glycoform analysis and enzymatic measurements in fibroblasts are recommended. Due to lack of facilities, additional enzymatic testing is not common practice in many centers nor a tailored long-term follow-up is performed.

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect.

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.

Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

PURPOSE: Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). METHODS: Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. RESULTS: Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively. CONCLUSIONS: 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

An Intramolecular Ionic Interaction Linking Defective Sodium/Iodide Symporter Transport to the Plasma Membrane and Dyshormonogenic Congenital Hypothyroidism.

Background: The sodium/iodide symporter (NIS) mediates active iodide accumulation in the thyroid follicular cell. Autosomal recessive iodide transport defect (ITD)-causing loss-of-function NIS variants lead to dyshormonogenic congenital hypothyroidism due to deficient iodide accumulation for thyroid hormonogenesis. Here, we aimed to identify, and if so to functionally characterize, novel ITD-causing NIS pathogenic variants in a patient diagnosed with severe dyshormonogenic congenital hypothyroidism due to a defect in iodide accumulation in the thyroid follicular cell, as suggested by nondetectable radioiodide accumulation in a normally located thyroid gland, as well as in salivary glands. Methods: The proposita NIS-coding SLC5A5 gene was sequenced using Sanger sequencing. In silico analysis and functional in vitro characterization of the novel NIS variants were performed. Results: Sanger sequencing revealed novel compound heterozygous SLC5A5 gene variants (c.970-3C>A and c.1106A>T, p.D369V). In silico analysis suggested that c.970-3C>A disrupts the canonical splice acceptor site located in intron 7. Splicing minigene reporter assay revealed that c.970-3C>A causes exon 8 skipping during NIS pre-mRNA splicing leading to the NIS pathogenic variant p.Y324Hfs*148. Moreover, in silico analysis indicated p.D369V as pathogenic. Functional in vitro studies demonstrated that p.D369V NIS does not mediate iodide accumulation, as p.D369V causes NIS to be retained in the endoplasmic reticulum. Mechanistically, we propose an intramolecular ionic interaction involving the ß carboxyl group of D369 and the guanidinium group of R130, located in transmembrane segment 4. Of note, an Asp residue at position 369-which is highly conserved in SLC5A family members-is required for functional NIS expression at the plasma membrane. Conclusions: We uncovered a critical intramolecular interaction between R130 and D369 required for NIS maturation and plasma membrane expression. Moreover, we identified the first intronic variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape in the SLC5A5 gene leading to dyshormonogenic congenital hypothyroidism.

Update on Neonatal Isolated Hyperthyrotropinemia: A Systematic Review.

The purpose of this paper was to systematically summarize the published literature on neonatal isolated hyperthyrotropinemia (HTT), with a focus on prevalence, L-T4 management, re-evaluation of thyroid function during infancy or childhood, etiology including genetic variation, thyroid imaging tests, and developmental outcome. Electronic and manual searches were conducted for relevant publications, and a total of 46 articles were included in this systematic review. The overall prevalence of neonatal HTT was estimated at 0.06%. The occurrence of abnormal imaging tests was found to be higher in the persistent than in the transient condition. A continuous spectrum of thyroid impairment severity can occur because of genetic factors, environmental factors, or a combination of the two. Excessive or insufficient iodine levels were found in 46% and 16% of infants, respectively. Thirty-five different genetic variants have been found in three genes in 37 patients with neonatal HTT of different ethnic backgrounds extracted from studies with variable design. In general, genetic variants reported in the TSHR gene, the most auspicious candidate gene for HTT, may explain the phenotype of the patients. Many practitioners elect to treat infants with HTT to prevent any possible adverse developmental effects. Most patients with thyroid abnormalities and/or carrying monoallelic or biallelic genetic variants have received L-T4 treatment. For all those neonates on treatment with L-T4, it is essential to ensure follow-up until 2 or 3 years of age and to conduct medically supervised trial-off therapy when warranted. TSH levels were found to be elevated following cessation of therapy in 44% of children. Withdrawal of treatment was judged as unsuccessful, and medication was restarted, in 78% of cases. Finally, data extracted from nine studies showed that none of the 94 included patients proved to have a poor developmental outcome (0/94). Among subjects presenting with normal cognitive performance, 82% of cases have received L-T4 therapy. Until now, the precise neurodevelopmental risks posed by mild disease remain uncertain.

Current Practices and Challenges in the Diagnosis and Management of PKU in Latin America: A Multicenter Survey.

This study aimed to describe the current practices in the diagnosis and dietary management of phenylketonuria (PKU) in Latin America, as well as the main barriers to treatment. We developed a 44-item online survey aimed at health professionals. After a pilot test, the final version was sent to 25 practitioners working with inborn errors of metabolism (IEM) in 14 countries. Our results include 22 centers in 13 countries. Most countries (12/13) screened newborns for PKU. Phenylalanine (Phe) targets at different ages were very heterogeneous among centers, with greater consistency at the 0-1 year age group (14/22 sought 120-240 µmol/L) and the lowest at >12 years (10 targets reported). Most countries had only unflavored powdered amino acid substitutes (10/13) and did not have low-protein foods (8/13). Only 3/13 countries had regional databases of the Phe content of foods, and only 4/22 centers had nutrient analysis software. The perceived obstacles to treatment were: low purchasing power (62%), limited/insufficient availability of low-protein foods (60%), poor adherence, and lack of technical resources to manage the diet (50% each). We observed a heterogeneous scenario in the dietary management of PKU, and most countries experienced a lack of dietary resources for both patients and health professionals.

Improving safety in paediatric thyroidectomy by PTH measurements.

OBJETIVE: We followed our previously reported algorithm based on intra and postoperative parathyroid hormone (PTH) levels to predict postthyroidectomy hypoparathyroid hypocalcemia. The objective of the study was to assess if this strategy is useful and safe to reduce hypocalcemia, hospitalisation length and postsurgery calcium sampling. DESIGN, PATIENTS, MEASSUREMENTS: We classified our series of 66 patients according to their risk of hypoparathyroidism based on PTH determinations. We treated high-risk patients with calcium and vitamin D1-25 supplementation and obtained routine daily calcium samples to control low-risk patients until 48 h postsurgery. We compared the outcomes and overall results of this new approach with those of a historical control group of patients with equivalent PTH measurements who were treated only if they presented hypocalcemia. RESULTS: In the high-risk subgroup (n = 30), five patients had hypocalcemia within the first 24 h. Compared with the high-risk control subgroup, the incidence of hypocalcemia fell from 100% to 17% (p < .001), and the median hospitalisation length from 6 to 3 days (p < .001). In the low-risk subgroup (n = 36), 28 patients remained normocalcemic with significantly less calcium sampling (p < .001). Eight patients had hypocalcemia; seven of them required neck dissection, which was the only risk factor related to postsurgical hypoparathyroidism (RR: 2.1 [confidence interval 95%: 1.4-3.1]; p < .001). The overall incidence of hypocalcemia decreased by 58% in our patients compared to the control group. CONCLUSIONS: Assessing PTH levels to classify the risk of hypoparathyroidism and to initiate preventive therapy was an effective approach that improved the safety of our paediatric patients by reducing the incidence of hypocalcemia and the length of hospitalisation after thyroidectomy in paediatric patients.

A novel mutation in intron 11 donor splice site, responsible of a rare genotype in thyroglobulin gene by altering the pre-mRNA splincing process. Cell expression and bioinformatic analysis.

Thyroglobulin (TG) is a homodimeric glycoprotein synthesized by the thyroid gland. To date, two hundred twenty-seven variations of the TG gene have been identified in humans. Thyroid dyshormonogenesis due to TG gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. The purpose of the present study was to identify and characterize new variants in the TG gene. We report an Argentine patient with congenital hypothyroidism, enlarged thyroid gland and low levels of serum TG. Sequencing of DNA, expression of chimeric minigenes as well as bioinformatics analysis were performed. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the maternal mutation consists of a c.3001+5G > A, whereas the paternal mutation consists of p.Arg296*. Minigen analysis of the variant c.3001+5A performed in HeLa, CV1 and Hek293T cell lines, showed a total lack of transcript expression. So, in order to validate that the loss of expression was caused by such variation, site-directed mutagenesis was performed on the mutated clone, which previously had a pSPL3 vector change, to give rise to a wild-type clone c.3001+5G, endorsing that the mutation c.3001+5G > A is the cause of the total lack of expression. In conclusion, we demonstrate that the c.3001+5G > A mutation causes a rare genotype, altering the splicing of the pre-mRNA. This work contributes to elucidating the molecular bases of TG defects associated with congenital hypothyroidism and expands our knowledge in relation to the pathologic roles of the position 5 in the donor splice site.

Parenting Styles and Coping Strategies in PKU Early Detected Children

Abstract Phenylketonuria (PKU) requires tight control to prevent neurocognitive impairment but reports show that patients may present mild cognitive defects related to higher impulsivity. We hypothesize that chronic intervention may influence the parents and child bonding and the child´s resources to face problems. To describe the PKU parenting styles perceived by the children (PS) and their coping strategies (CS) assessing their relationship with impulsivity, 30 early diagnosed and adequately treated PKU children and 30 non PKU aged-paired controls (CG) were compared. The Argentine Children´s Coping Questionnaire, Argentine Scale Perception of the Relationship with Parents, WISC IV Comprehension Subtest, and CPT II test were administered. PKU PS were based on control: strict to pathologic in the mother and acceptable in the father (both p<0.05 vs. CG). Children significantly sought greater support and showed less emotional control when facing conflicts. These characteristics positively correlated with maternal control r:.383 and r:.398 (both p<0.05). Impulsivity was higher in PKU (p<0.05) but didn´t associate with PS or CS. Maternal strict control wasn´t linked to the higher impulsivity found (possibly neurobiologically based). Nevertheless, if both factors are present, patients may develop a psychological and/or behavioral trait of greater dependency and impulsivity that must be considered in their follow-up.

The Genetic Landscape and Epidemiology of Phenylketonuria.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

Novel Sodium/Iodide Symporter Compound Heterozygous Pathogenic Variants Causing Dyshormonogenic Congenital Hypothyroidism.

Iodide transport defect (ITD) is an autosomal recessive disorder caused by deficient iodide accumulation into the thyroid follicular cell. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that results from inactivating mutations in the sodium/iodide symporter (NIS)-coding SLC5A5 gene. NIS is a key basolateral plasma membrane glycoprotein that efficiently mediates active iodide uptake in the thyroid-constituting the first step in the biosynthesis of the iodine-containing thyroid hormones-and other tissues, including salivary glands, lactating breast, and small intestine. The proposita, a 20-day-old female born in 1992, was diagnosed with congenital hypothyroidism through newborn screening. ITD was suspected on the basis of nondetectable radioiodide accumulation in a normally located nongoitrous thyroid gland, as well as in salivary glands. Sanger sequencing revealed nonpreviously reported compound heterozygous missense SLC5A5 gene variants (c.991G>A, p.D331N and c.1.641C>A, p.S547R). Notably, these variants have not been reported in public databases (i.e., Exome Aggregation Consortium, 1000 Genomes, and Single Nucleotide Polymorphism). In silico analysis using prediction softwares (i.e., SIFT, Polyphen-2, and MutationTaster2) support the pathologic significance of p.D331N and p.S547R NIS. Moreover, functional in vitro studies demonstrate that D331N and S547R NIS severely reduce iodide uptake when the proteins are heterologously expressed in HEK-293T cells because of a pronounced impairment of D331N and S547R NIS targeting to the plasma membrane. Of note, a charged residue at position 331 and a serine residue at position 547-which are highly conserved in SLC5A family members-are required for NIS plasma membrane targeting. We report two novel missense pathogenic variants in a compound heterozygous state in the SLC5A5 gene, detected through Sanger sequencing, in a pediatric female patient with dyshormonogenic congenital hypothyroidism.

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria.

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 µmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 µmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

Abstract Phenylketonuria (PKU, OMIM 261600) is predominantly caused by mutations in the PAH gene. One hundred and three Argentine PKU patients were studied by Sanger sequencing; 101 were completely characterized (90.3% were compound heterozygotes). Fifty-four different pathogenic variants were identified. Mutations were distributed all along the PAH gene but concentrated in exon 7 (26%), 12 (12%), 11 (10%), and 6 (10%). 77% were missense, and 77% affected the enzyme catalytic domain, nine mutations accounted for 57% of 179 studied alleles: p.Arg261Gln (Allele frequency(AF):10.6%), c.1066-11G>A (AF:9,5%), p.Arg408Trp (AF:8,3%), p.Tyr414Cys (AF:5,5%), p.Ala403Val, p.Val388Met, and p.Arg158Gln (AF: 5% each), p.Leu48Ser, and p.Ile65Thr (AF:4% each). The predicted phenotype was assigned by Guldberg´s arbitrary value (AV) and compared with the clinical phenotype based in tolerance to Phe intake. 29.1% (n:30) were hyperphenylalaninemias, 18.5% (n:19) mild-PKU, 27.2% (n:28) moderate-PKU and 25.2 % (n:26) classical-PKU. Genotype/phenotype correlation was statistically significant (p<0.001) Overall concordance was 62,5%: 93.3% in hyperphenylalaninemia, 64.7% in mild-PKU and 65.4% in classical patients. The moderate-PKU showed a weak concordance (17%) with milder AV prediction than clinical assessment. 74% of discordant moderate patients harbored p.Arg261Gln, and p.Val388Met. Our cohort is highly heterogeneous, with predominant Mediterranean influence (mainly Spanish), but with differences with other Latin-American countries.

Nódulos tiroideos en pediatría: predictores de malignidad / Pediatric thyroid nodules: predictors of malignancy

Introducción: La caracterización de los nódulos tiroideos en pediatría no ha sido aún bien comunicada. El riesgo de malignidad es mayor que en adultos por lo que requieren una evaluación exhaustiva. Objetivo: caracterizar una cohorte de pacientes pediátricos con nódulos tiroideos e identificar predictores de malignidad. Pacientes y métodos: se analizaron los hallazgos demográficos, clínicos, bioquímicos, ecográficos y citológicos de una cohorte prospectiva de 106 pacientes <19 años que consultó por nódulo tiroideo a nuestro centro entre 2008-2017. 89 pacientes alcanzaron el diagnóstico de nódulo benigno o maligno por cirugía y 17 luego de un seguimiento clínico mínimo de 2 años. Retrospectivamente se analizaron las diferencias entre los nódulos benignos y malignos. Resultados: la edad mediana fue 13,9 años, con franco predominio de mujeres puberales. 88% presentó una función tiroidea normal. 88/106 nódulos fueron benignos. El carcinoma papilar de tiroides (CPT) fue la única lesión maligna hallada (17%). El análisis estadístico mostró una asociación significativa de CPT con TSH >2,5mU/l, nódulo sólido, márgenes irregulares, microcalcificaciones y adenopatías cervicales patológicas. Un resultado citológico Bethesda V/VI tuvo un valor predictivo (VP) positivo de 87,5% y VP negativo de 96,4%. Conclusiones: El nódulo tiroideo en pediatría es más frecuentemente maligno. La evaluación sistemática permitió identificar ciertos hallazgos clínicos, bioquímicos, ecográficos y citológicos predictores de malignidad que deben ser considerados al decidir el enfoque diagnóstico

Introduction: Published data on pediatric thyroid nodule´s characterization is scarce. With higher risk of malignancy than in adults, they require an exhaustive diagnostic work-up. Objective: To characterize a pediatric cohort with thyroid nodules to identify predictors of malignancy. Patients and methods: Demographic, clinical, biochemical, ultrasonographical and cytological data were analyzed prospectively in 106 patients <19 years that consulted with a thyroid nodule to our center (2008-2017). 89 patients reached final diagnosis (benign or malignant nodule) after surgery and 17 after a minimum follow-up of 2years. Differences between benign and malignant nodules were analyzed retrospectively. Results: median age was 13.9 years, with predominant pubertal females. 88% was euthyroid. 88/106 nodules were benign. Thyroid papillary carcinoma (TPC) was the only malignancy found (17%). Statistical analysis showed significant association of TPC with TSH levels >2.5mU/l, solid nodules, irregular margins, microcalcifications and pathologic adenopathies. Cytological results Bethesda V/VI showed positive and negative predictive values of 87.5% and 96.4% respectively. Conclusions: Pediatric thyroid nodules are more frequently malignant. The systematic evaluation of our cohort allowed the identification of clinical, biochemical ultrasonographical and cytological predictors of malignancy that have to be considered when deciding the diagnostic approach

Genetics and genomic medicine in Argentina.

A historical summary of genetics and genomic medicine in Argentina. We go through the achievements and difficulties in the implementation of genetic and genomic services both in academia and health care.

Estilos parentales y estrategias de afrontamiento en pacientes con hipotiroidismo congénito detectado y tratado en forma temprana / Parenting styles and coping strategies among patients with early detected and treated congenital hypothyroidism

El hipotiroidismo congénito (HC) como enfermedad crónica impacta en la vinculación padres-hijo y en recursos del niño para afrontar situaciones conflictivas. Objetivos. Describir estilos parentales desde la percepción del hijo con HC y sus estrategias de afrontamiento. Población y métodos. Niños de entre 9 y 10 años con HC detectado por pesquisa neonatal y adecuadamente tratado y un grupo sin HC (grupo control). Se utilizó el cuestionario argentino de afrontamiento y la escala argentina de percepción de la relación con los padres y el subtest comprensión de la Wechsler Intelligence Scale for Children III (WISC III). Se compararon los resultados con el análisis multivariante de la varianza (multivariate analysis of variance; MANOVA, por sus siglas en inglés). Resultados. Se incluyeron 60 niños con HC; percibían a su madre con una modalidad de control estricto y a su padre con más aceptación. Buscaban mayor apoyo y se paralizaban más ante situaciones conflictivas que los 60 niños sin patología. Conclusión. Estos hallazgos podrían asociarse a mayor dependencia. Deben considerarse en la atención del HC.

Congenital hypothyroidism (CH), as any chronic disease, has an impact on the parent-child relationship and on the child's resources to cope with conflicting situations. Objectives. To describe parenting styles according to the perception of children with CH and their coping strategies. Population and methods. Children aged 9-10 years who had CH detected by newborn screening and had received adequate treatment and a group without CH (control group). The Argentine Coping Questionnaire, the Argentine Scale for the Perception of Parent Relations, and the comprehension subtest of the Wechsler Intelligence Scale for Children III (WISC III) were used. Results were compared using a multivariate analysis of variance (MANOVA). Results. Sixty children with CH were included; they perceived that their mothers exercised a strict control and that their fathers showed more acceptance. They sought more support and became paralyzed more often in conflicting situations than the 60 children without CH. Conclusion. These findings may be associated with a higher level of dependence. They should be taken into consideration in CH care.

Parenting styles and coping strategies among patients with early detected and treated congenital hypothyroidism. / Estilos parentales y estrategias de afrontamiento en pacientes con hipotiroidismo congénito detectado y tratado en forma temprana.

INTRODUCTION: Congenital hypothyroidism (CH), as any chronic disease, has an impact on the parent-child relationship and on the child's resources to cope with conflicting situations. OBJECTIVES: To describe parenting styles according to the perception of children with CH and their coping strategies. POPULATION AND METHODS: Children aged 9-10 years who had CH detected by newborn screening and had received adequate treatment and a group without CH (control group). The Argentine Coping Questionnaire, the Argentine Scale for the Perception of Parent Relations, and the comprehension subtest of the Wechsler Intelligence Scale for Children III (WISC III) were used. Results were compared using a multivariate analysis of variance (MANOVA). RESULTS: Sixty children with CH were included; they perceived that their mothers exercised a strict control and that their fathers showed more acceptance. They sought more support and became paralyzed more often in conflicting situations than the 60 children without CH. CONCLUSION: These findings may be associated with a higher level of dependence. They should be taken into consideration in CH care.

INTRODUCCIÓN: El hipotiroidismo congénito (HC) como enfermedad crónica impacta en la vinculación padres-hijo y en recursos del niño para afrontar situaciones conflictivas. OBJETIVOS: Describir estilos parentales desde la percepción del hijo con HC y sus estrategias de afrontamiento. POBLACIÓN Y MÉTODOS: Niños de entre 9 y 10 años con HC detectado por pesquisa neonatal y adecuadamente tratado y un grupo sin HC (grupo control). Se utilizó el cuestionario argentino de afrontamiento y la escala argentina de percepción de la relación con los padres y el subtest comprensión de la Wechsler Intelligence Scale for Children III (WISC III). Se compararon los resultados con el análisis multivariante de la varianza (multivariate analysis of variance; MANOVA, por sus siglas en inglés). RESULTADOS: Se incluyeron 60 niños con HC; percibían a su madre con una modalidad de control estricto y a su padre con más aceptación. Buscaban mayor apoyo y se paralizaban más ante situaciones conflictivas que los 60 niños sin patología. CONCLUSIÓN: Estos hallazgos podrían asociarse a mayor dependencia. Deben considerarse en la atención del HC.