Nonalcoholic fatty liver disease in adolescents with phenylketonuria

Abstract Objective: This study aimed to investigate non-alcoholic fatty liver disease (NAFLD) occurrence and factors associated with the disease in phenylketonuria (PKU) patients undergoing exclusive dietary treatment. Method: This cross-sectional study included 101 adolescents 10 to < 20 years of age with PKU, who were undergoing exclusive dietary treatment and monitored since early diagnosis at a single reference service. Anthropometric and biochemical assessments were performed and food intake was documented, and an ultrasound diagnosis of NAFLD was established. Data were evaluated using the Student's t-test for continuous variables, the chi-square for categorical variables, and logistic regression using the Wald chi-squared test; differences with p < 0.05 were considered to be statistically significant. Results: NAFLD was detected in 26 (25.7%) teenagers. There was no difference in prevalence between the sexes or nutritional status. The final logistic regression model revealed low sensitivity (26.1%) and high specificity (94.7%). The specificity suggested a lower likelihood of NAFLD in older adolescents, in the presence of normal or high levels of alkaline phosphatase, lower carbohydrate intake, and adequate protein and lipid intake. Conclusions: The prevalence of NAFLD in adolescents with PKU was higher than that found in healthy Brazilian adolescents and similar to that found in obese Brazilian children, suggesting a higher risk for NAFLD in patients with PKU treated exclusively by dietary modification.

Novel mutations in GJA1 in two Brazilian families with oculodentodigital dysplasia.

Oculodentodigital dysplasia (ODDD; MIM #164200), a rare genetic disorder characterized by abnormal craniofacial, dental, ocular, and digital features, is caused by mutations in GJA1 (gap junction alpha-1) gene and inherited in an autosomal dominant pattern. However, an autosomal recessive pattern is also reported. Here we described 2 families with members affected by ODDD. In the first family, the c.752G>C (p.S251T) and c.848C>T (p.P283L) heterozygous missense mutations and the c.825C>T (p.T275T) silent mutation were identified in the proband, which showed mild ODDD phenotypes, and in his mother, which displayed hemolytic anemia and thrombocytopenia. In the second family, the patients displayed typical features of ODDD, and Sanger sequencing identified a novel homozygous c.604C>T (p.R202C) missense mutation, whereas the parents carried the mutation. Together, these findings suggest that homozygous mutation in GJA1 induces a more severe ODDD phenotype, though interfamilial phenotype variability was observed, whereas compound heterozygous mutations in GJA1 cause a mild phenotype.

Nonalcoholic fatty liver disease in adolescents with phenylketonuria.

OBJECTIVE: This study aimed to investigate non-alcoholic fatty liver disease (NAFLD) occurrence and factors associated with the disease in phenylketonuria (PKU) patients undergoing exclusive dietary treatment. METHOD: This cross-sectional study included 101 adolescents 10 to < 20 years of age with PKU, who were undergoing exclusive dietary treatment and monitored since early diagnosis at a single reference service. Anthropometric and biochemical assessments were performed and food intake was documented, and an ultrasound diagnosis of NAFLD was established. Data were evaluated using the Student's t-test for continuous variables, the chi-square for categorical variables, and logistic regression using the Wald chi-squared test; differences with p < 0.05 were considered to be statistically significant. RESULTS: NAFLD was detected in 26 (25.7%) teenagers. There was no difference in prevalence between the sexes or nutritional status. The final logistic regression model revealed low sensitivity (26.1%) and high specificity (94.7%). The specificity suggested a lower likelihood of NAFLD in older adolescents, in the presence of normal or high levels of alkaline phosphatase, lower carbohydrate intake, and adequate protein and lipid intake. CONCLUSIONS: The prevalence of NAFLD in adolescents with PKU was higher than that found in healthy Brazilian adolescents and similar to that found in obese Brazilian children, suggesting a higher risk for NAFLD in patients with PKU treated exclusively by dietary modification.

Overweight/obesity in adolescents with phenylketonuria: protective and predisposing factors

Abstract Objective: To estimate the prevalence and factors associated with overweight/obesity development in adolescents with early diagnosed phenylketonuria treated exclusively by diet. Methodology: In this cross-sectional study anthropometric measurements, serum phenylalanine levels, and 10 metabolites associated with lipid and carbohydrate metabolism were analyzed in 101 adolescents aged 10-20 years. Adolescents were categorized into overweight/obesity and eutrophic/low body mass index groups. These patients were compared using Student's t-test, Pearson's chi-square test, Wald's chi-square test for multivariate analysis. Further, to verify whether the prevalence of overweight/obesity found in the study population was similar to that in the general population, the authors compared the nutritional status of 46 patients aged 13-17 years with that of healthy students of the same age from the National School Health Survey using the chi-square test for adherence. The significance threshold was p < 0.5. Results: The prevalence of overweight/obesity in adolescents was 27.7%. There was no difference in prevalence between sexes. Older age was a protective factor and Increased Homeostasis Model Assessment Insulin Resistance index and high phenylalanine and low-density lipoprotein cholesterol levels were predictive factors for overweight/obesity. The equality hypothesis was not rejected in the comparison of nutritional states of 46 patients aged 13-17 years and healthy students of the same age. Conclusion: The prevalence of overweight/obesity in phenylketonuria adolescents was similar to what is found in healthy adolescents.

Overweight/obesity in adolescents with phenylketonuria: protective and predisposing factors.

OBJECTIVE: To estimate the prevalence and factors associated with overweight/obesity development in adolescents with early diagnosed phenylketonuria treated exclusively by diet. METHODOLOGY: In this cross-sectional study anthropometric measurements, serum phenylalanine levels, and 10 metabolites associated with lipid and carbohydrate metabolism were analyzed in 101 adolescents aged 10-20 years. Adolescents were categorized into overweight/obesity and eutrophic/low body mass index groups. These patients were compared using Student's t-test, Pearson's chi-square test, Wald's chi-square test for multivariate analysis. Further, to verify whether the prevalence of overweight/obesity found in the study population was similar to that in the general population, the authors compared the nutritional status of 46 patients aged 13-17 years with that of healthy students of the same age from the National School Health Survey using the chi-square test for adherence. The significance threshold was p < 0.5. RESULTS: The prevalence of overweight/obesity in adolescents was 27.7%. There was no difference in prevalence between sexes. Older age was a protective factor and Increased Homeostasis Model Assessment Insulin Resistance index and high phenylalanine and low-density lipoprotein cholesterol levels were predictive factors for overweight/obesity. The equality hypothesis was not rejected in the comparison of nutritional states of 46 patients aged 13-17 years and healthy students of the same age. CONCLUSION: The prevalence of overweight/obesity in phenylketonuria adolescents was similar to what is found in healthy adolescents.

High-level mosaic monosomy 21 in a 13-year-old girl: Case report and review of the literature.

Monosomy 21 is an exceedingly rare and fatal chromosomal anomaly. Mosaic monosomy 21, however, can be observed in living patients. There have been discussions on whether there are liveborn cases with true mosaic full monosomy 21. Here, we report the case of a 13-year-old patient with mosaic full monosomy 21 who presented with postnatal microcephaly, low weight, facial dysmorphisms, developmental delay, and severe intellectual disability. To the best of our knowledge, this is the oldest patient with mosaic full monosomy 21 described so far and the first reported in Brazil.

Body fat percentage in adolescents with phenylketonuria and associated factors.

OBJECTIVE: To evaluate the percentage of body fat (% BF) in adolescents with PKU and to relate it to protein consumption, physical activity level, body mass index (BMI), sexual maturity and metabolic control. METHOD: This is a cross-sectional study conducted with 94 adolescents between 10 and 20 years of age, with early diagnosis and continuous treatment. Bioimpedance, weight measurements, height and BMI calculation were performed. Questionnaires were applied to quantify protein ingestion and establish the level of physical activity. Sexual maturity was assessed using the Tanner criteria. The annual mean of serum phenylalanine was used as a control parameter of the disease. A multivariate linear regression analysis was performed. RESULTS: Overweight, obesity, the female sex and the percentage of protein consumption explain 94.1% of the % BF of the patients (p < .05). The overweight prevalence was 19.1%. It was verified that 96.7% of the sample were sedentary. Only 50 (53.2%) of the adolescents had good treatment compliance, and no relationship was found between this variable and the % BF (p = .706). CONCLUSIONS: Being female and presenting high BMI values are important factors associated with % BF in phenylketonuric adolescents. Disease control and protein consumption do not seem to influence the body composition.

BH4 deficiency identified in a neonatal screening program for hyperphenylalaninemia / Deficiências de BH4identificadas em um programa de triagem neonatal para hiperfenilalaninemias

Abstract Objectives To show the general prevalence and to characterize tetrahydrobiopterin (BH4) deficiencies with hyperphenylalaninemia, identified by the Neonatal Screening Program of the State of Minas Gerais. Methods Descriptive study of patients with BH4 deficiency identified by the Neonatal Screening Program of the State of Minas Gerais. Results The prevalence found was 2.1 for 1,000,000 live births, with a frequency of 1.71% among hyperphenylalaninemias. There were four cases (40%) with 6-pyruvoyl-tetrahydropterin synthase deficiency, three with GTP cyclohydrolase I - autosomal recessive form deficiency, and three with dihydropteridine reductase deficiency (30% each). Six patients were diagnosed due to clinical suspicion and four cases due to systematic screening in neonatal screening. After the start of the treatment, patients identified by neonatal screening had rapid improvement and improved neuropsychomotor development compared to those diagnosed by the medical history. Conclusions The prevalence of BH4 deficiencies in Minas Gerais was slightly higher than that found in the literature, but the frequency among hyperphenylalaninemias was similar. Although rare, they are severe diseases and, if left untreated, lead to developmental delays, abnormal movements, seizures, and premature death. Early treatment onset (starting before 5 months of age) showed good results in preventing intellectual disability, justifying the screening of these deficiencies in newborns with hyperphenylalaninemia identified at the neonatal screening programs for phenylketonuria.

Resumo Objetivos Apresentar a prevalência geral e caracterizar as deficiências de tetrahidrobiopterina - BH4 - com hiperfenilalaninemia, identificadas pelo Programa de Triagem Neonatal do Estadode Minas Gerais. Métodos Estudo descritivo de pacientes com deficiência de BH4 do Programa de Triagem Neonatal do Estado de Minas Gerais. Resultados A prevalência encontrada foi de 2,1 para 1.000.000 recém-nascidos vivos e a frequência de 1,71%, dentre as hiperfenilalaninemias. Quatro casos (40%) com deficiência de 6-piruvoil-tetrahidropterina sintase, três com deficiência de GTP ciclohidrolase I e três com deficiência de dihidropteridina redutase (30% cada um). Seis pacientes foram diagnosticadospor suspeita clínica e quatro pela pesquisa sistemática na triagem neonatal. Após o início do tratamento, os pacientes identificados pela triagem neonatal tiveram melhora rápida e melhor desenvolvimento neuropsicomotor em comparação com aqueles diagnosticados pela história clínica. Conclusões A prevalência das deficiências de BH4 em Minas Gerais foi um pouco maior que a encontrada na literatura, mas a frequência, entre as hiperfenilalaninemias, foi semelhante. Embora raras, são graves e, se não tratadas, levam a atraso de desenvolvimento, movimentos anormais, convulsões e morte precoce. O tratamento precoce (início antes dos 5 meses) mostrou bons resultados na prevenção de deficiência intelectual, justificando a pesquisa dessas deficiências nos recém-nascidos com hiperfenilalaninemia pelos programas de triagem neonatalpara fenilcetonúria.

Oral findings in Williams-Beuren syndrome

Background: Williams-Beuren syndrome (WBS; OMIM #194050) is a developmental disorder characterized by congenital heart disease, intellectual disability, dysmorphic facial features and ophthalmologic abnormalities. Oral abnormalities are also described in clinical manifestations of the disease. This paper describes orofacial features in patients with WBS. Material and Methods: Seventeen patients with a confirmed molecular diagnosis of WBS were examined for oral abnormalities through clinical oral evaluations and panoramic radiography. Results: Malocclusion, specifically with dental midline deviation, and high-arched palate were the most common findings. Conclusions: The present results contribute to knowledge on the orofacial manifestations of WBS. Since such patients with WBS may develop severe oral abnormalities, early detection and treatment can help improve their quality of life (AU

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BH4 deficiency identified in a neonatal screening program for hyperphenylalaninemia.

OBJECTIVES: To show the general prevalence and to characterize tetrahydrobiopterin (BH4) deficiencies with hyperphenylalaninemia, identified by the Neonatal Screening Program of the State of Minas Gerais. METHODS: Descriptive study of patients with BH4 deficiency identified by the Neonatal Screening Program of the State of Minas Gerais. RESULTS: The prevalence found was 2.1 for 1,000,000 live births, with a frequency of 1.71% among hyperphenylalaninemias. There were four cases (40%) with 6-pyruvoyl-tetrahydropterin synthase deficiency, three with GTP cyclohydrolase I - autosomal recessive form deficiency, and three with dihydropteridine reductase deficiency (30% each). Six patients were diagnosed due to clinical suspicion and four cases due to systematic screening in neonatal screening. After the start of the treatment, patients identified by neonatal screening had rapid improvement and improved neuropsychomotor development compared to those diagnosed by the medical history. CONCLUSIONS: The prevalence of BH4 deficiencies in Minas Gerais was slightly higher than that found in the literature, but the frequency among hyperphenylalaninemias was similar. Although rare, they are severe diseases and, if left untreated, lead to developmental delays, abnormal movements, seizures, and premature death. Early treatment onset (starting before 5 months of age) showed good results in preventing intellectual disability, justifying the screening of these deficiencies in newborns with hyperphenylalaninemia identified at the neonatal screening programs for phenylketonuria.

Nutritional management and postoperative prognosis of newborns submitted to primary surgical repair of gastroschisis / Manejo nutricional e prognóstico pós-operatório do recém-nascido submetido à correção cirúrgica primária de gastrosquise

Abstract Objective Gastroschisis is a defect of the abdominal wall, resulting in congenital evisceration and requiring neonatal intensive care, early surgical correction, and parenteral nutrition. This study evaluated newborns with gastroschisis, seeking to associate nutritional characteristics with time of hospital stay. Methods This was a retrospective cohort study of 49 newborns undergoing primary repair of gastroschisis between January 1995 and December 2010. The newborns’ characteristics were described with emphasis on nutritional aspects, correlating them with length of hospital stay. Results The characteristics that influenced length of hospital stay were: (1) newborn small for gestational age (SGA); (2) use of antibiotics; (3) day of life when enteral feeding was started; (4) day of life when full diet was reached. SGA infants had longer length of hospital stay (24.2%) than other newborns. The length of hospital stay was increased by 2.1% for each additional day taken to introduce enteral feeding. However, slower onset of full enteral feeding acted as a protective factor, decreasing length of stay by 3.6%. The volume of waste drained by the stomach catheter in the 24 h prior the start of enteral feeding was not associated with the timing of diet introduction or length of hospital stay. Conclusion Early start of enteral feeding and small, gradual increase of volume can shorten the use of parenteral nutrition. This management strategy contributes to reduce the incidence of infection and length of hospital stay of newborns with gastroschisis.

Resumo Objetivo A gastrosquise é uma malformação da parede abdominal que resulta em evisceração congênita e requer tratamento intensivo neonatal, correção cirúrgica precoce e nutrição parenteral. Investigaram-se neste estudo os recém-nascidos com gastrosquise e procurou-se correlacionar as suas características nutricionais com o tempo da internação hospitalar. Métodos Estudo de coorte retrospectivo de 49 recém-nascidos submetidos à correção primária de gastrosquise de janeiro de 1995 a dezembro de 2010. As características dos neonatos foram descritas com ênfase nos aspectos nutricionais e relacionadas com o tempo de internação hospitalar. Resultados As características que influenciaram a duração da internação foram: 1) recém-nascidos pequenos para a idade gestacional (PIG); 2) uso de antibióticos; 3) dia de vida ao iniciar a dieta enteral; 4) dia de vida ao atingir a dieta plena. Recém-nascidos PIG tiveram maior tempo de internação (24,2%) do que demais neonatos. O tempo de internação foi aumentado em 2,1% para cada dia a mais que se demorou a introduzir a dieta enteral. Entretanto, atingir mais lentamente o aporte pleno da dieta enteral agiu como fator protetor, diminuiu 3,6% no tempo de internação. O volume de resíduo drenado pelo cateter gástrico, nas últimas 24 horas antes do início da dieta enteral, não apresentou correlação com o momento da introdução da dieta nem com a duração da hospitalização. Conclusão Iniciar a dieta enteral precocemente, com aumento gradativo em pequenos volumes, pode abreviar a duração da nutrição parenteral. Esse manejo contribui para a diminuição da incidência de infecções e do tempo de hospitalização de recém-nascidos com gastrosquise.

Nutritional management and postoperative prognosis of newborns submitted to primary surgical repair of gastroschisis.

OBJECTIVE: Gastroschisis is a defect of the abdominal wall, resulting in congenital evisceration and requiring neonatal intensive care, early surgical correction, and parenteral nutrition. This study evaluated newborns with gastroschisis, seeking to associate nutritional characteristics with time of hospital stay. METHODS: This was a retrospective cohort study of 49 newborns undergoing primary repair of gastroschisis between January 1995 and December 2010. The newborns' characteristics were described with emphasis on nutritional aspects, correlating them with length of hospital stay. RESULTS: The characteristics that influenced length of hospital stay were: (1) newborn small for gestational age (SGA); (2) use of antibiotics; (3) day of life when enteral feeding was started; (4) day of life when full diet was reached. SGA infants had longer length of hospital stay (24.2%) than other newborns. The length of hospital stay was increased by 2.1% for each additional day taken to introduce enteral feeding. However, slower onset of full enteral feeding acted as a protective factor, decreasing length of stay by 3.6%. The volume of waste drained by the stomach catheter in the 24h prior the start of enteral feeding was not associated with the timing of diet introduction or length of hospital stay. CONCLUSION: Early start of enteral feeding and small, gradual increase of volume can shorten the use of parenteral nutrition. This management strategy contributes to reduce the incidence of infection and length of hospital stay of newborns with gastroschisis.

Deficiência de vitamina B12 e fenilcetonúria / Vitamin B 12 deficiency and phenylketonuria

A fenilcetonúria, doença metabólica hereditária, autossômica recessiva, é a mais frequente das aminoacidopatias. Quando não diagnosticada e tratada precocemente, causa retardo mental grave. Os programas de triagem neonatal transformaram a histó- ria natural dessa doença, possibilitando o diagnóstico neonatal e a instituição imediata do tratamento dietético. Atualmente, os pacientes com controle adequado têm vida normal. Nas últimas décadas, alterações nutricionais têm sido relacionadas ao tratamento dietético e aos seus desvios, especialmente após a primeira década de vida. Neste artigo apresenta-se o caso de um adolescente que desenvolveu anemia megaloblástica por deficiente ingestão de vitamina B12 e uma revisão da literatura sobre o tema.(AU)

Phenylketonuria, inherited metabolic disease, autosomal recessive, is the most common of aminoacidopathies. If not diagnosed and treated early, causes severe mental retardation. The newborn screening programs have transformed the natural history of this disease, allowing the neonatal diagnosis and the immediate institution of dietary treatment. Currently, patients with adequate control have normal life. In recent decades, nutritional changes have been related to dietary treatment and its deviations, especially after the first decade of life. In this article we present the case of a teenager who developed megaloblastic anemia due to poor intake of vitamin B12 and a literature review on the topic(AU)

Are 22q11.2 distal deletions associated with math difficulties?

Approximately 6% of school-aged children have math difficulties (MD). A neurogenetic etiology has been suggested due to the presence of MD in some genetic syndromes such as 22q11.2DS. However, the contribution of 22q11.2DS to the MD phenotype has not yet been investigated. This is the first population-based study measuring the frequency of 22q11.2DS among school children with MD. Children (1,564) were identified in the schools through a screening test for language and math. Of these children, 152 (82 with MD and 70 controls) were selected for intelligence, general neuropsychological, and math cognitive assessments and for 22q11.2 microdeletion screening using MLPA. One child in the MD group had a 22q11.2 deletion spanning the LCR22-4 to LCR22-5 interval. This child was an 11-year-old girl with subtle anomalies, normal intelligence, MD attributable to number sense deficit, and difficulties in social interactions. Only 19 patients have been reported with this deletion. Upon reviewing these reports, we were able to characterize a new syndrome, 22q11.2 DS (LCR22-4 to LCR22-5), characterized by prematurity; pre- and postnatal growth restriction; apparent hypotelorism, short/upslanting palpebral fissures; hypoplastic nasal alae; pointed chin and nose; posteriorly rotated ears; congenital heart defects; skeletal abnormalities; developmental delay, particularly compromising the speech; learning disability (including MD, in one child); intellectual disability; and behavioral problems. These results suggest that 22q11.2 DS (LCR22-4 to LCR22-5) may be one of the genetic causes of MD.

A new case of keratoconus associated with Williams-Beuren syndrome.

BACKGROUND: Williams-Beuren syndrome is a multisystemic genetic disorder caused by a contiguous gene deletion at 7q11.23. Keratoconus is a complex disease and it is suspected to have a genetic origin, although the specific gene responsible for keratoconus has not been identified. Although there are several ocular features in Williams-Beuren syndrome, keratoconus is not regularly described as part of this syndrome. PURPOSE: To report a new patient with keratoconus and Williams-Beuren syndrome. DISCUSSION: This is the third case of an association between Williams-Beuren syndrome and keratoconus. The authors believe that the Williams-Beuren syndrome chromosome region can be a possible target for further investigation as the genetic basis of keratoconus.

Avaliação de estratégia combinada de eletroforese capilar e PCR triplo metilação-específica para diagnóstico molecular da Síndrome do X Frágil / Assessment of a combined strategy of capillary electrophoresis and methylation-specific triple polymerase chain reaction for molecular diagnosis of the Fragile X Syndrome

Introdução: a síndrome do X frágil é a principal causa de retardo mental de natureza familiar. Suas características clínicas pouco marcantes fazem com que um diagnóstico de certeza a partir de testes moleculares seja imprescindível. Objetivo: descrever e avaliar as vantagens e desvantagens de uma estratégia combinada de PCR triplo metilação-específica e eletroforese capilar para o diagnóstico molecular da síndrome do X frágil, visando baixo custo, exequibilidade, reprodutibilidade e sensibilidade. Métodos: foram coletadas 43 amostras de sanguede pacientes com déficit cognitivo e de suas mães, quando indicado. Tais indivíduos possuíam exame citogenético positivo, fenótipo e/ou história familiar sugestivas de síndrome do X frágil. Após extração de DNA, foi realizada eletroforese capilar com marcadores fluorescentes,tratamento com bissulfito de sódio e três reações de PCR metilação-específicas em cada amostra. Resultados: foi possível determinar o genótipo em 29 pacientes: 23 (14 homens e nove mulheres) apresentavam alelos com tamanho normal e seis (todos do sexo masculino) possuíam alelos na faixa de mutação completa. Em outras seis amostras, todas do sexo feminino, foi possível determinar um alelo na faixa normal e outro alelo alterado, entretanto, sem diferenciação entre faixa de pré-mutação ou de mutação completa. Nas demais oito amostras(cinco homens e três mulheres), não se pôde determinar o genótipo. Conclusões: a técnica proposta faz uma triagem de pacientes, mas apresenta desvantagens, como não terem sido obtidos resultados satisfatórios com as reações para alelos metilados e a análise dos rastrosdas PCRs com três primers ter se mostrado difícil e dependente de observador.

Introduction: The fragile X syndrome is the main cause of inherited mental retardation. Its very small remarkable clinical characteristics make that a surely diagnosis from molecular tests be indispensable. Objective: To describe and assess the advantages and disadvantages of a combined strategy of methylation-specific triple polymerase chain reaction (PCR)and capillary electrophoresis for the molecular diagnosis of the fragile X syndrome, seeking low cost, feasibility, reproducibility, and sensibility. Methods: 43 blood samples were collected from patients with cognitive deficit and their mothers, when indicated. Such subjects presented a positive cytogenetic exam, phenotype and/or familiar history suggestive of the fragile X syndrome. After DNA extraction, capillary electrophoresis with fluorescent markers, treatment with sodium bisulfite, and three methylation-specific PCR reactions were performed in each sample. Results: It was possible to determine the genotype in 29 patients: 23 (14 men and 9 women) presented alleles with normal size and six (all male) had them in the complete mutation range. In other six female samples, it was possible to determine an allele in the normal range and another altered; nevertheless, without differentiation between the pre-mutation or complete mutation ranges. In the other eight samples (five men and threewomen), it was not possible to establish the genotype. Conclusions: The suggested technique does a patient?s screening, but it has some disadvantages such as non-satisfying results been seen with the reactions for methylated alleles and analysis of the PCRs tracks with three primers being difficult and dependent on the observer.