Hyaline fibromatosis syndrome: Clinical update and phenotype-genotype correlations.

Hyaline fibromatosis syndrome (HFS) is the unifying term for infantile systemic hyalinosis and juvenile hyaline fibromatosis. HFS is a rare autosomal recessive disorder of the connective tissue caused by mutations in the gene for anthrax toxin receptor-2 (ANTXR2). It is characterized by abnormal growth of hyalinized fibrous tissue with cutaneous, mucosal, osteoarticular, and systemic involvement. We reviewed the 84 published cases and their molecular findings, aiming to gain insight into the clinical features, prognostic factors, and phenotype-genotype correlations. Extreme pain at minimal handling in a newborn is the presentation pattern most frequently seen in grade 4 patients (life-limiting disease). Gingival hypertrophy and subcutaneous nodules are some of the disease hallmarks. Though painful joint stiffness and contractures are almost universal, weakness and hypotonia may also be present. Causes of death are intractable diarrhea, recurrent infections, and organ failure. Median age of death of grade 4 cases is 15.0 months (p25-p75: 9.5-24.0). This review provides evidence to reinforce the previous hypothesis that missense mutations in exons 1-12 and mutations leading to a premature stop codon lead to the severe form of the disease, while missense pathogenic variants in exons 13-17 lead to the mild form of the disease. Multidisciplinary team approach is recommended.

Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

A capillary electrophoresis procedure for the screening of oligosaccharidoses and related diseases.

The most widely used method for the biochemical screening of oligosaccharidoses is the analysis of the urinary oligosaccharide pattern by thin-layer chromatography on silica gel plates. However, this method is not always sensitive enough, and it is extremely time-consuming and laborious. In this work, the analysis of the urine oligosaccharide pattern was standardized for the first time by using capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection (Beckman P/ACE MDQ) with a 488-nm argon ion laser module. All of the analyses were conducted using the Carbohydrate Labeling and Analysis Kit (Beckman-Coulter), which derivatizes samples with 8-aminopyrene-1,3,6-trisulfonate. Urine samples from 40 control subjects (age range, 1 week to 16 years) and from ten patients diagnosed with eight different lysosomal diseases (six of them included in the Educational Oligosaccharide Kit from ERNDIM EQA schemes) were analyzed. Two oligosaccharide excretion patterns were established in our control population according to age (younger or older than 1 year of age). Abnormal peaks with slower migration times than the tetrasaccharide position were observed for fucosidosis, α-mannosidosis, GM1 gangliosidosis, GM2 gangliosidosis variant 0, Pompe disease, and glycogen storage disease type 3. In conclusion, the first CE-LIF method to screen for oligosaccharidoses and related diseases, which also present oligosacchariduria, has been standardized. In all of the cases, the urine oligosaccharide analysis was strongly informative and showed abnormal patterns that were not present in any of the urine samples from the control subjects. Only urine from patients with aspartylglucosaminuria and Schindler disease displayed normal results.

Association between coenzyme Q10 and glucose transporter (GLUT1) deficiency.

BACKGROUND: It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient. CASE PRESENTATION: We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls. CONCLUSION: Our results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.

Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency.

Our aim was to report two new cases of hyperlysinemia type I describing the clinical, biochemical and molecular features of the disease and the outcome of lysine restriction. Two children presented with febrile seizures followed by developmental delay, clumsiness and epilepsy. At age 2 and 8 years a biochemical and genetic diagnosis of hyperlysinemia type I was confirmed and lysine-restricted diet was started in both cases. Three years after initiation of lysine restriction, case 1 had not suffered further seizures. In case 2, tremor and dysmetria improved, but fine motor clumsiness persisted. Mild cognitive impairment was present in both patients despite dietary treatment. Laboratory studies: Plasma, urine and cerebrospinal fluid amino acid concentrations were measured by ion exchange chromatography. Mutation analysis of the AASS gene was performed by directly sequencing the PCR products. The plasma lysine values were higher than 1200 µmol/L in both cases. Additionally, an increase in dibasic aminoaciduria was observed. Lysine restriction decreased plasma lysine values and nearly normalised dibasic aminoaciduria. Mutational screening of the AASS gene revealed that case 1 was a compound heterozygote for c.2662 + 1_2662 + 5delGTAAGinsTT and c.874A>G and that case 2 was a compound heterozygote for c.976_977delCA and c.1925C>G. In conclusion, we present two children with hyperlysinemia type I and neurological impairment in which implementation of lysine-restricted diet achieved a mild improvement of symptoms but did not reverse cognitive impairment. The partial decrease of lysine concentrations and the normalisation of urine excretion of dibasic amino acids after lysine restriction further reinforce the possibility of this therapeutic intervention, although further investigations seem necessary.

[Neonatal repercussions of immigration in Spain: comparison of periods 2003-2004 and 2007-2008]. / Repercusión neonatal de la inmigración: comparación de los periodos 2003-2004 y 2007-2008.

BACKGROUND AND OBJECTIVES: To describe the characteristics of immigrant women's newborns in our environment, and to compare them with those of native women. PATIENTS AND METHODS: All newborns attended in the Neonatology Unit of Hospital del Mar in Barcelona, Spain, between January 2007-December 2008 were included (n=3,177). Pregnant immigrant women were classified in six regions. Twelve diagnoses were defined and their relative risks were calculated. The results were compared with the results obtained in a previous study of the period 2003-2004. RESULTS: There were 1,373 native newborns and 1,743 of immigrant origin. Immigrant women showed a higher rate of HBsAg carrier status (RR 4.33), neonatal infection risk (RR 1.24) and also macrosomia (RR 1.4). There were 6 HIV positive pregnant immigrant women compared with 8 Spanish women, and drug abuse was lower in the immigrant group (RR 0.15). There were no significant differences in the rate of other diagnoses. In the comparative rates between both periods there was an increased rate of immigrant women's newborn. We did not find any differences in the mean birth weight among newborns of immigrant women during both periods of time. HIV and hepatitis C infection remained higher in native pregnant women and hepatitis B infection in immigrant women and gypsy native women. CONCLUSIONS: The study shows similar results between the two periods with persistence of complications secondary to an inadequate prenatal care, lower drug abuse and moderate increase in HIV and VHC infection in immigrant women and hepatitis B infection in immigrant women and gypsy native women.

Efficacy of the Ketogenic Diet for the Treatment of Refractory Childhood Epilepsy: Cerebrospinal Fluid Neurotransmitters and Amino Acid Levels.

OBJECTIVE: The mechanisms of the ketogenic diet remain unclear, but several predictors of response have been proposed. We aimed is to study the relationship between the etiology of epilepsy, cerebrospinal fluid neurotransmitters, pterins, and amino acids, and response to a ketogenic diet. METHODS: We studied 60 patients who began classic ketogenic diet treatment for refractory epilepsy. In 24 of 60 individuals, we analyzed cerebrospinal fluid neurotransmitters, pterins, and amino acids in baseline conditions. Mean age at epilepsy onset was 24 months, 83.3% were focal epilepsies, and in 51.7% the etiology of the epilepsy was unknown. RESULTS: Six months after initiating the ketogenic diet, it was effective (greater than a 50% reduction in seizure frequency) in 31.6% of patients. We did not find a link between rate of efficacy for the ketogenic diet and etiologies of epilepsy, nor did we find a link between the rate of efficacy for the ketogenic diet and cerebrospinal fluid pterins and biogenic amines concentrations. However, we found statistically significant differences for lysine and arginine values in the cerebrospinal fluid between ketogenic diet responders and nonresponders, but not for the other amino acids analyzed. SIGNIFICANCE: The values of some amino acids were significantly different in relationship with the ketogenic diet efficacy; however, the epilepsy etiology and the cerebrospinal fluid biogenic amine and pterin values were not.

Alternating hemiplegia of childhood with a de novo mutation in ATP1A3 and changes in SLC2A1 responsive to a ketogenic diet.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare condition characterized by an early onset of hemiplegic episodes and other paroxysmal or permanent neurological dysfunctions. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. Regarding the differential diagnosis of AHC, glucose transporter 1 deficiency syndrome may be considered because these two disorders share some paroxystic and nonparoxystic features. PATIENT AND RESULTS: We report a typical case of AHC harboring a de novo mutation in the ATP1A3 gene, together with a duplication and insertion in the SLC2A1 gene who exhibited marked clinical improvement following ketogenic diet. CONCLUSION: Because the contribution of the SLC2A1 mutation to the clinical phenotype cannot be definitely demonstrated, the remarkable clinical response after ketogenic diet led us to the hypothesis that ketogenic diet might be effective in AHC as it provides an alternative energy source for the brain.

Utilidad de la determinación de cobre en periodo neonatal. Enfermedad de Menkes / Usefulness of Cu determination in the neonatal period. Menkes disease

Bajas concentraciones séricas de Cu en neonatos pueden ser la primera señal de una ingesta deficiente de este elemento o, alternativamente, de enfermedades genéticas que afectan su metabolismo. Desgraciadamente, es difícil la interpretación de las concentraciones de Cu en esta población, ya que están influenciadas por distintos factores, entre ellos la prematuridad, el tipo de alimentación y la presencia de un estado inflamatorio. Sin embargo, en el caso que aquí se describe fue la baja concentración sérica de Cu la primera pista para el diagnóstico de enfermedad de Menkes. Se demuestra así la utilidad de la determinación de Cu dentro de protocolos neurometabólicos y de retraso psicomotor en población neonatal y lactante (AU)

Low serum Cu concentrations in newborns can be the first indication of a severe Cu deficient intake or, alternatively, of genetic diseases affecting Cu metabolism. Unfortunately, interpretation of serum Cu concentrations in this population is difficult because they also influenced by several variables, such as, prematurity, type of feeding and inflammatory conditions. However, in the case described in this paper was a low serum Cu concentration the first clue for diagnosing Menkes disease. It is so demonstrated the usefulness of Cu determination within neurometabolic or psychomotor retardation protocols for newborn and infant populations (AU)

Adolescent amb dolor abdominal recurrent i manifestacions neuropsiquiàtriques / No disponible

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Macrostomía bilateral aislada congénita / Congenital isolated bilateral macrostomia

Introducción. Dentro de las malformaciones craneofaciales, la macrostomía bilateral aislada es una de las malformaciones más inhabituales, con una frecuencia del 0,3% de los niños con fisuras faciales. Consiste en una hendidura orofacial entre el maxilar superior y el inferior derivada de una alteración del primer arco branquial. Su etiología es desconocida, pero una de las teorías más establecidas es el error de fusión entre el maxilar superior y el inferior durante el desarrollo embrionario. Suele aparecer de manera aislada, sin estar asociada a otros defectos, en contraposición a la macrostomía unilateral, que normalmente forma parte de un síndrome específico. Observación clínica. Exponemos el caso de un recién nacido de sexo femenino que presenta a la exploración un alargamiento bilateral de la comisura bucal de un centímetro de longitud mostrando una apertura amplia, sin otra malformación externa asociada. Todas las exploraciones complementarias que se realizaron para detectar malformaciones asociadas fueron normales. La evolución el periodo neonatal fue correcta, salvo una succión débil en las primeras horas de vida que desapareció progresivamente. Comentarios. Es importante realizar una minuciosa exploración física y diferentes exploraciones complementarias, como ecografía transfontanelar y abdominal, serie ósea y ecocardiograma para encontrar otras anormalidades, en especial si es de presentación unilateral. El tratamiento es quirúrgico con una evolución favorable y donde el proceso de deglución y fonación está conservado(AU)

Introduction. Isolated bilateral macrostomia is one of the rarest malformations within the craniofacial defects, with a frequency of 0.3% of children with facial clefts. It is defined by the presence of an orofacial cleft between the upper and lower jawbone caused by an alteration of the first branchial arch. Its etiology is unknown but one of the most established theories is the error of fusion between upper and lower jaw during embryonic development. Usually it appears isolated, without being associated with other defects, in contrast to unilateral macrostomia, which most often presents in the context of a specific syndrome. Case report. We describe the case of a female newborn that presented a bilateral one-centimeter elongation of the mouth, showing a large opening without other associated external malformations. Imaging studies excluded internal malformations. The evolution was optimal in the neonatal period except for a weak suction in the first hours of life that gradually improved. Comments. In the presence of macrostomia, it is important to perform a thorough evaluation, including physical examination and imaging studies such as transfontanellar and abdominal ultrasound, echocardiography and skeletal series to evaluate for other abnormalities, especially in cases of unilateral presentation. Surgical treatment usually results in successful outcome with preservation of swallowing and phonation(AU)

Nena de 7 anys amb pruïja a làrea genital / No disponible

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Rectocolitis a proteïnes de llet de vaca / Rectocolitis a proteínas de leche de vaca / Proctocolitis secondary to intolerance to cow's milk protein

Introducció. La proctocolitis és una causa de rectorràgia en lactants inclosa dins les reaccions adverses a proteïnes alimentàries. L’objectiu d’aquest treball és revisar de manera prospectiva l’evolució en un grup de lactants amb aquesta sospita clínica. Mètode. Estudiar de manera prospectiva un grup de lactants visitats en el nostre centre amb clínica de rectorràgia i sospita de rectocolitis analitzant clínica, analítica i endoscòpia. Resultats. Vam visitar un total de nou pacients, dos dels quals van ser diagnosticats de colitis infecciosa i colitis ulcerosa, respectivament. La clínica es va manifestar amb rectorràgies acompanyades de bon estat general. La majoria dels restants (5/7) prenien lactància materna en el moment del debut. A tots se’ls va fer un estudi analític bàsic i una cerca de gèrmens en el coprocultiu. No van presentar anèmia (excepte un pacient), ni eosinofília perifèrica, ni hipoalbuminèmia. El diagnòstic es va fer sobre la base d’una bona història clínica i una hipòtesi diagnòstica. També se’ls va fer rectoscòpia amb presa de biòpsies en les quals es mostraven unes lesions característiques en la histologia (>20 eosinòfils per camp), però no patognomòniques. Conclusions. La rectocolitis a proteïnes de llet de vaca constitueix una entitat clínica pròpia que el pediatre general ha de reconèixer i incloure dins del diagnòstic diferencial dels lactants amb rectorràgia. Té una evolució clínica i una resolució excel•lents, i la rectoscòpia i la presa de biòpsies són necessàries per fer-ne la confirmació (AU)

Introducción. La proctocolitis es una causa de rectorragia en los lactantes, cuya naturaleza se encuentra dentro de las reacciones adversas a proteínas alimentarias. El objetivo del presente trabajo es revisar de forma prospectiva la evolución en un grupo de lactantes con sospecha de esta entidad. Método. Estudiar prospectivamente a un grupo de lactantes llegados a nuestro servicio con clínica de rectorragia y sospecha de rectocolitis analizando clínica, analíticas y endoscopia. Resultados. Visitamos a un total de nueve pacientes, dos de los cuales fueron diagnosticados de colitis infecciosa y colitis ulcerosa, respectivamente. La clínica se manifestó con rectorragias y buen estado general. La mayoría de los restantes (5/7) recibían lactancia materna en el momento del debut. En todos se realizó estudio analítico básico y búsqueda de gérmenes en los coprocultivos. No presentaron anemia (excepto un paciente), ni eosinofilia periférica, ni hipoalbuminemia. El diagnóstico se realizó en base a una buena historia clínica y una hipótesis diagnóstica. En todos se realizó rectoscopia con toma de biopsias, mostrando unas lesiones características en la histología (>20 eosinófilos por campo), pero no patognomónicas. Todos realizaron una dieta de exclusión materna de proteínas vacunas y suplementos con leches especiales (tres con hidrolizado y tres con fórmula elemental). Sólo uno mejoró con dieta de exclusión materna. La reintroducción se realizó sin problemas a partir del año de edad. Conclusiones. La rectocolitis a proteínas de leche de vaca constituye una entidad clínica propia que el pediatra general debe reconocer e incluir dentro del diagnóstico diferencial de los lactantes con rectorragia. Su evolución clínica y su resolución es excelente, y es conveniente y necesaria la rectoscopia y la toma de biopsias para su confirmación (AU)

Background. Proctocolitis is one of the causes of rectal bleeding in infants, and it is probably related to food protein intolerance. We prospectively reviewed the clinical course and outcome of a group of infants with rectal bleeding and suspected cow's milk protein intolerance. Method. We performed a prospective evaluation of a group of patients with rectal bleeding. We analyzed the clinical presentation, laboratory evaluation, and colonoscopy findings. Results. The group includes 9 infants; two of them were eventually diagnosed with infectious colitis and ulcerative colitis and were excluded from further analysis. Clinical presentation was characterized by rectal bleeding and a good general condition. Five of the 7 patients were breastfed at the time of presentation. Infectious etiology was excluded in all patients. One patient had mild anemia, and none of the patients presented with eosinophilia or hypoproteinemia. All patients underwent a rectoscopy with biopsy, and pathology showed eosinophilic infiltrates, suggestive of protein intolerance. All patients responded well to maternal restriction of cow protein and 6 patients also required supplementation with hydrolyzed (3 patients) or elemental (3 patients) formulas. After 12 months, cow's milk reintroduction was performed successfully in all cases. Conclusions. Food protein intolerance is one of the most common causes of rectal bleeding in infants, and this diagnosis should be included in the differential diagnosis of infants with bloody stools. Colonoscopy and biopsy are necessary for the diagnosis. Clinical course and outcome are excellent after exclusion of the offending protein (AU)

Hepatitis per virus B i C en la infància (i II): hepatitis C / No disponible

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Hepatitis per virus B i C en la infància (I): hepatitis B / No disponible

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