Fractures of the lateral condyle of the humerus associated with elbow dislocation in children. A systematic review of the literature. / Fracturas del cóndilo lateral del húmero asociadas a luxación de codo en niños. Una revisión sistemática de la literatura.

BACKGROUND: Lateral humeral condyle fractures are the second most common fracture around the elbow in children. However, the association of an elbow dislocation is a rare entity. Therefore, literature on young patients with this uncommon combination is sparse. We aimed to perform a systematic review of the literature searching for pediatric lateral condyle humerus fractures associated to elbow dislocation. METHODS: A systematic review of the PubMed and Embase databases was conducted for peer-reviewed literature between 1960 and 2020. Two reviewers filtered the results, looking for articles in English and Spanish that reported fractures of the lateral condyle of the humerus associated to elbow dislocation in skeletally immature patients. Outcomes included patient and injury characteristics, treatment strategies, complications, and final outcomes including range of motion. RESULTS: The initial search yielded a total of 851 studies. After initial screening, 16 studies were included, with 67 patients available for review. Age reported at the time of injury ranged from 2 to 12 years. The lesion occurred more commonly in males (60%) with Milch II, and Jakob type 3 fractures. The direction of the dislocation was posteromedial in most cases. Open reduction by lateral approach and Kirschner pin placement was the most performed treatment. The reported follow-up ranged from 3 to 156 months. Fourteen studies reported complications in 1/3 of the patients including: limited range of motion, cubitus varus, instability, hardware prominence, delayed union, nonunion, malunion, heterotopic ossification, neurological injury, and hardware failure. Thirteen studies reported clinical outcomes, which were rated as fair or poor in 2out of 10patients. CONCLUSIONS: Current evidence is level IV and suggests that the complication rate after surgical management of lateral condyle fractures is substantial in the context of an associated elbow dislocation, with an elevated percentage of suboptimal results. The most frequent complications in this series were elbow stiffness and cubitus varus.

Fracturas del cóndilo lateral del húmero asociadas a luxación de codo en niños. Una revisión sistemática de la literatura / Fractures of the lateral condyle of the humerus associated with elbow dislocation in children. A systematic review of the literature

Introducción: Las fracturas de cóndilo humeral lateral (FCHL) representan del 12 al 17% de las fracturas de codo pediátrico. La asociación de esta fractura con luxación de codo es poco común, siendo escasa la bibliografía y generalmente limitada a reportes de casos. Nuestro objetivo fue revisar sistemáticamente la literatura sobre las fracturas del cóndilo lateral del húmero asociadas a luxación de codo en niños. Métodos: Se realizó una revisión sistemática mediante una búsqueda exhaustiva en las bases de datos PubMed y Embase de literatura revisada por pares entre 1960 y 2020. Dos revisores filtraron los resultados y buscaron artículos en inglés o español que reportan pacientes esqueléticamente inmaduros con fracturas del cóndilo lateral del húmero asociadas a luxación de codo. Los resultados analizados incluyeron características del paciente y de la lesión, estrategias de tratamiento, complicaciones y resultados finales. Resultados: La búsqueda inicial arrojó un total de 851 estudios. Después de la revisión, se incluyeron 16 estudios, con 67 pacientes disponibles para revisión. Las edades reportadas al momento de la lesión variaron entre 2 y 12 años. La lesión se presentó más comúnmente en varones con fracturas tipo Milch II, Jakob tipo 3. La dirección de la luxación fue posteromedial en la mayoría de los casos. La reducción abierta por abordaje lateral y la colocación de clavijas Kirschner fue el tratamiento más comúnmente realizado. El seguimiento reportado se presentó en un rango 3 a 156 meses. Catorce estudios informaron complicaciones en un tercio de los pacientes, que incluyen: limitación del rango de movimiento, cúbito varo, inestabilidad, prominencia del implante, retraso de la consolidación, seudoartrosis, consolidación viciosa, osificación heterotópica, lesión neurológica y fallo del implante. Trece estudios informaron resultados clínicos, que se calificaron como regulares o pobres en 2de cada 10pacientes.(AU)

Background: Lateral humeral condyle fractures are the second most common fracture around the elbow in children. However, the association of an elbow dislocation is a rare entity. Therefore, literature on young patients with this uncommon combination is sparse. We aimed to perform a systematic review of the literature searching for pediatric lateral condyle humerus fractures associated to elbow dislocation. Methods: A systematic review of the PubMed and Embase databases was conducted for peer-reviewed literature between 1960 and 2020. Two reviewers filtered the results, looking for articles in English and Spanish that reported fractures of the lateral condyle of the humerus associated to elbow dislocation in skeletally immature patients. Outcomes included patient and injury characteristics, treatment strategies, complications, and final outcomes including range of motion. Results: The initial search yielded a total of 851 studies. After initial screening, 16 studies were included, with 67 patients available for review. Age reported at the time of injury ranged from 2 to 12 years. The lesion occurred more commonly in males (60%) with Milch II, and Jakob type 3 fractures. The direction of the dislocation was posteromedial in most cases. Open reduction by lateral approach and Kirschner pin placement was the most performed treatment. The reported follow-up ranged from 3 to 156 months. Fourteen studies reported complications in 1/3 of the patients including: limited range of motion, cubitus varus, instability, hardware prominence, delayed union, nonunion, malunion, heterotopic ossification, neurological injury, and hardware failure. Thirteen studies reported clinical outcomes, which were rated as fair or poor in 2out of 10patients.(AU)

Fractures of the lateral condyle of the humerus associated with elbow dislocation in children. A systematic review of the literature / Fracturas del cóndilo lateral del húmero asociadas a luxación de codo en niños. Una revisión sistemática de la literatura

Background: Lateral humeral condyle fractures are the second most common fracture around the elbow in children. However, the association of an elbow dislocation is a rare entity. Therefore, literature on young patients with this uncommon combination is sparse. We aimed to perform a systematic review of the literature searching for pediatric lateral condyle humerus fractures associated to elbow dislocation. Methods: A systematic review of the PubMed and Embase databases was conducted for peer-reviewed literature between 1960 and 2020. Two reviewers filtered the results, looking for articles in English and Spanish that reported fractures of the lateral condyle of the humerus associated to elbow dislocation in skeletally immature patients. Outcomes included patient and injury characteristics, treatment strategies, complications, and final outcomes including range of motion. Results: The initial search yielded a total of 851 studies. After initial screening, 16 studies were included, with 67 patients available for review. Age reported at the time of injury ranged from 2 to 12 years. The lesion occurred more commonly in males (60%) with Milch II, and Jakob type 3 fractures. The direction of the dislocation was posteromedial in most cases. Open reduction by lateral approach and Kirschner pin placement was the most performed treatment. The reported follow-up ranged from 3 to 156 months. Fourteen studies reported complications in 1/3 of the patients including: limited range of motion, cubitus varus, instability, hardware prominence, delayed union, nonunion, malunion, heterotopic ossification, neurological injury, and hardware failure. Thirteen studies reported clinical outcomes, which were rated as fair or poor in 2out of 10patients.(AU)

Introducción: Las fracturas de cóndilo humeral lateral (FCHL) representan del 12 al 17% de las fracturas de codo pediátrico. La asociación de esta fractura con luxación de codo es poco común, siendo escasa la bibliografía y generalmente limitada a reportes de casos. Nuestro objetivo fue revisar sistemáticamente la literatura sobre las fracturas del cóndilo lateral del húmero asociadas a luxación de codo en niños. Métodos: Se realizó una revisión sistemática mediante una búsqueda exhaustiva en las bases de datos PubMed y Embase de literatura revisada por pares entre 1960 y 2020. Dos revisores filtraron los resultados y buscaron artículos en inglés o español que reportan pacientes esqueléticamente inmaduros con fracturas del cóndilo lateral del húmero asociadas a luxación de codo. Los resultados analizados incluyeron características del paciente y de la lesión, estrategias de tratamiento, complicaciones y resultados finales. Resultados: La búsqueda inicial arrojó un total de 851 estudios. Después de la revisión, se incluyeron 16 estudios, con 67 pacientes disponibles para revisión. Las edades reportadas al momento de la lesión variaron entre 2 y 12 años. La lesión se presentó más comúnmente en varones con fracturas tipo Milch II, Jakob tipo 3. La dirección de la luxación fue posteromedial en la mayoría de los casos. La reducción abierta por abordaje lateral y la colocación de clavijas Kirschner fue el tratamiento más comúnmente realizado. El seguimiento reportado se presentó en un rango 3 a 156 meses. Catorce estudios informaron complicaciones en un tercio de los pacientes, que incluyen: limitación del rango de movimiento, cúbito varo, inestabilidad, prominencia del implante, retraso de la consolidación, seudoartrosis, consolidación viciosa, osificación heterotópica, lesión neurológica y fallo del implante. Trece estudios informaron resultados clínicos, que se calificaron como regulares o pobres en 2de cada 10pacientes.(AU)

Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency.

This study aimed to investigate the clinical variability and factors implied in the outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSd). Biochemical and clinical phenotype, treatment variables, and 6-pyruvoyl-tetrahydropterin synthase (PTS) genotype, were explored retrospectively in 19 Italian patients (12 males and 7 females, aged 4 months to 33 years). According to the level of biogenic amines in cerebrospinal fluid (CSF) at the diagnosis, the patients were classified as mild (6) (normal level) or severe (13) (abnormal low level) form (MF and SF, respectively). Blood Phe ranged from 151 to 1053 micromol/l in MF (mean +/- SD: 698 +/- 403) and 342-2120 micromol/l in SF (mean +/- SD: 1175 +/- 517) (p = 0.063). Patients with MF showed a normal neurological development (a transient dystonia was detected in one), while all SF patients except one presented with severe neurological impairment and only four had a normal neurological development. The outcome of the SF was influenced by the precocity of the treatment. Serial CSF examinations revealed a decline of 5-hydroxyindolacetic acid in MFs and an incomplete restoration of neurotransmitters in SFs: neither obviously affected the prognosis. PTS gene analysis detected 17 different mutations (seven so far unreported) (only one affected allele was identified in three subjects). A good correlation was found between genotype and clinical and biochemical phenotype. The occurrence of brain neurotransmitter deficiency and its early correction (by the therapy) are the main prognostic factors in PTPSd.

Dopamine agonists in 6-pyruvoyl tetrahydropterin synthase deficiency.

OBJECTIVE: To report the efficacy, tolerability, and safety of the dopamine agonist pramipexole in a series of 5 patients affected by inherited 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency and needing l-3,4 dihydroxyphenylalanine (l-dopa) therapy. METHODS: Patients included 4 males and 1 female with ages ranging from 2 to 26 years. Their medication included tetrahydrobiopterin (BH4), 5-hydroxytryptophan, l-dopa, carbidopa, selegiline, and entacapone. All experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of l-dopa therapy, associated with fluctuating hyperprolactinemia. Patients had full assessment of clinical and biochemical condition, including evaluation by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of plasma prolactin (PRL) and catecholamines, before and after a 6-week trial with pramipexole. Pramipexole was administered twice daily as an adjunct to l-dopa therapy in dosages upwardly titrated, with a concurrent reduction of l-dopa dosage. Clinical follow-up went on for 1 year. RESULTS: Pramipexole was well tolerated by all patients, with marked improvement and stabilization of their clinical picture. The mean improvement on the total UPDRS score was 43% (range 33.3%-55.6%) from baseline. Diurnal profiles of plasma PRL normalized and plasma catecholamine levels lasted unchanged. The daily administrations of l-dopa were curtailed from 3 or 4 to 2, and the l-dopa dosage was reduced up to 40%. CONCLUSIONS: The addition of pramipexole to the treatment of 6-pyruvoyl tetrahydropterin synthase deficiency improves the results of l-3,4 dihydroxyphenylalanine therapy. Similar benefits may be expected in other forms of inherited tetrahydrobiopterin deficiency.

A novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome detected by neonatal screening for galactosaemia.

A patient affected by Fanconi-Bickel syndrome detected by neonatal screening for galactosaemia is reported. Molecular studies of the GLUT2 gene led to the identification of a novel mutation of the glucose transporter.

Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families.

OBJECTIVE: To report clinical, neuroradiologic, neurophysiologic, and genetic findings on 16 patients from 11 unrelated families with a remarkable uniform phenotype characterized by infantile ascending hereditary spastic paralysis (IAHSP). METHODS: Sixteen patients from 11 families, originating from North Africa and Europe, who presented severe spastic paralysis and ascending progression were studied. RESULTS: Spastic paraplegia started in the first 2 years of life in most patients and extended to the upper limbs by the end of the first decade. The disease progressed to tetraplegia, anarthria, dysphagia, and slow eye movements in the second decade. The clinical course showed a long survival and preservation of intellectual skills. Clinical, neuroradiologic, and neurophysiologic findings were consistent with a relatively selective early involvement of the corticospinal and corticobulbar pathways. No signs of lower motor neuron involvement were observed, whereas motor evoked potentials demonstrated predominant involvement of the upper motor neurons. MRI was normal in young patients but showed brain cortical atrophy in the oldest, predominant in the motor areas, and T2-weighted bilateral hyperintense signals in the posterior arm of the internal capsule. The ALS2 gene, recently found mutated in consanguineous Arabic families with either an ALS2 phenotype or a juvenile-onset primary lateral sclerosis, was analyzed. Alsin mutations were found in only 4 of the 10 families, whereas haplotype analysis excluded the ALS2 locus in one family. CONCLUSIONS: The syndrome of IAHSP is genetically heterogeneous, and no clinical sign can help to distinguish patients with and without Alsin mutations.

Genetic heterogeneity in five Italian regions: analysis of PAH mutations and minihaplotypes.

Molecular analysis of 289 chromosomes has been performed in a cohort of phenylketonuria (PKU) patients whose ancestors lived in five Italian regions, Calabria, Campania, Piemonte, Puglia/Basilicata and Sicilia. Phenylalaninehydroxylase (PAH) gene mutations and minihaplotypes (combinations of PAH gene STR and VNTR systems) have been determined for 78.5 and 64%, respectively, of the chromosomes studied. 21 different minihaplotypes and 24 PKU mutations were found. Heterogeneity tests carried out for the frequencies of mutations and minihaplotypes show that the distribution of eight mutations and four minihaplotypes is statistically heterogeneous in the five Italian regions. Although the evolutionary rate of microsatellites or the age of these mutations is difficult to estimate with accuracy, our findings taken together show a genetic stratification of the Italian population. These results rule out allelic homogeneity of PKU at the molecular level between regions of Italy, yet minihaplotype data may be of practical use for a multistep approach to PAH gene genotyping.

Cystinuria phenotyping by oral lysine and arginine loading.

BACKGROUND: Cystinuria is an inherited disorder of cystine and dibasic amino acids transport that results in urolithiasis because of poor cystine solubility. Three cystinuria phenotypes, differentiated according to urinary amino acid excretion in obligate heterozygotes, were regarded as allelic variants of a monogenic disease. Two mutated amino acid transporter genes, however, have been recently identified as responsible for cystinuria. Mutations in the SLC3A1 gene. encoding for the heavy subunit of the transporter protein rBAT, were associated with type I cystinuria, whereas type II and III cystinuria were associated with mutations in the SLC7A9 gene, encoding for a light subunit of rBAT. Lysine and arginine metabolism have, therefore, been evaluated in cystinuria homozygotes and heterozygotes to better define the cystinuria phenotypes and their correlations with these emerging genotypes. PATIENTS AND METHODS: Lysine and arginine intestinal absorption and renal excretion were assessed by oral loading and compared to normal controls. Seven cystinuria homozygotes and 7 obligate heterozygotes belonging to the different types received alternately an oral dose of 0.5 mmol/kg body weight lysine or arginine. Plasma concentrations of lysine, arginine, ornithine (derived from rapid arginine conversion) were measured 0, 1, 2, and 3 hours after loading. Their urinary concentrations were measured in morning urine and in urine collected 0-6 hours after loading. RESULTS: Gut lysine absorption was deficient in type II and III, and normal in type I cystinuria homozygotes. Impaired arginine intestinal absorption, as well as massive lysine, arginine, and ornithine hyperexcretion were shared by all homozygotes, irrespective of the type. All heterozygotes shared normal lysine absorption, whereas arginine absorption was slightly impaired in type II and III heterozygotes, which also displayed high lysine, arginine, and ornithine urinary excretion after loading. CONCLUSIONS: Two cystinuria phenotypes, type I and non-type I, can be identified in both homozygous and heterozygous cystinuric subjects by oral loading tests with lysine and arginine. In agreement with recent molecular findings, non-type I cystinuria comprises mentioned type II and type III, which constitute allelic variants of a cystine and dibasic amino acid transport disorder distinct from type I cystinuria.

Fifth International Mutation Detection Workshop, May 13-16, 1999, Vicoforte, Italy.

The Fifth International Mutation Detection Workshop brought together inventors and major users of mutation detection methodology in a freshly refurbished 17(th) century monastery in northern Italy. There were over 120 registrants from 22 nations, all of which gave either a poster or oral presentation, making it difficult to distill the meeting into a few pages. Here we review the meeting by method type and describe highlights within each. It was clear, however, that with the imminent completion of the Human Genome Project and the recent emphasis on the utility of single nucleotide polymorphisms (SNPs), many presenters emphasized the high-throughput aspect of their methods as well as cost.

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations.

Dihydropteridine reductase (DHPR) is an enzyme involved in recycling of tetrahydrobiopterin (BH4), the cofactor of the aromatic amino acid hydroxylases. Its deficiency is characterized by hyperphenylalaninemia due to the secondary defect of phenylalanine hydroxylase and depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases. The DHPR cDNA has been cloned and mapped on 4p15.3. In the present study we report the genomic structure of the DHPR gene (QDPR). This gene includes seven exons within a range of 84-564 bp; the corresponding introns are flanked by canonic splice junctions. We also present a panel of PCR primers complementary to intronic sequences that greatly facilitates amplification of the gene and provides a genomic DNA approach for mutation detection. We have used this approach to study six patients with DHPR deficiency. Four known mutations (G23D, H158Y, IVS5G+ 1A, R221X) and two new mutations (Y150C and G218ins9bp) were found. The Y150C mutation was found in compound heterozygosity with G23D, a mutation always associated with a severe phenotype in homozygous patients. This patient has an intermediate phenotype (good response to monotherapy with BH4). The mutant enzyme for Y150C was expressed in an E. coli system. Comparison of its kinetic parameters with those of the G23D mutant enzyme showed that it is not as effective as the wild-type enzyme, but is more active than the G23D mutant. This patient's intermediate phenotype is thus due to the mild DHPR mutation Y150C. Correlations between genotypes and phenotypes were also found for the other mutations.

A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.

Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes (I, II, and III) have been described. An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. Mutational and linkage analysis demonstrated the presence of genetic heterogeneity in which the SLC3A1 gene is responsible for type I cystinuria but not for type II or type III. In this study, we report the identification of the cystinuria type III locus on the long arm of chromosome 19 (19q13.1), obtained after a genomewide search. Pairwise linkage analysis in a series of type III or type II families previously excluded from linkage to the cystinuria type I locus (SLC3A1 gene) revealed a significant maximum LOD score (zeta max) of 13.11 at a maximum recombination fraction (theta max) of .00, with marker D19S225. Multipoint linkage analysis performed with the use of additional markers from the region placed the cystinuria type III locus between D19S414 and D19S220. Preliminary data on type II families also seem to place the disease locus for this rare type of cystinuria at 19q13.1 (significant zeta max = 3.11 at theta max of .00, with marker D19S225).