Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

Prenatal diagnosis of Greig Cephalopolysyndactyly Syndrome. When to suspect it.

Greig Cephalopolysyndactyly Syndrome (GCPS) is a very rare multiple congenital anomaly with an estimated incidence of 1-9:1,000,000 in newborns with principal findings of macrocephaly, ocular hypertelorism, and polysyndactyly (preaxial or mixed preaxial and postaxial). Very few cases of prenatal diagnoses have been reported. The postnatal diagnosis is based on clinical findings and family background. GLI3, the only gene associated with this anomaly, is altered in more than 75% of cases. Deletions over 1 Mb and involving other genes yield severe clinical cases, which are known collectively as Greig Cephalopolysyndactyly-contiguous gene Syndrome. We report a case in which, despite early polydactyly findings on week 16, the diagnosis was established during the third trimester of pregnancy due to the late presentation of other anomalies corresponding to this syndrome.

Congenital hyperinsulinism in Gran Canaria, Canary Isles.

INTRODUCTION: Congenital hyperinsulinism (CH) is a severe disorder characterised by the appearance of severe hypoglycaemia. Pathogenic mutations in the ABCC8 and KCNJ11 genes are the most frequent cause, although its appearance also been associated to mutations in other genes (GCK, GLUD1, HADH, HNF1A, HNF4A, SLC16A1, UCP2, HK1), and with different syndromes. MATERIALS AND METHODS: Retrospective review of patients diagnosed with CH in this unit during the last 18 years (2001-2018). Genetic analysis included screening for 11 genes in genomic DNA from peripheral blood (ABCC8, GCK, GLUD1, HADH, HNF1A, HNF4A, INSR, KCNJ11, SLC16A1, UCP2, and SLC25A15). OBJECTIVE: To carry out a clinical and genetic characterisation of the diagnosed cases of CH in Gran Canaria. RESULTS: There have been 10 cases of persistent HC since 2001. Seven of them had mutations in the ABCC8 gene, one in the HNF4α gene, and in two patients, no pathogenic mutations were found in the analysed genes. Four patients presented with previously undescribed mutations. Pancreatectomy was performed in two of the cases. The minimum insulin value detected in hypoglycaemia was 6.81 µIU/mL. The incidence of persistent CH for Gran Canaria and Lanzarote is 1/15,614. CONCLUSIONS: Four patients had previously undescribed mutations. The most frequently affected gene was ABCC8. Pancreatectomy was required in 20% of the patients. An insulin value of ≥6.81 µIU/mL was observed in all patients at the time of diagnosis. The incidence of CH in Gran Canaria is high.

The solitary median maxillary central incisor (SMMCI) syndrome: Associations, prenatal diagnosis, and outcomes.

Solitary median maxillary central incisor (SMMCI) syndrome is a complex disorder consisting of multiple, developmental defects involving midline structures of the head, which includes the cranial bones, the maxilla, and its container dentition (specifically the central incisor tooth germ), together with other midline structures of the body. SMMCI may appear as an isolated trait or in association with other midline developmental anomalies. We describe the case of a patient with SMMCI. He presented with a solitary median maxillary incisor, short stature, corpus callosum anomalies and a microform of holoprosencephaly (HPE), diabetes insipidus, and neurodevelopmental delay. The diagnosis was performed postnatally based on clinical features, radiological imaging, and a comprehensive genetic study. SMMCI can be diagnosed during the prenatal or neonatal periods or during infancy. Evaluation of the superior maxillary bone is important for prenatal diagnosis. Direct evaluation through bidimensional ultrasound or the use of multiplanar ultrasound or tridimensional reconstruction should be performed in cases of brain or face malformations. Early diagnosis can contribute to improved prenatal assessment and postnatal management.

Evaluation of family history of permanent hearing loss in childhood as a risk indicator in universal screening. / Evaluación de la historia familiar de hipoacusia permanente en la infancia como factor de riesgo en el cribado universal.

INTRODUCTION AND OBJECTIVE: Sixty percent of prelingual hearing loss is of genetic origin. A family history of permanent childhood hearing loss is a risk factor. The objective of the study is to determine the relationship between this risk factor and hearing loss. We have evaluated clinical and epidemiological characteristics and related nonsyndromic genetic variation. MATERIAL AND METHOD: This was a retrospective, descriptive and observational study of newborns between January 2007 and December 2010 with family history as risk factor for hearing loss using transient evoked otoacoustic emissions and auditory brainstem response. RESULTS: A total of 26,717 children were born. Eight hundred and fifty-seven (3.2%) had family history. Fifty-seven(0.21%) failed to pass the second test. A percentage of 29.1 (n=16) had another risk factor, and 17.8% (n=9) had no classical risk factor. No risk factor was related to the hearing loss except heart disease. Seventy-six point four percent had normal hearing and 23.6% hearing loss. The mean of family members with hearing loss was 1.25. On genetic testing, 82.86% of homozygotes was normal, 11.43% heterozygosity in Connexin 26 gene (35delG), 2.86% R143W heterozygosity in the same gene and 2.86% mutant homozygotes (35delG). We found no relationship between hearing loss and mutated allele. CONCLUSIONS: The percentage of children with a family history and hearing loss is higher than expected in the general population. The genetic profile requires updating to clarify the relationship between hearing loss and heart disease, family history and the low prevalence in the mutations analyzed.

[X-linked hereditary spastic paraplegia due to mutation in the L1CAM gene: three cases reports of CRASH syndrome]. / Paraplejía espástica hereditaria ligada al cromosoma X por mutación en el gen L1CAM: presentación de tres casos del síndrome CRASH.

INTRODUCTION: Hereditary spastic paraplegia (HSP) is a set of neurodegenerative clinical features characterised by a progressive loss of strength in the lower limbs together with spasticity. It is the result of an axonal lesion in the corticospinal tracts. Type 1, known as SPG1, is the most common form of X-linked HSP. This is produced by a mutation in the gene for the L1 cell adhesion molecule (L1CAM). SPG1 presents with CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). CASE REPORTS: We report the cases of three males, two brothers and a cousin (on the mother's side), with clinical features including intellectual disability, spastic paraparesis, long tract signs, facial dysmorphism and adducted thumbs. Neuroimaging revealed agenesis of the corpus callosum and ventriculomegaly in all three of them. Neurophysiological and metabolic studies were normal. The genetic study evidenced a specific mutation of the L1CAM gene (Xq28) in all three cases. CONCLUSION: We describe the clinical-radiological findings in three males with CRASH syndrome due to mutation c.516G>A in exon 5 of the L1CAM gene. These seem to be the first cases reported in Spain, according to the current literature. We recommend suspecting this syndrome when spastic paraparesis, intellectual disability and adducted thumbs are associated.

TITLE: Paraplejia espastica hereditaria ligada al cromosoma X por mutacion en el gen L1CAM: presentacion de tres casos del sindrome CRASH.Introduccion. La paraplejia espastica hereditaria (PEH) representa un conjunto de cuadros clinicos neurodegenerativos que se caracteriza por perdida progresiva de fuerza en los miembros inferiores con espasticidad. Esto se debe a una lesion axonal en los haces corticoespinales. La de tipo 1, conocida como SPG1, es la forma mas comun de PEH ligada al cromosoma X. Esta se produce por una mutacion en el gen de la molecula de adhesion celular L1 (L1CAM). La SPG1 se manifiesta con el sindrome CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). Casos clinicos. Tres varones, dos hermanos y un primo (materno), con un cuadro clinico de discapacidad intelectual, paraparesia espastica, piramidalismo, dismorfias faciales y pulgares en aduccion. La neuroimagen mostro agenesia del cuerpo calloso y ventriculomegalia en los tres. Los estudios neurofisiologico y metabolico fueron normales. El estudio genetico evidencio en todos ellos una mutacion concreta en el gen L1CAM (Xq28). Conclusion. Se describen los hallazgos clinicorradiologicos de tres varones afectos de sindrome CRASH por mutacion c.516G>A en el exon 5 del gen L1CAM. Estos parecen ser los primeros casos descritos en España segun la bibliografia actual. Recomendamos sospechar este sindrome cuando se asocian paraparesia espastica, discapacidad intelectual y pulgares aductos.

Stem cells protect the bronchial stump in rat, increasing Sox6, Col2a1, and Agc1 expression.

BACKGROUND: Post-pneumonectomy bronchopleural fistulas (BPFs) are associated with high morbidity and mortality. Currently, since the management of BPFs is difficult to assess, the best therapeutic approach is prevention. Our objective was to evaluate the effects of adipose-derived stem cells (ASCs) on the healing of the bronchial stump in an experimental animal model. METHODS: Left pneumonectomy was performed in 37 Sprague-Dawley rats. Animals were randomly assigned to a control group (n = 13), an ASC group (n = 12), and an ASC plus Tissucol(®) group (ASCT) (n = 12). The ASCs and ASCTs were locally administered at the bronchial stump after surgical pneumonectomy. Animals were killed at 10 and 20 days. We analyzed histological changes and changes in the expression of relevant genes involved in wound repair in the bronchial stump. RESULTS: Two control animals, one animal from the ASC group, and one from the ASCT group died from early BPF. All the remaining animals had an adequate postoperative outcome. ASCs and ASCTs significantly decreased the necrosis and ulcerations of the bronchial stump at 10 and 20 days. ASCs significantly decreased mRNA expression of Igf1 at 10 days and Igf1, Tgfb1, Vegfa, and Col2a1 at 20 days, whereas there was increased expression of Agc1 and Col2a1 at 10 days and Sox6 at 20 days. CONCLUSIONS: Our findings indicate that local ASCs protected the bronchial stump after pneumonectomy and induced local changes in gene expression related to their protective action. These results could lead to a potential new therapeutic modality for the prevention of BPF.

[Three cases of Pallister-Killian syndrome]. / Presentacion de tres casos de sindrome de Pallister-Killian.

INTRODUCTION: Pallister-Killian syndrome is characterised by intellectual disability, hypotonia, motor disability and a characteristic phenotype in which notable features include a rugged-looking face, alterations affecting the pigmentation of the skin and bitemporal alopecia. It is often associated with seizures and malformations in other organs and systems. The main cause is mosaicism for tetrasomy of chromosome 12p. CASE REPORTS: We present three new paediatric cases of this rare entity, its clinical features are described and a literature review is carried out. CONCLUSIONS: It is important to be familiar with the syndrome so that it can be diagnosed, since what commonly happens is that, without performing a skin biopsy or buccal smear, the chromosomal abnormality goes undetected if the classic cytogenetic techniques are used. Nowadays, the diagnosis can be performed in blood by means of CGH-array or SNP-array, although the chances of finding the chromosomal anomaly depend on the percentage of mosaicism.

TITLE: Presentacion de tres casos de sindrome de Pallister-Killian.Introduccion. El sindrome de Pallister-Killian se caracteriza por discapacidad intelectual, hipotonia, retraso motor y un fenotipo caracteristico en el que destaca un aspecto facial tosco, alteraciones pigmentarias de la piel y alopecia bitemporal. Es frecuente que se asocie a crisis convulsivas y a malformaciones en otros organos y sistemas. Tiene como causa principal el mosaicismo para la tetrasomia del cromosoma 12p. Casos clinicos. Se presentan tres nuevos casos pediatricos afectos de esta rara entidad, se describen las caracteristicas clinicas y se realiza una revision de la bibliografia. Conclusiones. Debe resaltarse la importancia del conocimiento del sindrome para poder llevar a cabo su diagnostico, puesto que lo habitual es que, sin practicar la biopsia cutanea o el frotis de mucosa bucal, la anomalia cromosomica pasa desapercibida si se usan tecnicas citogeneticas clasicas. Hoy en dia, es posible realizar el diagnostico en sangre mediante array-CGH o array-SNP, si bien la posibilidad de encontrar la anomalia cromosomica depende del porcentaje de mosaicismo.

[Familial hemiplegic migraine type 2: two paediatric case reports]. / Migraña hemipléjica familiar tipo II:a propósito de dos casos pediátricos.

INTRODUCTION: Familial hemiplegic migraine is a rare subtype of migraine with aura that includes, as it progresses, a motor defect together with visual or sensory symptoms or speech disorders. It may be associated to symptoms such as basilar migraine, coma and convulsions. Familial hemiplegic migraine type 2 accounts for 25% of them. CASE REPORTS: Two patients, who started at the age of 4 years with episodes of motor deficits or seizures, together with an important sensory disorder that lasted for hours, which were sometimes triggered by banal traumatic injuries. A detailed description of the clinical and developmental features, as well as the studies conducted, is provided. The genetic study revealed mutations in gene ATP1A2: in one case this consisted in a nucleotide substitution in exon 18 (G2501A) that had already been reported, while in the other case there was a previously unknown change (c.381+3 G>T) in intron 4. CONCLUSIONS: We recommend that this condition should be suspected when a disagreement between the duration or the severity of the seizures and the duration and characteristics of the ensuing stupor is detected.

Up-regulation of gelatinases in the colorectal adenoma-carcinoma sequence.

Gelatinase activity has been associated with colorectal cancer (CRC) invasion and metastasis. However, it remains unresolved whether these proteases participate in early colorectal carcinogenesis. The activity of metalloproteinases (MMP) 2 and 9 were measured by zymography in 122 colorectal adenomas, 22 CRC samples, 12 hyperplasic polyps and in 114 matched normal mucosal samples from 114 patients undergoing colonoscopy. There was a progressive and significant increase of pro-MMP-9 activity from adenoma to CRC tissue, whereas the activity of the latent and active forms of MMP-2 was exclusively up-regulated in CRC samples. Among neoplastic polyps, pro-MMP-9 activity was significantly higher in advanced versus non-advanced adenomas and in those harbouring high grade dysplasia. In addition, a positive correlation was observed between MMP-9 activity and the size of the adenomas. The present study demonstrates that MMP-9 is markedly up-regulated in the adenomatous tissue and suggests that this gelatinase might be a marker for early colorectal carcinogenesis.