Oral Manifestations of Wolf-Hirschhorn Syndrome: Genotype-Phenotype Correlation Analysis

Background: Wolf-Hirschhorn syndrome (WHS) is a rare disease caused by deletion in the distal moiety of the short arm of chromosome 4. The objectives of this study were to report the most representative oral findings of WHS, relate them with other clinical characteristics of the disease, and establish possible phenotype-genotype correlation. Methods: The study was conducted at 6 reference centers distributed throughout Spain during 2018-2019. The study group consisted of 31 patients with WHS who underwent a standardized oral examination. Due to behavioral reasons, imaging studies were performed on only 11 of the children 6 years of age or older. All participants had previously undergone a specific medical examination for WHS, during which anatomical, functional, epilepsy-related, and genetic variables were recorded. Results: The most prevalent oral manifestations were delayed tooth eruption (74.1%), bruxism (64.5%), dental agenesis (63.6%), micrognathia (60.0%), oligodontia (45.5%), and downturned corners of the mouth (32.3%). We detected strong correlation between psychomotor delay and oligodontia (p = 0.008; Cramér's V coefficient, 0.75). The size of the deletion was correlated in a statistically significant manner with the presence of oligodontia (p = 0.009; point-biserial correlation coefficient, 0.75). Conclusion: Certain oral manifestations prevalent in WHS can form part of the syndrome's phenotypic variability. A number of the characteristics of WHS, such as psychomotor delay and epilepsy, are correlated with oral findings such as oligodontia and bruxism. Although most genotype-phenotype correlations are currently unknown, most of them seem to be associated with larger deletions, suggesting that some oral-facial candidate genes might be outside the critical WHS region, indicating that WHS is a contiguous gene syndrome

DNA integrity and viability of testicular cells from diverse wild species after slow freezing or vitrification

Introduction and objectiveCryopreservation of testicular tissues offers new possibilities to protect endangered species, genetically valuable individuals or even the fertility potential of prepubertal individuals who have died unexpectedly. However, the use of this technique still remains a challenge. In this study, slow freezing and vitrification of testicular tissue was investigated to find out which cryopreservation method could better preserve the viability and DNA integrity of testicular germ cells in diverse wild species.MethodsTestes were obtained post-mortem from 18 artiodactyls (wild boar, roe deer, dwarf goat, mhor gazelle, European mouflon, African forest buffalo, Malayan tapir, dorcas gazelle, Iberian ibex, gnu, red river hog), 5 primates (colobus monkey, capuchin monkey, mandrill), 8 carnivores (gray wolf, Persian leopard, binturong, European mink, American black bear, suricata), and 2 rodents (Patagonian mara). The testicles belonged to adult individuals and were cut into small pieces and cryopreserved by needle immersed vitrification or uncontrolled slow freezing using a passive cooling device. After warming or thawing, testicular tissues were enzymatically digested and two germ cell types were differentiated based on their morphology: rounded cells (spermatogonia, spermatocytes, and early spermatids) and elongated cells (elongated spermatids and spermatozoa). Cell viability was assessed by SYBR-14/propidium iodide while DNA fragmentation by TUNEL assay with fluorescence microscope.Results and discussionOur preliminary results revealed that our uncontrolled slow freezing method better preserved the viability and DNA integrity of elongated cells than vitrification. Such trend was observed in all species, being significant in artiodactyls, carnivores, and primates. Similarly, the viability and DNA integrity of rounded cells was also better maintained in primates by uncontrolled slow freezing, while in carnivores, vitrification by needle immersion showed better results in this type of cells. In artiodactyls and rodents both techniques preserved the viability of rounded cells in a similar manner, although the DNA integrity of these cells was greater after needle immersed vitrification in artiodactyls.ConclusionsIn conclusion, the effectiveness of each cryopreservation method is affected by the phylogenetic diversity between species and cell type

Osteoporosis-pseudoglioma Syndrome: A pediatric case of primary osteoporosis

La osteoporosis es un trastorno para tener en cuenta en niños con patologías crónicas graves o con algunas enfermedades genéticas que predisponen al incremento de la fragilidad ósea. La osteoporosis primaria es una entidad con etiologías emergentes y puede ocurrir en forma sindrómica. La asociación con pliegues retinianos congénitos debe orientar al diagnóstico de osteoporosis-pseudoglioma (OMIM 259770), síndrome poco frecuente (prevalencia de 1/2000000), que se origina por la pérdida de función de la proteína LRP5 (low-density lipoprotein receptor-related protein 5) y compromete la vía de señalización de Wnt/β-catenina. Se presenta el caso de un niño con pliegues retinianos congénitos, ceguera progresiva y múltiples fracturas cuyo estudio clínico, bioquímico y genético confirmó el diagnóstico de osteoporosis primaria debido a una nueva variante inactivante en el gen LRP5 en homocigosis.Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. Its association with congenital retinal folds should guide the diagnosis to the Osteoporosis-Pseudoglioma syndrome (OMIM 259770), a rare disease (prevalence of 1/2000000), caused by the loss of function of the protein LRP5 (low-density lipoprotein receptor-related protein 5) resulting in the alteration of the Wnt/β-catenin signalling pathway. We report the case of a child with congenital retinal folds, progressive loss of vision and multiple fractures whose clinical, biochemical and genetic studies confirmed the diagnosis of primary osteoporosis due to a novel homozygous inactivating variant in LRP5.Fil: Braslavsky, Débora. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Scaglia, Paula Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Sanguineti, Nora María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Aza Carmona, Miriam. Universidad Autónoma de Madrid; EspañaFil: Nevado Blanco, Julián. Universidad Autónoma de Madrid; EspañaFil: Lapunzina Badia, Pablo D.. Universidad Autónoma de Madrid; EspañaFil: Fernandez, Maria del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Ruiz, Olivia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Carmona, Alejandra. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Szlago, Marina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Arberas, Claudia Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Cassinelli, Hamilton Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Heath, Karen. Universidad Autónoma de Madrid; EspañaFil: Rey, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Bergadá, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentin

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Relación funcional entre las vías constitutiva e inducible de utilización de hexosas en "Saccharomyces cerevisiae"

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica y Biología Molecular. Fecha de lectura: 08-07-1995El sistema de transporte constitutivo de hexosas en Saccharomyces cerevisiae ha sido revisado con un nuevo abordaje experimental, diseñado para distinguir si el proceso de transporte conlleva ó no la fosforilación del azucar. Nuestros resultados, empleando una cepa de levadura silvestre y un sustrato fermentable, indican que el transporte de hexosas en levadura no implica la fosforilación del sustrato. Hemos revisado, con este nuevo abordaje, otras características del sistema de transporte constitutivo de hexosas en levadura. Se ha estudiado también la posible relación funcional entre las vías de utilización de glucosa y galactosa en Saccharomyces cerevisiae. La galactosa (que es transportada y fosforilada por sistemas inducibles) inhibe fuertemente la utilización de glucosa, fructosa ó manosa (que comparten los mismos sistemas de transporte y fosforilación constitutivos). Paralelamente, glucosa, fructosa y manosa inhiben la utilización de galactosa, aunque con una menor eficiencia. Estas inhibiciones cruzadas sólo tienen lugar en células adaptadas a galactosa ó en mutantes de levadura que utilizan galactosa de manera constitutiva. La eficiencia de galactosa como inhibidor, es mayor que la que muestra cada una de las tres hexosas en inhibirse mutuamente. La fosforilación del inhibidor no parece ser requerida, aunque la integridad funcional del transporte de galactosa y de la la galactokinasa es necesaria para que la galactosa inhiba. Las inhibiciones cruzadas entre galactosa y glucosa, fructosa ó manosa no suponen la utilización de un azucar a expensas del otro. Parece por tanto, que el crecimiento de levadura en medios con galactosa induce la síntesis ó la modificación de una proteína, que una vez unida a la galactosa ó a cualquiera de las otras tres hexosas, interacciona de manera cruzada con el sistema constitutivo ó inducible de transporte respecivamente, bloqueando su función. Por otro lado, hemos encontrado que la galactosa induce en Saccharomyces cerevisiae sensibilidad de la utilización de hexosas a inhibición por glucosamina. La intensidad de la inhibición va paralelamente asociada a la inducción-desinducción de la vía de utilización de galactosa. Los cambios inducidos por el crecimiento de la levadura en medios con galactosa responsables de la adquisición de sensibilidad a glucosamina, están bajo el control de los genes GAL4 y GALBO. Estos resultados contrastan con el hecho de que la glucosamina es sustrato de los sistemas constitutivos de transporte y fosforilación de la glucosa, pero no de los sistemas inducibles de la galactosa. La inhibición por glucosamina depende del pH del medio, y principalmente de la fosforilación de la hexosamina y no es consecuencia del descenso de los niveles de ATP de la célula. La acumulación de derivados-fosforilados de la glucosamina inhibe el transporte de glucosa y manosa en células crecidas en galactosa pero no en glucosa ó en etanol. La inhibición cruzada de la utilización de hexosas entre galactosa y los otros tres azúcares ferrnentables, por una parte, y la inducción por galactosa de sensibilidad a inhibición por glucosamina por otra, abren una nueva perspectiva sobre la interrelación funcional entre las vías de utilización de glucosa y galactosa. El análisis genético de la segregación del carácter de resistencia a 2-desoxiglucosa en el mutante de levadura resistente a 2% de 2-desoxiglucosa (CJM-152 R2) ha revelado que, la adquisición de esta resistencia es consecuencia de la alteración de, al menos, dos genes.The constitutive transport of hexoses in Saccharomyces cerevisiae has been reexaminated with a new radioactive experimental approach devised to distinguish between association or independence of the transport step with phosphorylation of the sugar substrate. Our results, with a wild-type yeast and a fermentable sugar, support the view that the transport of hexoses in yeast does not involve phosphorylation of the substrate. Other features of the transport process have been examined using this experimental procedure and are also reported. The relationship between the pathways of glucose and galactose utilization in Saccharomyces cerevisiae has been studied. Galactose (wich is transported and phosphorylated by inducible systems) is a strong inhibitor of the utilization of glucose, fructose or mannose (wich have the same constitutive transport and phosphorylation systems). Conversely, al1 these three hexoses inhibit the galactose utilzation, though with poorer efficiency. These cross-inhibitions only occur in yeast adapted to galactose or in galactose-constitutive mutants. The efficiency of galactose as inhibitor is even greater than the efficiencies of each of the other three hexoses to inhibit the utilization of each other. Phosphorylation is not involved, but the functional integrity of the galactose transport system and galactokinase is neccessary for the inhibition by the galactose. The cross-inhibitions between galactose and either glucose, fructose or mannose do not implicate utilization of one hexose at the expense of the other. It seems that, by growing the yeast in galactose, a protein component is synthesized, or alternatively modified, that once bound to either galactose or any one of the other three hexoses, cross-interacts respectively with the constitutive or the inducible transport systems, impairing their function. On the other hand, this work shows that galactose induces in Saccharomyces cerevisiae sensitivity of the utilization of hexoses to inhibition by glucosamine. The intensity of the inhibition parallels the induction-deinduction of the galactose pathway. The changes induced by growing the yeast in galactose that render the cells sensitive to glucosamine, are under the control of the GALBO and GAL4 genes. These findings contrast with the fact that glucosamine is substrate of the constitutive glucose, but not of the inducible galactose transport and phosphorylation systems. The inhibition by glucosamine is pH dependent and its extent mainly depends on the phosphorylation of the hexosamine and it is not a consequence of ATP depletion of the cell. lntracellular accumulated glucosamine derivatives impairs the transport of glucose and mannose in galactose, but not in glucose or ethanol, grown yeast cells. The cross-lnhibition of sugar utilization between galactose and any one of glucose, fructose and mannose, on one hand, and the induction by galactose of the inhibition of glycolysis by glucosamine, on the other hand, open new views on the inter-relationship of the early steps of glucose and galactose metabolic pathways. Genetic analysis of the segregation of the character of resistance to 2-deoxyglucose in a yeast mutant (CJM-152R2) shows that, this resistance is a consequence of mutations at least in two genes

A Spanish Family with Gordon Syndrome Due to a Variant in the Acidic Motif of <i>WNK1</i>

(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS

Prevalencia del síndrome de Phelan-Mcdermid en españa

Background: Phelan-McDermid syndrome is a rare genetic condition caused by a deletion of the terminal end of chromosome 22 in the 13.3 region, as well as, by point mutations within SHANK3 gene. The aims of this research were to determine the prevalence of the disease in the Spanish population, to establish the geographical distribution of the syndrome among the different autonomous communities, to elucidate the age range that affects more patients, to study the disease-sex relationship, as well as the age at diagnosis. Methods: For the research, patients diagnosed with the disease for twelve years were recruited throughout the Spanish territory. The clinical patient information was obtained from the referral doctors using two standardized questionnaires completed with data from the medical reports and the interview with the parents. The molecular diagnosis of the disease was carried out using different formats of microarrays. Data were processed using Microsoft Excel and Statgraphics Centurion XVII. Results: Currently in Spain there are 201 people diagnosed with the disease. Currently in Spain there are 201 people diagnosed with the disease, its prevalence being 4x10-4/10,000 inhabitants. The community with the most diagnosed patients was Madrid and there were no significant differences in terms of sex and disease, the mean age at diagnosis was around 6.67 years. Conclusions: The prevalence of the disease in Spain is very low, and it can be stated that it is very likely that there are more people with this syndrome in the population.Fundamentos: El Síndrome de Phelan-McDermid es una enfermedad poco frecuente de origen genético causada por la deleción del extremo terminal del cromosoma 22 región q13.3 o por mutaciones puntuales que afectan al gen SHANK3. Los objetivos de este trabajo fueron determinar la prevalencia de la enfermedad en la población española, establecer la distribución geográfica del síndrome entre las distintas comunidades autónomas, dilucidar el rango de edad en el que existen más pacientes y estudiar la relación enfermedad-sexo así como la edad media al diagnóstico. Métodos: Para la investigación se reclutaron pacientes diagnósticados con la enfermedad durante doce años en todo el territorio español. La información clínica de los pacientes se obtuvo de los médicos de referencia mediante dos cuestionarios estandarizados completados con datos de los informes médicos y la entrevista a los padres. El diagnóstico molecular de la enfermedad se realizó utilizando diferentes formatos de microarrays. Los datos se trataron utilizando Microsoft Excel y Statgraphics Centurion XVII. Resultados: Actualmente en España existen 201 personas diagnosticadas con la enfermedad siendo su prevalencia de 4x10-4/10.000 habitantes. La comunidad con más pacientes diagnosticados fue Madrid y no hubo diferencias significativas en cuanto al sexo y la enfermedad, la edad media al diagnóstico se sitúa en torno a los 6,67 años. Conclusiones: La prevalencia de la enfermedad en España es muy baja pudiéndose afirmar que es muy probable que en la población existan más personas con este síndrome

Prevalence and geographic distribution of the wolf-hirschhorn syndrome in Spain

Referencias bibliográficas: • Battaglia A, Filippi T, Carey JC. Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision. Am. J. Med. Genet. C Semin. Med. Genet. 2008; 148C: 246-251. • Battaglia A, Carey JC, South ST. Wolf-Hirschhorn syndrome: A review and update. Am. J. Med. Genet. Part. C Semin. Med. Genet. 2015; 169: 216–223. • Nevado J, Ho KS, Zollino M, Blanco R, Cobaleda C, Golzio C, Beaudry-Bellefeuille I, Berrocoso S, Limeres J, Barrúz P, Serrano-Martín C, Cafiero C, Málaga I, Marangi G, Campos-Sánchez E, Moriyón-Iglesias T, Márquez S, Markham L, Twede H, Lortz A, Olson L, Sheng X, Weng C, Wassman ER III, Newcomb T, Wassman ER, Carey JC, Battaglia A, López-Granados E, Wolf-Hirschhorn Spain’s Working Group, Douglas D, Lapunzina P. International meeting on Wolf-Hirschhorn syndrome: Update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay. Proc. Am. J. Med. Genet. Part A. 2020; 182: 257–267. • Battaglia A, Carey JC. The delineation of the Wolf-Hirschhorn syndrome over six decades: Illustration of the ongoing advances in phenotype analysis and cytogenomic technology. Am J Med Genet A. 2021;185(9):2748-2755. • South ST, Whitby H, Battaglia A, Carey JC, Broth-man AR. Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations. European Journal of Human Genetics.2008; 16: 45–52. • Blanco-Lago R, Malaga-Dieguez I, Granizo-Martinez JJ, Carrera-Garcia L, Barruz-Galian P, Lapunzina P, Nevado-Blanco J, En Representacion Del Grupo Colaborativo Para El Estudio Del Sindrome de Wolf-Hirschhorn ERDGCPEEDSW. Wolf-Hirschhorn syndrome. Description of a Spanish cohort of 51 cases and a literature review. Rev Neurol. 2017 May 1;64(9):393-400.PMID: 28444681 • Limeres J, Serrano C, De Nova JM, Silvestre-Rangil J, Machuca G, Maura I, Cruz Ruiz-Villandiego J, Diz P, Blanco-Lago R, Nevado J, Diniz-Freitas M. Oral Manifestations of Wolf-Hirschhorn Syndrome: Genotype-Phenotype Correlation Analysis. J. Clin. Med. 2020; 9(11): 3556. • Battaglia A, Lortz A, Carey JC. Natural history study of adults with Wolf-Hirschhorn syndrome 1: Case series of personally observed 35 individuals. Am. J. Med. Genet. A. 2021;185(6):1794-1802. • Carey JC, Lortz A, Mendel A, Battaglia A. Natural history study of adults with Wolf-Hirschhorn syndrome 2: Patient-reported outcomes study. Am. J. Med. Genet. A. 2021;185(7): 2065-2069. • Shannon NL, Maltby EL, Rigby AS, Quarrell OWJ. An epidemiological study of Wolf-Hirschhorn syndrome: life expectancy and cause of mortality. J. Med. Genet. 2001; 38: 674-679. • Taruscio, D, Vittozi L, Rocchetti A, Torreri P, Ferrari L. The Occurrence of 275 Rare Diseases and 47 Rare Disease Groups in Italy. Results from the National Registry of Rare Diseases. International Journal of Environmental Research and Public Health. 2018:15:1470-88. • Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, Neri G. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am. J. Med. Genet. C Semin. Med. Genet. 2008; 148C (4): 257-269. • Corrêa T, Mergener R, Leite JCL, Galera MF, Moreira LMA, Vargas JE, Riegel M. Cytogenomic Integrative Network Analysis of the Critical Region Associated with Wolf-Hirschhorn Syndrome. Biomed Res Int. 2018; 5436187. • Blanco-Lago R, Malaga-Dieguez I, Granizo-Martinez JJ, Carrera-Garcia L, Barruz-Galian P, Lapunzina P, Nevado-Blanco J, En representacion del Grupo Colaborativo para el Estudio del Sindrome de Wolf-Hirschhorn ERDGCPEEDSW. Wolf-Hirschhorn syndrome. Description of a Spanish cohort of 51 cases and a literature review. Rev Neurol. 2017 May 1;64(9):393-400. PMID: 28444681 • Gavril EC, Luca AC, Curpan AS, Popescu R, Resmerita I, Panzaru MC, Butnariu LI, Gorduza EV, Gramescu M, Rusu C. Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review. Children (Basel). 2021; 8(9):751. • Shimizu K, Wakui K, Kosho T, Okamoto N, Mizuno S, Itomi K, Hattori S, Nishio K, Samura O, Kobayashi Y, Kako Y, Arai T, Tsutomu OI, Kawame H, Narumi Y, Ohashi H, Fukushima Y. Microarray and FISH-based genotype-phenotype analysis of 22 Japanese patients with Wolf-Hirschhorn syndrome. Am. J. Med. Genet. A. 2014; 164A (3): 597-609.FUNDAMENTOS // El Síndrome de Wolf-Hirschhorn es una enfermedad poco frecuente de origen genético causada por la deleción del extremo distal del cromosoma 4, que incluye preferentemente la región p16.3. Los objetivos de este trabajo fueron determinar la prevalencia de la enfermedad en la población española, así como establecer la distribución geográfica del síndrome a lo largo de la geografía nacional, dilucidando el rango de edad en el que existían más pacientes afectados. MÉTODOS // Para la investigación se reclutaron 80 pacientes diagnosticados con el síndrome en el periodo 2013-2021, en todo el territorio español, gracias a los acuerdos con la Asociación Española de Síndrome Wolf-Hirschhorn (AESWH). La información clínica de los pacientes se obtuvo mediante dos cuestionarios estandarizados que fueron cumplimentados por médicos de referencia y los padres, siendo completados y corroborados con los distintos informes médicos de cada paciente y, al menos, una entrevis- ta una entrevista a los padres. La caracterización molecular de la enfermedad se realizó mediante el uso de microarrays de SNP (del inglés, single nucleotide polymorphism) (CytoSNP 850K, Illumina). Los datos se trataron estadísiticamente utilizando los softwares Microsoft Excel (Microsoft Corporation) y SPSS (IBM), mediante las comparaciones entre dos grupos s con la prueba t de Student (para variables continuas) o con pruebas de Chi cuadrado (para las categóricas). Para más de dos grupos se realizó análisis ANOVA (seguido de las pruebas post hoc de Bonferroni o T3-Dunnett) para variables continuas y pruebas z entre proporciones de columna para variables categóricas. RESULTADOS // En España (hasta 2021) están diagnosticadas ochenta personas con este síndrome, estimándose su prevalencia en 1,69x10-4 por cada 10.000 habitantes y/o 1/172.904 por cada recién nacido vivo. En este trabajo se constató la existencia de importantes diferencias de prevalencia entre las comunidades autónomas de nuestro país. La comunidad con más pacientes diagnosticados fue Madrid, aunque la mayor prevalencia se observó en Asturias. Se establecieron diferencias estadísticamente significativas en cuanto al sexo y la enfermedad (proporción de mujeres sobre varones de 2:1), así como se estableció la edad media al diagnóstico en 7,20 años. CONCLUSIONES // La prevalencia de este síndrome en España se estima muy por debajo de la prevalencia que se maneja en los textos científicos (1 por cada 50.000 recién nacidos). Adicionalmente, hemos determinado que esta prevalencia muestra grandes dife- rencias geográficas, lo que nos permite afirmar que este síndrome podría encontrarse infra-diagnosticado en nuestro país. La mayor parte de los pacientes incluidos en esta cohorte se encuentran en edad pediátrica. No se ha podido corroborar que la mortalidad en este síndrome, en nuestra población, ocurra preferentemente durante los dos primeros años de vida, como se venía afirmando.BACKGROUND // Wolf-Hirschhorn syndrome is a rare disease of genetic origin caused by the deletion of the distal end of chromo- some 4, including at least the region p16.3. The objectives of this work were to determine the prevalence of the disease in the Spanish population, as well as to establish the geographical distribution of the syndrome throughout the Spanish geography, elucidating the age range in which there are more patients. METHODS // Patients diagnosed with the disease for nine years (2013-2021) throughout the Spanish territory were recruited for the research, thanks to agreements with the Spanish Association of Wolf-Hirschhorn Syndrome (AESWH). The clinical information of the patients was obtained from referring physicians using two standardized questionnaires completed with data from medical reports and the parent interview. The molecular characterization of the disease was made using SNP (single nucleotide polymorphism) microarrays (cytoSNP850K, Illumina, USA). The data were statistically processed using Microsoft Excel (Microsoft Corporation) and SPSS (IBM) software, using comparisons between two groups s with Student’s t-test (for continuous variables) or with Chi-square tests (for categorical ones). For more than two groups, ANOVA analyses were performed (followed by Bonferroni or T3-Dunnett post hoc tests) for continuous varia- bles and z-tests between column proportions for categorical variables. RESULTS // In Spain (until 2021) eighty people are diagnosed with this syndrome, estimating its prevalence at 1.69x10-4 per 10,000 inhabitants and / or 1/172,904 for each live newborn. This paper remarks the existence of important differences in prevalence between the different regions in Spain. The region with the most diagnosed patients was Madrid, although the highest prevalence was obser- ved in Asturias. Significant differences have been established in terms of sex and disease (ratio of women to men of 2:1), and the mean age at diagnosis has been established at 7.20 years. CONCLUSIONS // The prevalence of this syndrome in Spain has been estimated well below the prevalence that is handled in scien- tific texts (1/50,000 newborns). In addition, we have determined that this prevalence shows large geographical differences, which allows us to affirm that this syndrome could be under-diagnosed in our country. Most of the patients included in this cohort are of paediatric age. It has not been possible to corroborate that mortality in this syndrome, in our population, occurs preferably during the first two years of life, as has been claimedDepto. de Investigación y Psicología en EducaciónFac. de EducaciónTRUEpu

Description of Two New Cases of <i>AQP1</i> Related Pulmonary Arterial Hypertension and Review of the Literature

Pulmonary arterial hypertension (PAH) is a severe clinical condition characterized by an increase in mean pulmonary artery pressure, which leads to a right ventricular hypertrophy and potentially heart failure and death. In the last several years, many genes have been associated with PAH, particularly in idiopathic and heritable forms but also in associated forms. Here we described the identification of two unrelated families in which the AQP1 variant was found from a cohort of 300 patients. The variants were identified by whole exome sequencing (WES). In the first family, the variant was detected in three affected members from a hereditary PAH, and in the second family the proband had PAH associated with scleroderma. In addition, we have reviewed all cases published in the literature thus far of patients with PAH and AQP1 variants. Functional studies have led to some contradictory conclusions, and the evidence of the relationship of AQP1 and PAH is still limited. However, we describe two further families with PAH and variants in AQP1, expanding both the number of cases and the clinically associated phenotype. We provide further evidence of the association of AQP1 and the development of hereditary and associated forms of PAH