PICO questions and DELPHI methodology for improving the management of patients with acute hepatic porphyria.

BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

Paquioniquia congénita: nuevo caso asociado al gen KRT17 / Congenital pachyonychia: a new case associated with theKRT17 gene

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Porfiria aguda intermitente en población pediátrica de la región de Murcia: fenotipo y prevalencia / Acute intermittent porphyria in a paediatric population in the region of Murcia: Phenotype and prevalence

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Síndrome Schinzel-Giedion: nueva mutación en SETBP1 / Schinzel-Giedion syndrome: A new mutation in SETBP1

El síndrome Schinzel-Giedion (SSG) (#MIM 269150) es una enfermedad genética infrecuente, caracterizada por dismorfia cráneo-facial específica, anomalías congénitas múltiples y discapacidad intelectual grave. La mayoría de los pacientes fallece en los primeros años de vida. Se debe a mutaciones en el gen SETBP1, habiéndose descrito a la fecha un reducido número de pacientes con confirmación molecular. Presentamos a un paciente de 4 años con SSG asociado a la mutación c.2608G>T (p.Gly870Cys) en el gen SETBP1, no descrita previamente. Se revisan las características clínicas de esta enfermedad y su diagnóstico diferencial. Los rasgos dismórficos son muy característicos en el SSG. Su reconocimiento clínico es fundamental para alcanzar un diagnóstico precoz, planificar un correcto seguimiento y ofrecer asesoramiento genético familiar adecuado. A la fecha, este es el decimoséptimo paciente ublicado con mutación en el gen SETBP1, primero en España, contribuyendo a ampliar el conocimiento clínico y molecular de esta entidad

Schinzel-Giedion syndrome (SGS) (#MIM 269150) is a rare genetic disorder characterized by very marked craniofacial dysmorphism, multiple congenital anomalies and severe intellectual disability. Most affected patients die in early childhood. SETBP1 was identified as the causative gene, but a limited number of patients with molecular confirmation have been reported to date. The case is reported of a 4 and a half year-old male patient, affected by SGS. SETBP1 sequencing analysis revealed the presence of a non-previously described mutation: c.2608G>T (p.Gly870Cys). The clinical features and differential diagnosis of this rare condition are reviewed. Dysmorphic features are strongly suggestive of SGS. Its clinical recognition is essential to enable an early diagnosis, a proper follow-up, and to provide the family with genetic counseling. To date, this is the seventeenth SGS patient published with SETBP1 mutation, and the first in Spain, helping to widen clinical and molecular knowledge of the disease

[Schinzel-Giedion syndrome: a new mutation in SETBP1]. / Síndrome Schinzel-Giedion: nueva mutación en SETBP1.

Schinzel-Giedion syndrome (SGS) (#MIM 269150) is a rare genetic disorder characterized by very marked craniofacial dysmorphism, multiple congenital anomalies and severe intellectual disability. Most affected patients die in early childhood. SETBP1 was identified as the causative gene, but a limited number of patients with molecular confirmation have been reported to date. The case is reported of a 4 and a half year-old male patient, affected by SGS. SETBP1 sequencing analysis revealed the presence of a non-previously described mutation: c.2608G>T (p.Gly870Cys). The clinical features and differential diagnosis of this rare condition are reviewed. Dysmorphic features are strongly suggestive of SGS. Its clinical recognition is essential to enable an early diagnosis, a proper follow-up, and to provide the family with genetic counseling. To date, this is the seventeenth SGS patient published with SETBP1 mutation, and the first in Spain, helping to widen clinical and molecular knowledge of the disease.

The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor.

Homozygous mutations of the telomeric SMN1 gene lead to degeneration of motor neurons causing spinal muscular atrophy (SMA). A highly similar centromeric gene (SMN2) can only partially compensate for SMN1 deficiency. The c.859G>C variant in SMN2 has been recently reported as a positive disease modifier. We identified the variant in 10 unrelated chronic SMA patients with a wide spectrum of phenotypes ranging from type II patients who can only sit to adult walkers. Haplotype analysis strongly suggests that the variant originated from a common ancestor. Our results confirm that the c.859G>C variant is a milder SMN2 allele and predict a direct correlation between SMN activity and phenotypic severity.

A compound heterozygous mutation in the EDAR gene in a Spanish family with autosomal recessive hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterised by sparse hair, lack of sweat glands and malformation of teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of HED cases. Autosomal forms result from mutations in either the EDAR or the EDARADD gene. The X-linked and autosomal forms are phenotypically indistinguishable. For the purpose of genetic counselling, it is, therefore, important to know which gene is involved. In this study, we ascertained a Spanish family demonstrating the autosomal recessive form of HED. Affected individuals in the family showed the characteristic features of HED, including fine and sparse scalp hair, sparse eyebrows and eyelashes, periorbital hyperpigmentation, prominent lips, hypodontia and conical teeth, reduced sweating, and dry and thin skin. Sequence analysis of the EDAR gene revealed a novel compound heterozygous mutation [c.52-2A>G; c.212G>A (p.Cys71Tyr)]. Our finding extends the body of evidence that supports the significance of the EDAR signalling pathway in the ectodermal morphogenesis.

Genética clínica y dismorfología: generalidades / Clinical genetics and dysmorphology: generalities

La genética clínica (GC) es la parte de la genética humana que se ocupa de la salud de los individuos y sus familias. Es la ciencia y la práctica del diagnóstico, la prevención y el manejo de las enfermedades genéticas (EG). Las EG tiene un gran impacto en la salud de los individuos y contribuyen significativamente al aumento de la morbimortalidad. La mayoría de las EG se consideran enfermedades raras, las cuales constituyen actualmente una prioridad en los planes de investigación y salud pública. La GC es reconocida como especialidad en la mayoría de los países desarrollados de la Unión Europea, no así en España. Para muchas de la EG que no cuentan con diagnóstico genético específico, los médicos genetistas tienen un papel fundamental como dismorfólogos. La dismofología se ocupa del estudio de las malformaciones congénitas. Otra parte crucial de la GC es el asesoramiento genético, básico en la medicina actual y que debe proporcionarse por profesionales expertos. La Genética está experimentado un rápido progreso y el genetista clínico también debe velar por el respecto de la privacidad y confidencialidad de los datos genéticos de los individuos para preservarlos de la discriminación (AU)

Clinical Genetics (CG) is the field of Human Genetics concerned with the health of individual humans and their families. It is defined as the science and practice of diagnosis, prevention, and management of genetic disorders (GD). These have a significant impact in the health of individuals and their contribution to morbidity and mortality is high. Most GD are rare diseases and currently considered a priority in research and public health programmes. CG is recognized specialty is most developed countries of the European Union, not yet in Spain. For many GD, without a specific laboratory diagnostic test, clinical geneticists play an important role as dysmorphologists. Dysmorphology studies human malformations. Genetic counseling is an important part of CG and medicine in general and must be provided by specialist. Genetics is currently undergoing extraordinary developments, promoting the importance of prognosis and prediction which has to be translated to public health. Clinical geneticists must protect the privacy and confidentiality of the individual´s genetic information in order to avoid discrimination (AU)

[Review of 22 patients with 22q11.2 deletion syndrome: phenotype spectrum]. / Revisión de 22 casos de deleción 22q11.2: espectro fenotípico.

INTRODUCTION: The 22q11.2 deletion syndrome is a contiguous gene deletion syndrome with an incidence rate of 1/4,000-6,000 live births. The most specific clinical features are: congenital conotruncal heart diseases, palate anomalies, hypocalcaemia, immunity and learning problems, and a characteristic facial phenotype. The objective of this work is to review the presenting phenotype and clinical features of children with 22q11.2 deletion syndrome as a guide for early diagnosis. PATIENTS AND METHODS: Retrospective study of 22 patients with 22q11.2 deletion syndrome diagnosed at our hospital in the time period 2004-2007. Variables analyzed: incidence, sex, age at diagnosis, presenting phenotype, clinical features, positive family history, mortality and natural history. RESULTS: From a total of 22 patients, 63 % were males, and the median age at diagnosis was of 4.5 years. Presenting pheno-type: congenital heart disease, milestones delay, velopharyngeal incompetence, hypocalcaemia, and mental retardation/psychiatric disturbances. CLINICAL FEATURES: congenital heart disease (84 %), velopharyngeal incompetence (47 %), milestones delay and learning disabilities (79 %). All of the deletions were de novo, except in one case where the deletion was present as mosaicism in the father. Three patients died, due to congenital heart disease. CONCLUSIONS: Clinical expression is widely variable, although a characteristic phenotype exists. Patients with heart disease are diagnosed earlier than other patients with unusual presenting phenotype such as congenital dysphagia. It is important to recognize less common phenotypes at early ages in order to provide multidisciplinary monitoring and accurate genetic counselling.

Revisión de 22 casos de deleción 22q11.2: espectro fenotípico / Review of 22 patients with 22q11.2 deletion syndrome: phenotype spectrum

Introducción: El síndrome de deleción 22q11.2 es un síndrome de genes contiguos con una incidencia de un caso por cada 4.000-6.000 recién nacidos. Posee una amplia variabilidad clínica y sus características clínicas más frecuentes son cardiopatía conotruncal, anomalías palatinas, hipocalcemia, problemas de inmunidad y de aprendizaje, y un fenotipo facial característico. El objetivo de este estudio es revisar las formas de presentación y las manifestaciones clínicas de los niños con deleción 22q11.2 como guía para su diagnóstico precoz. Pacientes y métodos: Estudio retrospectivo de 22 casos de deleción 22q11.2 diagnosticados en nuestro hospital entre los años 2004 y 2007, en que se analizan las siguientes variables: incidencia, sexo, edad en el momento del diagnóstico, forma de presentación, características clínicas, antecedentes familiares, mortalidad y evolución. Resultados: De los 22 pacientes, el 63 % fueron varones y la edad media en el momento de realizar el diagnóstico fue de 4,5 años. Las formas de presentación fueron cardiopatía, retraso psicomotor, insuficiencia velopalatina, hipocalcemia y retraso mental o alteraciones psiquiátricas. Las principales manifestaciones clínicas fueron cardiopatía (84 %), insuficiencia velopalatina (47 %), retraso psicomotor y problemas de aprendizaje (79 %). Todos los casos fueron deleciones de novo, salvo un caso en el que se identificó la deleción "en mosaico" en el padre. Fallecieron 3 pacientes a causa de cardiopatía. Conclusiones: La expresión clínica es muy variable, aunque existe un fenotipo característico. Los niños con cardiopatía conotruncal son diagnosticados más tempranamente, pero en otras formas de presentación, como la disfagia congénita, el diagnóstico se retrasa más. Es necesario tener en cuenta las formas de presentación menos habituales para identificar en edades tempranas a estos pacientes y proporcionarles una atención multidisciplinaria temprana y un asesoramiento genético familiar adecuado (AU)

Introduction: The 22q11.2 deletion syndrome is a contiguous gene deletion syndrome with an incidence rate of 1/4,000-6,000 live births. The most specific clinical features are: congenital conotruncal heart diseases, palate anomalies, hypocalcaemia, immunity and learning problems, and a characteristic facial phenotype. The objective of this work is to review the presenting phenotype and clinical features of children with 22q11.2 deletion syndrome as a guide for early diagnosis. Patients and methods: Retrospective study of 22 patients with 22q11.2 deletion syndrome diagnosed at our hospital in the time period 2004-2007. Variables analyzed: incidence, sex, age at diagnosis, presenting phenotype, clinical features, positive family history, mortality and natural history. Results: From a total of 22 patients, 63 % were males, and the median age at diagnosis was of 4.5 years. Presenting pheno-type: congenital heart disease, milestones delay, velopharyngeal incompetence, hypocalcaemia, and mental retardation/psychiatric disturbances. Clinical features: congenital heart disease (84 %), velopharyngeal incompetence (47 %), milestones delay and learning disabilities (79 %). All of the deletions were de novo, except in one case where the deletion was present as mosaicism in the father. Three patients died, due to congenital heart disease. Conclusions: Clinical expression is widely variable, although a characteristic phenotype exists. Patients with heart disease are diagnosed earlier than other patients with unusual presenting phenotype such as congenital dysphagia. It is important to recognize less common phenotypes at early ages in order to provide multidisciplinary monitoring and accurate genetic counseling (AU)

Neurofibromatosis tipo I y fobia escolar / Type I neurofibromatosis and school phobia

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Duplication 19q13-qter and deletion 19p13-pter arising from an inversion (19)(p13.3q13.3) of maternal origin.

Pericentric inversion of chromosome 19 appears to be a rare abnormality with only a few families reported. As far as we are aware, none of them were ascertained because of a recombinant individual. We describe the first identified case due to an affected patient, with duplication deficiency for chromosome 19 arising from a maternal inversion confirmed by FISH and CGH. His features included prenatal growth retardation, microcephaly, dysmorphic facies, congenital heart defect, hypoplasia of corpus callosum and psychomotor delay. The identification of recombinant individuals contribute to calculate a precise risk for inv (19) carriers and to provide a more accurate genetic counselling.