Smith-Lemli-Opitz syndrome

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCThe Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital anomaly/mental retardation pattern caused by an inborn error of cholesterol metabolism. Deficient cholesterol synthesis is caused by inherited mutations of 7-dehydrocholesterol reductase gene, that catalyzes the final step of the pathway: the conversion of 7-dehydrocholesterol to cholesterol. To date, more than 125 different mutations have been identified and more than 750 patients have been reported with an extremely broad clinical spectrum. This paper describes two patients with a neonatal diagnosis and reviews the syndrome with special insights into genetics, pathogenesis, diagnosis, prenatal included, and treatmentN

Analysis of the holm oak (Quercu Ilex subs ballota) pollen proteome by using NLC-MS/MS

Comunicaciones a congreso

Sorsby syndrome: Report of a case representing the second reported family

Dismorfología y Genética ClínicaIn 1935, Sorsby [Br J Ophthalmol. 1935; 19:65-90] described a family with several affected individuals presenting with bilateral coloboma of macula, type B brachydactyly affecting hands and feet, and unilateral renal agenesis in one of its members. We describe a newborn girl presenting with the same pattern of congenital anomalies as the patients of the family originally described by Sorsby (OMIM 120400). However, the current case has as additional findings a single umbilical artery, and an anomaly of pulmonary vascularization consisting in: a ring in the lower right lobar artery and sequestration of the lower right lung lobe. Therefore, despite that our patient adds new clinical variability, it is not possible to disregard the diagnosis of Sorsby syndrome, because such clinical variability was also observed in the affected members of the original family described by Sorsby and some individuals of the next generations of the same family, according to the report by Thompson and Baraitser [J Med Genet. 1988; 25:313-321]. Based on the observed genealogy pattern of affected members in the only family published, it is considered that this syndrome is due to an autosomal dominant gene. The baby described here, is the first case in the family. She had a normal karyotype (~850 bands) and the subtelomeric Multi-FISH was also normal. Her father was 39 years old and, therefore, an age-related new mutation could be evaluated. The frequency of Sorsby syndrome is unknown, since only the original family has been published so far. However, as the case described here is part of the ECEMC Registry, we can estimate that its frequency is at least 1:2,750,000 newborn infants. We consider that, even in the “molecular era”, it remains important to clinically describe those extremely rare syndromes, in order to define their characteristics and clinical expressions. These aspects are essential to define the prognosis, clinical management and information to the family, and can help also to determine the gene(s) or pathogenetic pathways involved in their origin.N

The spectrum of Apert syndrome: phenotype, particularities in orthodontic treatment, and characteristics of orthognathic surgery

In the PubMed accessible literature, information on the characteristics of interdisciplinary orthodontic and surgical treatment of patients with Apert syndrome is rare. The aim of the present article is threefold: (1) to show the spectrum of the phenotype, in order (2) to elucidate the scope of hindrances to orthodontic treatment, and (3) to demonstrate the problems of surgery and interdisciplinary approach. Children and adolescents who were born in 1985 or later, who were diagnosed with Apert syndrome, and who sought consultation or treatment at the Departments of Orthodontics or Craniomaxillofacial Surgery at the Dental School of the University Hospital of Münster (n = 22; 9 male, 13 female) were screened. Exemplarily, three of these patients (2 male, 1 female), seeking interdisciplinary (both orthodontic and surgical treatment) are presented. Orthodontic treatment before surgery was performed by one experienced orthodontist (AH), and orthognathic surgery was performed by one experienced surgeon (UJ), who diagnosed the syndrome according to the criteria listed in OMIM™. In the sagittal plane, the patients suffered from a mild to a very severe Angle Class III malocclusion, which was sometimes compensated by the inclination of the lower incisors; in the vertical dimension from an open bite; and transversally from a single tooth in crossbite to a circular crossbite. All patients showed dentitio tarda, some impaction, partial eruption, idopathic root resorption, transposition or other aberrations in the position of the tooth germs, and severe crowding, with sometimes parallel molar tooth buds in each quarter of the upper jaw. Because of the severity of malocclusion, orthodontic treatment needed to be performed with fixed appliances, and mainly with superelastic wires. The therapy was hampered with respect to positioning of bands and brackets because of incomplete tooth eruption, dense gingiva, and mucopolysaccharide ridges. Some teeth did not move, or moved insufficiently (especially with respect to rotations and torque) irrespective of surgical procedures or orthodontic mechanics and materials applied, and without prognostic factors indicating these problems. Establishing occlusal contact of all teeth was difficult. Tooth movement was generally retarded, increasing the duration of orthodontic treatment. Planning of extractions was different from that of patients without this syndrome. In one patient, the sole surgical procedure after orthodontic treatment with fixed appliances in the maxilla and mandible was a genioplasty. Most patients needed two- jaw surgery (bilateral sagittal split osteotomy [BSSO] with mandibular setback and distraction in the maxilla). During the period of distraction, the orthodontist guided the maxilla into final position by means of bite planes and intermaxillary elastics. To our knowledge, this is the first article in the PubMed accessible literature describing the problems with respect to interdisciplinary orthodontic and surgical procedures. Although the treatment results are not perfect, patients undergoing these procedures benefit esthetically to a high degree. Patients need to be informed with respect to the different kinds of extractions that need to be performed, the increased treatment time, and the results, which may be reached using realistic expectations

Síndromes muy poco frecuentes

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCSince the year 2002, this Section of the Boletín del ECEMC: Revista de Dismorfología y Epidemiología, is dedicated to dysmorphology, cytogenetics and clinical analysis of congenital anomalies, and includes a chapter on syndromes with very low frequency. The aim of this chapter is to summarize the most important characteristics, the etiology, and the mechanisms involved in the selected syndromes. The low frequency of these syndromes, together with their probable decreasing birth prevalence due to the impact of prenatal diagnosis, imply that pediatricians and other health professionals would have less opportunity to know their clinical characteristics. This circumstance together with the overlapping of the clinical features among some of the syndromes, make difficult to perform an early diagnosis, which is important for genetic counselling, and to provide the most suitable treatment to each pacient. The syndromes included are: Aarskog, Freeman-Sheldon, Cleidocranial dysplasia, Noonan, Cardio-Facio-Cutaneous and Costello. In addition, a short summary about the differential diagnosis among Noonan, Cardio-Facio-Cutaneous and Costello syndromes is also included.N

Pacientes españoles con síndrome de hipoventilación central incluidos en el Registro europeo. Datos del 2015

Introducción El síndrome de hipoventilación central congénita (SHCC) es una enfermedad genética muy rara causada por mutaciones en PHOX2B; en 2010 se creó el Consorcio Europeo del Síndrome de Hipoventilación Central, que en 2012 implantó un Registro online de pacientes para optimizar su cuidado. Objetivo Conocer las características y la evolución de los pacientes españoles con SHCC y detectar áreas de mejora. Materiales y método Se analizaron los datos actualizados en diciembre del 2015 de los pacientes españoles del Registro europeo. Resultados Se registró a 38 pacientes, nacidos entre 1987 y 2013, procedentes de 18 hospitales. El 34, 2% eran mayores de 18 años. Han fallecido 3 pacientes. Aportaban estudio del gen PHOX2B 37 (97, 3%), 32 (86, 5%) con mutación. Los genotipos 20/25, 20/26 y 20/27 representaron el 84, 3% de las mutaciones. Las disautonomías fueron más frecuentes y graves en portadores de genotipos con mayores expansiones de polialaninas. El 47% de pacientes asociaba alteraciones oculares, el 16% Hirschsprung, el 13% hipoglucemias y el 5% tumores. Treinta pacientes (79%) debutaron en el periodo neonatal y 8 (21%) posteriormente (inicio/diagnóstico tardío). Ocho niños (21%) recibieron inicialmente ventilación domiciliaria con mascarilla; 5 eran lactantes con comienzo neonatal, 2 de ellos precisaron cambio a traqueostomía tras presentar parada cardiorrespiratoria; ambos tenían mutaciones graves. Han sido decanulados y transferidos a mascarilla el 34, 3% de los pacientes (edad media: 13, 7 años). El 29, 4% de los niños escolarizados precisaron refuerzo educativo. Conclusión La implementación del Registro en España de pacientes con SHCC ha permitido identificar aspectos relevantes para optimizar sus cuidados, tales como la importancia del estudio genético para el diagnóstico y la estimación de gravedad, la frecuencia elevada de alteraciones oculares y de necesidad de refuerzo educativo, y algunas limitaciones de las técnicas ventilatorias. Introduction Congenital Central Hypoventilation Syndrome (CCHS) is a very rare genetic disease. In 2012 the European Central Hypoventilation Syndrome (EuCHS) Consortium created an online patient registry in order to improve care. Aim To determine the characteristics and outcomes of Spanish patients with CCHS, and detect clinical areas for improvement. Materials and method An assessment was made on the data from Spanish patients in the European Registry, updated on December 2015. Results The Registry contained 38 patients, born between 1987 and 2013, in 18 hospitals. Thirteen (34.2%) were older than 18 years. Three patients had died. Genetic analysis identified PHOX2B mutations in 32 (86.5%) out of 37 patients assessed. The 20/25, 20/26 and 20/27 polyalanine repeat mutations (PARMs) represented 84.3% of all mutations. Longer PARMs had more, as well as more severe, autonomic dysfunctions. Eye diseases were present in 47%, with 16% having Hirschsprung disease, 13% with hypoglycaemia, and 5% with tumours. Thirty patients (79%) required ventilation from the neonatal period onwards, and 8 (21%) later on in life (late onset/presentation). Eight children (21%) were using mask ventilation at the first home discharge. Five of them were infants with neonatal onset, two of them, both having a severe mutation, were switched to tracheostomy after cardiorespiratory arrest at home. Approximately one-third (34.3%) of patients were de-cannulated and switched to mask ventilation at a mean age of 13.7 years. Educational reinforcement was required in 29.4% of children attending school. Conclusion The implementation of the EuCHS Registry in Spain has identified some relevant issues for optimising healthcare, such as the importance of genetic study for diagnosis and assessment of severity, the high frequency of eye disease and educational reinforcement, as well as some limitations in ventilatory techniques

Very low frequency Syndromes

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCThe aim of this chapter is to summarize updated knowledge about the clinical characteristics, etiology, genetic and molecular aspects, as well as mechanisms involved in syndromes having very low frequency, in order to promote their better recognition. During the last five years, a total of 30 syndromes have been published in this chapter of the Boletín del ECEMC. This issue includes the following selected syndromes: Crouzon, Pfeiffer, Apert, Saethre-Chotzen, Carpenter and Muenke. All share craniosynostosis as the main clinical feature but also present with other birth defects, the most important being limb malformations, specially syndactyly and polydactyly. Over 100 syndromes with craniosynostosis have been described, usually involving multiple sutures, and several of them are associated with limb malformations. The clinical overlapping between those syndromes makes difficult to perform a neonatal diagnosis, based on their clinical findings. However, molecular genetic testing, specifically of the FRGR1-3 and TWIST1 genes, could help to establish the diagnosis of some of them. Early diagnosis is important for establishing the most suitable treatment for each patient, as well as to offer an accurate genetic counselling and the possibility of preimplantational and/or prenatal diagnosis.N

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life