RESUMO
OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.
Assuntos
Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Mutação , Hipertensão Arterial Pulmonar/epidemiologia , Hipertensão Arterial Pulmonar/genética , Receptores de Activinas Tipo II/genética , Adolescente , Aracnodactilia/complicações , Aracnodactilia/epidemiologia , Aracnodactilia/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Criança , Pré-Escolar , Contratura/complicações , Contratura/epidemiologia , Contratura/genética , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Dosagem de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , Lactente , Masculino , Proteínas do Tecido Nervoso/genética , Países Baixos/epidemiologia , Síndrome de Noonan/complicações , Síndrome de Noonan/epidemiologia , Síndrome de Noonan/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Estudos Prospectivos , Proteínas Serina-Treonina Quinases/genética , Sistema de Registros , Proteínas com Domínio T/genética , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/epidemiologia , Deficiência de Vitamina B 12/genéticaRESUMO
The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4-6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60-80% of patients have a cardiac malformation most commonly including a subset of conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B), conoventricular and/or atrial septal defects, and aortic arch anomalies. Cardiac patients with a 22q11.2 deletion do not generally experience higher mortality upon surgical intervention but suffer more peri-operative complications than their non-syndromic counterparts. New guidelines suggest screening for a 22q11.2 deletion in the patient with tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, conoventricular septal defects as well as those with an isolated aortic arch anomaly. Early identification of a 22q11.2 deletion in the neonate or infant when other syndromic features may not be apparent allows for timely parental screening for reproductive counseling and anticipatory evaluation of cardiac and noncardiac features. Screening the at-risk child or adult allows for important age-specific clinical, neurodevelopmental, psychiatric, and reproductive issues to be addressed.
Assuntos
Aorta Torácica/anormalidades , Aracnodactilia/epidemiologia , Craniossinostoses/epidemiologia , Síndrome de DiGeorge/epidemiologia , Cardiopatias Congênitas/epidemiologia , Síndrome de Marfan/epidemiologia , Aorta Torácica/patologia , Aracnodactilia/complicações , Aracnodactilia/genética , Deleção Cromossômica , Craniossinostoses/complicações , Craniossinostoses/genética , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/genética , Guias como Assunto , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Tetralogia de Fallot/complicações , Tetralogia de Fallot/epidemiologia , Tetralogia de Fallot/genética , Tronco Arterial/patologiaRESUMO
Shprintzen-Goldberg Syndrome is an extremely infrequent disorder of connective tissue, characterized by craniosynostosis and marfanoid features, also known as Marfanoid Craniosynostosis syndrome. The syndrome was first introduced by Sugarman and Vogel' (1981) however, Shprintzen and Goldberg established this as a separate clinical entity in the year 1982. Since then, approximately sixty such cases have been set down in writing in the medical literature. Herein, we present a short review of literature of this rare connective disorder, in order to create awareness about this condition, as the magnitude of this disorder is not measured properly due to the paucity of literature.
