Case Report
FOXG1, a new gene responsible for the congenital form of Rett syndrome
FOXG1, un nuevo gen responsable de la forma congénita del síndrome de Rett
Rev Neurol 2011
, 52(10),
597–602;
https://doi.org/10.33588/rn.5210.2010725
Abstract
INTRODUCTION Rett syndrome (RS) is a neurodevelopmental disorder that affects girls almost exclusively. The identification of mutations in the MECP2 and CDKL5 genes offers genetic confirmation of the clinical diagnosis. The FOXG1 gene appears to be a novel cause of the congenital variant of RS.
CASE REPORT We describe the first Spanish patient with the atypical (congenital) variant of RS with mutation of the FOXG1 gene and the case is compared with 12 patients previously reported in the literature; clinical criteria that suggest alterations in FOXG1 are proposed. The patient was referred at the age of 6 months due to overall retardation, axial hypotonia, microcephaly and a peculiar phenotype. Magnetic resonance imaging of the brain revealed hypoplasia of the corpus callosum, frontal atrophy and ventriculomegaly. The appearance of hand-to-mouth stereotypic movements at 12 months pointed the clinical diagnosis towards an atypical variant of RS, the congenital form; there was progressive improvement of visual contact and interest in her surroundings. Frequent respiratory infections and obstructive sleep apnoea syndrome. At the age of 5 years there was partial control over the axial tone, grasping with the hands, good contact and babbling, without epilepsy or behavioural disorders. The MECP2 and subtelomeric deletion study did not reveal any alterations; two polymorphisms were identified in the CDKL5 gene and a pathogenic mutation was found in FOXG1 (c.624C>G p.Tyr203X).
CONCLUSIONS It has been shown that 92% of patients with mutations in the FOXG1 gene present the congenital form of RS with severe generalised hypotonia, early acquired microcephaly (–3 to –6 standard deviations) and peculiar phenotype. When faced with a diagnosis of RS with no alterations in the MECP2 and CDKL5 genes, especially in the case of the congenital variant, the FOXG1 gene must be investigated. The molecular diagnosis confirms the clinical diagnosis and provides the family with genetic counselling.
CASE REPORT We describe the first Spanish patient with the atypical (congenital) variant of RS with mutation of the FOXG1 gene and the case is compared with 12 patients previously reported in the literature; clinical criteria that suggest alterations in FOXG1 are proposed. The patient was referred at the age of 6 months due to overall retardation, axial hypotonia, microcephaly and a peculiar phenotype. Magnetic resonance imaging of the brain revealed hypoplasia of the corpus callosum, frontal atrophy and ventriculomegaly. The appearance of hand-to-mouth stereotypic movements at 12 months pointed the clinical diagnosis towards an atypical variant of RS, the congenital form; there was progressive improvement of visual contact and interest in her surroundings. Frequent respiratory infections and obstructive sleep apnoea syndrome. At the age of 5 years there was partial control over the axial tone, grasping with the hands, good contact and babbling, without epilepsy or behavioural disorders. The MECP2 and subtelomeric deletion study did not reveal any alterations; two polymorphisms were identified in the CDKL5 gene and a pathogenic mutation was found in FOXG1 (c.624C>G p.Tyr203X).
CONCLUSIONS It has been shown that 92% of patients with mutations in the FOXG1 gene present the congenital form of RS with severe generalised hypotonia, early acquired microcephaly (–3 to –6 standard deviations) and peculiar phenotype. When faced with a diagnosis of RS with no alterations in the MECP2 and CDKL5 genes, especially in the case of the congenital variant, the FOXG1 gene must be investigated. The molecular diagnosis confirms the clinical diagnosis and provides the family with genetic counselling.
Resumen
Introducción El síndrome de Rett (SR) es un trastorno del neurodesarrollo que afecta casi exclusivamente a niñas. La identificación de mutaciones en los genes MECP2 y CDKL5 aporta una confirmación genética del diagnóstico clínico. El gen FOXG1 se perfila como un nuevo responsable de la variante congénita del SR.
Caso clínico Se describe la primera paciente española con variante atípica (congénita) del SR con mutación en el gen FOXG1, y se compara con 12 pacientes publicados en la bibliografía; se proponen criterios clínicos sugestivos de alteraciones en el FOXG1. La paciente fue remitida a los 6 meses por retraso global, hipotonía axial, microcefalia y fenotipo peculiar. Resonancia magnética cerebral: hipoplasia del cuerpo calloso, atrofia frontal y ventriculomegalia. Aparición de estereotipias mano-boca a los 12 meses que orientan hacia el diagnóstico clínico de variante atípica del SR, forma congénita; mejoría progresiva del contacto visual e interés por el medio. Infecciones respiratorias frecuentes y síndrome de apnea obstructiva del sueño. A los 5 años existe un control parcial del tono axial, prensión manual, buen contacto y balbuceo, sin epilepsia ni alteraciones conductuales. El estudio de MECP2 y deleciones subteloméricas no mostró alteraciones; se identificaron dos polimorfismos en el gen CDKL5 y una mutación patogénica en el FOXG1 (c.624C>G p.Tyr203X).
Conclusiones El 92% de pacientes con mutaciones en el gen FOXG1 presenta la forma congénita del SR con una grave hipotonía generalizada, microcefalia adquirida precoz (–3 a –6 desviaciones estándares) y fenotipo peculiar. Ante un diagnóstico de SR sin alteración en los genesMECP2 y CDKL5, especialmente en la variante congénita, debe investigarse el gen FOXG1. El diagnóstico molecular confirma el diagnóstico clínico y aporta un consejo genético a la familia.
Caso clínico Se describe la primera paciente española con variante atípica (congénita) del SR con mutación en el gen FOXG1, y se compara con 12 pacientes publicados en la bibliografía; se proponen criterios clínicos sugestivos de alteraciones en el FOXG1. La paciente fue remitida a los 6 meses por retraso global, hipotonía axial, microcefalia y fenotipo peculiar. Resonancia magnética cerebral: hipoplasia del cuerpo calloso, atrofia frontal y ventriculomegalia. Aparición de estereotipias mano-boca a los 12 meses que orientan hacia el diagnóstico clínico de variante atípica del SR, forma congénita; mejoría progresiva del contacto visual e interés por el medio. Infecciones respiratorias frecuentes y síndrome de apnea obstructiva del sueño. A los 5 años existe un control parcial del tono axial, prensión manual, buen contacto y balbuceo, sin epilepsia ni alteraciones conductuales. El estudio de MECP2 y deleciones subteloméricas no mostró alteraciones; se identificaron dos polimorfismos en el gen CDKL5 y una mutación patogénica en el FOXG1 (c.624C>G p.Tyr203X).
Conclusiones El 92% de pacientes con mutaciones en el gen FOXG1 presenta la forma congénita del SR con una grave hipotonía generalizada, microcefalia adquirida precoz (–3 a –6 desviaciones estándares) y fenotipo peculiar. Ante un diagnóstico de SR sin alteración en los genesMECP2 y CDKL5, especialmente en la variante congénita, debe investigarse el gen FOXG1. El diagnóstico molecular confirma el diagnóstico clínico y aporta un consejo genético a la familia.
Keywords
Congenital variant of Rett syndrome
FOXG1
Hypotonia
Microcephaly
Phenotype
Rett syndrome
Palabras Claves
FOXG1
Fenotipo
Hipotonía
Microcefalia
Síndrome de Rett
Variante congénita del síndrome de Rett