RESUMEN
Setleis syndrome is characterized by bitemporal scar-like lesions and other characteristic facial features. It results from recessive mutations that truncate critical functional domains in the basic helix-loop-helix (bHLH) transcription factor, TWIST2, which regulates expression of genes for facial development. To date, only four nonsense or small deletion mutations have been reported. In the current report, the clinical findings in a consanguineous Turkish family were characterized. Three affected siblings had the characteristic features of Setleis syndrome. Homozygosity for the first TWIST2 missense mutation, c.326T>C (p.Leu109Pro), was identified in the patients. In silico analyses predicted that the secondary structure of the mutant protein was sustained, but the empirical force field energy increased to an unfavorable level with the proline substitution (p.Leu109Pro). On a crystallographically generated dimer, p.Leu109 lies near the dimer interface, and the proline substitution is predicted to hinder dimer formation. Therefore, p.Leu109Pro-TWIST2 alters the three dimensional structure and is unable to dimerize, thereby hindering the binding of TWIST2 to its target genes involved in facial development.
Asunto(s)
Hipoplasia Dérmica Focal/genética , Mutación Missense , Proteínas Represoras/genética , Enfermedades de la Piel/genética , Proteína 1 Relacionada con Twist/genética , Adolescente , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Niño , Simulación por Computador , Cristalografía , Displasia Ectodérmica , Femenino , Hipoplasia Dérmica Focal/diagnóstico , Hipoplasia Dérmica Focal/patología , Displasias Dérmicas Faciales Focales , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Proteínas Represoras/metabolismo , Alineación de Secuencia , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/patología , Turquía , Proteína 1 Relacionada con Twist/metabolismo , Población Blanca/genéticaAsunto(s)
Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Enfermedades del Oído/congénito , Oído Externo/anomalías , Polimorfismo Genético , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Apoptosis/genética , Proliferación Celular , Enfermedades del Oído/epidemiología , Enfermedades del Oído/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Incidencia , Síndrome , Turquía/epidemiología , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominantly inherited disorder characterized mainly by hypoplasia/aplasia of lacrimal and salivary tracts, small cup-shaped and/or malformed ears, sensorineuronal or conductive hearing loss, abnormalities of the teeth, and variable anomalies of the hands and feet. In this case report, general and dentofacial features of 2 siblings and their father are described. Both siblings presented hypoplastic lacrimal puncta, cup-shaped/low-set ears with bilateral sensorineuronal hearing loss, broad first toes, and bilateral clinodactyly of the fifth toes. The 17-year-old female revealed mainly peg-shaped incisors, long thin-rooted teeth, malformed molars, microdontia, and enamel hypoplasia; and the 10-year-old male showed a short lingual frenulum, peg-shaped incisors, shallow cusps, agenesis of mandibular second premolars, and taurodontism. Father exhibited hypoplastic puncta, hypolacrimia, mild bilateral sensorineural hearing loss, taurodontism, and absence of some teeth. In conclusion, this case report of a family has demonstrated the various general and orofacial features encountered in LADD syndrome.
