RESUMEN
RIPPLY2 is an essential part of the formation of somite patterning during embryogenesis and in establishment of rostro-caudal polarity. Here, we describe three individuals from two families with compound-heterozygous variants in RIPPLY2 (NM_001009994.2): c.238A > T, p.(Arg80*) and c.240-4 T > G, p.(?), in two 15 and 20-year-old sisters, and a homozygous nonsense variant, c.238A > T, p.(Arg80*), in an 8 year old boy. All patients had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of SCDO6 including scoliosis, mild facial asymmetry, spinal spasticity and hemivertebrae. The nonsense variant can be classified as likely pathogenic based on the ACMG criteria while the splice variants must be classified as a variant of unknown significance. With this report on two further families, we confirm RIPPLY2 as the gene for SCDO6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum.
Asunto(s)
Vértebras Cervicales/anomalías , Disostosis/congénito , Proteínas Represoras/genética , Alelos , Niño , Codón sin Sentido , Disostosis/genética , Disostosis/patología , Cara/anomalías , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación Missense , Sitios de Empalme de ARN , Costillas/anomalías , Escoliosis/genética , Somitos/patología , Médula Espinal/anomalías , Estenosis Espinal/genética , Secuenciación del ExomaRESUMEN
Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout the arterial tree. The genetic cause is heterogeneous and includes mutations in genes encoding for components of the transforming growth factor beta (TGFß) signalling pathway: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3. Despite the loss of function nature of these mutations, the patient-derived aortic tissues show evidence of increased (rather than decreased) TGFß signalling. These insights offer new options for therapeutic interventions.
Asunto(s)
Disección Aórtica , Síndrome de Loeys-Dietz , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Mutación , Receptores de Factores de Crecimiento Transformadores beta/genéticaRESUMEN
The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.
Asunto(s)
Anomalías Múltiples/genética , Hernia Diafragmática/genética , Síndrome de Klippel-Feil/genética , Anomalías Musculoesqueléticas/genética , Proteínas Represoras/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Vértebras Cervicales/diagnóstico por imagen , Femenino , Hernia Diafragmática/diagnóstico por imagen , Hernia Diafragmática/patología , Homocigoto , Humanos , Síndrome de Klippel-Feil/diagnóstico por imagen , Síndrome de Klippel-Feil/patología , Imagen por Resonancia Magnética , Anomalías Musculoesqueléticas/diagnóstico por imagen , Anomalías Musculoesqueléticas/patología , Mutación/genética , Radiografía , Secuenciación del ExomaRESUMEN
Cornelia de Lange syndrome (CdLS) is a complex genetic disease with skeletal involvement mostly related to upper limb malformations. We report on three males with clinical and molecular diagnoses of CdLS. Besides typical CdLS features, all showed different cervical spine malformations. To the best of our knowledge, this is an unusual malformation in the CdLS phenotypic spectrum.