Stickler syndrome

¿Que es Stickler syndrome?

Stickler es un grupo progresivo y hereditario de síndrome. Esto significa síntomas asociados y desencadenados por esta rara enfermedad empeoran con el tiempo.

Síntomas pueden variar ampliamente en su tipo y gravedad entre individuos. Sin embargo, las características más serias del síndrome puede causar problemas de visión y audición, así como problemas en las articulaciones.

Individuos con el síndrome tiene cantidades anormales de colágeno que afectan principalmente a anomalías auditivas, oculares, esqueléticas y orofaciales. A menudo, las personas con síndrome tener una apariencia facial aplanada.

Síndrome Sinónimos:
OMA Artrooftalmopatía Marshall- Stickler syndrome WZS

¿Qué causan los cambios genéticos Stickler syndrome?

Las mutaciones en seis genes son responsables del síndrome. Estos genes incluyen COL2A1, COL11A1, COL9A1, COL9A2, COL9AE.

Dependiendo de la mutación genética, esta rara enfermedad puede heredarse con un patrón autosómico dominante o autosómico recesivo.

En el caso de la herencia autosómica dominante, solo uno de los padres es el portador de la mutación genética y tiene un 50% de posibilidades de transmitirla a cada uno de sus hijos. Los síndromes heredados en una herencia autosómica dominante son causados por una sola copia de la mutación genética.

La herencia autosómica recesiva significa que un individuo afectado recibe una copia de un gen mutado de cada uno de sus padres, dándoles dos copias de un gen mutado. Los padres, que portan sólo una copia de la mutación genética, generalmente no mostrarán ningún síntoma, pero tienen un 25% de posibilidades de transmitir las copias de las mutaciones genéticas a cada uno de sus hijos.

¿Cuales son los principales síntomas de Stickler syndrome?

El principal síntomas incluyen numerosos problemas oculares y visuales. Estos incluyen miopía, desprendimiento de retina, cataratas, astigmatismo, ojos cruzados y glaucoma.

Las infecciones de oído recurrentes y frecuentes también son un síntoma y puede provocar una pérdida de audición interna.

Otras condiciones de salud afectan principalmente a las articulaciones, como dolor articular, articulaciones flojas, osteoartritis y el desarrollo de artritis a una edad muy temprana, escoliosis y degeneración de la cadera.

Los rasgos faciales únicos incluyen mejillas planas y puente nasal. Una mandíbula pequeña y úvula dividida. La secuencia de Pierre-Robin también se asocia con la síndrome y esto significa un paladar hendido, un mentón pequeño y una lengua colocados más atrás en la boca.

Posibles rasgos / características clínicas:
Displasia epifisaria, Epífisis femoral de capital plano, Vitreorretinopatía degenerativa, Miopía alta, Cara plana, Epífisis femoral de capital irregular, Estatura baja, Genu valgum, Deficiencia auditiva neurosensorial, Herencia autosómica recesiva, Astigmatismo

¿Cómo se hace la prueba a alguien? Stickler syndrome?

La prueba inicial para Stickler syndrome puede comenzar con la detección del análisis facial, a través de la plataforma FDNA Telehealth de telegenética, que puede identificar los marcadores clave del síndrome y describa la necesidad de realizar más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista. 

Sobre la base de esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.

Información médica sobre Stickler Síndrome

As pointed out by Opitz, this autosomal dominant syndrome can be extremely variable. At birth the only features may be those of Pierre Robin association (cleft palate, micrognathia and glossoptosis). van den Elzen et al., (2001) found that 15% of a series of children with Pierre Robin association had Stickler syndrome. Holder-Espinasse et al., (2001) also found that about 15% of cases presenting at birth with Pierre-Robin syndrome had Stickler syndrome. Radiological examination at this time may reveal coronal clefts of the vertebrae, mild platyspondyly and flaring of the metaphyses of the long bones (features of the Weissenbacher-Zweymuller syndrome). As the child grows older these features become normal, although a mild epiphyseal dysplasia may develop. Harkey et al., (1989) reported a case with disc herniation causing paraplegia and Noel et al., (1992) reported cervical spinal canal stenosis leading to a Brown-Sequard syndrome. Rose et al., (2001) studied 53 patients in 24 families. 34% of patients had scoliosis, 74% vertebral endplate abnormalities, 64% Schmorl's nodes, 43% platyspondyly and 43% Sheuermann-like kyphosis. 85% of adults reported chronic back pain. Although it has been suggested that mitral valve prolapse is common in Stickler syndrome, Ahmad et al., (2003) could find no evidence for this in a very well characterised cohort of 78 patients from 25 pedigrees with both COL2A1 and COL11A1 mutations. About 40% of patients have, a mostly subtle, high frequency hearing loss, but stapes ankylosis has been reported (Baijens et al., 2004). Snead and Yates (1999) provide a good review.
The main cause of morbidity after the neonatal period is a severe myopia with the risk of retinal detachment. Thus any child with Pierre Robin association should have careful ophthalmic follow-up.
A single case was reported by Rogers and Strachan (1995) of a girl, with normal intelligence, who was born with a cleft palate, small jaw and glossoptosis, who later was found to have myopia, a hypopigmented fundus and proptosis. On further examination, there was no foveal reflex and no differentiation of the macula. Five years later she was found to have posterior cortical and subcapsular cataracts. These progressed and later autolysed. The authors considered Stickler, and rejected it, but we are unsure.
Baraitser (1981) suggests that this syndrome is identical to Marshall syndrome, although this is still disputed by Ayme and Preus (1984).

GENETICS
Francomano et al., (1987), Knowlton et al., (1989) and Priestley et al., (1990) reported close linkage to COL2A1 in several families. COL2A1 mutations have been reported in some families, including the original Stickler kindred (Williams et al., 1996). Vintiner et al., (1991) studied six families with the COL2A1 probe and showed that two were not linked to this locus. In one family the disease co-segregated with a balanced 5;17 translocation in four individuals, suggesting a separate locus at one of these breakpoints. Faber et al., (2000) stress that expression can be very variable in cases with COL2A1 mutations. Fryer et al., (1990) and Bonaventure et al., (1992) also reported families where the gene did not appear to be linked to COL2A1. Brunner et al., (1994) found evidence for linkage to 6p22-p21.3, close to the COL11A2 gene, in a large Dutch kindred. Vikkula et al., (1995) then found a splice donor site mutation resulting in in-frame exon skipping in the COL11A2 gene in this family. They also found a glycine to arginine substitution in the gene in a family with a more severe recessive form of Stickler syndrome. Families mapping to the COL11A2 gene do not appear to have eye abnormalities (Sirko-Osadsa et al.,1998), and this is thought to be because in mammalian vitreous the COL5A2 product replaces the alpha2 chain of type XI collagen.
Richards et al., (1996) found a mutation in the COL11A1 gene in a family segregating for Stickler syndrome with vitreous and retinal abnormalities. Richards et al., (2000) suggest that individuals with a premature stop codon in the COL2A1 gene have a characteristic congenital ""membranous"" anomaly of the vitreous, whereas patients with dominant negative mutations in COL11A1 have a different ""beaded"" vitreous phenotype. These authors also reported a R365C mutation in COL2A1 in two unrelated individuals who had a membranous vitreous anomaly. They also reported a L467F mutation which gave an ""afibrillar"" vitreous anomaly. Both of these mutations were thought to be dominant negative. Griffith et al., (1998) reported a family with the Marshall syndrome phenotype and demonstrated a mutation in the COL11A1 locus. See the comments by Shanske et al., (1998) and Warman et al., (1998). Annunen et al., (1999) demonstrated an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null mutations in the COL2A1 were shown to lead to a typical Stickler phenotype, however other mutations in the COL11A1 gene resulted in overlapping phenotypes of Marshall and Stickler syndromes. The authors pointed out that early onset hearing loss was common with COL11A1 mutations. Further mutations in the COL11A1 gene were reported by Martin et al., (1999).
It is of interest that some autosomal dominant families segregating for early onset primary osteoarthritis associated with a mild chondrodysplasia also show linkage to, or mutations in, the COL2A1 gene (Palotie et al., 1989; Knowlton et al., 1990; Ala-Kokko et al., 1990; Katzenstein et al., 1990; Eyre et al., 1991; Vikkula et al., 1993; Williams et al., 1993; Pun et al., 1994; Ritvaniemi et al., 1994; Winterpacht et al., 1994; Bleasel et al., 1996). However Meulenbelt et al., (1997) could not find linkage to several collagen loci in a dominant family segregating for osteoarthritis without bone dysplasia.
Ahmad et al., (1991) and (1993) reported mutations of the COL2A1 gene leading to a premature stop codon in two separate families. Freddi et al., (2000) and Wilkin et al., (2000) reported a screening strategy for stop codons in the COL2A1 gene. Bleasal et al., (1995) reported two cases with tall stature, spondyloepiphyseal dysplasia, and early osteoarthritis with COL2A1 mutations. They may well have had Stickler syndrome but the case report is inadequate.
The condition is sometimes called Wagner- Stickler syndrome. Wagner (1938) reported individuals with a form of erosive vitreo-retinopathy who showed ophthalmological similarities to the COL2A1-linked form of Stickler syndrome. In Wagner disease rhegmatogenous retinal detachments are uncommon and retinal pigment epithelial changes, poor night vision, visual field defects, and abnormal ERG findings are found. Furthermore the locus maps to 5q13-14 (Brown et al., 1995). Korkko et al., (1993) reported three patients with the Wagner phenotype who had COL2A1 mutations, but Brown et al., (1995) considered that the diagnosis in these cases was most likely Stickler syndrome, especially since radiographs were not examined. A mutation in the gene chondroitin sulfate proteoglycan 2 (GSPG2) at 5q13 has now been reported by Miyamoto et al., (2005).
Ballo et al., (1998) reported a mother and three children with a dominant negative mutation of the COL2A1 gene with features of Stickler syndrome, but also with brachydactyly.
Pihlajamaa et al., (1998) demonstrated a mutation in the COL11A2 gene in the patient originally described as having Weissenbacher-Zweymuller syndrome (qv) (Weissenbacher and Zweymuller 1964). This would suggest that the Weissenbacher-Zweymuller phenotype can be part of OSMED syndrome. Spranger et al., (1998) reviews condition caused by mutations in the type XI collagen genes. He recognises a dominant and recessive form of OSMED, together with a phenotype classified as Stickler syndrome type II.
Sangsin et al. (2016), reported a family with a novel variant of type 2 collagenopathy caused by truncating mutation in COL2A1. The mutation described was the farthest reported mutation from the 3’ end of the gene. Clinical characteristics included flattened facial profile, disproportionate short stature with short trunk and kyphosis, barrel chest, platyspondyly, and epiphyseal involvement. Affected individuals also had severe hip dysplasia and dislocation. The proband’s father had retinal detachment and severe early-onset myopia.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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