Paula and Bobby
Parents of Lillie
What is Stickler syndrome?
Stickler is a hereditary, progressive group of syndromes. This means symptoms associated with, and triggered by this rare disease worsen over time.
Symptoms may vary widely in their type and severity between individuals. However the most serious features of the syndrome can cause vision and hearing impairment, as well as problems with the joints.
Individuals with the syndrome have abnormal amounts of collagen which mainly affects auditory, ocular, skeletal, and orofacial abnormalities. Often individuals with the syndrome have a flattened facial appearance.
AOM Arthro-ophthalmopathy Marshall- Stickler syndrome WZS
What gene changes cause Stickler syndrome?
Mutations in six genes are responsible for the syndrome. These genes include COL2A1, COL11A1, COL9A1, COL9A2, COL9AE.
Depending on the gene mutation, this rare disease can be inherited in an autosomal dominant or autosomal recessive pattern.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
What are the main symptoms of Stickler syndrome?
The main symptoms include numerous eye and vision problems. These include myopia, retinal detachment, cataracts, astigmatism, crossed eyes, and glaucoma.
Recurrent and frequent ear infections are also a symptom and can lead to inner hearing loss.
Other health conditions mainly affect the joints- including joint pain, loose joints, osteoarthritis and the development of arthritis at a very young age, scoliosis and hip degeneration.
Unique facial features include flat cheeks and nasal bridge. A small jaw and split uvula. Pierre-Robin sequence is also associated with the syndrome and this means a cleft palate, small chin and a tongue positioned further back in the mouth.
Possible clinical traits/features:
Epiphyseal dysplasia, Flat capital femoral epiphysis, Degenerative vitreoretinopathy, High myopia, Flat face, Irregular capital femoral epiphysis, Short stature, Genu valgum, Sensorineural hearing impairment, Autosomal recessive inheritance, Astigmatism
How does someone get tested for Stickler syndrome?
The initial testing for Stickler syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Stickler Syndrome
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).
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.
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