Clinical and molecular genetics of Stickler syndrome

Stickler syndrome is an autosomal dominant disorder with characteristic ophthalmological and orofacial features, deafness, and arthritis. Abnormalities of vitreous gel architecture are a pathognomonic feature, usually associated with high myopia which is congenital and non-progressive. There is a substantial risk of retinal detachment. Less common ophthalmological features include paravascular pigmented lattice degeneration and cataracts. Non-ocular features show great variation in expression. Children with Stickler syndrome typically have a flat midface with depressed nasal bridge, short nose, anteverted nares, and micrognathia. These features can become less pronounced with age. Midline clefting, if present, ranges in severity from a cleft of the soft palate to Pierre-Robin sequence. There is joint hypermobility which declines with age. Osteoarthritis develops typically in the third or fourth decade. Mild spondyloepiphyseal dysplasia is often apparent radiologically. Sensorineural deafness with high tone loss may be asymptomatic or mild. Occasional findings include slender extremities and long fingers. Stature and intellect are usually normal. Mitral valve prolapse was reported to be a common finding in one series but not in our experience. The majority of families with Stickler syndrome have mutations in the COL2A1 gene and show the characteristic type 1 vitreous phenotype. The remainder with the type 2 vitreous phenotype have mutations in COL11A1 or other loci yet to be identified. Mutations in COL111A2 can give rise to a syndrome with the systemic features of Stickler syndrome but no ophthalmological abnormality.     

Variability of Stickler syndrome

Stickler syndrome is a dominantly inherited disorder characterized by ocular and nonocular manifestations. The phenotype of the affected patients is known to be variable. Our study of 3 families and a review of the literature show that the variability is mostly interfamilial while in each family less variability is present. In one family all the patients had high myopia and most developed a retinal detachment at a young age. In the second family the major symptoms were cleft palate and characteristic facial changes in presence of mild ocular changes. In the third family, all patients had a marfanoid habitus, high myopia, and mental retardation. Interfamilial variability coupled with intrafamilial similarities in clinical manifestation may indicate that the so-called Stickler syndrome represents in fact a phenotype and not a single genetic entity.     

Mosaicism in Stickler syndrome

Stickler syndrome is a heterogeneous condition due to mutations in COL2A1, COL11A1, COL11A2, and COL9A1. To our knowledge, neither non-penetrance nor mosaicism for COL2A1 mutations has been reported for Stickler syndrome. We report on a family with two clinically affected sibs with Stickler syndrome who have clinically unaffected parents. Both sibs have a novel heterozygous mutation in exon 26 of COL2A1 (c.1525delT); this results in a premature termination codon downstream of the mutation site. One parent was found to have low level mosaicism in DNA extracted from whole blood. This scenario encourages consideration of molecular testing in seemingly unaffected parents for recurrence risks and potential screening for mild age-related manifestations.     

Marshall/Stickler syndrome

A family originally reported as a variant of Marshall syndrome is re-examined. The clinical picture now encompasses both the Marshall and Stickler syndromes and it is suggested that the distinction between the two should be abandoned.     

Variability of Stickler syndrome.

Stickler syndrome is a dominantly inherited disorder characterized by ocular and nonocular manifestations. The phenotype of the affected patients is known to be variable. Our study of 3 families and a review of the literature show that the variability is mostly interfamilial while in each family less variability is present. In one family all the patients had high myopia and most developed a retinal detachment at a young age. In the second family the major symptoms were cleft palate and characteristic facial changes in presence of mild ocular changes. In the third family, all patients had a marfanoid habitus, high myopia, and mental retardation. Interfamilial variability coupled with intrafamilial similarities in clinical manifestation may indicate that the so-called Stickler syndrome represents in fact a phenotype and not a single genetic entity.     

一例小儿肝衰竭综合征2型患儿的临床特征及基因变异分析

目的:分析1例小儿肝衰竭综合征2型患儿的临床特征及基因变异特点,探讨其分子遗传学发病机制。方法:对1例小儿肝衰竭综合征2型患儿进行临床特点总结、二代测序及基因致病性分析。结果:发现患儿 NBAS基因存在复合杂合变异,包括一个位于第24外显子的新杂合无义变异c.2746A>T(p.R916X,1456)与一个...     

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type

BACKGROUND: Ehlers-Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. METHODS: We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. RESULTS: Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. CONCLUSIONS: Although most affected patients survive the first and second major complications, Ehlers-Danlos syndrome type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.     

Clinical features and genetic testing of a child with hepatic failure syndrome type 2CSCD

Objective To explore the genetic basis for a child with infantile liver failure syndrome type 2 (ILFS type 2). Methods Clinical features of the child were analyzed. Next generation sequencing was also carried out for him. Results The child was found to harbor compound heterozygous variants of the NBAS gene, which included a novel nonsense c. 2746A>T (p.R916X, 1456) variant in exon 24 and a missense c. 3596G>A (p.C1199Y) mutation in exon 31, which has been associated with ILFS type 2. The two variants were respectively inherited from his father and mother. Conclusion The compound heterozygous variants of c. 3596G>A and c. 2746A>T of the NBAS gene probably underlay the ILFS type 2 in this child. © 2022 West China University of Medical Sciences. All rights reserved.     

Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2

Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole‐exome sequence analysis identified a homozygous missense variant in AMPD2 (NM_001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical “Figure 8” appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM_001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data.     

Genetic and clinical heterogeneity of Stickler syndrome

We have studied 6 multigeneration Stickler syndrome families. Manifestations of the syndrome in the families included myopia, deafness, arthritis, characteristic facial changes with “flat” midface and cleft palate, although not all these were present in all families. COL2A1 has been implicated as a gene which can give rise to Stickler syndrome based on evidence from 2 large families which each showed significant linkage between the disease locus and restriction fragment length polymorphisms for the gene (Francomano CA, Lieberfarb RM, Hirose T, Maumenee IH, Streeten EA, Meyers DA, Pyeritz RE (1987): Genomics 1:293–296; Knowlton RG, Weaver EJ, Struyk AF, Knobloch WH, King RA, Norris K, Shamban A, Uitoo J, Jimenez SA, Prockop DJ (1989): Am J Hum Genet 45:681–688). We have found crossovers between the disease locus and COL2A1 in 2 families with Stickler syndrome. This could be explained by either genetic heterogeneity or the actual mutation being in a closely linked, currently unrecognized gene. We found a weakly positive overall lod score (z = 0.96 at θ = 0.10) suggesting that genetic heterogeneity is a more likely explanation. In one family, with typical findings, a translocation t5;17 (q15:q23) was found to segregate with the disease in 4 affected relatives. In view of the possible heterogeneity, although no crossovers with COL2A1 were seen in this family, either of these breakpoints could be the position of a further disease causing gene.     

The Stickler syndrome (Hereditary arthro-ophthalmopathy)

Three patients with Stickler syndrome are reported. Two of the patients were found among the 26 children attending a special pre-school for the visually impaired. One of the patients had bilateral choanal atresia which may represent an extreme example of the mid-facial hypoplasia commonly seen in these patients. It appears that Stickler syndrome may not be as rare as previously thought.     

Prevalence of mitral valve prolapse in Stickler syndrome

A single nucleotide polymorphism (SNP) in chromosome Y has been associated with blood pressure. In men, the risk of suffering from cardiovascular diseases, including coronary artery disease, could be influenced by one or more loci on chromosome Y. We genotyped 208 men who had suffered an early episode of myocardial infarction (MI) (< or =55 years) and 178 healthy control men for two Y-polymorphisms (a HindIII polymorphism in an alphoid satellite in the centromeric non-recombining region and the -2627 T/C in the SRY gene). Frequencies were compared through a chi(2)-test. Frequencies for the two polymorphisms did not differ between patients and controls. The alphoid-HindIII polymorphism was not related to blood pressures in our population (HindIII+: diastolic, 80 +/- 2; systolic, 129 +/- 5. HindIII-: diastolic, 80 +/- 2; systolic, 128 +/- 3). Seventy-six patients (37%) were hypertensives and had a significantly higher frequency of the HindIII+ allele compared to the normotensive patients (46 and 26%, respectively; P = 0.028). According to our data, the alphoid-HindIII polymorphism in chromosome Y was not associated with differences in blood pressure in men from Asturias (Northern Spain). However, the HindIII+ allele increased the risk of suffering an early episode of MI among hypertensives.     

Genetic and clinical heterogeneity of Stickler syndrome.

We have studied 6 multigeneration Stickler syndrome families. Manifestations of the syndrome in the families included myopia, deafness, arthritis, characteristic facial changes with "flat" midface and cleft palate, although not all these were present in all families. COL2A1 has been implicated as a gene which can give rise to Stickler syndrome based on evidence from 2 large families which each showed significant linkage between the disease locus and restriction fragment length polymorphisms for the gene (Francomano CA, Lieberfarb RM, Hirose T, Maumenee IH, Streeten EA, Meyers DA, Pyeritz RE (1987): Genomics 1:293-296; Knowlton RG, Weaver EJ, Struyk AF, Knobloch WH, King RA, Norris K, Shamban A, Uitoo J, Jimenez SA, Prockop DJ (1989): Am J Hum Genet 45:681-688). We have found crossovers between the disease locus and COL2A1 in 2 families with Stickler syndrome. This could be explained by either genetic heterogeneity or the actual mutation being in a closely linked, currently unrecognized gene. We found a weakly positive overall lod score (z = 0.96 at theta = 0.10) suggesting that genetic heterogeneity is a more likely explanation. In one family, with typical findings, a translocation t5;17 (q15:q23) was found to segregate with the disease in 4 affected relatives. In view of the possible heterogeneity, although no crossovers with COL2A1 were seen in this family, either of these breakpoints could be the position of a further disease causing gene.     

A mild form of Stickler syndrome type II caused by mosaicism of COL11A1

Stickler syndrome, a clinically as well as molecularly heterogeneous connective tissue disorder, is predominantly inherited in an autosomal dominant manner and is considered complete penetrant. Previously, mosaicism in Stickler syndrome has been reported in only a few cases. We describe a child with Stickler syndrome due to a novel splice site mutation in COL11A1. Initially, Sanger sequencing of both parents showed normal test results for the mutation. Due to mild phenotypic traits, the father was tested again using a more sensitive method (NGS), and was found to have low-grade mosaicism in various tissue samples (range 7–22% of the DNA). Therefore, we recommend using sensitive genetic testing when mosaicism is suspected. Furthermore, we support previous suggestions of parental testing even when the parents of an affected patient do not have obvious phenotypic signs of Stickler syndrome.     

Prevalence of mitral-valve prolapse in the Stickler syndrome

An increased prevalence of mitral-valve prolapse occurs in several connective tissue dysplasias, including Marfan syndrome, Ehlers-Danlos syndrome, and pseudoxanthoma elasticum. We evaluated 57 patients diagnosed as having the Stickler syndrome for mitral-valve prolapse by auscultation and two-dimensional echocardiography. The diagnosis was made on the basis of craniofacial and musculoskeletal abnormalities, sensorineural hearing loss, eye defects, and a family history of Stickler syndrome. Twenty-six patients (45.6%) had mitral-valve prolapse, including 11 of 22 females (50.0%) and 15 of 35 males (42.9%). The age range of our study population was 4 to 60 years. Prevalence of mitral-valve prolapse did not increase with age. Nine patients (34.6% of those with mitral-valve prolapse) had the click-murmur syndrome; only one of them was symptomatic. Because of the growing list of complications associated with mitral-valve prolapse, all patients with Stickler syndrome should be evaluated by auscultation, electrocardiogram, and echocardiography. Those with mitral-valve prolapse should be advised to have periodic follow-up and to instruct physicians caring for them of their need for antibiotic prophylaxis with certain surgical procedures.     

Stickler syndrome: clinical characteristics and diagnostic criteria

The purpose of this study was to establish diagnostic criteria for Stickler syndrome. Ninety patients from 38 families had complete evaluations for possible Stickler syndrome. Molecular confirmation of COL2A1 mutation status (type I Stickler syndrome) was available on 25 patients from six families. In the remaining 65 patients, 47 from 25 families were affected with Stickler syndrome and 18 from seven families were unaffected with Stickler syndrome. A diagnostic nosology based on type I Stickler patients with known COL2A1 mutations was applied to clinically affected and unaffected patients. A diagnostic scale of 9 points evaluated molecular data or family history data and characteristic ocular, orofacial, auditory, and musculoskeletal findings. A score of > or =5 was diagnostic of Stickler syndrome. These criteria demonstrate 100% sensitivity when applied to type I Stickler syndrome patients with known COL2A1 mutations, 98% sensitivity when applied to clinically affected Stickler patients, and 86% specificity when applied to patients unaffected based on clinical and/or molecular analysis. We conclude that diagnostic criteria based on type I Stickler patients with molecularly confirmed COL2A1 mutations appear to be sensitive and specific for the diagnosis of this syndrome and should be helpful to clinicians when making the diagnosis.     

Occurrence of deletion of a COL2A1 allele as the mutation in Stickler syndrome shows that a collagen type II dosage effect underlies this syndrome

We describe a novel type of mutation in the COL2A1 gene in a family with Stickler syndrome, namely a deletion of an entire COL2A1 allele. Until now, almost all COL2A1 mutations found in this syndrome are nucleotide substitutions, small deletions, or insertions, resulting in premature translation termination. Since the phenotype in this family is not different from cases with a truncated alpha-chain, our finding supports the suggestion that a dosage effect is underlying Stickler syndrome. Moreover, in mutation screening protocols for COL2A1 one should be aware of the possibility of large deletions, which are not detected by generally used PCR-based methods.