Stickler syndrome, affecting one in 7500 to 9000 newborns, is a hereditary autosomal dominant disorder (MIM 108300). The condition is characterized by typical facial, ocular, articular, and auditory features [1, 2, 3]. The most common reported manifestation of the cases with Stickler syndrome are wuth vitreoretinal degeneration, cleft palate, retinal detachment, osteoarthritis, sensorineural-hearing loss, high myopia and midfacial hypoplasia. Marshall’s syndrome features are also similar (MIM 154780) [4, 5] that provoke continuing debate is a different condition of one syndrome or two single syndromes [5, 6, 7, 8, 9]. Some researchers have classified Marshall syndrome as a variant of Stickler syndrome while others consider it to be a separate disorder (MIM 154780) [4, 5]. The clinical manifestations of these two conditions are summarized in Table 1.
Clinical manifestations of the Marshall and Stickler syndromes [5] (with modifications).
Findings | Marshall Syndrome | Stickler Syndrome |
---|---|---|
Head | brachycephaly; thickened calvaria | normocephaly |
Midface | flat; retracted | dish-shaped; flat |
Nose | small, short saddle nose with flat bridge | long nose with prominent nasal bridge |
Ocular hyperterlorism/ other ocular findings | yes/high myopia; glaucome; retinal detachment; no astigmatism | no/high myopia; vitreoretinal degeneration; astigmatism |
Hearing loss | frequent; sensorineural | mild |
Stature | short and stocky | normal or tall and thin |
Skeletal abnormalities | spondyloepiphyseal abnormalities | osteochondrodysplasia; spondyloepiphyseal dysplasia |
Joints | hypoextensible | hypoextensible; arthropathy with degenerative arthritis |
Inheritance | autosomal dominant | autosomal dominant |
no | yes |
All the genes that are associated with Marshall-Stickler syndrome provide instructions for making components of collagens. They are complex molecules modeling the structure and affirming the strength of the connective tissue and supporting the body joints and organs [10]. If collagen molecules are irregulated or their amounts are reduced, then collagen impairs the development of connective tissues in many different parts of the body, leading to a wide variety of syndromic features [11]. Mutations in the
Here, we report a novel splice-site mutation in the triple-helical domain of the
The proband’s father is 38 years old and has ocular hypertelorism and an inner canthal distance of 40 mm (>97th percentile) (Figure 2). His phenotypic features include broad flat nasal bridge, relative mandibular prognathism, midface hypoplasia with primary telecanthus and nasal hypoplasia. He presents a tall thin stature and mild hearing loss. Psycho developmental evaluation demonstrates moderate intellectual disability. Both patients, the 2-year-old girl and her father, have been diagnosed clinically as Marshall-Stickler syndrome. The family photographs, provided by the father, showed the same facial dysmorphism in the paternal grandfather (Figure 3).
Informed consent was obtained from the patient’s father prior to genetic testing. The study was approved by the Ethics Committee of Sofia Medical University, Sofia, Bulgaria.
The mutation c.3474+1G>A at intron 44 affects the donor splice-site, and as a result of altered splicing, gives a nonfunctional protein. The variant is localized in the region encoding the major triple-helical domain that represents a hot-spot for mutations on the
In the present genetic variant, the purine nucleotide guanine (G) is substituted by the purine nucleotide adenine (A), an event known as transition. We analyzed the neighboring sequence of 22 bp upstream and 22 bp downstream of the mutation. The surrounding area is abundant with repeated elements (AA, GG and TT) and trinucleotide palindromic sequence AAA/TTT, closely situated to the position of the substitution (Figure 4). The repeated and palindromic sequences might play a role in a G>A substitution and the transition fixation in the genome. The DNA polymerase proof-reading activity at this position might be impaired by a secondary structure formation, making chemically identical substitutions difficult to recognize and remove, thus leading to their fixation in the genome.
In conclusion, the present report concerns the first familial case spread through at least three generations, genetically verified case of Marshall-Stickler syndrome in Bulgaria, caused by a novel splice-site mutation in the triple-helical domain of the