NOVEL MUTATION IN THE COL11A1 GENE CAUSING
MARSHALL-STICKLER SYNDROME IN THREE
GENERATIONS OF A BULGARIAN FAMILY Mladenova M1,2,*, Todorov T2, Grozdanova L3, Mitev V1, Todorova A1,2 *Corresponding Author: Dr. Mihaela Mladenova, Department of Medical Chemistry and Biochemistry,
Medical University Sofia, 15 Acad. Ivan Geshov Str. Sofia, Bulgaria. Tel.: +359-9520-522. Fax:
+359-2-9155-049. E-mail: mihaela.mladenova@gmail.com page: 95
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INTRODUCTION
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 [1-3]. 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 [5-9]. 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.
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 COL2A1, COL11A1 and COL11A2 procollagen genes
cause Stickler syndrome. Marshall syndrome, caused by a
COL11A1 gene mutation, has clinical overlap with Stickler
syndrome.. About 80.0-90.0% of all cases are caused by
mutations in the COL2A1 gene. The remaining ~20.0%
of cases result from mutations in the COL11A1 gene [5].
Here, we report a novel splice-site mutation in the
triple-helical domain of the COL11A1 gene in a Bulgarian
patient. This is first genetically verified familial case of
Marshall-Stickler syndrome in our country. Clinical Data. The proband, a 2-year-old girl, has
craniofacial dysplasia, ocular hypertelorism, small saddle
nose with flat bridge and midface hypoplasia (Figure 1).
At this age she does not yet demonstrate hearing loss and
she presents with a normal stature.
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).
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