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

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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