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- Genetics
- paediatric radiology
- clinical genetics
- metabolic disorders
- molecular genetics
- mitochondrial disorders
Recently, Tompson et al1 described the use of autozygosity mapping and expression studies to identify compound heterozygous mutations (c.2386G>C/c.3943G>T; c.1786dupG/c.3124G>A) in the COL11A1 gene in two unrelated patients as a cause of fibrochondrogenesis (MIM 228520). They concluded that fibrochondrogenesis, a short-limbed skeletal dysplasia, represents the most severe end of a spectrum of disorders caused by a COL11A1 defect to date.1 Subsequently, dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2, were described.2 Mutations in these two genes along with COL2A1 were previously reported to cause autosomal dominant forms of Stickler (MIM 604841) and Marshall syndromes (MIM 154780).3–5 COL9A1 and COL9A2 defects, on the other hand, were identified as causing forms of Stickler syndrome with an autosomal recessive inheritance pattern.6 7 Here we report the first evidence that adds COL11A1 defect as a cause of Marshall syndrome with a recessive mode of inheritance.
The proband is a Saudi boy born at term after an uneventful pregnancy to consanguineous parents. He was referred to us at the age of 16 months because of mild motor, speech delay, and dysmorphic facial features (figure 1 A,B). He had ocular hypertelorism with midface hypoplasia and a broad, flat nasal bridge, anteverted nares, and long philtrum. He also had sparse lusterless scalp hair. He had normal palate, teeth, nails, and skin with normal hidrosis. Ophthalmological examination showed progressive high myopia (−12 Diopters), iridodenesis and subluxation of lenses nasally with loss of zonules temporally resulting in notching of the lenses. Mild myopic degenerative changes were noted; discs and maculae were unremarkable. Hearing assessment revealed mild to moderate sensorineural hearing loss. Chromosomal analysis was normal. Bone age was consistent with the chronological age. A thick calvarium was noted on skeletal survey. Spinal x-rays showed widening of atlantoaxial distance (8.3 mm) and platyspondyly with irregular end plates and anterior central protrusion in T12 and L1 vertebrae (figure 1E,G). An abdominal ultrasound examination was normal. The patient is currently 14 years old, weighs 34.3 kg (−2.8 SD), has a height of 138.5 cm (−3.3 SD), and an occipitofrontal circumference of 56 cm (95th centile). He has normal cognitive development and motor and social skills, but has significant expressive language delay. He has a younger brother, now 7 years old, who is similarly affected with hypertelorism, midface hypoplasia (figure 1C,D), high myopia (−9 Diopters) with lens subluxation (figure 1H), mild to moderate sensorineural hearing loss, thick calvarium, increased atlantodental distance (6 mm), and platyspondyly. His weight was 29 kg (50th centile), height was 120 cm (10–25th centile), and occipitofrontal circumference was 56 cm (3 SD). He had normal palate, teeth, hair and other skin appendages. He developed cataract in the right eye with subsequent total retinal detachment resulting in loss of vision (figure 1I). An x-ray of the left hand and wrist at 7.3 years showed an advanced bone age of 10 years with an SD of 10 months (figure 1F).
Although there is an overlap between Stickler syndrome and Marshall syndrome, striking ocular hypertelorism and abnormalities in the ectodermal derivatives have been reported only in Marshall syndrome.8 The clinical findings in the two brothers of deafness, facial appearance (ocular hypertelorism, retracted midface, flat nasal bridge, short nose, anteverted nostrils, and a long philtrum without the cleft palate), ectodermal changes (patient 1), and platyspondyly were highly suggestive of Marshall syndrome. Direct COL11A1 gene sequencing revealed a homozygous c.2702G>A (p.Gly901Glu) transition in exon 35 (figure 1J). Triple helical domain glycine substitutions in the Gly-X-Y repeats of fibrillar collagens are known to be pathogenic.9 This alteration was not found in 200 ethnically matched controls. In addition to the parents, we identified two other carriers of the c.2702G>A mutation among the five healthy children. As part of an approved research project at King Faisal Specialist Hospital and Research Centre (ORA 2 111 045), the carriers underwent clinical, audiological, ophthalmological, and radiological examination. The parents had mild mixed hearing loss, but appeared phenotypically normal with an unremarkable eye examination. The two carrier adult siblings also had normal appearance, hearing, and vision. All the four carriers had mild short stature and thick calvaria.
There has been some debate about whether Marshall syndrome is a distinct entity10 and whether the cases described by Griffith et al3 was an example of Marshall syndrome.8 Patient 1, in fact, in this report appears to more closely represent Marshall syndrome than patients with the dominant COL11A1 defects previously reported by Griffith et al3 and Annunen et al.11 In general, the ocular manifestations in patients with COL11A1 defects variably include high myopia, cataract, vitreoretinal degeneration, and retinal detachment.11 Our patients had significantly severe ocular involvement, possibly related to the homozygous COL11A1mutations. As ectopia lentis is not usually seen in Marshall syndrome, we screened our patients for the genes that are most often associated with lens dislocation. Direct sequencing of the entire coding regions for two autosomal dominantly inherited genes FBN1 and FBN2, as well as ADAMTS10, ADAMTS17, and ADAMTSL4 (three autosomal recessive genes that were previously reported to cause ectopia lentis in the geographical region),12 13 did not detect any mutations. Plasma homocysteine concentration was also normal. Although the facial gestalt may suggest Shprintzen–Goldberg syndrome,14 our patients did not have the common manifestations such as craniosynostosis, marfanoid habitus, and intellectual disability.
Remarkably, the two patients had some variation in the clinical manifestations: whereas ectodermal abnormalities were seen in the older patient, advanced bone age was noted in the younger patient, probably explaining why he did not have short stature. Ectodermal changes were previously reported in the original family with Marshall syndrome.15 In Marshall syndrome, the majority of the mutations in COL11A1 affect the splicing of 54 bp exons in a region spanning exons 38–54 of the gene.11 Interestingly, all fibrochondrogenesis patients reported with COL11A1 defects were at least heterozygous for a null allele: the loss-of-function allele (p.Gly1315X; p.Ala596GlyfsX8) in each of the two patients reported by Tompson et al,1 as well as the homozygous null alleles (p.R1362X; c.3708+437T>G) in the two families reported by Akawi et al.16 This might plausibly explain the severity of the fibrochondrogenesis phenotype compared to the homozygosity for missense mutation (p.Gly373Glu) in our patients with a milder form of skeletal dysplasia (Marshall syndrome). It is noteworthy that the disease presents in the carriers in this report as a very mild phenotype (thick calvaria, mild short stature, and mild hearing loss); therefore, it is possible that the glycine substitution in our family is expressed as a mild dominant form in the heterozygous individuals and a double dominant disorder (akin to homozygosity for the FGFR3 mutation seen in achondroplasia) manifesting as Marshall syndrome in the patients.
In addition to fibrochondrogenesis, this report broadens the clinical spectrum of the recessive form of type XI collagenopathy to include Marshall syndrome. Furthermore, it expands the list of autosomal recessive genes of the clinically overlapping Stickler and Marshall syndromes to include COL11A1.
Acknowledgments
We thank the family for the participation in this study. We are also grateful to Dr Leena Ala-Kokko for her expert opinion.
References
Footnotes
Competing interests None.
Patient consent Obtained.
Ethics approval The ethics approval was provided by the Research Advisory Council at King Faisal Specialist Hospital and Research Centre, Saudi Arabia.
Provenance and peer review Not commissioned; externally peer reviewed.