Branchio-oculo-facial syndrome
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《美国医学杂志》
Department of Pediatrics, JJM Medical College, Davangere - 577 004, India
Abstract
Branchio-oculo-facial syndrome (BOFS) is a very rare autosomal dominant disorder with incomplete penetrance and variable expression; with phenotypic variation ranging from mild to severe forms, involving eye, ear, oral and craniofacial structure. We report three members of one family, showing great variability in its phenotypic expression and review the recent literature.
Keywords: Branchio-oculo-facial syndrome; Pseudo cleft
Branchio oculo facial syndrome (BOFS) is a very rare genetic disorder inherited as an autosomal dominant trait. Incomplete penetrance and variable expressivity are common with phenotypic variation ranging from mild to severe forms, consisting of eye, ear, oral and craniofacial abnormalities.[1], [2]
It is characterized by pseudocleft of the upper lip resembling a poorly repaired cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears and branchial cleft sinuses and/or linear skin lesions behind the ears.[2], [3]
We report branchio oculo facial syndrome in 3 members from one family, showing great variability in its phenotypic expression.
Case report
A 15yr-old-boy with pseudocleft of the upper lip came to our hospital with his mother and sister. He was the product of non-consanguineously married couple.
On examination, the boy had congenital pseudocleft of upper lip on left side, telecanthus, myopia, flat nasal bridge with flattened tip, long philtrum, micrognathia, low set ears, sparse hair, dental anomalies, high arched palate, pectus excavatum and short stature. Figure1 & Figure2 His height was 150cm and weight 30Kg, both values were less than 5th centile on NCHS charts. The boy did not have hemangioma.
The mother had prominent ridges of philtrum, telecanthus, myopia and flattened tip of the nose Figure3. Mother did not have premature graying of hair.
The patient's sister, aged 10 year had microcephaly (head circumference 46cm), frontal bossing, telecanthus, flattened tip of the nose, long philtrum, micrognathia, low set ears, dental anomalies Figure4, high arched palate and short stature. Her birth weight was 1.5Kg. Her present weight and height were 20 Kg and 123 cm respectively, both falling below 5th centile on NCHS charts.
The IQ and hearing assessment of all three members were normal. There were no lacrimal abnormalities, no preauricular pits, sinuses or scars in any one of them. Ultrasonography of abdomen done in all 3 members did not reveal any renal anomalies.
Discussion
In this family study, the 10 year-old-girl with microcephaly, frontal bossing, telecanthus, flattened tip of the nose, long philtrum, micrognathia, low set ears, dental anomalies, high arched palate and short stature was seen first and a suspicion of branchio-oculo-facial syndrome arose when we saw prominent ridges of long philtrum in her mother along with telecanthus and flattened tip of the nose. Our suspicion resolved when we saw the 15 year-old-boy with classic lateral pseudocleft on left side (appearance of repaired cleft lip - Figure1. Lateral pseudocleft, uni or bilateral is almost diagnostic of BOFS. Middle pseudocleft is found in oral-facial-digital syndrome, type 8 and Branchio-oto-renal syndrome (BORS).
Branchio oculo facial syndrome, also known as lip-pseudocleft hemangiomatous branchial cyst syndrome is rare genetic disorder of autosomal dominant inheritance first described by Lee et al and Hall et al in 1980's.[1],[2],[3],[4]
Incomplete penetrance and variable expressively are common with phenotypic variation ranging from mild to severe forms between families and within families.
Fujimoto et al described the characteristic non-midline pseudocleft of the upper lip, malformed nose with broad bridge and flattened-tip, lacrimal duct obstruction, malformed ears and branchial cleft sinuses and/or linear ears skin lesions behind the ears in several persons in 3 families.[2]
Other anomalies include coloboma, microphathalmia, auricular pits, lip pits highly arched palate, dental anomalies and subcutaneous cysts of the scalp.[2],[5],[6] Premature graying of hair has been reported in affected adults. Growth retardation, developmental delay and hand anomalies are variable components of the syndrome.[1], [2] Stenotic external auditory canals, conductive or sensorineural hearing loss are associated with inner ear dysplasias in BOFS.[7] Renal malformations are frequent.[1]
Although branchio oculo facial syndrome and branchio-oto-renal syndrome are sufficiently distinctive that they should not be confused, both can be associated with naso-lacrimal duct stenosis, deafness, prehelical pits, malformed pinna and renal anomalies.[8], [9] Furthermore, a father and son with features of both conditions are described.[10] In the light of these issues, Lin et al performed mutation search of the EYA 1 gene in five BOFS patients and found no EYA 1 gene mutation suggesting that BOFS is not allelic to the BORS.[10] He emphasized that the unusual areas of thin erythematous wrinkled skin of the neck or infra/supra auricular region of BOFS differ from the discrete cervical pits, cysts and fistulas of the BORS.[11]
The variations seen in this disorder and the overlap between this condition and the BORS may represent different mutations within a single gene or may be contiguous gene deletion syndrome.[12] Mutation in a gene responsible for the ordered closure of the foetal fissure and fusion of facial structures is supposed to be one of the candidate genes in BOFS.[4]
An interesting finding is that, thymic tissue at the skin appears to be unique of B.O.F.S and in any given case may provide clue to the diagnosis of this syndrome.[13] High index of suspicion especially when patients have mild expression, like the one in our cases (case 3) helps in proper diagnosis and in appropriate genetic counseling.[14]
References
1. Lin AE, Gorlin RJ, Lurie IW, Brunner HG, Van der Burgt I, Naumchik IV et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet 1995; 28 (1): 96-102.
2. Fujimoto A, Lipson M, Lacro RV, Shinno NW, Boelter WD, Jones KL et al. New autosomal dominant branchio-oculo-facial syndrome. Am J Med Genet 1987; 27 (4): 943-951.
3. Lee WK, Root AW, Fenske N. Bilateral branchial cleft sinuses associated with intrauterine and postnatal growth retardation, premature aging and unusual facial appearance: a new syndrome with dominant transmission. Am J Med Genet 1982; 11(3): 345-352.
4. Hall BD, deLorimier A, Foster LH. Brief clinical report: a new syndrome of hemangiomatous branchial clefts, lip pseudoclefts, and unusual facial appearance. Am J Med Genet 1983; 14(1): 135-138.
5. Richardson E, Davison C, Moore AT. Colobomatous microphthalmia with mid facial clefting: part of the spectrum of branchio-oculo-facial syndrome Ophthalmic Genet 1996; 17 (2): 59-65.
6. Su CS, O' Hagen SB, Sullivan TJ. Ocular anomalies in the branchio-oculo-facial syndrome. Aust N Z J Ophthalmol 1998; 26 (1): 43-46.
7. Raveh E, Papsin BC, Forte V. Branchio-oculo-facial syndrome. Int J Pediatr Otorhinolaryngol 2000; 53(2): 149-156.
8. Gowrisankar K, Andal, Nammalwar BR. Branchio-oto-renal syndrome. Indian J Pediatr 2004; 71(3): 276-277.
9. Stratakis CA, Lin JP, Rennert OM. Description of a large kindred with autosomal dominant inheritance of branchial arch anomalies, hearing loss, and ear pits and exclusion of branchio-oto-renal (BOR) syndrome gene locus (chromosome 8q 13.3). Am J Med Genet 1998; 79(3): 209-214.
10. Legius E, Fryns JP, Van Den Berghe H. Dominant branchial cleft syndrome with characteristics of both brancho-oto-renal and branchio-oculo-facial syndrome. Clin Genet 1990; 37(5): 347-350.
11. Lin AE, Semina EV, Daack Hirsch S, Roeder ER, Curry CJ, Rosenbaum K et al. Exclusion of the branchio-oto-renal syndrome locus (EYA I) from patients with branchio-oculo-facial syndrome. Am J Med Genet 2000; 93 (5): 387-390.
12. McCool M, Weaver DD. Branchio-oculo-facial syndrome: Broadening the spectrum. Am J Med Genet 1994; 49 (4): 414-21.
13. Drut R, Galliani C. Thymic tissue in the skin: a clue to the diagnosis of the branchio-oculo-facial syndrome. Int J Surg Pathol 2003; 11(1): 25-28.
14. Lin AE, Losken H.W, Jaffe R, Biglan AW. The branchio oculo facial syndrome. Cleft Palate Craniofac J 1991; 28(1): 96-102.(Kulkarni ML, Deshmukh Shi)
Abstract
Branchio-oculo-facial syndrome (BOFS) is a very rare autosomal dominant disorder with incomplete penetrance and variable expression; with phenotypic variation ranging from mild to severe forms, involving eye, ear, oral and craniofacial structure. We report three members of one family, showing great variability in its phenotypic expression and review the recent literature.
Keywords: Branchio-oculo-facial syndrome; Pseudo cleft
Branchio oculo facial syndrome (BOFS) is a very rare genetic disorder inherited as an autosomal dominant trait. Incomplete penetrance and variable expressivity are common with phenotypic variation ranging from mild to severe forms, consisting of eye, ear, oral and craniofacial abnormalities.[1], [2]
It is characterized by pseudocleft of the upper lip resembling a poorly repaired cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears and branchial cleft sinuses and/or linear skin lesions behind the ears.[2], [3]
We report branchio oculo facial syndrome in 3 members from one family, showing great variability in its phenotypic expression.
Case report
A 15yr-old-boy with pseudocleft of the upper lip came to our hospital with his mother and sister. He was the product of non-consanguineously married couple.
On examination, the boy had congenital pseudocleft of upper lip on left side, telecanthus, myopia, flat nasal bridge with flattened tip, long philtrum, micrognathia, low set ears, sparse hair, dental anomalies, high arched palate, pectus excavatum and short stature. Figure1 & Figure2 His height was 150cm and weight 30Kg, both values were less than 5th centile on NCHS charts. The boy did not have hemangioma.
The mother had prominent ridges of philtrum, telecanthus, myopia and flattened tip of the nose Figure3. Mother did not have premature graying of hair.
The patient's sister, aged 10 year had microcephaly (head circumference 46cm), frontal bossing, telecanthus, flattened tip of the nose, long philtrum, micrognathia, low set ears, dental anomalies Figure4, high arched palate and short stature. Her birth weight was 1.5Kg. Her present weight and height were 20 Kg and 123 cm respectively, both falling below 5th centile on NCHS charts.
The IQ and hearing assessment of all three members were normal. There were no lacrimal abnormalities, no preauricular pits, sinuses or scars in any one of them. Ultrasonography of abdomen done in all 3 members did not reveal any renal anomalies.
Discussion
In this family study, the 10 year-old-girl with microcephaly, frontal bossing, telecanthus, flattened tip of the nose, long philtrum, micrognathia, low set ears, dental anomalies, high arched palate and short stature was seen first and a suspicion of branchio-oculo-facial syndrome arose when we saw prominent ridges of long philtrum in her mother along with telecanthus and flattened tip of the nose. Our suspicion resolved when we saw the 15 year-old-boy with classic lateral pseudocleft on left side (appearance of repaired cleft lip - Figure1. Lateral pseudocleft, uni or bilateral is almost diagnostic of BOFS. Middle pseudocleft is found in oral-facial-digital syndrome, type 8 and Branchio-oto-renal syndrome (BORS).
Branchio oculo facial syndrome, also known as lip-pseudocleft hemangiomatous branchial cyst syndrome is rare genetic disorder of autosomal dominant inheritance first described by Lee et al and Hall et al in 1980's.[1],[2],[3],[4]
Incomplete penetrance and variable expressively are common with phenotypic variation ranging from mild to severe forms between families and within families.
Fujimoto et al described the characteristic non-midline pseudocleft of the upper lip, malformed nose with broad bridge and flattened-tip, lacrimal duct obstruction, malformed ears and branchial cleft sinuses and/or linear ears skin lesions behind the ears in several persons in 3 families.[2]
Other anomalies include coloboma, microphathalmia, auricular pits, lip pits highly arched palate, dental anomalies and subcutaneous cysts of the scalp.[2],[5],[6] Premature graying of hair has been reported in affected adults. Growth retardation, developmental delay and hand anomalies are variable components of the syndrome.[1], [2] Stenotic external auditory canals, conductive or sensorineural hearing loss are associated with inner ear dysplasias in BOFS.[7] Renal malformations are frequent.[1]
Although branchio oculo facial syndrome and branchio-oto-renal syndrome are sufficiently distinctive that they should not be confused, both can be associated with naso-lacrimal duct stenosis, deafness, prehelical pits, malformed pinna and renal anomalies.[8], [9] Furthermore, a father and son with features of both conditions are described.[10] In the light of these issues, Lin et al performed mutation search of the EYA 1 gene in five BOFS patients and found no EYA 1 gene mutation suggesting that BOFS is not allelic to the BORS.[10] He emphasized that the unusual areas of thin erythematous wrinkled skin of the neck or infra/supra auricular region of BOFS differ from the discrete cervical pits, cysts and fistulas of the BORS.[11]
The variations seen in this disorder and the overlap between this condition and the BORS may represent different mutations within a single gene or may be contiguous gene deletion syndrome.[12] Mutation in a gene responsible for the ordered closure of the foetal fissure and fusion of facial structures is supposed to be one of the candidate genes in BOFS.[4]
An interesting finding is that, thymic tissue at the skin appears to be unique of B.O.F.S and in any given case may provide clue to the diagnosis of this syndrome.[13] High index of suspicion especially when patients have mild expression, like the one in our cases (case 3) helps in proper diagnosis and in appropriate genetic counseling.[14]
References
1. Lin AE, Gorlin RJ, Lurie IW, Brunner HG, Van der Burgt I, Naumchik IV et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet 1995; 28 (1): 96-102.
2. Fujimoto A, Lipson M, Lacro RV, Shinno NW, Boelter WD, Jones KL et al. New autosomal dominant branchio-oculo-facial syndrome. Am J Med Genet 1987; 27 (4): 943-951.
3. Lee WK, Root AW, Fenske N. Bilateral branchial cleft sinuses associated with intrauterine and postnatal growth retardation, premature aging and unusual facial appearance: a new syndrome with dominant transmission. Am J Med Genet 1982; 11(3): 345-352.
4. Hall BD, deLorimier A, Foster LH. Brief clinical report: a new syndrome of hemangiomatous branchial clefts, lip pseudoclefts, and unusual facial appearance. Am J Med Genet 1983; 14(1): 135-138.
5. Richardson E, Davison C, Moore AT. Colobomatous microphthalmia with mid facial clefting: part of the spectrum of branchio-oculo-facial syndrome Ophthalmic Genet 1996; 17 (2): 59-65.
6. Su CS, O' Hagen SB, Sullivan TJ. Ocular anomalies in the branchio-oculo-facial syndrome. Aust N Z J Ophthalmol 1998; 26 (1): 43-46.
7. Raveh E, Papsin BC, Forte V. Branchio-oculo-facial syndrome. Int J Pediatr Otorhinolaryngol 2000; 53(2): 149-156.
8. Gowrisankar K, Andal, Nammalwar BR. Branchio-oto-renal syndrome. Indian J Pediatr 2004; 71(3): 276-277.
9. Stratakis CA, Lin JP, Rennert OM. Description of a large kindred with autosomal dominant inheritance of branchial arch anomalies, hearing loss, and ear pits and exclusion of branchio-oto-renal (BOR) syndrome gene locus (chromosome 8q 13.3). Am J Med Genet 1998; 79(3): 209-214.
10. Legius E, Fryns JP, Van Den Berghe H. Dominant branchial cleft syndrome with characteristics of both brancho-oto-renal and branchio-oculo-facial syndrome. Clin Genet 1990; 37(5): 347-350.
11. Lin AE, Semina EV, Daack Hirsch S, Roeder ER, Curry CJ, Rosenbaum K et al. Exclusion of the branchio-oto-renal syndrome locus (EYA I) from patients with branchio-oculo-facial syndrome. Am J Med Genet 2000; 93 (5): 387-390.
12. McCool M, Weaver DD. Branchio-oculo-facial syndrome: Broadening the spectrum. Am J Med Genet 1994; 49 (4): 414-21.
13. Drut R, Galliani C. Thymic tissue in the skin: a clue to the diagnosis of the branchio-oculo-facial syndrome. Int J Surg Pathol 2003; 11(1): 25-28.
14. Lin AE, Losken H.W, Jaffe R, Biglan AW. The branchio oculo facial syndrome. Cleft Palate Craniofac J 1991; 28(1): 96-102.(Kulkarni ML, Deshmukh Shi)