Clinical Genetics 1979: 16: 301-304
An autosomal dominantly inherited syndrome of facial asymmetry, esotropia, amblyopia, and submucous cleft palate (Bencze syndrome) DAVIDKURNITV,JUDITH G . HALL'+'?, DAVIDB. sHUR'ILEFF3, AND M. MICHAEL COHENJr.3,4 Division of Medical Genetics, Departments of 2 Medicine, 3 Pediatrics, and Oral & Maxillofacial Surgery, University of Washington, Seattle, Washington, U. S. A. This is the second report of a dominantly inherited syndrome of facial asymmetry, esotropia, and amblyopia (Bencze syndrome). The phenotypic spectrum is expanded to include submucous cleft palate. The observation for the first time of male-to-male transmission seems to confirm an autosomal dominant mode of inheritance. The facial asymmetry in this family was mild and did not require surgical intervention. With the exception of one patient who had other abnormalities, intelligence was normal. Received 30 October 1978, revised 25 April, accepted f o r publication 26 April 1979 Key words: Amblyopia; Bencze syndrome; cleft palate; facial asymmetry; genetic syn-
drome; strabismus. Clinical asymmetry is etiologically and pathogenetically heterogeneous and may be localized or generalized. Causes may include (among other things) trauma, infection, neurologic damage, chromosomal anomalies, and monogenic inheritance. Distinctions between various types of asymmetry have been made (Warkany 1971, Cohen 1976) and include hemihypertrophy, hemihyperplasia, hemidystrophy, and hemiatrophy. Gorlin et al. (1976) have discussed various syndromes with asymmetry as one feature. Congenital facial asymmetry occurs as an isolated finding or with asymmetry of other parts of the body. Most reported cases are sporadic, although familial instances are known (Arnold 1933, Rudolph & Norvold 1944, Rowe 1962, Persson 1973). In partic0009-9163/79/110301-04$02.50/0
ular, Bencze et al. (1973) reported a dominantly inherited disorder of facial asymmetry, strabismus, and amblyopia. In this paper we report a second family with the same syndrome. The phenotypic spectrum is expanded to include submucous cleft palate, and the observation of male-to-male transmission seems to confirm an autosomal dominant mode of inheritance. Case Reports
The pedigree is illustrated in Figure 1 . The proband IV-1 was a n 11-year-old boy. He was the product of a 40-week gestation, and was 53 cm in length (75th percentile) and weighed 3.8 kg (75th percentile) at birth. The mother, a 22-year-old white woman, had a viral illness without rash during the 0 1979 Munksgaard, Copenhagen
KURNIT, HALL, SHURTLEFF AND COHEN
302
w
I
t
t
t
1
I
t
Flg. 1. Pedigree showing autosomal dominant inheritance with expressivity.
complete
penetrance
and variable
Fig. 2. Proband (IV-1). Primary telecanthus, strabismus and malocclusion.
fifth month of pregnancy for which she was treated with unknown medications. She smoked one pack of cigarettes per day throughout the entire pregnancy. Birth was vaginal vertex with a nuchal cord. The neonatal period was uncomplicated. Developmental landmarks were delayed: he had poor neonatal head control, sat at 9 months, talked at 18 months, and walked a t 2 years. Esotropia was surgically repaired a t age 2. Surgery for hyperextensible knees was carried out at age 5. H e had recurrent sinus and ear infections. Multiple tympanic membrane drainage tubes were placed, and at 5 years of age, tonsillectomy and adenoidectomy were performed. He was enrolled in special education classes and required therapy for indistinct speech. At 1 1 years, with formal testing, IQ was estimated in the 60-70 range. Physical examination at 11 years of age revealed a short, slim boy with mild facial asymmetry (Fig‘ 2 ) . Height (125 cm) and weight (26.8 kg) were below the 3rd per-
Fig. 3. 111-2. Facial asymmetry, strabismus and upslanting palpebral fissure on hypoplastic side
303
BENCZE SYNDROME
Table 1 Features of affected family members Pedigree notation
Facial asymmetry (hypoplastic side denoted)
Submucous cleft palate
Esotropia (side affected denoted)
Amblyopia (side affected denoted)
~
1-1' 11-1' 11-2 111-1 111-2 111-4
IV-1 (proband)"
(?I
+ (7)
+
+ (9)
+ (?)
+ (left) + (left) + (left) + (left)
+ (left) + (left)
+ (right)
+ (right) -
+ (left)
* Not available for examination. Clinical findings by history. *' Other abnormalities present (see text).
centile. Head circumference was 54 cm (70th percentile) and parietal hair whorls were present bilaterally. The left side of the face was mildly hypoplastic. The inner canthal distance was 3.5 cm (greater than the 97th percentile); outer canthal distance was 9.9 cm (85th percentile). A submucous cleft of the hard palate was palpable. Malocclusion and malformed teeth were also evident. Skeletal anomalies included mild pectus carinatum and minimal thoracolumbar scoliosis (not secondary to leg length asymmetry). The palms were short (less than the 3rd percentile) with normally-sized fingers (50th percentile). The feet were relatively long and thin (25th percentile). Bone age was estimated at 7% years. The left frontal sinus was undeveloped. Other abnormalities included mild coxa valga and narrow iliac wings. An R-banded karyotype was normal. The findings in other affected members of the family are summarized in Table 1. All had normal intelligence and were of normal stature. Affected members had mild facial asymmetry with an upslanting palpebra1 fissure on the hypoplastic side. Malocclusion was present in each case. Absence of the maxillary canines was noted in 111-2. Other body proportions were symmetric in
all affected family members examined. The proband's brother (IV-2) was found to be unaffected. The family was of German extraction and there was no known consanguinity. Comment
The family presented here has seven affected members through four generations.
Flg. 4. 111-4. Facial asymmetry and upslanting palpebra1 fissure on hypoplastic side.
304
KURNIT, HALL, SHURTLEFF AND COHEN
The presence of male-to male transmission seems to establish autosomal dominant inheritance, although the possibility of etiologic heterogeneity cannot be ruled out. In addition to the facial asymmetry, strabismus, and amblyopia found in the family reported by Bencze et al. (1973), some affected members in our family had submucous cleft palate. Several features of the proband were not found in any other affected family members, nor in the family described by Bencze et al. (1973). These features include growth deficiency of postnatal onset, mental deficiency, primary telecanthus, mild thoracolumbar scoliosis, and hyperextensible knees. It is conceivable that such diverse findings represent severe manifestations of the Bencze syndrome. However, a t the present time we favor the alternative hypothesis that they result from causes other than the abnormal gene in question. The major clinical importance of the Bencze syndrome is the associated strabismus which, if untreated in childhood, can result in amblyopia. In our family, the affected eye was on the relatively hypoplastic side of the face. However, in the family of Bencze et al. (1973), the affected eye was not restricted to the hypoplastic side, and in two instances, eye involvement was bilateral. Thus, the role, if any, that facial asymmetry plays in causing esotropia is unclear. Facial asymmetry in our family and in Bencze’s family (1973) was mild and was not the reason for presentation t o medical personnel. Thus, the true prevalences of the Bencze syndrome in the general pop-
ulation and in the specific population with amblyopia secondary to esotropia are unknown.
Acknowledgments
This study was supported in part by USPHS Grant No. R01 DE04502 and in part by Center for Inherited Diseases Grant No. G M 15253-10. References
Arnold, E. B. (1933). Case of hemiacromegaly. Int. J . Orthodont. 22, 1228-1233. Bencze, J., A. Schnitzler & J. Walawska (1973). Dominant inheritance of hemifacial hyperplasia associated with strabismus. Oral Surg. 35, 489-501. Cohen, M. M., Jr. (1976). Syndromes with craniofacial malformations. Oral Facial Genetics, ed. R. E. Stewart & G. Prescott. St. Louis, C.V. Mosby Company. Gorlin, R. J., J. J. Pindborg & M. M. Cohen, Jr. (1976). Syndromes o f the Head and Neck, 2nd Ed. New York, McGraw-Hill Company. Persson, M. (1973). Mandibular asymmetry of hereditary origin. Amer. J . Orthodont. 63, 1-11.
Rowe, H. N. (1962). Hemifacial hypertrophy. Oral Surg. 15, 572-587. Rudolph, C.E. & R. W. Norvold (1944). Congenital partial hemihypertrophy involving marked malocclusion. J . dent. Res. 23, 133139. Warkany, J. (1971). Congenital Malformations. Chicago, Yearbook Medical Publishers Inc. Address: M . Michael Cohcn, Jr., D . M . D . , Ph.D. Health Sciences Building, SB-24 University o f Washington Seattle, Washington 98195 U . S.A .
An autosomal dominantly inherited syndrome of facial asymmetry, esotropia, amblyopia, and submucous cleft palate (Bencze syndrome) DAVIDKURNITV,JUDITH G . HALL'+'?, DAVIDB. sHUR'ILEFF3, AND M. MICHAEL COHENJr.3,4 Division of Medical Genetics, Departments of 2 Medicine, 3 Pediatrics, and Oral & Maxillofacial Surgery, University of Washington, Seattle, Washington, U. S. A. This is the second report of a dominantly inherited syndrome of facial asymmetry, esotropia, and amblyopia (Bencze syndrome). The phenotypic spectrum is expanded to include submucous cleft palate. The observation for the first time of male-to-male transmission seems to confirm an autosomal dominant mode of inheritance. The facial asymmetry in this family was mild and did not require surgical intervention. With the exception of one patient who had other abnormalities, intelligence was normal. Received 30 October 1978, revised 25 April, accepted f o r publication 26 April 1979 Key words: Amblyopia; Bencze syndrome; cleft palate; facial asymmetry; genetic syn-
drome; strabismus. Clinical asymmetry is etiologically and pathogenetically heterogeneous and may be localized or generalized. Causes may include (among other things) trauma, infection, neurologic damage, chromosomal anomalies, and monogenic inheritance. Distinctions between various types of asymmetry have been made (Warkany 1971, Cohen 1976) and include hemihypertrophy, hemihyperplasia, hemidystrophy, and hemiatrophy. Gorlin et al. (1976) have discussed various syndromes with asymmetry as one feature. Congenital facial asymmetry occurs as an isolated finding or with asymmetry of other parts of the body. Most reported cases are sporadic, although familial instances are known (Arnold 1933, Rudolph & Norvold 1944, Rowe 1962, Persson 1973). In partic0009-9163/79/110301-04$02.50/0
ular, Bencze et al. (1973) reported a dominantly inherited disorder of facial asymmetry, strabismus, and amblyopia. In this paper we report a second family with the same syndrome. The phenotypic spectrum is expanded to include submucous cleft palate, and the observation of male-to-male transmission seems to confirm an autosomal dominant mode of inheritance. Case Reports
The pedigree is illustrated in Figure 1 . The proband IV-1 was a n 11-year-old boy. He was the product of a 40-week gestation, and was 53 cm in length (75th percentile) and weighed 3.8 kg (75th percentile) at birth. The mother, a 22-year-old white woman, had a viral illness without rash during the 0 1979 Munksgaard, Copenhagen
KURNIT, HALL, SHURTLEFF AND COHEN
302
w
I
t
t
t
1
I
t
Flg. 1. Pedigree showing autosomal dominant inheritance with expressivity.
complete
penetrance
and variable
Fig. 2. Proband (IV-1). Primary telecanthus, strabismus and malocclusion.
fifth month of pregnancy for which she was treated with unknown medications. She smoked one pack of cigarettes per day throughout the entire pregnancy. Birth was vaginal vertex with a nuchal cord. The neonatal period was uncomplicated. Developmental landmarks were delayed: he had poor neonatal head control, sat at 9 months, talked at 18 months, and walked a t 2 years. Esotropia was surgically repaired a t age 2. Surgery for hyperextensible knees was carried out at age 5. H e had recurrent sinus and ear infections. Multiple tympanic membrane drainage tubes were placed, and at 5 years of age, tonsillectomy and adenoidectomy were performed. He was enrolled in special education classes and required therapy for indistinct speech. At 1 1 years, with formal testing, IQ was estimated in the 60-70 range. Physical examination at 11 years of age revealed a short, slim boy with mild facial asymmetry (Fig‘ 2 ) . Height (125 cm) and weight (26.8 kg) were below the 3rd per-
Fig. 3. 111-2. Facial asymmetry, strabismus and upslanting palpebral fissure on hypoplastic side
303
BENCZE SYNDROME
Table 1 Features of affected family members Pedigree notation
Facial asymmetry (hypoplastic side denoted)
Submucous cleft palate
Esotropia (side affected denoted)
Amblyopia (side affected denoted)
~
1-1' 11-1' 11-2 111-1 111-2 111-4
IV-1 (proband)"
(?I
+ (7)
+
+ (9)
+ (?)
+ (left) + (left) + (left) + (left)
+ (left) + (left)
+ (right)
+ (right) -
+ (left)
* Not available for examination. Clinical findings by history. *' Other abnormalities present (see text).
centile. Head circumference was 54 cm (70th percentile) and parietal hair whorls were present bilaterally. The left side of the face was mildly hypoplastic. The inner canthal distance was 3.5 cm (greater than the 97th percentile); outer canthal distance was 9.9 cm (85th percentile). A submucous cleft of the hard palate was palpable. Malocclusion and malformed teeth were also evident. Skeletal anomalies included mild pectus carinatum and minimal thoracolumbar scoliosis (not secondary to leg length asymmetry). The palms were short (less than the 3rd percentile) with normally-sized fingers (50th percentile). The feet were relatively long and thin (25th percentile). Bone age was estimated at 7% years. The left frontal sinus was undeveloped. Other abnormalities included mild coxa valga and narrow iliac wings. An R-banded karyotype was normal. The findings in other affected members of the family are summarized in Table 1. All had normal intelligence and were of normal stature. Affected members had mild facial asymmetry with an upslanting palpebra1 fissure on the hypoplastic side. Malocclusion was present in each case. Absence of the maxillary canines was noted in 111-2. Other body proportions were symmetric in
all affected family members examined. The proband's brother (IV-2) was found to be unaffected. The family was of German extraction and there was no known consanguinity. Comment
The family presented here has seven affected members through four generations.
Flg. 4. 111-4. Facial asymmetry and upslanting palpebra1 fissure on hypoplastic side.
304
KURNIT, HALL, SHURTLEFF AND COHEN
The presence of male-to male transmission seems to establish autosomal dominant inheritance, although the possibility of etiologic heterogeneity cannot be ruled out. In addition to the facial asymmetry, strabismus, and amblyopia found in the family reported by Bencze et al. (1973), some affected members in our family had submucous cleft palate. Several features of the proband were not found in any other affected family members, nor in the family described by Bencze et al. (1973). These features include growth deficiency of postnatal onset, mental deficiency, primary telecanthus, mild thoracolumbar scoliosis, and hyperextensible knees. It is conceivable that such diverse findings represent severe manifestations of the Bencze syndrome. However, a t the present time we favor the alternative hypothesis that they result from causes other than the abnormal gene in question. The major clinical importance of the Bencze syndrome is the associated strabismus which, if untreated in childhood, can result in amblyopia. In our family, the affected eye was on the relatively hypoplastic side of the face. However, in the family of Bencze et al. (1973), the affected eye was not restricted to the hypoplastic side, and in two instances, eye involvement was bilateral. Thus, the role, if any, that facial asymmetry plays in causing esotropia is unclear. Facial asymmetry in our family and in Bencze’s family (1973) was mild and was not the reason for presentation t o medical personnel. Thus, the true prevalences of the Bencze syndrome in the general pop-
ulation and in the specific population with amblyopia secondary to esotropia are unknown.
Acknowledgments
This study was supported in part by USPHS Grant No. R01 DE04502 and in part by Center for Inherited Diseases Grant No. G M 15253-10. References
Arnold, E. B. (1933). Case of hemiacromegaly. Int. J . Orthodont. 22, 1228-1233. Bencze, J., A. Schnitzler & J. Walawska (1973). Dominant inheritance of hemifacial hyperplasia associated with strabismus. Oral Surg. 35, 489-501. Cohen, M. M., Jr. (1976). Syndromes with craniofacial malformations. Oral Facial Genetics, ed. R. E. Stewart & G. Prescott. St. Louis, C.V. Mosby Company. Gorlin, R. J., J. J. Pindborg & M. M. Cohen, Jr. (1976). Syndromes o f the Head and Neck, 2nd Ed. New York, McGraw-Hill Company. Persson, M. (1973). Mandibular asymmetry of hereditary origin. Amer. J . Orthodont. 63, 1-11.
Rowe, H. N. (1962). Hemifacial hypertrophy. Oral Surg. 15, 572-587. Rudolph, C.E. & R. W. Norvold (1944). Congenital partial hemihypertrophy involving marked malocclusion. J . dent. Res. 23, 133139. Warkany, J. (1971). Congenital Malformations. Chicago, Yearbook Medical Publishers Inc. Address: M . Michael Cohcn, Jr., D . M . D . , Ph.D. Health Sciences Building, SB-24 University o f Washington Seattle, Washington 98195 U . S.A .
