American Journal of Medical Genetics 42793-799 (1992)
~~~~
~~
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~
~
~
New Familial Syndrome of Unilateral Upper Eyelid Coloboma, Aberrant Anterior Hairline Pattern, and Anal Anomalies in Manitoba Indians Sandra L. Marles, Cheryl R. Greenberg, Tkivedi V. N. Persaud, E. Paul Shuckett, and Albert E. Chudley Children’s Hospital and Departments of Pediatrics and Child Health and Human Genetics (S.L.M., C.R.G., A.E.C.) Ophthalmology (E.P.S.), and Anatomy (T.V.N.P.),University of Manitoba, Winnipeg, Manitoba, Canada We report on 6 (3 male, 3 female) Manitoba Indian children with hypertelorism and variable combinationsof unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. These children belong to 4 related families. The parents and 7 other sibs are clinically unaffected. The family histories are otherwise unremarkable. The presence of 2 major malformations in sibs and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. The differential diagnosis includes cryptophthalmos syndrome and several other related malformation syndromes. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution make autosomalrecessive inheritance more likely.
KEY WORDS: eye malformation, upper-eye-
land Lake. They have their own dialect, which is a mixture of SaulteaudOjibway with a heavy overlay of Cree. The population is inbred.
CLINICAL REPORTS These 6 children belong to 4 related families (Fig. 1). All children were born at term after normal pregnancies with no known intrauterine teratogen exposure. Labour and delivery were unremarkable in each case, except VI-2 who was born by cesarean section for fetal distress. Parental consanguinity is documented in case VI-2. Patient VI-2 This male infant had a wedge of scalp hair extending from the right frontotemporal region to the right upper eyelid, which had a coloboma of the medial third. He had hypertelorism and an oculopalpebral synechia. Otherwise his growth, developmental, and ophthalmologic status were normal.
Patient VI-4 This male infant had an aberrant anterior hairline extending from the left frontotemporal region to the left upper eyelid. He had left anophthalmia and hypertelorism. The inner canthal distance was 4.0 cm (greater INTRODUCTION than 97th centile) and the outer canthal distance was We describe 6 (3 male, 3 female) Manitoba Indian 9.0 cm (greater than 97th centile). He had bilateral children with hypertelorism and variable combinations obstruction of the nasolacrimal ducts, but the rest of the of unilateral eye malformations, aberrant anterolateral ocular structures was normal. He had a slight groove of scalp hairline, and nasal and anal anomalies. The par- the nasal tip. His head circumference was 48 cm, above ents and 7 other sibs are clinically unaffected. The fam- the 95th centile for age, with normal cranial ultrasound. ily histories are otherwise unremarkable. The 4 related Otherwise he was normal (Fig. 2). families live in an isolated part of northeastern Manitoba. The Island Lake region consists of 3 reservations Patient VI-7 on the northeastern, eastern, and western shores of IsThis 11-year-oldboy was the older brother of VI-8. He had a wedge of scalp hair extending from the left frontotemporal region to the left eyebrow. Hypertelorism (inner canthal distance, 3.5 cm, 95th centile, and outer Received for publication March 20, 1991; revision received Aucanthal distance, 10.5 cm, above 97th centile for age) gust 12, 1991. Address reprint requests to Dr. A. E. Chudley, Section of Clinical and normal eye findings were documented. He had anal Genetics, FE 231 Community Services Building, 840 Sherbrook stenosis requiring dilatation, but was otherwise normal (Fig. 3). St., Winnipeg, Manitoba R3A 1S1 Canada. lid coloboma, anal stenosis, recessive inheritance
0 1992 Wiley-Liss, Inc.
794
Marles et al. I II
111
IV V
I VI 1
2
3
4
5
6
7
f
8
9 1 0 1 1
12
13
14
Fig. 1. The pedigree 0personally examined, Flaberrant anterior hairline, 0 upper eyelid coloboma,0 abnormal placement of anus, 0 anal stenosis, El* unilateral anophthalmos.
Patient VI-8 This female infant had an aberrant anterior hairline extending from the left frontotemporal region to the left eyebrow. She had a coloboma of the medial half of the left upper eyelid. She had hypertelorism (inner canthal distance, 3.5 cm, 95th centile and outer canthal distance, 9.5 cm, 97th centile for age) and bilateral obstructed nasolacrimal ducts, with otherwise normal eye findings. She had a slight groove to the nasal tip. Other than anterior displacement of her anus without stenosis, she was normally developed (Fig. 4).
t
Patient VI-13 This female infant had an aberrant wedge of scalp hair extending from the left frontotemporal region to the left upper eyelid. She had a coloboma of the medial half of the left upper eyelid. Hypertelorism (inner canthal distance, 5 cm, and outer canthal distance, 12 cm, both above 97th centile for age) was the only other eye abnormality. She had an anteriorly displaced anus with stenosis requiring dilatation. The remainder of her physical
. -; rI
Fig 2. Pt VI-4 Note the aberrant antenor hairline m t h left anophthalmia and hypertelorisrn There is a slight groove ofhis nasal tlp
Fig 3 Pt VI-7 He has an anomalous wedge of scalp hair extending from the left frontotemporal region to the left eyebrow, which he shaves for cosmetic reasons Hypertelorism IS present
New Familial Syndrome
795
Fig. 6. Pt VI-14.She has a right aberrant wedge ofscalp hair with a large coloboma of the right upper eyelid. Hypertelorism is associated. Fig. 4. Pt VI-8. She has an aberrant wedge of scalp hair from the left frontotemporal region to the left eyebrow with a left upper eyelid coloboma. Hypertelorism is present. Her nasal tip has a slight groove.
was a t the 95th centile for age, but results of cranial ultrasound study were normal. The remainder of her physical findings and development was normal (Fig. 6). A summary of the clinical data and investigations is findings including growth and development were nor- presented in Table I and Table 11, respectively. mal (Fig. 5). DISCUSSION Patient VI-14 Jacques Guillemeau [1585] first described the simple This girl was the younger sib of case VI-13. She had an eyelid coloboma as “paupieres accourcies,” and Wilde aberrant anterior hairline extending from the right 118471called it “cleft eyelid [Duke-Elder, 19641. Simple frontotemporal region to the right upper eyelid, which eyelid colobomata are most commonly triangularalso had a coloboma of the medial two-thirds. Hyper- shaped with the base at the lid margin, but quadritelorism (inner canthal distance, 3 cm, and outer can- lateral, W-shape, and irregular shapes can occur. Althal distance, 8 cm, both above 97th centile for age) was though most commonly located on the inner half of the the only other ophthalmologic abnormality. She re- superior lid or the outer half of the lower lid, they have quired dilatation and surgical correction of her ante- been described in other locations and in various combiriorly displaced stenotic anus. Her head circumference nations including coloboma of all 4 lids. Colobomata vary in size from a small indentation of the free border of the eyelid to near absence of the entire lid. It may extend peripherally to involve the orbital margin with local absence of the eyebrow or there maybe an anomalous wedge of scalp hair extending down the forehead toward the coloboma, as seen in our patients. The coloboma is usually full-thickness with rounded edges covered by conjunctiva, which may therefore loosely connect the lid to the bulbar conjunctiva [Duke-Elder, 19643. Dermoid growths, dermatolipomata, or subconjunctival lipomata of the eyes, corneal opacities, oculopalpebral synechiae, and fundal coloboma have been associated with lid colobomata [Duke-Elder, 19641. Eyelid coloboma have been reported with nonocular defects such as anencephaly, hemicephaly, hydrocephalus, ventral hernia, syndactyly, and limb deficiencies [Duke-Elder, 19641 and the epidermal nevus syndrome [Gorlin et al., 19901. Eyelid coloboma have also been described as part of many craniofacial and multiple congenital anomaly (MCA) syndromes. Our patients share some ocular and nasal manifestations common with several of these syndromes, but many differences exist and our patients lack many of the associated anomFig. 5 . F’t VI-13. The upper eyelidfollowingrepairofcoloboma.Note the hypertelorism, aberrant wedge of scalp hair, and slight groove to alies or do not clinically resemble these syndromes summarized below and in Table 111.
=
absent; N
-
-
-
=
Neonate
VI-14
present; -
Neonate
VI-13
=
10 wks
VI-8
+
11 yrs
VI-7
*Key:
-
Neonate
VI-4
-
+
+
Neonate
VI-2
normal.
+ + +
+ +
Hypertelorism
Parental consanguinity
Age a t exam
Trait Case
Left side
Left side
+
Rieht side
Rieht side
Left side
Left side
+ +
+ + Left side + Left side +
Left side
+
Right side Anophthalmia
Right side
+
+
Upper eyelid coloboma
-
-
+
-
+
Obstructed nasolacrimal ducts -
TABLE I. Clinical Data*
+
Aberrant anterior frontatemporal scalp hair
-
-
+
+ +
-
Mild groove nasal tip
N
N
N
N
N
N
Growth
N
N
N
N
N
N
Development
+
+
-
+
-
-
Anal stenosis
+
+ +
-
-
-
Anteriorly displaced anus
New Familial Syndrome
797
TABLE 11. Investigations* Investigation Cranial U/S Skull X-ray Cervical spine X-ray Renal U/S Echocardiogram Audiology Q-banded chromosome analysis *Key: N = normal; NA
=
Case VI-2
Case VI-4
Case VI-8
Case VI-13
NA NA NA N N L minor dysfunction NA
N N NA NA NA N
NA N N N NA N
N NA N N N N
Case VI-14 N NA N N NA N
NA
N
N
N
not available.
Cryptophthalmos (hidden eye) in an infant was first described by Zehender and Munz in 1872.It has been reported as an isolated malformation as well as part of an autosomal recessive MCA syndrome [Thomas et al., 1986; Mina et al., 19881. Cryptophthalmos varies in severity and presentation from bilateral complete to unilateral partial. The complete form consists of absent palpebral fissures with anomalous extension of the skin of the forehead to completely cover the affected eye [Bieber et al., 19821.In some cases, an aberrant wedge of scalp hair extends onto the lateral margin of the orbit [Thomas et al., 19861. Partial cryptophthalmos may present with short palpebral fissures or absent eyelid or coloboma of the eyelid. The skin of the brow may be attached to the cornea or sclera [Thomas et al., 19861. Thomas et al. [19861suggested diagnostic criteria to identify cases of cryptophthalmos syndrome, also known as Fraser syndrome. The diagnosis can be made in patients with a t least 2 major criteria (cryptophthalmos, syndactyly, abnormal genitalia, or sib with cryptophthalmos syndrome) and one minor criterion, or one major criterion, and 4 minor criteria (congenital malformations of nose, ears, or larynx, cleft lip and/or palate, skeletal defects, umbilical hernia, renal agenesis, mental retardation). Cryptophthalmos is not a constant finding in this syndrome [Boyd et al., 19881. Associated anal atresia was reported by Codere et al. [1981].Our patients do not fulfill the diagnostic criteria suggested for this syndrome. Median cleft face anomaly (MCFA, frontonasal dysplasia sequence) shows a variable phenotype of true hypertelorism with combinations of cranium bifidum occultum, median cleft of the palate, upper lip or nose with a low V-shape frontal hairline [Musarella and Young, 1986;Jones, 19881.Gorlin et al. [19901reports that oblique facial clefting may be associated with upper or lower eyelid coloboma. Goldenhar sequence (oculoauricular vertebral spectrum) is associated with primary defects in morphogenesis of the first and second branchial arches, vertebral and/or ocular anomalies [Jones, 19881.Gorlin et al. 119901 reports that 50-60% of patients with epibulbar dermoids also have unilateral coloboma of the
superior eyelid, although bilateral superior lid coloboma and coloboma of the upper eyelid and lower lids have been described. Lower lid colobomata are present in 75% of cases of Treacher-Collins syndrome (mandibulofacial dysostosis), although upper eyelid coloboma have been occasionally described [Gorlin et al., 19901.This condition is associated with other major facial anomalies; congenital heart defects occur, but anal malformations are not generally associated [Jones, 19881.Nager syndrome (acrofacial dysostosis) is a mandibulofacial dysostosis associated with radial defects. The facial changes resemble those of Treacher-Collins syndrome, but the frequency of lower lid colobomata is significantly less [Halal et al., 1983;Jones, 19881. The cat-eye syndrome is characterized by anal atresia and coloboma of the iris and choroid. Most patients also have a supernumerary bisatellited chromosome 22 with either 3 or 4 copies of the DNA sequence from chromosome 22qll [Pinsky, 1978; McDermid et al., 1986; Jones, 19881. Lenz microphthalmia syndrome and ablepharon macrostoma were excluded [Gorlin et al., 19901. Our 6 Manitoba Indian patients present with a unique association of unilateral eye malformations, including upper eyelid coloboma, aberrant anterior forehead hairline, and nasal and anal anomalies. Chromosomes were normal in those examined and no intrauterine teratogen exposures were identified. The presence of a specific pattern of 2 major malformations in siblings and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution of affected cases involving both sexes equally make autosomal recessive inheritance the most parsimonious explanation.
ACKNOWLEDGMENTS We thank the children and their families for their cooperation; Josie Diato and Michelle Jubenvill for expert secretarial assistance; and the Children’s Hospital Research Foundation for financial assistance.
*Key: N = normal; + dominant. =
Aberrant -anterior hairline Nasal cleftlgroove Facial clefting Ear anomaly Vertebral anomaly Hand abnormality CVS malformation Fknal malformation Anal malformation CNS development Inheritance
Hypertelorisrn Eyelid coloboma
Trait
often present; ++
?AR
N
++ =
t
+
+
+ t+f +++
-
with epibulbar dermoids
=
N AD
I
t -
-
f++ -
++
-
+
=
=
Unknown
N
-
++ +++ +-
++
-
+
N+ delayed AR
f
+ + ++
++ + ++
+++
Cryptophthalmos
+
Fraser
autosomal-recessive;AD = autosomal
Mild delay Chromosomal
+
++
++
+ ++
-
-
+ Coloboma of iridchoroid
Lower lid
Cat eye
Nager
not present; AR
75% lower lid
x
"reacher Collins
very frequently present; -
Sporadic
N j m i l d delay
+
Goldenhar
frequently present; +++
N-mild delay Sporadic
-
-t -
+
+++
+
+++
++
++- +
Median Cleft face anomaly
fff
Our patients
TABLE 111. Differential Diagnosis"
New Familial Syndrome
REFERENCES Bieber FR, Page DV, Holrnes LB (1982):Variation in expression of the cryptophthalmos syndrome. Am J Hum Genet 34:81A. Boyd PA, Keeling JW, Lindenbaum RH (1988):F’raser syndrome (cryptophthalmos-syndactyly syndrome): A review of eleven cases with postmortem findings. Am J Med Genet 31:159-168. Codere F, Brownstein S, Chen MF (1981):Cryptophthalmos syndrome with bilateral renal agenesis. Am J Ophth 737-742. Duke-Elder S (1964):Part 2. Congenital deformities. In Duke-Elder, S (ed): “Normal and Abnormal Development in System of Ophthalmology.” London: Henry Klimpton, pp 836-840. Gorlin RJ, Cohen MM, Jr, Levin LS ( 1990):“Syndromesof the Head and Neck,” 3rd ed. New York: Oxford University Press, 1990 pp 95,96, 362-365,641-646,649-654,744,785-788,816-819. Guillemeau J (1585): Trait6 des muladies de l’oeil. Paris. 43. Halal F, Herrmann J, Pallister PD, Opitz JM, DesGranges MF, Grenier G (1983):Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209-224. Jones KL (1988): Smiths recognizable patterns of human malforma-
799
tion. Philadelphia: W.B. Saunders, pp 62, 63, 202, 203, 584-587, 210, 211, 216, 217, 204, 205. McDermid H, Duncan AMV, Brasch KR, Holden JJA, Magenis E, Sheehy R, Burn J , Kardon N, Noel B, Schinzel A, Teshima I, White BN (1986):Characterization of the supernumerary chromosome in cat eye syndrome. Science 232:646-648. Mina MMF, Greenberg CR, Levin B (1988):ENT abnormalities associated with b a s e r syndrome: Case report and literature review. J Otolaryng 17233-236. Musarella MA, Young ID (1986): A patient with median cleft face anomaly and bilateral Goldenhar anomaly. Am J Med Genet Supp 2:135-141. Pinsky L (1978):The syndromology of anorectal malformation (atresia, stenosis, ectopia). Am J Med Genet 1:461-74. Thomas IT, Frias JL, Felix V, de Leon LS, Hernandez RA, Jones MC (1986):Isolated and syndromic cryptophthalmos. Am J Med Genet 25935-98. Wilde (1847):Report on the progress of ophthalmic surgery. Dublin. 5. Zehender W (1872): Ein Missgeburt mit hautuber wachsenen augen oder kryptophthalmus. Klin Monatshl Augenheilkd. 10:225-249.
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New Familial Syndrome of Unilateral Upper Eyelid Coloboma, Aberrant Anterior Hairline Pattern, and Anal Anomalies in Manitoba Indians Sandra L. Marles, Cheryl R. Greenberg, Tkivedi V. N. Persaud, E. Paul Shuckett, and Albert E. Chudley Children’s Hospital and Departments of Pediatrics and Child Health and Human Genetics (S.L.M., C.R.G., A.E.C.) Ophthalmology (E.P.S.), and Anatomy (T.V.N.P.),University of Manitoba, Winnipeg, Manitoba, Canada We report on 6 (3 male, 3 female) Manitoba Indian children with hypertelorism and variable combinationsof unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. These children belong to 4 related families. The parents and 7 other sibs are clinically unaffected. The family histories are otherwise unremarkable. The presence of 2 major malformations in sibs and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. The differential diagnosis includes cryptophthalmos syndrome and several other related malformation syndromes. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution make autosomalrecessive inheritance more likely.
KEY WORDS: eye malformation, upper-eye-
land Lake. They have their own dialect, which is a mixture of SaulteaudOjibway with a heavy overlay of Cree. The population is inbred.
CLINICAL REPORTS These 6 children belong to 4 related families (Fig. 1). All children were born at term after normal pregnancies with no known intrauterine teratogen exposure. Labour and delivery were unremarkable in each case, except VI-2 who was born by cesarean section for fetal distress. Parental consanguinity is documented in case VI-2. Patient VI-2 This male infant had a wedge of scalp hair extending from the right frontotemporal region to the right upper eyelid, which had a coloboma of the medial third. He had hypertelorism and an oculopalpebral synechia. Otherwise his growth, developmental, and ophthalmologic status were normal.
Patient VI-4 This male infant had an aberrant anterior hairline extending from the left frontotemporal region to the left upper eyelid. He had left anophthalmia and hypertelorism. The inner canthal distance was 4.0 cm (greater INTRODUCTION than 97th centile) and the outer canthal distance was We describe 6 (3 male, 3 female) Manitoba Indian 9.0 cm (greater than 97th centile). He had bilateral children with hypertelorism and variable combinations obstruction of the nasolacrimal ducts, but the rest of the of unilateral eye malformations, aberrant anterolateral ocular structures was normal. He had a slight groove of scalp hairline, and nasal and anal anomalies. The par- the nasal tip. His head circumference was 48 cm, above ents and 7 other sibs are clinically unaffected. The fam- the 95th centile for age, with normal cranial ultrasound. ily histories are otherwise unremarkable. The 4 related Otherwise he was normal (Fig. 2). families live in an isolated part of northeastern Manitoba. The Island Lake region consists of 3 reservations Patient VI-7 on the northeastern, eastern, and western shores of IsThis 11-year-oldboy was the older brother of VI-8. He had a wedge of scalp hair extending from the left frontotemporal region to the left eyebrow. Hypertelorism (inner canthal distance, 3.5 cm, 95th centile, and outer Received for publication March 20, 1991; revision received Aucanthal distance, 10.5 cm, above 97th centile for age) gust 12, 1991. Address reprint requests to Dr. A. E. Chudley, Section of Clinical and normal eye findings were documented. He had anal Genetics, FE 231 Community Services Building, 840 Sherbrook stenosis requiring dilatation, but was otherwise normal (Fig. 3). St., Winnipeg, Manitoba R3A 1S1 Canada. lid coloboma, anal stenosis, recessive inheritance
0 1992 Wiley-Liss, Inc.
794
Marles et al. I II
111
IV V
I VI 1
2
3
4
5
6
7
f
8
9 1 0 1 1
12
13
14
Fig. 1. The pedigree 0personally examined, Flaberrant anterior hairline, 0 upper eyelid coloboma,0 abnormal placement of anus, 0 anal stenosis, El* unilateral anophthalmos.
Patient VI-8 This female infant had an aberrant anterior hairline extending from the left frontotemporal region to the left eyebrow. She had a coloboma of the medial half of the left upper eyelid. She had hypertelorism (inner canthal distance, 3.5 cm, 95th centile and outer canthal distance, 9.5 cm, 97th centile for age) and bilateral obstructed nasolacrimal ducts, with otherwise normal eye findings. She had a slight groove to the nasal tip. Other than anterior displacement of her anus without stenosis, she was normally developed (Fig. 4).
t
Patient VI-13 This female infant had an aberrant wedge of scalp hair extending from the left frontotemporal region to the left upper eyelid. She had a coloboma of the medial half of the left upper eyelid. Hypertelorism (inner canthal distance, 5 cm, and outer canthal distance, 12 cm, both above 97th centile for age) was the only other eye abnormality. She had an anteriorly displaced anus with stenosis requiring dilatation. The remainder of her physical
. -; rI
Fig 2. Pt VI-4 Note the aberrant antenor hairline m t h left anophthalmia and hypertelorisrn There is a slight groove ofhis nasal tlp
Fig 3 Pt VI-7 He has an anomalous wedge of scalp hair extending from the left frontotemporal region to the left eyebrow, which he shaves for cosmetic reasons Hypertelorism IS present
New Familial Syndrome
795
Fig. 6. Pt VI-14.She has a right aberrant wedge ofscalp hair with a large coloboma of the right upper eyelid. Hypertelorism is associated. Fig. 4. Pt VI-8. She has an aberrant wedge of scalp hair from the left frontotemporal region to the left eyebrow with a left upper eyelid coloboma. Hypertelorism is present. Her nasal tip has a slight groove.
was a t the 95th centile for age, but results of cranial ultrasound study were normal. The remainder of her physical findings and development was normal (Fig. 6). A summary of the clinical data and investigations is findings including growth and development were nor- presented in Table I and Table 11, respectively. mal (Fig. 5). DISCUSSION Patient VI-14 Jacques Guillemeau [1585] first described the simple This girl was the younger sib of case VI-13. She had an eyelid coloboma as “paupieres accourcies,” and Wilde aberrant anterior hairline extending from the right 118471called it “cleft eyelid [Duke-Elder, 19641. Simple frontotemporal region to the right upper eyelid, which eyelid colobomata are most commonly triangularalso had a coloboma of the medial two-thirds. Hyper- shaped with the base at the lid margin, but quadritelorism (inner canthal distance, 3 cm, and outer can- lateral, W-shape, and irregular shapes can occur. Althal distance, 8 cm, both above 97th centile for age) was though most commonly located on the inner half of the the only other ophthalmologic abnormality. She re- superior lid or the outer half of the lower lid, they have quired dilatation and surgical correction of her ante- been described in other locations and in various combiriorly displaced stenotic anus. Her head circumference nations including coloboma of all 4 lids. Colobomata vary in size from a small indentation of the free border of the eyelid to near absence of the entire lid. It may extend peripherally to involve the orbital margin with local absence of the eyebrow or there maybe an anomalous wedge of scalp hair extending down the forehead toward the coloboma, as seen in our patients. The coloboma is usually full-thickness with rounded edges covered by conjunctiva, which may therefore loosely connect the lid to the bulbar conjunctiva [Duke-Elder, 19643. Dermoid growths, dermatolipomata, or subconjunctival lipomata of the eyes, corneal opacities, oculopalpebral synechiae, and fundal coloboma have been associated with lid colobomata [Duke-Elder, 19641. Eyelid coloboma have been reported with nonocular defects such as anencephaly, hemicephaly, hydrocephalus, ventral hernia, syndactyly, and limb deficiencies [Duke-Elder, 19641 and the epidermal nevus syndrome [Gorlin et al., 19901. Eyelid coloboma have also been described as part of many craniofacial and multiple congenital anomaly (MCA) syndromes. Our patients share some ocular and nasal manifestations common with several of these syndromes, but many differences exist and our patients lack many of the associated anomFig. 5 . F’t VI-13. The upper eyelidfollowingrepairofcoloboma.Note the hypertelorism, aberrant wedge of scalp hair, and slight groove to alies or do not clinically resemble these syndromes summarized below and in Table 111.
=
absent; N
-
-
-
=
Neonate
VI-14
present; -
Neonate
VI-13
=
10 wks
VI-8
+
11 yrs
VI-7
*Key:
-
Neonate
VI-4
-
+
+
Neonate
VI-2
normal.
+ + +
+ +
Hypertelorism
Parental consanguinity
Age a t exam
Trait Case
Left side
Left side
+
Rieht side
Rieht side
Left side
Left side
+ +
+ + Left side + Left side +
Left side
+
Right side Anophthalmia
Right side
+
+
Upper eyelid coloboma
-
-
+
-
+
Obstructed nasolacrimal ducts -
TABLE I. Clinical Data*
+
Aberrant anterior frontatemporal scalp hair
-
-
+
+ +
-
Mild groove nasal tip
N
N
N
N
N
N
Growth
N
N
N
N
N
N
Development
+
+
-
+
-
-
Anal stenosis
+
+ +
-
-
-
Anteriorly displaced anus
New Familial Syndrome
797
TABLE 11. Investigations* Investigation Cranial U/S Skull X-ray Cervical spine X-ray Renal U/S Echocardiogram Audiology Q-banded chromosome analysis *Key: N = normal; NA
=
Case VI-2
Case VI-4
Case VI-8
Case VI-13
NA NA NA N N L minor dysfunction NA
N N NA NA NA N
NA N N N NA N
N NA N N N N
Case VI-14 N NA N N NA N
NA
N
N
N
not available.
Cryptophthalmos (hidden eye) in an infant was first described by Zehender and Munz in 1872.It has been reported as an isolated malformation as well as part of an autosomal recessive MCA syndrome [Thomas et al., 1986; Mina et al., 19881. Cryptophthalmos varies in severity and presentation from bilateral complete to unilateral partial. The complete form consists of absent palpebral fissures with anomalous extension of the skin of the forehead to completely cover the affected eye [Bieber et al., 19821.In some cases, an aberrant wedge of scalp hair extends onto the lateral margin of the orbit [Thomas et al., 19861. Partial cryptophthalmos may present with short palpebral fissures or absent eyelid or coloboma of the eyelid. The skin of the brow may be attached to the cornea or sclera [Thomas et al., 19861. Thomas et al. [19861suggested diagnostic criteria to identify cases of cryptophthalmos syndrome, also known as Fraser syndrome. The diagnosis can be made in patients with a t least 2 major criteria (cryptophthalmos, syndactyly, abnormal genitalia, or sib with cryptophthalmos syndrome) and one minor criterion, or one major criterion, and 4 minor criteria (congenital malformations of nose, ears, or larynx, cleft lip and/or palate, skeletal defects, umbilical hernia, renal agenesis, mental retardation). Cryptophthalmos is not a constant finding in this syndrome [Boyd et al., 19881. Associated anal atresia was reported by Codere et al. [1981].Our patients do not fulfill the diagnostic criteria suggested for this syndrome. Median cleft face anomaly (MCFA, frontonasal dysplasia sequence) shows a variable phenotype of true hypertelorism with combinations of cranium bifidum occultum, median cleft of the palate, upper lip or nose with a low V-shape frontal hairline [Musarella and Young, 1986;Jones, 19881.Gorlin et al. [19901reports that oblique facial clefting may be associated with upper or lower eyelid coloboma. Goldenhar sequence (oculoauricular vertebral spectrum) is associated with primary defects in morphogenesis of the first and second branchial arches, vertebral and/or ocular anomalies [Jones, 19881.Gorlin et al. 119901 reports that 50-60% of patients with epibulbar dermoids also have unilateral coloboma of the
superior eyelid, although bilateral superior lid coloboma and coloboma of the upper eyelid and lower lids have been described. Lower lid colobomata are present in 75% of cases of Treacher-Collins syndrome (mandibulofacial dysostosis), although upper eyelid coloboma have been occasionally described [Gorlin et al., 19901.This condition is associated with other major facial anomalies; congenital heart defects occur, but anal malformations are not generally associated [Jones, 19881.Nager syndrome (acrofacial dysostosis) is a mandibulofacial dysostosis associated with radial defects. The facial changes resemble those of Treacher-Collins syndrome, but the frequency of lower lid colobomata is significantly less [Halal et al., 1983;Jones, 19881. The cat-eye syndrome is characterized by anal atresia and coloboma of the iris and choroid. Most patients also have a supernumerary bisatellited chromosome 22 with either 3 or 4 copies of the DNA sequence from chromosome 22qll [Pinsky, 1978; McDermid et al., 1986; Jones, 19881. Lenz microphthalmia syndrome and ablepharon macrostoma were excluded [Gorlin et al., 19901. Our 6 Manitoba Indian patients present with a unique association of unilateral eye malformations, including upper eyelid coloboma, aberrant anterior forehead hairline, and nasal and anal anomalies. Chromosomes were normal in those examined and no intrauterine teratogen exposures were identified. The presence of a specific pattern of 2 major malformations in siblings and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution of affected cases involving both sexes equally make autosomal recessive inheritance the most parsimonious explanation.
ACKNOWLEDGMENTS We thank the children and their families for their cooperation; Josie Diato and Michelle Jubenvill for expert secretarial assistance; and the Children’s Hospital Research Foundation for financial assistance.
*Key: N = normal; + dominant. =
Aberrant -anterior hairline Nasal cleftlgroove Facial clefting Ear anomaly Vertebral anomaly Hand abnormality CVS malformation Fknal malformation Anal malformation CNS development Inheritance
Hypertelorisrn Eyelid coloboma
Trait
often present; ++
?AR
N
++ =
t
+
+
+ t+f +++
-
with epibulbar dermoids
=
N AD
I
t -
-
f++ -
++
-
+
=
=
Unknown
N
-
++ +++ +-
++
-
+
N+ delayed AR
f
+ + ++
++ + ++
+++
Cryptophthalmos
+
Fraser
autosomal-recessive;AD = autosomal
Mild delay Chromosomal
+
++
++
+ ++
-
-
+ Coloboma of iridchoroid
Lower lid
Cat eye
Nager
not present; AR
75% lower lid
x
"reacher Collins
very frequently present; -
Sporadic
N j m i l d delay
+
Goldenhar
frequently present; +++
N-mild delay Sporadic
-
-t -
+
+++
+
+++
++
++- +
Median Cleft face anomaly
fff
Our patients
TABLE 111. Differential Diagnosis"
New Familial Syndrome
REFERENCES Bieber FR, Page DV, Holrnes LB (1982):Variation in expression of the cryptophthalmos syndrome. Am J Hum Genet 34:81A. Boyd PA, Keeling JW, Lindenbaum RH (1988):F’raser syndrome (cryptophthalmos-syndactyly syndrome): A review of eleven cases with postmortem findings. Am J Med Genet 31:159-168. Codere F, Brownstein S, Chen MF (1981):Cryptophthalmos syndrome with bilateral renal agenesis. Am J Ophth 737-742. Duke-Elder S (1964):Part 2. Congenital deformities. In Duke-Elder, S (ed): “Normal and Abnormal Development in System of Ophthalmology.” London: Henry Klimpton, pp 836-840. Gorlin RJ, Cohen MM, Jr, Levin LS ( 1990):“Syndromesof the Head and Neck,” 3rd ed. New York: Oxford University Press, 1990 pp 95,96, 362-365,641-646,649-654,744,785-788,816-819. Guillemeau J (1585): Trait6 des muladies de l’oeil. Paris. 43. Halal F, Herrmann J, Pallister PD, Opitz JM, DesGranges MF, Grenier G (1983):Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209-224. Jones KL (1988): Smiths recognizable patterns of human malforma-
799
tion. Philadelphia: W.B. Saunders, pp 62, 63, 202, 203, 584-587, 210, 211, 216, 217, 204, 205. McDermid H, Duncan AMV, Brasch KR, Holden JJA, Magenis E, Sheehy R, Burn J , Kardon N, Noel B, Schinzel A, Teshima I, White BN (1986):Characterization of the supernumerary chromosome in cat eye syndrome. Science 232:646-648. Mina MMF, Greenberg CR, Levin B (1988):ENT abnormalities associated with b a s e r syndrome: Case report and literature review. J Otolaryng 17233-236. Musarella MA, Young ID (1986): A patient with median cleft face anomaly and bilateral Goldenhar anomaly. Am J Med Genet Supp 2:135-141. Pinsky L (1978):The syndromology of anorectal malformation (atresia, stenosis, ectopia). Am J Med Genet 1:461-74. Thomas IT, Frias JL, Felix V, de Leon LS, Hernandez RA, Jones MC (1986):Isolated and syndromic cryptophthalmos. Am J Med Genet 25935-98. Wilde (1847):Report on the progress of ophthalmic surgery. Dublin. 5. Zehender W (1872): Ein Missgeburt mit hautuber wachsenen augen oder kryptophthalmus. Klin Monatshl Augenheilkd. 10:225-249.
