American Journal of Medical Genetics 39:102-105 (1991)
Unique Phenotype Associated With a Pericentric Inversion of Chromosome 6 in Three Generations -~
~
~
Katharine D. Wenstrom, Ann C. Muilenburg, Shivanand R. Patil, and James W. Hanson Department of Obstetrics and Gynecology (K.D.W.) and Department of Pediatrics (A.C.M.,S.RS.,J.W.H.), University of Iowa Hospital, Iowa City
high-frequency hearing loss (Table I). BS also had three sibs who were normal (DE, BEM, and CE), although one had died of cancer at age 33 years (CE). EE’s mother, also deceased, was reported to have had congenital cataracts as well. No other medical problems were known in the family, and there was no history of spontaneous abortion, miscarriage, or infertility. BS’s husband, VS, and his family had no medical problems or history of reproductive difficulty or losses. The abnormalities found in BS and her family were similar to those seen in the Rieger syndrome, which has been associated with chromosomal aberrations [McKusick, 19881. Blood was drawn for chromosome study on BS and EE. BS also subsequently underwent amniocentesis for advanced maternal age, and chromosomes were studied on her husband VS, her mother KEY WORDS: Rieger’s syndrome DME, her affected sibs GE and RE, and her unaffected sibs DE and BEM. Results (Fig. 2) demonstrated that the fetus and all affected individuals had the identical pericentric inversion of chromosome 6 [46, XX or XY, INTRODUCTION Numerous cases of autosomal pericentric inversions inv(6)(p23q23.1)1(Fig. 3). Based on high-resolution chrohave been described [Kaiser, 19841.Although most indi- mosome analysis, there was no detectable recombinant chromosome 6. viduals with inversions are phenotypically normal, BS and her husband desired to continue the pregsome are phenotypically abnormal. We report on the nancy. After a n anteparturn course complicated by preassociation of a pericentric inversion of chromosome 6 mature labor, their son was born by vaginal delivery at with a unique phenotype in three generations of one 36 weeks gestation. He weighed 2,905 g and had Apgar family.
We observed a pericentric inversion of chromosome 6 in three generations of one family. Carriers had several phenotypic alterations including congenital cataracts, hearing loss, dental anomalies, ear anomalies, premature graying, unilateral strabismus, coloboma, and mild mental retardation. These manifestations may all be explained by a failure or delay in development of tissues derived from neural crest cells and are similarto these seen in the Rieger syndrome. The description of this family extends the known phenotypic abnormalities associated with alterations of chromosome 6.
CLINICAL REPORT BS (Fig. 1),a 40 year old woman, presented during her first pregnancy for prenatal genetic counseling a t 15 weeks gestation. She was noted to have bilateral colobomatous micropthalmia with partial cataract, amblyopia O.D. due to severe optic nerve and retinal dysplasia, hearing loss, small posteriorly angulated ears with incompletely folded helices, premature graying, tooth abnormalities (partially edentalous with a few peg-like teeth), and mild mental retardation. She reported that two brothers (GE, age 45, and RE, age 34) had similar abnormalities and that her father (EE, age 77) had congenital cataracts and bilateral sensorineural Received for publication April 16, 1990; revision received July 16, 1990. Address reprint requests to Katharine D. Wenstrom, M.D., Department of Obstetrics and Gynecology, University of Iowa Hospital, Iowa City, IA 52242.
o 1991 Wiley-Liss, Inc.
RE
EE
GE
DME
DE
Fig. 1. Our patient, BS,and her family.
BS
Pericentric Inversion of Chromosome 6
103
TABLE I. Clinical Manifestations
BS
-
~
GE
RE
EE
Infant
+ + + + +
+ + + + +
+ +
+
~- -
Congenital cataracts Hearing loss Dental anomalies Ear anomalies Premature graying Unilateral strabismus Mild mental retardation Coloboma
+
+
+
W
GE
BEM
CE
RE
of
relatives.
DE
BS
Fig. 2. Pedigree O)inv(6Kp23q23.1)
and
chromosomes
(M,
scores of 1a t 1minute and 5 at 5 minutes. Neonatally, he was found to have cataracts and ear anomalies (Table I).
DISCUSSION Pericentric inversions are usually not associated with phenotypic abnormalities and often only come to light while investigating either fetal chromosome abnormalities detected during amniocentesis or a phenotypically abnormal individual with a recombinant chromosome. Family studies of inversion carriers in general show a n approximate 1: 1 segregation in meiosis without alteration in the rate of fertility, stillbirths, or spontaneous abortions [Kaiser, 19841. The occurrence of recombinants in offspring is not uncommon and appears to be related to the absolute size of the inversion segment as well as to the inherent characteristics of that segment and to the size of the imbalance which results [Kaiser, 19841. Three families have been described in which phenotypically normal carriers of a pericentric inversion of chromosome 6 have been observed in association with a phenotypically abnormal duplication-deletion propositus. All three propositi were noted to be abnormal a t birth. Although neither the three propositi nor the 13 inversion carriers described in these reports had changes similar to those of the individuals in the family under study, they did share traits with each other (Table 11). However, phenotypic abnormalities are not confined to carriers of duplication-deletion recombinants. The occurrence of mental retardation and physical anomalies in individuals with balanced inversions is reported not infrequently and is present in the family we describe. Such phenotypic alteration can be explained in several ways: These “balanced” inversions may actually include microscopic deletions or duplications not detect-
Fig. 3. Inv(6)(p23q23.1).
able by routine banding techniques. Alternatively, if the break leading to inversion occurred within a cistron, the genetic information so determined could be “misinterpreted.’’ It is also possible that, a s a result of inver-
104
Wenstrom et al. TABLE 11. Clinical and Cytogenetic Findings in Three Patients with Chromosome 6 Inversions References
Aneusomic individual
Inversion
Schroer et al. [1980]
inv(6)(p25q25)five individuals in three generations
rec(6) dup q, inv(6Hp25q25)
Magenis et al. [19781
inv(6)(pter+p23: : q23jp23: :q23+) three individuals in three generations
rec(6)(qter+q23: : p23jqter)
Pearson et a1 [19791
inv(6)(pter+p21: : q27jp21:: q 2 7 j q t e r j ) five individuals in four generations
rec(6)inv dup 6pterj6p21, def 6q27-6qter (pterjp21:: q27-+p21: : p2ljpter)
a
Findings in propositus Growth retardation Developmental delay" Hypertelorism" Minor facial anomalies" Flexion deformities of interphalangeal jointsa Alive at age 13 months Developmental delay" Cleft lip and palate Talipes equinovarus" Hypertelorism" Large simple ears Ankylosis of distal interphalangeal joints" Alive at age 2 years Minor facial anomalies" Craniosynostosis Microphthalmia Blepharophimosis Multiple hemangiomas Talipes equinovarusa Persistent ductus arteriosus Absence of uterus and upper vagina Polymicrogyria Arrhinencephaly Dead at age 2 months
Common findings.
sion, genetic material newly positioned near heterochromatin could be inactivated. Our observation can probably be explained by one of these events, but is unusual because the same genetic alteration has been transmitted apparently unchanged through three generations. To our knowledge, the association of a "balanced" inversion of chromosome 6 in association with phenotypic abnormalities in more than one generation has been reported in only one other family. The description of this family by Heinemann et al. [19791 is of interest because the two individuals carrying the inversion also had some signs of the Rieger syndrome. The 10 year old girl had an abnormally thickened and centrally displaced ridge of Schwalbe's line, numerous iris processes, atrophic irides with hypoplasia of the anterior stroma, hypoplasia of the maxilla, and microdontia. Her 36 year old father had a prominent Schwalbe line and iris mounds bilaterally. Both carried a pericentric inversion of chromosome 6. However, breakpoints were not determined and the inversion was simply described as 6p + q - . In these individuals and in the family we describe, molecular studies are essential to determine the identity of any microscopic additions, deletions, or position effects and might be useful in illuminating a possible relationship between the findings of the Rieger syndrome and other ectodermal abnormalities and certain loci on chromosome 6. It is also of interest that, although all patients carried the identical inversion, they did not all have identical manifestations. The degree of effect ranged from severe
in BS (with eight abnormalities) to relatively mild in EE (only two). However, such variability is not surprising, particularly in the Rieger syndrome. Shields et al. [19851 suggested that the phenotypic abnormalities of Rieger syndrome result from a failure or delay in development of tissues derived from neural crest cells. As the neural crest cells give rise to mesenchyme of the forebrain, bone and cartilage of the upper face, dental papillae, and pigment cells of iris, choroid, skin, and hair, this theory seems consistent with the clinical findings in our patients. The degree of developmental delay, and, hence, the degree of effect, may be related to environmental influences and other epigenetic factors. Clinically different outcomes would therefore be expected in individuals with identical genetic abnormalities if they were exposed to different modifiers during development. The fact that the Rieger syndrome has been seen in aberrations of chromosomes 4, 6, 9, 13, 18, and 21 [McKusick,19881suggests that the development of neural crest cell-derived structures is influenced by many genes. The clinical variability seen in the individuals we describe may therefore result from the interaction of environmental and genetic influences.
REFERENCES Heinemann MH, Breg R, Cotlier E 11979): Rieger's syndrome with pericentric inversion of chromosome 6. Br J Opthalmol 63:40-44. Kaiser P (1984): Pericentric inversions. Problems and significance for clinical genetics. Hum Genet 68:l-47. Magenis RE, Chamberlin J, Overton K, Lovrien E (1978): Linkage
Pericentric Inversion of Chromosome 6 relationships of HLA and a familial chromosome 6 inversion (pter- p23::q23-, p23::q23- qter): Lack of dose effect in duplication-deficient offspring. Cytogenet Clin Genet 22:418-420. McKusick VA (1988): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes,’’Eighth edition. Baltimore: The Johns Hopkins University Press, p 662. Pearson G, Mann JD, Bensen J , Bull RW (1979):Inversion duplication
105
of chromosome 6 with trisomic codominant expression of HLA antigens. Am J Hum Genet 31:29-34. Schroer RJ,Culp DM, Stevenson RE, Potts WE, Taylor HA, Simenson RJ (1980): Duplication-deletion syndrome in a family with pericentric inversion of chromosome 6 . Clin Genet 18:83-87. Shields B, Buckley E, Klintworth GK, Thresher R (1985): AxenfeldRieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 29:387-409.
Unique Phenotype Associated With a Pericentric Inversion of Chromosome 6 in Three Generations -~
~
~
Katharine D. Wenstrom, Ann C. Muilenburg, Shivanand R. Patil, and James W. Hanson Department of Obstetrics and Gynecology (K.D.W.) and Department of Pediatrics (A.C.M.,S.RS.,J.W.H.), University of Iowa Hospital, Iowa City
high-frequency hearing loss (Table I). BS also had three sibs who were normal (DE, BEM, and CE), although one had died of cancer at age 33 years (CE). EE’s mother, also deceased, was reported to have had congenital cataracts as well. No other medical problems were known in the family, and there was no history of spontaneous abortion, miscarriage, or infertility. BS’s husband, VS, and his family had no medical problems or history of reproductive difficulty or losses. The abnormalities found in BS and her family were similar to those seen in the Rieger syndrome, which has been associated with chromosomal aberrations [McKusick, 19881. Blood was drawn for chromosome study on BS and EE. BS also subsequently underwent amniocentesis for advanced maternal age, and chromosomes were studied on her husband VS, her mother KEY WORDS: Rieger’s syndrome DME, her affected sibs GE and RE, and her unaffected sibs DE and BEM. Results (Fig. 2) demonstrated that the fetus and all affected individuals had the identical pericentric inversion of chromosome 6 [46, XX or XY, INTRODUCTION Numerous cases of autosomal pericentric inversions inv(6)(p23q23.1)1(Fig. 3). Based on high-resolution chrohave been described [Kaiser, 19841.Although most indi- mosome analysis, there was no detectable recombinant chromosome 6. viduals with inversions are phenotypically normal, BS and her husband desired to continue the pregsome are phenotypically abnormal. We report on the nancy. After a n anteparturn course complicated by preassociation of a pericentric inversion of chromosome 6 mature labor, their son was born by vaginal delivery at with a unique phenotype in three generations of one 36 weeks gestation. He weighed 2,905 g and had Apgar family.
We observed a pericentric inversion of chromosome 6 in three generations of one family. Carriers had several phenotypic alterations including congenital cataracts, hearing loss, dental anomalies, ear anomalies, premature graying, unilateral strabismus, coloboma, and mild mental retardation. These manifestations may all be explained by a failure or delay in development of tissues derived from neural crest cells and are similarto these seen in the Rieger syndrome. The description of this family extends the known phenotypic abnormalities associated with alterations of chromosome 6.
CLINICAL REPORT BS (Fig. 1),a 40 year old woman, presented during her first pregnancy for prenatal genetic counseling a t 15 weeks gestation. She was noted to have bilateral colobomatous micropthalmia with partial cataract, amblyopia O.D. due to severe optic nerve and retinal dysplasia, hearing loss, small posteriorly angulated ears with incompletely folded helices, premature graying, tooth abnormalities (partially edentalous with a few peg-like teeth), and mild mental retardation. She reported that two brothers (GE, age 45, and RE, age 34) had similar abnormalities and that her father (EE, age 77) had congenital cataracts and bilateral sensorineural Received for publication April 16, 1990; revision received July 16, 1990. Address reprint requests to Katharine D. Wenstrom, M.D., Department of Obstetrics and Gynecology, University of Iowa Hospital, Iowa City, IA 52242.
o 1991 Wiley-Liss, Inc.
RE
EE
GE
DME
DE
Fig. 1. Our patient, BS,and her family.
BS
Pericentric Inversion of Chromosome 6
103
TABLE I. Clinical Manifestations
BS
-
~
GE
RE
EE
Infant
+ + + + +
+ + + + +
+ +
+
~- -
Congenital cataracts Hearing loss Dental anomalies Ear anomalies Premature graying Unilateral strabismus Mild mental retardation Coloboma
+
+
+
W
GE
BEM
CE
RE
of
relatives.
DE
BS
Fig. 2. Pedigree O)inv(6Kp23q23.1)
and
chromosomes
(M,
scores of 1a t 1minute and 5 at 5 minutes. Neonatally, he was found to have cataracts and ear anomalies (Table I).
DISCUSSION Pericentric inversions are usually not associated with phenotypic abnormalities and often only come to light while investigating either fetal chromosome abnormalities detected during amniocentesis or a phenotypically abnormal individual with a recombinant chromosome. Family studies of inversion carriers in general show a n approximate 1: 1 segregation in meiosis without alteration in the rate of fertility, stillbirths, or spontaneous abortions [Kaiser, 19841. The occurrence of recombinants in offspring is not uncommon and appears to be related to the absolute size of the inversion segment as well as to the inherent characteristics of that segment and to the size of the imbalance which results [Kaiser, 19841. Three families have been described in which phenotypically normal carriers of a pericentric inversion of chromosome 6 have been observed in association with a phenotypically abnormal duplication-deletion propositus. All three propositi were noted to be abnormal a t birth. Although neither the three propositi nor the 13 inversion carriers described in these reports had changes similar to those of the individuals in the family under study, they did share traits with each other (Table 11). However, phenotypic abnormalities are not confined to carriers of duplication-deletion recombinants. The occurrence of mental retardation and physical anomalies in individuals with balanced inversions is reported not infrequently and is present in the family we describe. Such phenotypic alteration can be explained in several ways: These “balanced” inversions may actually include microscopic deletions or duplications not detect-
Fig. 3. Inv(6)(p23q23.1).
able by routine banding techniques. Alternatively, if the break leading to inversion occurred within a cistron, the genetic information so determined could be “misinterpreted.’’ It is also possible that, a s a result of inver-
104
Wenstrom et al. TABLE 11. Clinical and Cytogenetic Findings in Three Patients with Chromosome 6 Inversions References
Aneusomic individual
Inversion
Schroer et al. [1980]
inv(6)(p25q25)five individuals in three generations
rec(6) dup q, inv(6Hp25q25)
Magenis et al. [19781
inv(6)(pter+p23: : q23jp23: :q23+) three individuals in three generations
rec(6)(qter+q23: : p23jqter)
Pearson et a1 [19791
inv(6)(pter+p21: : q27jp21:: q 2 7 j q t e r j ) five individuals in four generations
rec(6)inv dup 6pterj6p21, def 6q27-6qter (pterjp21:: q27-+p21: : p2ljpter)
a
Findings in propositus Growth retardation Developmental delay" Hypertelorism" Minor facial anomalies" Flexion deformities of interphalangeal jointsa Alive at age 13 months Developmental delay" Cleft lip and palate Talipes equinovarus" Hypertelorism" Large simple ears Ankylosis of distal interphalangeal joints" Alive at age 2 years Minor facial anomalies" Craniosynostosis Microphthalmia Blepharophimosis Multiple hemangiomas Talipes equinovarusa Persistent ductus arteriosus Absence of uterus and upper vagina Polymicrogyria Arrhinencephaly Dead at age 2 months
Common findings.
sion, genetic material newly positioned near heterochromatin could be inactivated. Our observation can probably be explained by one of these events, but is unusual because the same genetic alteration has been transmitted apparently unchanged through three generations. To our knowledge, the association of a "balanced" inversion of chromosome 6 in association with phenotypic abnormalities in more than one generation has been reported in only one other family. The description of this family by Heinemann et al. [19791 is of interest because the two individuals carrying the inversion also had some signs of the Rieger syndrome. The 10 year old girl had an abnormally thickened and centrally displaced ridge of Schwalbe's line, numerous iris processes, atrophic irides with hypoplasia of the anterior stroma, hypoplasia of the maxilla, and microdontia. Her 36 year old father had a prominent Schwalbe line and iris mounds bilaterally. Both carried a pericentric inversion of chromosome 6. However, breakpoints were not determined and the inversion was simply described as 6p + q - . In these individuals and in the family we describe, molecular studies are essential to determine the identity of any microscopic additions, deletions, or position effects and might be useful in illuminating a possible relationship between the findings of the Rieger syndrome and other ectodermal abnormalities and certain loci on chromosome 6. It is also of interest that, although all patients carried the identical inversion, they did not all have identical manifestations. The degree of effect ranged from severe
in BS (with eight abnormalities) to relatively mild in EE (only two). However, such variability is not surprising, particularly in the Rieger syndrome. Shields et al. [19851 suggested that the phenotypic abnormalities of Rieger syndrome result from a failure or delay in development of tissues derived from neural crest cells. As the neural crest cells give rise to mesenchyme of the forebrain, bone and cartilage of the upper face, dental papillae, and pigment cells of iris, choroid, skin, and hair, this theory seems consistent with the clinical findings in our patients. The degree of developmental delay, and, hence, the degree of effect, may be related to environmental influences and other epigenetic factors. Clinically different outcomes would therefore be expected in individuals with identical genetic abnormalities if they were exposed to different modifiers during development. The fact that the Rieger syndrome has been seen in aberrations of chromosomes 4, 6, 9, 13, 18, and 21 [McKusick,19881suggests that the development of neural crest cell-derived structures is influenced by many genes. The clinical variability seen in the individuals we describe may therefore result from the interaction of environmental and genetic influences.
REFERENCES Heinemann MH, Breg R, Cotlier E 11979): Rieger's syndrome with pericentric inversion of chromosome 6. Br J Opthalmol 63:40-44. Kaiser P (1984): Pericentric inversions. Problems and significance for clinical genetics. Hum Genet 68:l-47. Magenis RE, Chamberlin J, Overton K, Lovrien E (1978): Linkage
Pericentric Inversion of Chromosome 6 relationships of HLA and a familial chromosome 6 inversion (pter- p23::q23-, p23::q23- qter): Lack of dose effect in duplication-deficient offspring. Cytogenet Clin Genet 22:418-420. McKusick VA (1988): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes,’’Eighth edition. Baltimore: The Johns Hopkins University Press, p 662. Pearson G, Mann JD, Bensen J , Bull RW (1979):Inversion duplication
105
of chromosome 6 with trisomic codominant expression of HLA antigens. Am J Hum Genet 31:29-34. Schroer RJ,Culp DM, Stevenson RE, Potts WE, Taylor HA, Simenson RJ (1980): Duplication-deletion syndrome in a family with pericentric inversion of chromosome 6 . Clin Genet 18:83-87. Shields B, Buckley E, Klintworth GK, Thresher R (1985): AxenfeldRieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 29:387-409.
