Journal of Pediatric Ophthalmology and Strabismus

Deletion 3q in Two Patients With Blepharophimosis-ptosis-epicanthus Inversus Syndrome (BPES)

Teresa Costa, MD, MSc, FCCMG, FRCPC; Robert Pashby, MD, FRCSC; Marlene Huggins, MSc; Ikuko E Teshima, PhD, FCCMGm FACMG

Abstract

ABSTRACT

Background: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant condition mapped to chromosome 3q23. There are several reports of chromosomal abnormalities involving this region with a resultant phenotype that includes BPES.

Method: We reassessed two unrelated boys ages 3 and 5 with BPES and associated nonocular abnormalities. Karyotype, which had been previously reported as normal, was repeated using high-resolution banding techniques, to look specifically at 3q23. Clinical findings were tabulated and compared with previously reported cases.

Results: Both patients proved to have interstitial deletions of chromosome 3, the first Involving bands q22.2q25.1 and the second q22.2q24. The first patient exhibited prenatal and postnatal growth retardation, with global developmental delay, while the second patient had normal growth and development except for speech delay. Both had dysmorphic facies with BPES, flat philtrum, a thin upper Hp, and small chin. In addition, the first boy had an inguinal hernia and hypospadius; the second boy had abnormal auricles and metatarsus adductus.The eight cases of interstitial deletions of 3q2 and six rearrangements involving this region have a remarkably similar phenotype.

Conclusions: Deletion of 3q23 is a recognizable contiguous gene syndrome. Microdeletions of 3q23 should be ruled out in any sporadic case of BPES especially if there are associated nonocular abnormalities.

Abstract

ABSTRACT

Background: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant condition mapped to chromosome 3q23. There are several reports of chromosomal abnormalities involving this region with a resultant phenotype that includes BPES.

Method: We reassessed two unrelated boys ages 3 and 5 with BPES and associated nonocular abnormalities. Karyotype, which had been previously reported as normal, was repeated using high-resolution banding techniques, to look specifically at 3q23. Clinical findings were tabulated and compared with previously reported cases.

Results: Both patients proved to have interstitial deletions of chromosome 3, the first Involving bands q22.2q25.1 and the second q22.2q24. The first patient exhibited prenatal and postnatal growth retardation, with global developmental delay, while the second patient had normal growth and development except for speech delay. Both had dysmorphic facies with BPES, flat philtrum, a thin upper Hp, and small chin. In addition, the first boy had an inguinal hernia and hypospadius; the second boy had abnormal auricles and metatarsus adductus.The eight cases of interstitial deletions of 3q2 and six rearrangements involving this region have a remarkably similar phenotype.

Conclusions: Deletion of 3q23 is a recognizable contiguous gene syndrome. Microdeletions of 3q23 should be ruled out in any sporadic case of BPES especially if there are associated nonocular abnormalities.

INTRODUCTION

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant condition affecting the ocular adnexa.1 Typically, there is blepharoptosis with impaired function of the levator palpehrae superioris muscle, short palpebral fissures, ectropion of the lower lid, and a skin fold arising from the lower lid and extending medially and upward (epicanthus inversus). The gene for BPES was recently mapped2-3 by linkage analysis to 3q23. Previous reports of BPES with associated chromosomal abnormalities involving 3q23, including apparently balanced translocations and deletions, support this finding. Most of the cases reported have had, in addition to the ocular abnormalities, mental retardation, intrauterine and postnatal growth retardation, and characteristic craniofacial dysmorphism4-19 (Tables).

Table

TABLE 1Interstitial Deletions of 3q2 Associated With Blepharophlmosis-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 1

Interstitial Deletions of 3q2 Associated With Blepharophlmosis-ptosis-epicanthus Inversus Syndrome (BPES)

Table

TABLE 1Interstitial Deletions of 3q2 Associated With Blepharophlmosis-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 1

Interstitial Deletions of 3q2 Associated With Blepharophlmosis-ptosis-epicanthus Inversus Syndrome (BPES)

We report two boys with BPES and associated abnormalities. In each case, chromosome analysis in the newborn period was reported as normal. Given the ocular findings, the tests were repeated using higher resolution banding (550-600 G-band level) to look specifically at 3q23. Both boys were found to have deletions involving this region.

CASE REPORTS

Case 1 is a 3-year-old boy who was first assessed at 5 weeks of age because of craniofacial dysmorphism and growth retardation. He was delivered by cesarean section at 34 weeks gestation because of evidence of intrauterine growth retardation and for maternal preeclampsia. Birth weight was 1520 g (less than the third percentile). On initial examination, his craniofacial dysmorphism was striking (Fig 1). He had a small head (head circumference 31 cm, less than the second percentile), hypoplastic supraorbital area, short horizontal palpebrai fissures (less than the third percentile) with severe blepharophimosis and ptosis, flat philtrum, a thin upper lip, and a small chin.

He had a small umbilical hernia, bilateral hydrocele with reducible right inguinal hernia, coronal hypospadias with mild chordee, generalized cutis marmorata, and mild metatarsus adductus. At 7 months, bilateral ptosis repair was carried out with frontalis suspension using stored fascia lata because of concerns that his severe ptosis was compounding his developmental delay. Bilateral Roveda medial canthoplasties were performed at 19 months.

His general health has been good but when last seen at age 33 months, he remained small (length 89 cm, weight 10.5 kg, and head circumference 45 cm) and showed evidence of severe global developmental delay.

A head ultrasound in the newborn period showed multiple subependymal cysts hi the frontal horns, which were confirmed on computed tomography (CT) scan. Magnetic resonance imaging (MRI) of the brain at 24 months showed evidence of generalized atrophy with prominent sulcal pattern and mildly enlarged ventricles and basal cisterns; the cysts had resolved. An abdominal ultrasound in early infancy was normal. An echocardiogram showed a bicuspid aortic valve. The family history is negative. An older brother is normal.

Case 2 is a 5-year-old boy who was referred for genetic evaluation at 1 day of age because of dysmorphic features. He was born at 40 weeks' gestation after an uneventful pregnancy. Growth parameters at birth were normal (weight 3.7 kg, length 51 cm, and head circumference 34.5 cm). He had intermittent stridor on the first day of life but no other neonatal problems. He was noted to have severe BPES, micrognathia, abnormal auricles, and bilateral metatarsus adductus.

Fig 1: Case 1 at 5 weeks of age.

Fig 1: Case 1 at 5 weeks of age.

He has reactive airway disease, which has required a few admissions to hospital. His general health has otherwise been good. He has undergone Roveda bimedial canthoplasties and bilateral ptosis repair with frontalis suspension using stored fascia lata on two occasions. A large umbilical hernia resolved by the age of 2. His foot deformity has remained flexible and has been treated conservatively with corrective shoes.

His early milestones were normal. He walked at 14½ months and was toilet trained by 2½ years. However, he has had significant delays in speech and language development. He behaves appropriately for his age, and has integrated well in regular schooling. When last seen at age 5, he was growing appropriately: his weight was 17.7 kg (25th percentile) and height 108 cm (25th to 50th percentile). The head circumference was 50 cm (1 SD below the mean). He had obvious craniofacial dysmorphism Fig 2) with short palpebrai fissures, telecanthus and ptosis, small nose with upturned nares, long philtrum, and a thin upper lip. The auricles were abnormal with overfolding of the helix superiorly. A head ultrasound in the newborn period showed choroid plexus cysts. An abdominal ultrasound was normal. A speech assessment revealed normal receptive language skills but severe phonological deviations with decreased intelligibility of speech. The family history is negative. The mother's first pregnancy was spontaneously aborted at 6 weeks' gestation. Two younger brothers are healthy.

CYTOGENETIC ANALYSIS

Both patients had karyotypes done in infancy. No abnormalities were noted. Studies were repeated at 33 months in case 1 and at 5 years in case 2. G-banded chromosomes were obtained from cultured lymphocytes using the ethidium bromide method.20 In both children, a small interstitial deletion was found in the long arm of chromosome 3. The karyotypes were interpreted to be 46,XY,del(3)(q22.2q25.1) for case 1 and 46,XY,del(3) (q22.2q24) for case 2 (Fig 3). Parental chromosomes were normal in both families.

DISCUSSION

Our two patients bring to 16 the number of reported cases with chromosomal abnormalities involving 3q2 associated with BPES. All but two occurred de novo.3, 13 In the family reported by Williamson and colleagues.4 the proband had a deletion of 3q related to an apparently balanced insertion of a small segment of 3q into Uq in his phenotypically normal father. In the family described by De Die-Smulders and colleagues,15 both the proband and his father had BPES and an apparently balanced t(3;ll). The size of the deletion at the cytogenetic level varies, but there is marked phenotypic overlap among cases.

Table

TABLE 2Rearrangements Involving 3q2 Associated With Blepharophimosls-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 2

Rearrangements Involving 3q2 Associated With Blepharophimosls-ptosis-epicanthus Inversus Syndrome (BPES)

Table

TABLE 2Rearrangements Involving 3q2 Associated With Blepharophimosls-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 2

Rearrangements Involving 3q2 Associated With Blepharophimosls-ptosis-epicanthus Inversus Syndrome (BPES)

The craniofacial dysmorphism is strikingly similar. Aside from BPES, most cases have upturned nares, a long and relatively flat philtrum, a thin upper Up, micrognathia, and auricular abnormalities. Associated abnormalities are common: ventricular septal defect, foot deformities, and joint contractures. Except for case 2, all patients with visible deletions had microcephaly and growth retardation. The patients with translocations, and presumably smaller deletions, were less likely to be growth retarded. A similar pattern was seen for developmental delay.

We suggest that deletion of 3q23 is a recognizable contiguous gene syndrome.21 Blepharophimosis has also been described in deletion 3p23 and deletion Mq,24 but the associated phenotype was quite distinct from the one observed in deletion 3q23. The children reported here reinforce the need to search for a microdeletion in any case of BPES, especially if the ocular findings are associated with other abnormalities.

Fig 2: Case 2 at 5 years of age. Note persistent ocular abnormalities despite surgery.

Fig 2: Case 2 at 5 years of age. Note persistent ocular abnormalities despite surgery.

Fig 3: Chromosome 3 pairs from the two cases beside the ideogram derived from Franche,2* For each case, the normal chromosome 3 is on the left and the deleted chromosome 3 is on the right. The karyotypes are 46JCY,del(3)(22.2q25.1) for case 1; and 46J&,del(3Xq22.2q24) for case 2.

Fig 3: Chromosome 3 pairs from the two cases beside the ideogram derived from Franche,2* For each case, the normal chromosome 3 is on the left and the deleted chromosome 3 is on the right. The karyotypes are 46JCY,del(3)(22.2q25.1) for case 1; and 46J&,del(3Xq22.2q24) for case 2.

REFERENCES

1. Oley C, Baraitser M. Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES syndrome). J Med Genet. 1988;25:47-51.

2. Amati P, Chomel JC, Nivelon-Chevaiier A, et al. A gene for blepharophimosis-ptosis-epicanthus inversus syndrome maps to chromosome 3q23. Hum Genet. 1995;96:213-215.

3. Small KW, Stalvey M, Fisher L, et al. Blepharophimosis syndrome is linked to chromosome 3q. Hum Mol Genet. 1995;4:443-448.

4. Williamson RA, Donlan MA, Dolan CR, Thuline HC, Harrison MT, Hall JG. Familial insertional translocation of a portion of 3q into Uq resulting in duplication and deletion of region 3q22.1-q24 in different offspring. Am J Med Genet. 1981;9:105-111.

5. Martsolf JT, Ray M. Interstitial deletion of the long arm of chromosome 3. Ann Genet. 1983;26:98-99.

6. Alvarado M, Bocian M, Walker AP. Interstitial deletion of the long arm of chromosome 3: case report, review and definition of a phenotype. Am J Med Genet. 1987;27:781-786.

7. Fujita H, Meng J, Kawamura M, Tozuka N, Ishii F, Tanaka N. Boy with a chromosome deletion (3)(ql2q23) and blepharophimosis syndrome. Am J Med Genet. 1992;44:434436.

8. Fryns JP, Stromme P, van den Berghe H. Further evidence for the location of tbe blepharophimosis syndrome (BPES) at 3q22.3-q23. Clin Genet. 1993;44:149-151.

9. Jewett T, Rao PN, Weaver RG, Stewart W, Thomas IT, Pettenati MJ. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) associated with interstitial deletion of band 3q22: review and gene assignment to the interface of band 3q22.3 and 3q23. Am J Med Genet. 1993;47:1147-1150.

10. Ishikiriyama S, Goto M. Blepharophimosis sequence (BPES) and microcephaly in a girl with del(3) (q22.2q23): a putative gene responsible for microcephaly close to the BPES gene? Am J Med Genet. 1993;47:487-489.

11. Ishikiriyama S, Goto M. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) and microcephaly [letter]. Am J Med Genet. 1994;52:245.

12. Wolstenholme J, Brown J, Masters KG, Wright C, English CJ. Blepharophimosis sequence and diaphragmatic hernia associated with interstitial deletion of chromosome 3 (46,XY,del(3) (q21q23)). J Med Genet. 1994;3 1:647-648.

13. Al-Awadi SA, Naguib KK, Farag TI, et al. Complex translocation involving chromosomes Y, 1 and 3 resulting in deletion of segment 3q23-q25. J Med Genet, 1986;23:91-92.

14. Naguib KK, Al-Awadi SA, Farag TI, Mohammed PM. Penile enlargement in 3q23-»q25 deletion syndrome. Am J Med Genet. 1990;36:361.

15. De Die-Smulders CEM, Engelen JJM, Donk JM, Fryns JP. Further evidence for the localization of the BPES gene at 3q2. J Med Genet. 1991;28:725.

16. Fukushima Y, Wakui K, Nishida T, Ueoka Y. Blepharophimosis sequence and de novo balanced autosomal translocation [46,XY,t(3;4)(q23;pl5.2)]: possible assignment of the trait to 3q23. Am J Med Genet. 1991; 40:485-487.

17. Cabral de Almeida JC, Llenena JC, Gonçalves Neto JB, et al. Another example favouring the location of BPES at 3q2. J Med Genet. 1993;30:86.

18. Boccone L, Meloni A, Falchi AM, Usai V, Cao A. Blepharophimosis, ptosis, epicanthus inversus syndrome, a new case associated with de novo balanced autosomal translocation [46,XY,t(3;7)(q23;q32)]. Am J Med Genet. 1994;51:258-259.

19. Warburg M, Bugge M, Brondum-Nielsen K. Cytogenetic findings indicate heterogeneity in patients with blepharophimosis, epicanthus inversus, and developmental delay. J Med Genet. 1995;32: 19-24.

20. Ikeuchi T. Inhibitory effect of ethidium bromide on mitotic chromosome condensation and ita application to high-resolution chromosome banding. Cytogenet Cell Genet. 1984;38:5661.

21. Schmickel RD. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. 1986;109:231-241.

22. Moncla A, Philip N, Mattei JF. Blepharophimosis-mental retardation syndrome and terminal deletion of chromosome 3p. J Med Genet, 1995;32:245-246.

23. Mowrey PN, Chorney MJ1 Venditti CP, et al. Clinical and molecular analysis of deletion 3p25 - pter syndrome. Am J Med Genet. 1993;46:623-629.

24. Wintle RF, Costa T, Haslam RHA, Teshima IE1 Cox DW. Molecular analysis redefines three human chromosome 14 deletions. Hum Genet. 1995;95:495-500.

25. Francke U. Digitized and differentially shaded human chromosome ideograms for genomic applications. Cytogenet Cell Genet. 1994;65:206-219.

TABLE 1

Interstitial Deletions of 3q2 Associated With Blepharophlmosis-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 1

Interstitial Deletions of 3q2 Associated With Blepharophlmosis-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 2

Rearrangements Involving 3q2 Associated With Blepharophimosls-ptosis-epicanthus Inversus Syndrome (BPES)

TABLE 2

Rearrangements Involving 3q2 Associated With Blepharophimosls-ptosis-epicanthus Inversus Syndrome (BPES)

10.3928/0191-3913-19980901-06

Sign up to receive

Journal E-contents
click me