Blepharophimosis sequence (BPES) and microcephaly in a girl with del(3) (q22.2q23): A putative gene responsible for microcephaly close to the BPES gene?

We report on a girl with the blepharophimosis sequence (BPES), microcephaly of postnatal onset, mild developmental retardation, and a deletion: 46,XX,del(3) (q22.2q23) de novo. A gene for BPES is suspected to be located at 3q23. Almost all cases with interstitial deletions containing 3q23 have not only BPES but also microcephaly and developmental retardation, while those without deletions, including those with apparently balanced translocations, only have BPES. Thus, a putative gene responsible for microcephaly may exist close to BPES gene. BPES, microcephaly, developmental retardation, and primary amenorrhea might constitute a contiguous gene syndrome. © 1993 Wiley-Liss, Inc.     

Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23

Fryns JP, Strømme P, van den Berghe H. Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23.
Clin Genet 1993: 44: 149–151. © Munksgaard, 1993
We report a 6-year-old, mentally retarded boy with typical clinical signs and symptoms of the blepharophimosis syndrome ( b lepharophimosis, p tosis, e picanthus inversus s yndrome (BPES)), born to normal parents. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q22.3—q23). This observation reinforces previous suggestions that the location of the BPES gene is at 3q2, i.e. 3q22.3-q23.     

Blepharophimosis sequence and diaphragmatic hernia associated with interstitial deletion of chromosome 3 (46,XY,del(3)(q21q23)).

A case of blepharophimosis, ptosis, and epicanthus inversus (BPES) associated with prenatally diagnosed diaphragmatic hernia and interstitial deletion of the long arm of chromosome 3, del(3)(q21q23), is reported. Comparison with other cases of BPES resulting from 3q rearrangements indicate that this disorder, previously assigned to 3q2, can now be more accurately mapped to 3q23.     

Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.     

Blepharophimosis,ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female

Blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder whose main features are the abnormal shape, position and alignment of the eyelids. Type I refers to BPES with female infertility from premature ovarian failure while type II is limited to the ocular features. A causative gene, FOXL2, has been localized to 3q23. We report a black female who carried a de novo chromosomal translocation and 3.13 Mb deletion at 3q23, 1.2 Mb 5′ to FOXL2. This suggests the presence of distant cis regulatory elements at the extended FOXL2 locus. In spite of 21 protein coding genes in the 3.13 Mb deleted segment, the patient had no other malformation and a strictly normal psychomotor development at age 2.5 years. Our observation confirms panethnicity of BPES and adds to the knowledge of the complex cis regulation of human FOXL2 gene expression.     

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

We report on a child with blepharophimosis, ptosis, and epicanthus inversus (BPES), developmental delay and an interstitial deletion of band q22 of chromosome 3. A review of chromosome 3q anomalies associated with eye abnormalities, specifically blepharophimosis and ptosis, strongly suggests that a locus for eyelid development is present at the interface of bands 3q22.3 and 3q23. © 1993 Wiley-Liss, Inc.     

A novel case of unilateral blepharophimosis syndrome and mental retardation associated with de novo trisomy for chromosome 3q.

We have evaluated a 3 2/12 year old girl who presented with unilateral blepharophimosis, ptosis of the eyelid, and mental retardation. Additional dysmorphic features include microcephaly, high, narrow forehead, short stubby fingers, and adduction of the right first toe. Cytogenetic analysis showed an unbalanced karyotype consisting of 46,XX,add(7)(q+) that was de novo in origin. Fluorescence in situ hybridisation (FISH) using microdissected library probe pools from chromosomes 1,2,3,7, and 3q26-qter showed that the additional material on 7q was derived from the distal end of the long arm of chromosome 3. Our results indicate that the patient had an unbalanced translocation, 46,XX,der(7)t(3;7)(q26-qter;q+) which resulted in trisomy for distal 3q. All currently reported cases of BPES (blepharophimosis-ptosis-epicanthus inversus syndrome) with associated cytogenetic abnormalities show interstitial deletions or balanced translocations involving 3q22-q23 or 3p25.3. Our patient shares similar features to BPES, except for the unilateral ptosis and absence of epicanthus inversus. It is possible that our patient has a contiguous gene defect including at least one locus for a type of blepharophimosis, further suggesting that multiple loci exist for eyelid development.     

Delineation of a recognisable phenotype of interstitial deletion 3 (q22.3q25.1) in a case with previously unreported truncus arteriosus

Interstitial deletions of chromosome 3q22.3–25.1 are very rare with only five previous reports of deletions in this region [1], [2], [4], [7], [9]. We describe a case of a female infant with a de novo deletion. Dysmorphic features and congenital heart disease led to a clinical genetics assessment on day 1 of life. Chromosomal analysis showed an interstitial deletion with a female karyotype 46,XX,del (3)(q23q25.1)dn. Subsequent array CGH demonstrated the breakpoints as 3q22.3q25.1. This is the first documented association with a truncus arteriosus. We identify an emerging clinical phenotype of microphthalmia, microcephaly, congenital heart disease, slow feeding, skeletal abnormalities, with an abnormal facies and developmental delay. Array CGH demonstrated that the FOXL2 gene responsible for BPES was not deleted in this patient.     

Blepharophimosis,ptosis, epicanthus inversus syndrome,a new case associated with de novo balanced autosomal translocation [46,XY,t(3;7)(q23;q32)]

This paper reports a further case of blepharophimosis, ptosis, epicanthus inversus (BPES) syndrome associated with a reciprocal translocation [46,XY,t(3;7)(q23;q32)], involving band 3q23. This case supports the assignment of a BPES gene(s) to the 3q23 region. © 1994 Wiley-Liss, Inc.     

Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families

We report the genetic characterization of one family with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 and two families with BPES type 2 from a historically isolated population in northwest Colombia. Linkage and haplotype analyses indicate that BPES in these families is linked to 3q23. Mutation screening of FOXL2 in the family with BPES type 1 revealed a novel 394C --> T nonsense mutation which deletes the forkhead DNA binding domain. The two families with BPES type 2 both carry an in-frame 30 bp duplication that leads to the elongation of a polyalanine tract. This duplication has been previously reported in Europe, where recurrent mutation has been demonstrated in unrelated familial and sporadic BPES cases. The recurrent nature of this duplication seems to relate to the secondary structure of this DNA region. The genotype-phenotype correlation seen in the Colombian families is consistent with the recent proposal that BPES type 1 is caused by truncating mutations leading to haploinsufficiency, while BPES type 2 is due to mutations generating elongated protein products.     

Boy with a chromosome del (3)(q12q23) and Blepharophimosis syndrome

We report on a 6-year-old boy with de novo 46, XY, del(3)(q12q23) and bilateral blepharo-phimosis, ptosis, epicanthus inversus, in addition to multiple other anomalies. Since 4 previously reported cases of interstitial deletion of 3q involving 3q23 band are clinically similar, we propose this blepharophimosis sequence due to 3q23 deletion as a further “contiguous gene syndrome”.     

Boy with a chromosome del (3)(q12q23) and blepharophimosis syndrome.

We report on a 6-year-old boy with de novo 46,XY,del(3)(q12q23) and bilateral blepharophimosis, ptosis, epicanthus inversus, in addition to multiple other anomalies. Since 4 previously reported cases of interstitial deletion of 3q involving 3q23 band are clinically similar, we propose this blepharophimosis sequence due to 3q23 deletion as a further "contiguous gene syndrome."     

Definition of the blepharophimosis, ptosis, epicanthus inversus syndrome critical region at chromosome 3q23 based on the analysis of chromosomal anomalies

Blepharophimosis syndrome (BPES) is an autosomal dominant disorderof craniofacial development, the features of which are smallpalpebral fissures (blepharophimosis), drooping eyelids (ptosis)and a skin fold arising from the lower eyelid (epicanthus inversus).The chromosomal localization and identity of the BPES locusis not known with certainty. In the current paper, DNA samplesfrom three individuals with a clinical history of BPES, twowith Interstitial deletions (cases 1 and 2) and one with a balancedtranslocation (case 3) all involving chromosome 3q23, were analyzed.Allele loss studies using short tandem repeat markers in cases1 and 2 suggested that the region between the markers D3S1292and D3S1306 was deleted in both cases. Subsequently, the derivedchromosomes resulting from the translocation in case 3 weresegregated in interspecific somatic cell hybrids. Analysis ofthe resultant hybrids showed that D3S1615 was retained in thederived chromosome 3, whereas D3S1316 was retained in the derivedchromosome 4. In neither case was the marker present in thereciprocal hybrid. These results indicate that the BPES criticalregion lies in the D3S1615–D3S1316 interval.     

Interstitial deletion of the long arm of chromosome 3: case report, review, and definition of a phenotype

Interstitial deletions of 3q have, to our knowledge, been reported in only four patients. We present an additional patient with interstitial deletion of 3q, with breakpoints at 3q23 and 3q25. The patient was small for gestational age and had a multiple congenital anomalies (MCA) syndrome including microcephaly; unusual facial appearance with bilateral microphthalmia, blepharophimosis, and ptosis; ventricular septal defect; and bilateral clubfeet. Comparison between the clinical and cytogenetic findings of the present case and those of previously reported cases suggests that a recognizable phenotype may be associated with deletions of 3q2.     

Interstitial deletion of 14q24.3-q32.2 in a male patient with plagiocephaly, BPES features, developmental delay, and congenital heart defects

Distal interstitial deletions of chromosome 14 involving the 14q24‐q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically and genetically. Here we present a de novo interstitial deletion of chromosome 14q24.3‐q32.2 in a male patient with developmental delay, language impairment, plagiocephaly, BPES features (blepharophimosis, ptosis, epicanthus), and congenital heart defect. The deletion breakpoints were fine mapped using fluorescence in situ hybridization (FISH) and the size of the deletion is estimated to be approximately 23 Mb. Based on genotype–phenotype comparisons of the 10 previously published patients and the present case, we suggest that the shortest regions for deletion overlap may include candidate genes for speech impairment, mental retardation, and hypotonia. © 2010 Wiley‐Liss, Inc.     

Blepharophimosis syndrome is linked to chromosome 3q

Blepharophimosis syndrome (BPES, blepharophimosis eyelid syndrome)is a distinctive congenital eyelid malformation which can occursporadically or be inherited in an autosomal dominant fashion.Previous reports have described associated cytogenetic abnormalitieson chromosome 3q. We have ascertained and sampled two BPES familieswith apparent autosomal dominant inheritance and have testedfor linkage with 17 polymorphic markers on 3q. Multipoint analysisgenerated a maximum LOD score of 3.23 using the markers RHO,ACPP and D3S1238. No evidence of genetic heterogeneity was observed.These studies provide the first non—cytogenetic evidencethat a defective gene responsible for BPES is located on 3q22.     

Cytogenetic findings indicate heterogeneity in patients with blepharophimosis, epicanthus inversus, and developmental delay.

Three unrelated, mentally retarded boys with typical blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) were found to have chromosomal aberrations. One of them had a del(3)(p25), another patient had a de novo translocation t(2; 3), which after high resolution banding combined with chromosome painting was interpreted to be unbalanced with a loss of band q23. The third patient had a del(7)(q34). The phenotypes of the two patients with chromosome 3 related syndromes were similar, but the third also had genital malformations resembling the Smith-Lemli-Opitz syndrome. This patient had a palatal ridge, and a single mesial maxillary tooth suggesting the holoprosencephaly sequence, but CT scans of the brain were normal.