European Journal of Medical Genetics xxx (2015) 1e3
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings Claire Bailey 1, Alan E. Fryer 1, *, Mark Greenslade 2 1 2
Department of Clinical Genetics, Liverpool Women’s Hospital, Crown Street, Liverpool, L8 7SS, UK Bristol Genetics Laboratory, Southmead Hospital, Bristol, BS10 5NB
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 October 2014 Accepted 8 February 2015 Available online xxx
We report a new case of Warsaw Breakage syndrome (WABS) with 2 confirmed mutations in DDX11. Like the previous reported cases [Capo-Chichi et al., 2012; Van der Lelij et al., 2010], there was evidence of pre- and postnatal growth retardation, severe microcephaly, intellectual disability and facial dysmorphism. The patient had sensorineural hearing loss with evidence of bilateral hypoplastic cochleas on imaging, another feature which has been reported in the previous cases of WABS. In our case the patient exhibited a chronic rash of livedo reticularis with telangiectasia on her legs. Abnormally pigmented lesions and cutis mamorata were reported in the original WABS case. Ó 2015 Elsevier Masson SAS. All rights reserved.
Keywords: Warsaw Breakage Syndrome (WABS) DDX11 Cohesinopathy Cutaneous
1. Introduction
2. Clinical report
We report another case of Warsaw Breakage Syndrome (WABS). WABS is a cohesinopathy associated with mutations in the ironsulphur-containing DNA helicase DDX11 (ChlR1). The syndrome is associated with abnormalities in the cohesion of sister chromatids and also sensitivity to chemicals which induce replication stress, thus the syndrome is a combination of the cytogenetic features seen in both Roberts Syndrome and Fanconi anaemia. [Capo-Chichi et al., 2012; Van der Lelij et al., 2010] The syndrome was first in described in 2010 in a male individual with heterozygous mutations in DDX11. Since then, a further three siblings with consanguineous parents were identified as having a novel homozygous mutation in DDX11. Our case shares similar phenotypic features to the previous reported cases including preand postnatal growth retardation, severe microcephaly, intellectual disability, facial dysmorphism and hearing loss due to cochlea abnormalities. In addition to this our case also had a chronic petechial rash. Skin lesions were also reported in the original WABS case suggesting that cutaneous findings may be another feature of the phenotype.
The patient was the first child of non-consanguineous British parents. Antenatally, concerns regarding fetal growth were expressed and a reduction in amniotic fluid was noted. An amniocentesis was performed and analysis of the sample revealed a normal female karyotype. The child was born at 32 weeks with a birth weight of 664 g (approximately 300 g below 0.4th centile) and head circumference of 23 cm (3 cm below 0.4th centile). Postnatal investigations identified a patent ductus arteriosus and a left multicystic kidney. The patient also had a low thyroxine level with a high TSH and was treated for congenital hypothyroidism (though by 9 years of age her thyroid function appeared satisfactory and she was able to discontinue therapy). During infancy the patient had significant feeding problems and required a gastrostomy. At around 8 months of age, concerns about the patient’s hearing were raised. MRI Imaging revealed an abnormal cochlea on the right with impaired septation of the apical and middle turns with partial formation of a common cavity. The basal turn was hypoplastic causing a marked narrowing of the basal turn and an apparent single perilymph channel. There was a normal appearance to the vestibule and semi-circular canals. On the left there were similar (but milder) appearances to the right. The patient had bilateral cochlear implants inserted. At the age of 11 years the patient’s height was on the 9th centile and her head circumference was 45.7 cm, approximately -6SD making her strikingly microcephalic. The patient had clear facial dysmorphism with an elongated face, prominent eyes, a prominent
* Corresponding author. Tel.: þ44 (0) 151 802 5003; fax: þ44 (0) 151 802 5096. E-mail address: [email protected] (A.E. Fryer). http://dx.doi.org/10.1016/j.ejmg.2015.02.001 1769-7212/Ó 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Bailey C, et al., Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings, European Journal of Medical Genetics (2015), http://dx.doi.org/10.1016/j.ejmg.2015.02.001
2
C. Bailey et al. / European Journal of Medical Genetics xxx (2015) 1e3
Fig. 1. Patient aged 2 years and 8 months.
nose and a smooth philtrum. She also had a thin upper lip with a slightly small mouth. Anteverted ears, which were also seen in the patient’s father, were noted. The patient also had overlapping 2nd and 3rd toes bilaterally. Her facial appearance at ages 2 years 8 months and 9 years are shown in Figs. 1 and 2. The patient also had a chronic rash on the backs of her legs of livedo reticularis with telangiectasia (Fig. 3). At the age of 11 years the patient had entered puberty and had some breast development and pubic hair but had not reached menarche. An array-CGH showed no copy number changes. Testing showed that there was no evidence of spontaneous chromosome breakage or premature chromosome condensation. Analysis of chromosome damage in cultures exposed to the DEB showed a result of unclear significance e chromosome damage was identified in a higher proportion of metaphases relative to control samples but much lower than previously reported in published cases of WABS. A raised level of premature chromatid separation was found mostly in the form of tramline or railroad chromosomes and the level seen was again much lower than in the previous reports. Following these
results, analysis of 63 genes associated with chromosome instability/breakage disorders was performed. Two heterozygous variants (c.638 þ 1G > A and c.1888delC) were found in the DDX11 gene. Analysis of parental samples revealed that these variants were in trans thus confirming a diagnosis of WABS. The patient is now 13 years of age. She had mild intellectual disability and attends a school for deafchildren with low or moderate learning disability. The patient has recently begun to speak a few words and is able to put two to three words together. She uses British Sign Language. She can write her own name and a couple of other words. She is able to dress herself and manage her own hygiene needs. Her weight at 13 years and one month was 50.55 Kg (75th centile) and her height was 146.2 cm (9th centile). She suffers from constipation which occasionally results in overflow soiling. She also has a pollen allergy but does not suffer from recurrent infections. The patient is reported to have gone through menarche shortly after the age of 11 years. The patient’s parents describe her as having some behavioural issues saying that she often gets frustrated and can be slightly aggressive when frustrated.
Fig. 2. Patient aged 9 years.
Please cite this article in press as: Bailey C, et al., Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings, European Journal of Medical Genetics (2015), http://dx.doi.org/10.1016/j.ejmg.2015.02.001
C. Bailey et al. / European Journal of Medical Genetics xxx (2015) 1e3
3
Fig. 3. Chronic rash on patient’s legs.
3. Discussion Warsaw Breakage Syndrome was originally described in 2010 by van der Lelij et al. [Van der Lelij et al., 2010] They identified compound heterozygous mutations (IVS22 þ 2T > C and c.2689_2691del) in the iron-sulphur-containing DNA helicase DDX11 (ChlR1) in a male with severe intrauterine growth retardation and microcephaly. The individual was noted to have facial dysmorphism e small and elongated face, narrow bifrontal diameter, bilateral epicanthic folds, a relatively large mouth and cupshaped ears. He was also noted to have clinodactyly of the fifth fingers and syndactyly of the 2nd and 3rd toes. Like our patient, this individual was also deaf due to inner ear abnormalities e bilateral hypoplastic cochleas. He was also reported to have cutis marmorata and hypo and hyperpigmented lesions on the skin. Psychomotor and mental development was reported as being mildly retarded. The individual was also found to have a small ventricular septal defect. More recently, a novel homozygous mutation (c.788G > A) in DDX11 was identified in three consanguineous Lebanese siblings with severe intellectual disability. [Capo-Chichi et al., 2012] Two of the siblings were reported as having a birth weight, head circumference and length below the third percentile. All three of the siblings had sensorineural deafness and two were identified as having cochlea abnormalities. One of the siblings was found to have tetralogy of Fallot. The siblings all had similar dysmorphic facial features e small and receding forehead, short nose and small nares. One of the siblings was also noted to have clinodactyly of the fifth fingers and single palmar creases on both hands. Like the previous reported cases, our patient had pre and postnatal growth retardation and has significant microcephaly. She also has hearing impairment and was found to have hypoplastic cochleas on imaging. Similarly she has mild intellectual disability. The degree of the intellectual disability appears to vary amongst the reported cases e mild in the original case and severe in the consanguineous Lebanese siblings. Our patient also had a patent
ductus arteriosus. Two of the previous reported cases have been showed to have cardiac defects (a VSD and tetralogy of Fallot). Congenital cardiac anomalies may be a feature of the syndrome. Our patient also had congenital hypothyroidism and a multicystic kidney. There was a maternal family history of cystic kidneys and therefore it was thought that this was not likely to be part of the WABS phenotype. Of note two of the consanguineous Lebanese siblings were reported as having had normal abdominal ultrasonography. There are no previous reports of congenital hypothyroidism in Warsaw Breakage Syndrome. Like the original case our patient displayed cutaneous features e a chronic livedo reticularis rash on her legs. Cutaneous findings therefore seem to a feature of the syndrome.
4. Conclusion We describe the third family with WABS with identified heterozygous mutations in DDX11. WABS is characterised by pre- and postnatal growth retardation, severe microcephaly, deafness due to cochlea hypoplasia, intellectual disability and facial dysmorphism. Congenital cardiac defects have been reported in several of the cases suggesting that this may also be a feature of the syndrome. Abnormal skin lesions have now been seen in two individuals with the condition and therefore cutaneous findings may also be a significant feature of the syndrome. Identification of further cases of WABS will allow further delineation of the phenotype of the condition.
References Capo-Chichi JM, Bharti SK, Sommers JA, Yammine T, Chouery E, Patry L, et al. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw Breakage Syndrome. Hum. Mutat. 2012;34(1):103e7. Van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, et al. Warsaw Breakage Syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am. J. Hum. Genet. 2010;86(2):262e6.
Please cite this article in press as: Bailey C, et al., Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings, European Journal of Medical Genetics (2015), http://dx.doi.org/10.1016/j.ejmg.2015.02.001
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings Claire Bailey 1, Alan E. Fryer 1, *, Mark Greenslade 2 1 2
Department of Clinical Genetics, Liverpool Women’s Hospital, Crown Street, Liverpool, L8 7SS, UK Bristol Genetics Laboratory, Southmead Hospital, Bristol, BS10 5NB
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 October 2014 Accepted 8 February 2015 Available online xxx
We report a new case of Warsaw Breakage syndrome (WABS) with 2 confirmed mutations in DDX11. Like the previous reported cases [Capo-Chichi et al., 2012; Van der Lelij et al., 2010], there was evidence of pre- and postnatal growth retardation, severe microcephaly, intellectual disability and facial dysmorphism. The patient had sensorineural hearing loss with evidence of bilateral hypoplastic cochleas on imaging, another feature which has been reported in the previous cases of WABS. In our case the patient exhibited a chronic rash of livedo reticularis with telangiectasia on her legs. Abnormally pigmented lesions and cutis mamorata were reported in the original WABS case. Ó 2015 Elsevier Masson SAS. All rights reserved.
Keywords: Warsaw Breakage Syndrome (WABS) DDX11 Cohesinopathy Cutaneous
1. Introduction
2. Clinical report
We report another case of Warsaw Breakage Syndrome (WABS). WABS is a cohesinopathy associated with mutations in the ironsulphur-containing DNA helicase DDX11 (ChlR1). The syndrome is associated with abnormalities in the cohesion of sister chromatids and also sensitivity to chemicals which induce replication stress, thus the syndrome is a combination of the cytogenetic features seen in both Roberts Syndrome and Fanconi anaemia. [Capo-Chichi et al., 2012; Van der Lelij et al., 2010] The syndrome was first in described in 2010 in a male individual with heterozygous mutations in DDX11. Since then, a further three siblings with consanguineous parents were identified as having a novel homozygous mutation in DDX11. Our case shares similar phenotypic features to the previous reported cases including preand postnatal growth retardation, severe microcephaly, intellectual disability, facial dysmorphism and hearing loss due to cochlea abnormalities. In addition to this our case also had a chronic petechial rash. Skin lesions were also reported in the original WABS case suggesting that cutaneous findings may be another feature of the phenotype.
The patient was the first child of non-consanguineous British parents. Antenatally, concerns regarding fetal growth were expressed and a reduction in amniotic fluid was noted. An amniocentesis was performed and analysis of the sample revealed a normal female karyotype. The child was born at 32 weeks with a birth weight of 664 g (approximately 300 g below 0.4th centile) and head circumference of 23 cm (3 cm below 0.4th centile). Postnatal investigations identified a patent ductus arteriosus and a left multicystic kidney. The patient also had a low thyroxine level with a high TSH and was treated for congenital hypothyroidism (though by 9 years of age her thyroid function appeared satisfactory and she was able to discontinue therapy). During infancy the patient had significant feeding problems and required a gastrostomy. At around 8 months of age, concerns about the patient’s hearing were raised. MRI Imaging revealed an abnormal cochlea on the right with impaired septation of the apical and middle turns with partial formation of a common cavity. The basal turn was hypoplastic causing a marked narrowing of the basal turn and an apparent single perilymph channel. There was a normal appearance to the vestibule and semi-circular canals. On the left there were similar (but milder) appearances to the right. The patient had bilateral cochlear implants inserted. At the age of 11 years the patient’s height was on the 9th centile and her head circumference was 45.7 cm, approximately -6SD making her strikingly microcephalic. The patient had clear facial dysmorphism with an elongated face, prominent eyes, a prominent
* Corresponding author. Tel.: þ44 (0) 151 802 5003; fax: þ44 (0) 151 802 5096. E-mail address: [email protected] (A.E. Fryer). http://dx.doi.org/10.1016/j.ejmg.2015.02.001 1769-7212/Ó 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Bailey C, et al., Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings, European Journal of Medical Genetics (2015), http://dx.doi.org/10.1016/j.ejmg.2015.02.001
2
C. Bailey et al. / European Journal of Medical Genetics xxx (2015) 1e3
Fig. 1. Patient aged 2 years and 8 months.
nose and a smooth philtrum. She also had a thin upper lip with a slightly small mouth. Anteverted ears, which were also seen in the patient’s father, were noted. The patient also had overlapping 2nd and 3rd toes bilaterally. Her facial appearance at ages 2 years 8 months and 9 years are shown in Figs. 1 and 2. The patient also had a chronic rash on the backs of her legs of livedo reticularis with telangiectasia (Fig. 3). At the age of 11 years the patient had entered puberty and had some breast development and pubic hair but had not reached menarche. An array-CGH showed no copy number changes. Testing showed that there was no evidence of spontaneous chromosome breakage or premature chromosome condensation. Analysis of chromosome damage in cultures exposed to the DEB showed a result of unclear significance e chromosome damage was identified in a higher proportion of metaphases relative to control samples but much lower than previously reported in published cases of WABS. A raised level of premature chromatid separation was found mostly in the form of tramline or railroad chromosomes and the level seen was again much lower than in the previous reports. Following these
results, analysis of 63 genes associated with chromosome instability/breakage disorders was performed. Two heterozygous variants (c.638 þ 1G > A and c.1888delC) were found in the DDX11 gene. Analysis of parental samples revealed that these variants were in trans thus confirming a diagnosis of WABS. The patient is now 13 years of age. She had mild intellectual disability and attends a school for deafchildren with low or moderate learning disability. The patient has recently begun to speak a few words and is able to put two to three words together. She uses British Sign Language. She can write her own name and a couple of other words. She is able to dress herself and manage her own hygiene needs. Her weight at 13 years and one month was 50.55 Kg (75th centile) and her height was 146.2 cm (9th centile). She suffers from constipation which occasionally results in overflow soiling. She also has a pollen allergy but does not suffer from recurrent infections. The patient is reported to have gone through menarche shortly after the age of 11 years. The patient’s parents describe her as having some behavioural issues saying that she often gets frustrated and can be slightly aggressive when frustrated.
Fig. 2. Patient aged 9 years.
Please cite this article in press as: Bailey C, et al., Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings, European Journal of Medical Genetics (2015), http://dx.doi.org/10.1016/j.ejmg.2015.02.001
C. Bailey et al. / European Journal of Medical Genetics xxx (2015) 1e3
3
Fig. 3. Chronic rash on patient’s legs.
3. Discussion Warsaw Breakage Syndrome was originally described in 2010 by van der Lelij et al. [Van der Lelij et al., 2010] They identified compound heterozygous mutations (IVS22 þ 2T > C and c.2689_2691del) in the iron-sulphur-containing DNA helicase DDX11 (ChlR1) in a male with severe intrauterine growth retardation and microcephaly. The individual was noted to have facial dysmorphism e small and elongated face, narrow bifrontal diameter, bilateral epicanthic folds, a relatively large mouth and cupshaped ears. He was also noted to have clinodactyly of the fifth fingers and syndactyly of the 2nd and 3rd toes. Like our patient, this individual was also deaf due to inner ear abnormalities e bilateral hypoplastic cochleas. He was also reported to have cutis marmorata and hypo and hyperpigmented lesions on the skin. Psychomotor and mental development was reported as being mildly retarded. The individual was also found to have a small ventricular septal defect. More recently, a novel homozygous mutation (c.788G > A) in DDX11 was identified in three consanguineous Lebanese siblings with severe intellectual disability. [Capo-Chichi et al., 2012] Two of the siblings were reported as having a birth weight, head circumference and length below the third percentile. All three of the siblings had sensorineural deafness and two were identified as having cochlea abnormalities. One of the siblings was found to have tetralogy of Fallot. The siblings all had similar dysmorphic facial features e small and receding forehead, short nose and small nares. One of the siblings was also noted to have clinodactyly of the fifth fingers and single palmar creases on both hands. Like the previous reported cases, our patient had pre and postnatal growth retardation and has significant microcephaly. She also has hearing impairment and was found to have hypoplastic cochleas on imaging. Similarly she has mild intellectual disability. The degree of the intellectual disability appears to vary amongst the reported cases e mild in the original case and severe in the consanguineous Lebanese siblings. Our patient also had a patent
ductus arteriosus. Two of the previous reported cases have been showed to have cardiac defects (a VSD and tetralogy of Fallot). Congenital cardiac anomalies may be a feature of the syndrome. Our patient also had congenital hypothyroidism and a multicystic kidney. There was a maternal family history of cystic kidneys and therefore it was thought that this was not likely to be part of the WABS phenotype. Of note two of the consanguineous Lebanese siblings were reported as having had normal abdominal ultrasonography. There are no previous reports of congenital hypothyroidism in Warsaw Breakage Syndrome. Like the original case our patient displayed cutaneous features e a chronic livedo reticularis rash on her legs. Cutaneous findings therefore seem to a feature of the syndrome.
4. Conclusion We describe the third family with WABS with identified heterozygous mutations in DDX11. WABS is characterised by pre- and postnatal growth retardation, severe microcephaly, deafness due to cochlea hypoplasia, intellectual disability and facial dysmorphism. Congenital cardiac defects have been reported in several of the cases suggesting that this may also be a feature of the syndrome. Abnormal skin lesions have now been seen in two individuals with the condition and therefore cutaneous findings may also be a significant feature of the syndrome. Identification of further cases of WABS will allow further delineation of the phenotype of the condition.
References Capo-Chichi JM, Bharti SK, Sommers JA, Yammine T, Chouery E, Patry L, et al. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw Breakage Syndrome. Hum. Mutat. 2012;34(1):103e7. Van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, et al. Warsaw Breakage Syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am. J. Hum. Genet. 2010;86(2):262e6.
Please cite this article in press as: Bailey C, et al., Warsaw Breakage Syndrome e A further report, emphasising cutaneous findings, European Journal of Medical Genetics (2015), http://dx.doi.org/10.1016/j.ejmg.2015.02.001
