DOI: 10.1002/pd.4506
RESEARCH LETTER
Prenatal diagnosis of Greig cephalopolysyndactyly syndrome: a case report Laura Raposo1, Helena Fachada1, António Santos Paulo1, Isabel Cerveira1, Sérgio Castedo2,3 and Susana Pereira1 1
Unidade de Medicina Fetal, Departamento de Obstetrícia e Ginecologia, Centro Hospitalar Tondela-Viseu, Hospital de S. Teotónio, Viseu, Portugal GDPN—Genética Médica e Diagnóstico Pré-natal, Porto, Portugal 3 Departamento de Genética, Faculdade de Medicina, Porto, Portugal *Correspondence to: Laura Raposo. E-mail: [email protected] 2
Funding sources: None Conflicts of interest: None declared
The Greig cephalopolysyndactyly syndrome (GCPS) was initially described by David Middleton Greig in 1926.1 GCPS is a very rare multiple congenital anomaly syndrome, with an estimated incidence of 1–9:1 000 000. The primary findings are macrocephaly with high forehead, hypertelorism and polysyndactyly (Table 1). Other prenatal findings include agenesis of corpus callosum, mild degrees of hydrocephaly, cardiac defect, inguinal and umbilical hernia, cryptorchidism, hypospadias and craniosynostosis. After birth and throughout life other features can be detected as downslanting palpebral fissures, cognitive impairment, seizures, muscle fiber anomalies, advanced bone age, hyperglycemia or hirsutism.2 GCPS is caused by loss of function mutations in the GLI3 transcription factor gene located on chromosome 7p13 and is inherited in an autosomal dominant pattern. In addition to mutations, translocations that interrupt the gene, microdeletions and large cytogenetically detectable deletions have been described. The latter are associated with a more complex phenotype, involving additional abnormalities as a result of deletion of additional genes.2 There are multiple disorders with polydactyly, so the differential diagnosis with GCPS can be difficult. However, non-syndromic preaxial polydactylies such as preaxial polydactyly type 4 can be excluded if other dismorphic features of GCPS are recognizable.1 Other differential diagnoses include Pallister–Hall syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome and Teebi syndrome. The phenotype of individuals affected by Pallister– Hall syndrome includes postaxial polydactyly, bifid epiglottis, imperforate anus, hypothalamic neoplasia, panhypopituitarism and other conditions that may be life threatening in the neonatal period.3 Pallister–Hall syndrome is also due to mutations of GLI3 gene.2 The acrocallosal syndrome (ACS) includes features that overlap the GCPS as preaxial and Prenatal Diagnosis 2015, 35, 203–205
postaxial polysyndactyly, macrocephaly, agenesis of the corpus callosum, mental retardation, seizures and hernias.1 ACS is an autosomal recessive condition caused by mutations in the KIF7 gene (located in 15q26.1).6 Teebi syndrome shares craniofacial manifestations with GCPS, as hypertelorism, prominent forehead, hypertelorism, downslanting palpebral fissures, broad nasal tip, cardiac defects, umbilical hernia and cryptorchidism. Nevertheless other features, such as depressed nasal bridge, long philtrum, heavy and broad eyebrows, anterior hair implantation resembling a widow’s peak, neonatal teeth, thin upper lip, everted lower lip, small chin, low-set ears, preauricular fistulas and short neck, pectus excavatum, small omphalocele, minor anomalies of hands (clinodactyly of the 5th fingers or mild interdigital webbing), pes adductus, ectopic or cystic kidney and shawl scrotum and normal psychomotor development
Table 1 Incidence of typical abnormalities in Greig cephalopolysyndactyly syndrome 2
Greig cephalopolysyndactyly syndrome Abnormalities Craniofacies
Hands
Feet
Incidence Macrocephaly
52%
High forehead
70%
Frontal bossing
58%
Broad nasal root
79%
Postaxial polydactyly
78%
Broad tumbs
90%
Syndactyly (primarily in fingers 3 and 4)
82%
Preaxial polydactyly
81%
Broad halluces
89%
Syndactyly (primarily toes 1 to 3)
90%
© 2014 John Wiley & Sons, Ltd.
204
are not typically found in GCPS.4,5 In the Teebi syndrome the inheritance seems to be autosomal dominant pattern, but no causative gene has yet been identified.5 Carpenter syndrome is characterized by polysyndactyly, craniosynostosis and mental retardation and is caused by mutations in the RAB23 gene.1 Gorlin syndrome (nevoid basal cell carcinoma syndrome) also presents with macrocephaly, but rarely hypertelorism or polydactyly. This syndrome is caused by mutations in the PTCH1, another gene in the GLI-SHH pathway.1 The authors describe a case of a 33-year-old (gravida 2, para 1), Caucasian woman referred to the Fetal Medicine Unit of our institution at 12 weeks’ gestation for first trimester aneuploidy screening. Maternal blood sampling for β-HCG and PAPP-A measurement was performed on the first appointment at 11 weeks. This patient had a previous son with bilateral cleft lip and palate, diagnosed in routine 2nd trimester ultrasound. There was also a personal and family history of syndactyly of the 2nd and 3rd toes of both feet. The patient’s husband did not have any congenital abnormalities and was not consanguineous with the patient. The combined prenatal screening for trisomy 21 performed at 12 weeks, revealed low risk for trisomy 21 (1: 6810), with no anomalies detected in the first trimester scan. The second trimester anomaly scan revealed postaxial polydactyly in the left hand and syndactyly of the third and fourth fingers of both hands. Both feet had broad halluces. The fetal echocardiogram was normal (Figure 1). Amniocentesis was performed at 21 week gestation and a normal 46,XY karyotype was found. The hypothesis of GCPS was suspected based on ultrasound findings and personal and family history of syndactyly, which led to the study of the GLI3 gene. The GLI3 gene was analyzed by PCR and sequencing of both DNA strands of the entire coding region and the highly conserved exon–intron splice junctions. In addition, MLPA (multiplex ligation-dependent probe amplification) analysis was performed to test for large deletions or duplications within or including the GLI3 gene. To exclude maternal contamination, quantitative Multiplex-PCR was performed comparing fetal (amniocytes) and maternal (peripheral blood sample) genetic profiles. No GLI3 gene
Figure 1 Ultrasound image of fetal left hand with syndactyly of 3rd and 4th fingers
Prenatal Diagnosis 2015, 35, 203–205
L. Raposo et al.
deletions were detected by sequencing. However, the MLPA study revealed a large heterozygous deletion of the GLI3 gene encompassing exons 11, 12 and 13. The maternal blood was also studied for the GLI3 gene which was normal, excluding autosomal dominant hereditary transmission. These findings are consistent with a de novo mutation in the fetus GLI3 gene. The third trimester scan confirmed the previous ultrasound findings and showed macrocephaly, with the head circumference above the 95th centile. The baby was born at 39 weeks by lower segment cesarean section due to cephalopelvic disproportion. The birth weight was 3635 g, Apgar scores 9 and 10, at 5 and 10 min, respectively, and head circumference of 36 cm (75th centil). All the ultrasound findings were confirmed after birth and moreover the newborn had preaxial polydactyly and syndactyly (involving the supernumerary, 1st, 2nd and 3rd toes) in both feet. At 9 months of age the infant has normal psycho-motor development and normal weight/length evolution. The transfontanellar encephalic ultrasound and magnetic resonance did not reveal major malformations of the central nervous system and echocardiogram was normal. In this case surgical repair of the hands is important for both functional and esthetic reasons. However, the surgical repair of the feet is optional, as esthetic considerations are generally less pressing. The functional consequences of iatrogenic biomechanical problems after a preaxial polydactyly in the feet can be severe.1 The prognosis for typically affected patients is excellent.1 Ninety percent of carriers of this mutation have a normal psycho-motor development; however, patients with larger deletions may have a worse prognosis.1 In the current case report the brother of the affected patient had lip and palate cleft. In literature there are no cases of GCPS with this feature, so it seems it has a different etiology. Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly in at least one limb, hypertelorism and macrocephaly. The prenatal diagnosis is based in a fetus with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 mutation. In addition, a family history of this syndrome may suggest the prenatal diagnosis, since it typically has an autosomal dominant inheritance. In this case despite a heavy family history of both feet syndactyly, these findings seem to have no relation to GCPS detected in the fetus, since no GLI3 mutation was detected in the pregnant women. This finding, together with the fact that the masculine progenitor has no phenotypic characteristics of the syndrome (no genetic test performed), suggests the fetus has a new mutation, so the risk of recurrence for the couple is considered very low. However, it’s not possible to exclude gonadal mosaicism, so prenatal diagnosis should be suggested in future pregnancies. Prenatal diagnosis of Greig cephalopolysyndactyly syndrome is rarely reported in literature, and this achievement in the case reported was just possible with the multidisciplinary cooperation between obstetricians and geneticists. © 2014 John Wiley & Sons, Ltd.
Greig cephalopolysyndactyly syndrome
205
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?
WHAT DOES THIS STUDY ADD?
• Greig cephalopolysyndactyly syndrome (GCPS) is a rare multiple congenital anomaly syndrome with an autosomal dominant pattern of inheritance. Prenatal diagnosis is challenging because the ultrasound findings are relatively non-specific.
• Prenatal diagnosis of GCPS is difficult but possible. Ultrasound findings and family history play the main role that can lead to this diagnosis as in this case.
REFERENCES 1. Biesecker LG. The Greig cephalopolysyndactyly syndrome. Orphanet Journal of Rare Diseases 2008;3:10. 2. Jones K, Jones M, Campo M. Greig Cephapolysyndactyly Syndrome. In Smith’s Recognizable Patterns of Human Malformation (6th edn). Elsevier Saunders: Philadelphia, 2005;486–7. 3. Timor-Tritsch IE, Kapp S, Berg R, et al. Greig cephalopolysyndactyly syndrome: diagnosis based on prenatal sonographic features coupled
Prenatal Diagnosis 2015, 35, 203–205
with comparative genomic hybridization. Journal of Ultrasound in Medicine 2009;28:1735–42. 4. Hamosh A. Online Mendelian Inheritance in Man. Acrocallosal syndrome. URL http://www.omim.org/entry/200990 [accessed on 30 April 2014]. 5. Orphanet. Hypertelorism, Teebi type. URL http://www.orpha.net/consor/ cgi-bin/OC_Exp.php?lng=EN&Expert=1519 [accessed on 30 April 2014]. 6. Koenig R. Teebi hypertelorism syndrome. Clinical Dysmorphology 2003;12:187–9.
© 2014 John Wiley & Sons, Ltd.
RESEARCH LETTER
Prenatal diagnosis of Greig cephalopolysyndactyly syndrome: a case report Laura Raposo1, Helena Fachada1, António Santos Paulo1, Isabel Cerveira1, Sérgio Castedo2,3 and Susana Pereira1 1
Unidade de Medicina Fetal, Departamento de Obstetrícia e Ginecologia, Centro Hospitalar Tondela-Viseu, Hospital de S. Teotónio, Viseu, Portugal GDPN—Genética Médica e Diagnóstico Pré-natal, Porto, Portugal 3 Departamento de Genética, Faculdade de Medicina, Porto, Portugal *Correspondence to: Laura Raposo. E-mail: [email protected] 2
Funding sources: None Conflicts of interest: None declared
The Greig cephalopolysyndactyly syndrome (GCPS) was initially described by David Middleton Greig in 1926.1 GCPS is a very rare multiple congenital anomaly syndrome, with an estimated incidence of 1–9:1 000 000. The primary findings are macrocephaly with high forehead, hypertelorism and polysyndactyly (Table 1). Other prenatal findings include agenesis of corpus callosum, mild degrees of hydrocephaly, cardiac defect, inguinal and umbilical hernia, cryptorchidism, hypospadias and craniosynostosis. After birth and throughout life other features can be detected as downslanting palpebral fissures, cognitive impairment, seizures, muscle fiber anomalies, advanced bone age, hyperglycemia or hirsutism.2 GCPS is caused by loss of function mutations in the GLI3 transcription factor gene located on chromosome 7p13 and is inherited in an autosomal dominant pattern. In addition to mutations, translocations that interrupt the gene, microdeletions and large cytogenetically detectable deletions have been described. The latter are associated with a more complex phenotype, involving additional abnormalities as a result of deletion of additional genes.2 There are multiple disorders with polydactyly, so the differential diagnosis with GCPS can be difficult. However, non-syndromic preaxial polydactylies such as preaxial polydactyly type 4 can be excluded if other dismorphic features of GCPS are recognizable.1 Other differential diagnoses include Pallister–Hall syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome and Teebi syndrome. The phenotype of individuals affected by Pallister– Hall syndrome includes postaxial polydactyly, bifid epiglottis, imperforate anus, hypothalamic neoplasia, panhypopituitarism and other conditions that may be life threatening in the neonatal period.3 Pallister–Hall syndrome is also due to mutations of GLI3 gene.2 The acrocallosal syndrome (ACS) includes features that overlap the GCPS as preaxial and Prenatal Diagnosis 2015, 35, 203–205
postaxial polysyndactyly, macrocephaly, agenesis of the corpus callosum, mental retardation, seizures and hernias.1 ACS is an autosomal recessive condition caused by mutations in the KIF7 gene (located in 15q26.1).6 Teebi syndrome shares craniofacial manifestations with GCPS, as hypertelorism, prominent forehead, hypertelorism, downslanting palpebral fissures, broad nasal tip, cardiac defects, umbilical hernia and cryptorchidism. Nevertheless other features, such as depressed nasal bridge, long philtrum, heavy and broad eyebrows, anterior hair implantation resembling a widow’s peak, neonatal teeth, thin upper lip, everted lower lip, small chin, low-set ears, preauricular fistulas and short neck, pectus excavatum, small omphalocele, minor anomalies of hands (clinodactyly of the 5th fingers or mild interdigital webbing), pes adductus, ectopic or cystic kidney and shawl scrotum and normal psychomotor development
Table 1 Incidence of typical abnormalities in Greig cephalopolysyndactyly syndrome 2
Greig cephalopolysyndactyly syndrome Abnormalities Craniofacies
Hands
Feet
Incidence Macrocephaly
52%
High forehead
70%
Frontal bossing
58%
Broad nasal root
79%
Postaxial polydactyly
78%
Broad tumbs
90%
Syndactyly (primarily in fingers 3 and 4)
82%
Preaxial polydactyly
81%
Broad halluces
89%
Syndactyly (primarily toes 1 to 3)
90%
© 2014 John Wiley & Sons, Ltd.
204
are not typically found in GCPS.4,5 In the Teebi syndrome the inheritance seems to be autosomal dominant pattern, but no causative gene has yet been identified.5 Carpenter syndrome is characterized by polysyndactyly, craniosynostosis and mental retardation and is caused by mutations in the RAB23 gene.1 Gorlin syndrome (nevoid basal cell carcinoma syndrome) also presents with macrocephaly, but rarely hypertelorism or polydactyly. This syndrome is caused by mutations in the PTCH1, another gene in the GLI-SHH pathway.1 The authors describe a case of a 33-year-old (gravida 2, para 1), Caucasian woman referred to the Fetal Medicine Unit of our institution at 12 weeks’ gestation for first trimester aneuploidy screening. Maternal blood sampling for β-HCG and PAPP-A measurement was performed on the first appointment at 11 weeks. This patient had a previous son with bilateral cleft lip and palate, diagnosed in routine 2nd trimester ultrasound. There was also a personal and family history of syndactyly of the 2nd and 3rd toes of both feet. The patient’s husband did not have any congenital abnormalities and was not consanguineous with the patient. The combined prenatal screening for trisomy 21 performed at 12 weeks, revealed low risk for trisomy 21 (1: 6810), with no anomalies detected in the first trimester scan. The second trimester anomaly scan revealed postaxial polydactyly in the left hand and syndactyly of the third and fourth fingers of both hands. Both feet had broad halluces. The fetal echocardiogram was normal (Figure 1). Amniocentesis was performed at 21 week gestation and a normal 46,XY karyotype was found. The hypothesis of GCPS was suspected based on ultrasound findings and personal and family history of syndactyly, which led to the study of the GLI3 gene. The GLI3 gene was analyzed by PCR and sequencing of both DNA strands of the entire coding region and the highly conserved exon–intron splice junctions. In addition, MLPA (multiplex ligation-dependent probe amplification) analysis was performed to test for large deletions or duplications within or including the GLI3 gene. To exclude maternal contamination, quantitative Multiplex-PCR was performed comparing fetal (amniocytes) and maternal (peripheral blood sample) genetic profiles. No GLI3 gene
Figure 1 Ultrasound image of fetal left hand with syndactyly of 3rd and 4th fingers
Prenatal Diagnosis 2015, 35, 203–205
L. Raposo et al.
deletions were detected by sequencing. However, the MLPA study revealed a large heterozygous deletion of the GLI3 gene encompassing exons 11, 12 and 13. The maternal blood was also studied for the GLI3 gene which was normal, excluding autosomal dominant hereditary transmission. These findings are consistent with a de novo mutation in the fetus GLI3 gene. The third trimester scan confirmed the previous ultrasound findings and showed macrocephaly, with the head circumference above the 95th centile. The baby was born at 39 weeks by lower segment cesarean section due to cephalopelvic disproportion. The birth weight was 3635 g, Apgar scores 9 and 10, at 5 and 10 min, respectively, and head circumference of 36 cm (75th centil). All the ultrasound findings were confirmed after birth and moreover the newborn had preaxial polydactyly and syndactyly (involving the supernumerary, 1st, 2nd and 3rd toes) in both feet. At 9 months of age the infant has normal psycho-motor development and normal weight/length evolution. The transfontanellar encephalic ultrasound and magnetic resonance did not reveal major malformations of the central nervous system and echocardiogram was normal. In this case surgical repair of the hands is important for both functional and esthetic reasons. However, the surgical repair of the feet is optional, as esthetic considerations are generally less pressing. The functional consequences of iatrogenic biomechanical problems after a preaxial polydactyly in the feet can be severe.1 The prognosis for typically affected patients is excellent.1 Ninety percent of carriers of this mutation have a normal psycho-motor development; however, patients with larger deletions may have a worse prognosis.1 In the current case report the brother of the affected patient had lip and palate cleft. In literature there are no cases of GCPS with this feature, so it seems it has a different etiology. Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly in at least one limb, hypertelorism and macrocephaly. The prenatal diagnosis is based in a fetus with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 mutation. In addition, a family history of this syndrome may suggest the prenatal diagnosis, since it typically has an autosomal dominant inheritance. In this case despite a heavy family history of both feet syndactyly, these findings seem to have no relation to GCPS detected in the fetus, since no GLI3 mutation was detected in the pregnant women. This finding, together with the fact that the masculine progenitor has no phenotypic characteristics of the syndrome (no genetic test performed), suggests the fetus has a new mutation, so the risk of recurrence for the couple is considered very low. However, it’s not possible to exclude gonadal mosaicism, so prenatal diagnosis should be suggested in future pregnancies. Prenatal diagnosis of Greig cephalopolysyndactyly syndrome is rarely reported in literature, and this achievement in the case reported was just possible with the multidisciplinary cooperation between obstetricians and geneticists. © 2014 John Wiley & Sons, Ltd.
Greig cephalopolysyndactyly syndrome
205
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?
WHAT DOES THIS STUDY ADD?
• Greig cephalopolysyndactyly syndrome (GCPS) is a rare multiple congenital anomaly syndrome with an autosomal dominant pattern of inheritance. Prenatal diagnosis is challenging because the ultrasound findings are relatively non-specific.
• Prenatal diagnosis of GCPS is difficult but possible. Ultrasound findings and family history play the main role that can lead to this diagnosis as in this case.
REFERENCES 1. Biesecker LG. The Greig cephalopolysyndactyly syndrome. Orphanet Journal of Rare Diseases 2008;3:10. 2. Jones K, Jones M, Campo M. Greig Cephapolysyndactyly Syndrome. In Smith’s Recognizable Patterns of Human Malformation (6th edn). Elsevier Saunders: Philadelphia, 2005;486–7. 3. Timor-Tritsch IE, Kapp S, Berg R, et al. Greig cephalopolysyndactyly syndrome: diagnosis based on prenatal sonographic features coupled
Prenatal Diagnosis 2015, 35, 203–205
with comparative genomic hybridization. Journal of Ultrasound in Medicine 2009;28:1735–42. 4. Hamosh A. Online Mendelian Inheritance in Man. Acrocallosal syndrome. URL http://www.omim.org/entry/200990 [accessed on 30 April 2014]. 5. Orphanet. Hypertelorism, Teebi type. URL http://www.orpha.net/consor/ cgi-bin/OC_Exp.php?lng=EN&Expert=1519 [accessed on 30 April 2014]. 6. Koenig R. Teebi hypertelorism syndrome. Clinical Dysmorphology 2003;12:187–9.
© 2014 John Wiley & Sons, Ltd.
