CLINICAL REPORT
Polymicrogyria in a 10-Month-Old Boy with Mowat–Wilson Syndrome Susan B. Murray,1 Brooke B. Spangler,1,2 Benjamin M. Helm,1,2 and Samantha Schrier Vergano1,2* 1
Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia
2
Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, Virginia
Manuscript Received: 9 October 2014; Manuscript Accepted: 6 May 2015
Mowat-Wilson syndrome (MWS, OMIM# 235730) is a multiple congenital anomaly disorder characterized by intellectual disability, seizures, microcephaly, and distinct facial features. Additional findings include structural brain abnormalities, eye defects, congenital heart defects, Hirschsprung disease (HSCR), and genitourinary anomalies. It is caused by de novo heterozygous mutations or deletions of the ZEB2 gene on chromosome 2q21–q23. We report here on a 10-month-old boy with typical features of MWS who presented with the novel finding of polymicrogyria on brain magnetic resonance imaging. We also review the current literature regarding central nervous system anomalies in MWS. © 2015 Wiley Periodicals, Inc.
Key words: Mowat–Wilson syndrome; ZEB2; polymicrogyria; Hirschsprung disease
INTRODUCTION Mowat–Wilson syndrome (OMIM# 235730) was first reported in 1998 by Mowat et al., and was linked with either deletions or heterozygous single gene mutations of the ZEB2 gene on chromosome 2q21–q23. Since that time a multitude of cases have been reported in the medical literature with the consistent clinical findings of moderate to severe intellectual disability, microcephaly, seizures, and short stature [Mowat et al., 2003]. Characteristic facial features include hypertelorism, medially flared eyebrows, deep-set eyes, fleshy, up-turned ear lobes, a prominent, pointed nasal tip, and a pointed chin. Other anomalies include central nervous system abnormalities, congenital heart defects (CHD), and genitourinary anomalies (most commonly hypospadias) [Silengo et al., 2003; Silengo et al., 2004; Garavelli et al., 2009]. 57% of individuals have biopsy-proven (HSCR) and 26% have severe constipation without a pathologic diagnosis of HSCR [Garavelli and Mainardi, 2007]. We describe the case of a 10-month-old boy with who presented with typical clinical features of the disorder, including microcephaly, seizures, characteristic facial dysmorphisms, HSCR, hypospadias, and unilateral hydronephrosis. Along with a hypoplastic corpus callosum, a brain MRI was notable for diffuse polymicrogyria (PMG), which to our knowledge has not previously been reported with this syndrome.
© 2015 Wiley Periodicals, Inc.
How to Cite this Article: Murray SB, Spangler BB, Helm BM, Vergano SS. 2015. Polymicrogyria in a 10-month-old boy with Mowat–Wilson syndrome. Am J Med Genet Part A 167A:2402–2405.
CLINICAL REPORT The male proband was referred to the Medical Genetics clinic initially at 10 months of age for multiple congenital anomalies, including microcephaly, dysmorphic facial features, and hypospadias. He was the third child of this Caucasian couple and was born at 39 weeks gestation by repeat Cesarean. Consanguinity was denied. Prenatal ultrasounds were significant for moderate leftsided hydronephrosis which persisted postnatally. Microcephaly and mild hypospadias were noted at birth. Although he failed his newborn hearing screen, his initial newborn period was otherwise uncomplicated, and he was discharged home at 3 days of life. At one week of age, he was re-admitted to the hospital for diffuse diarrhea and failure to thrive. A head ultrasound obtained during this admission revealed abnormal echogenicities, and a subsequent MRI showed diffuse polymicrogyria, a thin corpus callosum, and simplified sylvian fissures (Fig. 2). A TORCH work-up, including a fundoscopic examination, was normal. An echocardiogram was obtained and showed a small atrial septal defect and mild pulmonic stenosis, which has persisted. The diarrhea resolved during this admission, although he continued to have problems with constipation; in retrospect, it is likely that the initial diarrhea was a result of overflow from stool impaction. Over the subsequent months, his family noted choking and wheezing after feeds, resulting in two additional hospitalizations. Conflict of interest: None. Correspondence to: Samantha Schrier Vergano, MD, FAAP, FACMG, Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, 601 Children’s Lane, Norfolk, VA 23507. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 26 May 2015 DOI 10.1002/ajmg.a.37171
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MURRAY ET AL. Home oxygen therapy was necessary at the time of his second discharge until 7 months of age. He was diagnosed with gastroesophageal reflux, and a laryngoscopy revealed tracheobronchomalacia and laryngomalacia. Audiology examination showed mild bilateral conductive hearing loss, for which tympanostomy tubes were placed at around 10 months. A sleep study revealed severe obstructive sleep apnea. An initial EEG was performed at a few months of life after concern for episodes of stiffening. This was reported as normal and the episodes were felt to be secondary to reflux. At about 7 months of age, he was noted to have staring spells; a repeat EEG showed generalized discharges, central discharges, photoparoxysmal discharges and intermittent occipital slowing, consistent with increased risk for both generalized and partial seizures. At the time of initial presentation to our Medical Genetics clinic, the proband was 10 months of age and was globally developmentally delayed, with gross, fine motor, social, and verbal milestones at the level of a 3–4 month-old infant. He could roll both directions but not sit unassisted or get to a sitting position. Fists remained clenched with no efforts to pick up objects. He did not consistently track with his gaze. He could smile and coo but not make any speech-like sounds. At 14 months of life a rectal biopsy was done in light of persistent constipation, and it confirmed partial colonic aganglionosis consistent with HSCR. Family history was significant for a history of a seizure disorder in the father which began at around age 20. Examination of brain
2403 imaging from the father after a recent trauma showed no abnormal gyral pattern. The proband’s 9-year-old brother also had seizures as an infant that resolved by six months of life; he is reported to have a brain MRI at birth that was also normal. This brother and the father are otherwise healthy without cognitive delays. There is another 3-year-old brother who has no history of seizures and is healthy. There is a paternal first cousin, once removed, with autism and intellectual disability of unknown etiology. The remainder of the family history was essentially otherwise noncontributory. On physical exam, the infant’s weight was 9.34 kg (13th centile), height was 72.5 cm (below the first centile), and head circumference was 42.5 cm (below the first centile and 50th centile for a 4-monthold). He was grossly microcephalic with bitemporal narrowing and a prominent supraorbital ridge, nasal bridge, and midface. Nasal tip was bulbous with columella below the nares. Ears were slightly lowset with a thickened crus and upturned earlobes bilaterally (Fig. 1). Philtrum was long and his upper lip was slightly tented. He was not able to track with his eyes, and he had notable spasticity of all four extremities with fists consistently clenched. Extremities were grossly normally formed. He had Tanner I male genitalia with mild hypospadias and testes descended bilaterally.
MATERIALS AND METHODS Approximately 3–5 ml of the proband’s peripheral blood was shipped at ambient temperature to Emory Genetics Laboratory
FIG. 1. The proband at age 18 months. (A) Left ear with classic “orecchietti pasta” formation to lobe. (B) Note relative microcephaly, deep-set eyes, and micrognathia. Arms held in flexion and wrists in fist formation.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2404
RESULTS A known, previously reported, nonsense mutation was detected in one copy of the ZEB2 gene; the mutation is denoted as c.2083C>T which leads to a premature stop codon in exon 8 (p.R695X).
DISCUSSION
FIG. 2. T2 weighted coronal (A) and axial (B) images of the proband demonstrating polymicrogyria in temporal, frontal, and parietal lobes.
(Decatur, GA) for ZEB2 gene sequencing. PCR was used to amplify the 9 coding exons and immediate flanking regions of the ZEB2 gene. The PCR products were sequenced in the forward and reverse directions. Intronic variants greater than 10 nucleotides from the exon/intron boundaries were not analyzed and variants greater than three nucleotides from the exon/intron boundary were not reported unless known to be pathogenic. Nucleotide numbering was based on GenBank accession number NM_014795.3; nucleotide one corresponds to the A of the start codon ATG (Fig. 2).
Our proband is a Caucasian male with multiple congenital anomalies including microcephaly, hypoplasia of the corpus callosum, seizures, global developmental delay, facial dysmorphisms characteristic of MWS, HSCR, hypospadias, and unilateral hydronephrosis. He also has diffuse polymicrogyria on brain MRI, which is notably absent from brain MRIs in two first-degree family members. He has a previously reported nonsense mutation in ZEB2 known to cause MWS. Studies of ZEB2 in mice have demonstrated that the gene is a member of the two-handed zinc-finger/homeodomain transcription factor family and that the protein that it encodes is important for neural crest development. In murine models, neurodevelopment relies on ZEB2 for differentiation and guidance of cortical neurons, and haploinsufficiency of its protein is thought to be the mechanism that underlies seizures in patients with MWS. The interaction of ZEB2 with SOX10, which encodes a protein that is critical in enteric nervous system development, is thought to explain the molecular basis of HSCR in MWS [Ghoumid et al., 2013]. The nonsense mutation detected in the proband was initially reported in four other cases of MWS by Yamada et al. [2001] and has been reported in numerous individuals since that time [Dastot-Le Moal et al., 2007]. Brain malformations in individuals with MWS are not uncommon; hypoplasia and agenesis of the corpus callosum are reported in up to 56% of individuals with MWS [Spaggiari et al., 2013]. Other reported anomalies include Chiari 1 malformation [Garavelli et al., 2009], cerebellar hypoplasia [Silengo et al., 2003; Silengo et al., 2004], ventriculomegaly [Adam et al., 2006], underdeveloped hippocampi [Kaariainen et al., 2001], and frontotemporal hypoplasia with temporal dysplasia [Cacheux et al., 2001]. Cortical malformations in the MWS literature include atrophy [Garavelli et al., 2003], and pachygyria and nodular subependymal heterotopia [Silengo et al., 2003; Silengo et al., 2004]. Polymicrogyria is a relatively common malformation of cortical development in which the cerebral cortex is notable for excessive folding and abnormal lamination. It is estimated to occur in approximately 20% of all cortical brain malformations [Stutterd and Leventer, 2014]. PMG has been attributed to both non-genetic and genetic causes, with multiple chromosomal loci and genes impacting a variety of cellular processes described in recent years. It has been associated with a number of genetic syndromes including 22q11.2 deletion, Zellweger, and Ehlers–Danlos [Guerrini and Dobyns, 2014; Squier and Jansen, 2014]. Non-genetic causes include intrauterine hypoxia and hypoperfusion, and infections such as congenital cytomegalovirus, syphilis, and varicella zoster. The clinical sequelae from PMG depend upon its underlying cause, associated syndromic features, and the extent and location of the PMG as well as the presence of any other intracranial abnormalities [Stutterd and Leventer, 2014].
MURRAY ET AL.
2405
The etiology and pathogenesis of this brain malformation remain subjects of active debate in the medical literature. It is suspected that PMG has a heterogeneous etiology with both environmental and genetic causes resulting in a similar phenotypic endpoint. The most current research, based on pathologic data, suggests that the anatomic change in most forms of PMG occurs after the majority of the neurons that will form the cerebral cortex have completed their migration from the periventricular region, thus classifying it as a “post-migrational” disorder [Stutterd and Leventer, 2014]. PMG has not previously been reported in association with MWS. Initial evaluations of the proband focused on the neuronal migration defect as the underlying cause of his other symptoms, possibly delaying the ultimate diagnosis. Although there are several individuals on the paternal side of the family with either a history of seizures or autism/intellectual disability, a review of their records and imaging did not indicate a heritable form of polymicrogyria or other disorder. Common non-genetic causes of PMG were not felt to be at play with our proband. Our patient’s specific mutation in the ZEB2 gene is a common pathogenic variant, and it has been reported in MWS patients without documented PMG [Dastot-Le Moal et al., 2007; Garavelli et al., 2009; Ghoumid et al., 2013]. It is worth noting that intracranial anomalies are likely underreported in MWS, as not all patients have had brain imaging [Garavelli et al., 2009]. The proband’s clinical picture is somewhat atypical for MWS in that he has diffuse spasticity and carries a diagnosis of spastic cerebral palsy involving all four extremities. While this is not characteristic of MWS, it is a relatively common finding in patients with PMG [Stutterd and Leventer, 2014]. The etiology of PMG in our patient is unclear and could well be derived from unidentified gene-gene interactions or non-genetic factors. Analysis of cerebral imaging in a larger subset of patients with MWS is needed to identify whether the presence of PMG is an isolated co-occurrence in our patient or a true association with MWS. Given the pathogenesis of MWS and the effects of haploinsufficiency of the ZEB2 gene product on neural crest development in murine models, the association of the two disorders is intriguing and could provide further insight into the etiology of PMG.
Dastot-Le Moal F, Wilson M, Mowat D, Collot N, Niel F, Goossens M. 2007. ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum Mutat 28:313–321.
ACKNOWLEDGMENTS
Silengo M, Ferrero GB, Wakamatsu N. 2004. Pachygyria and cerebellar hypoplasia in a patient with a 2q22-q23 deletion that includes the ZFHX1B gene. Am J Med Genet Part A 127A:109.
The authors wish to thank the proband and his family for their participation in this manuscript. Dr. Schrier Vergano is a member of the clinical advisory group for Ambry Genetics but has not received any additional funding or grants in support of this research. The remaining authors report no conflicts of interest.
REFERENCES Adam MP, Schelley S, Gallagher R, Brady AN, Barr K, Blumberg B, Shieh JTC, Graham J, Slavotinek A, Martin M, Keppler-Noreuil K, Storm AL, Hudgins L. 2006. Clinical features and management issues in Mowat-Wilson syndrome. Am J Med Genet 140A:2730–2741. Cacheux V, Dastot-Le Moal F, K€a€ari€ainen H, Bondurand N, Rintala R, Boissier B, Wilson M, Mowat D, Goossens M. 2001. Loss-of-function mutations in SIP1 Smad interacting protein 1 results in a syndromic Hirschsprung disease. Hum Mol Gene 10:1503–1510.
Garavelli L, Donadio A, Zanacca C, Della Guistina E, Bertani G, Albertini G, Zollino M, Rauch A, Banchini G, Neri G. 2003. Hirschsprung disease, mental retardation, characteristic facial features and mutation in the gene ZFHX1B (SIP1): Confirmation of the Mowat-Wilson syndrome. Am J Med Genet 116A:385–388. Garavelli L, Mainardi PC. 2007. Mowat-Wilson syndrome. Orphanet J Rare Dis 2:42. Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano F, Seri M, Wischmeijer, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti L, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R, Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S, Wakamatsu N, Neri G. 2009. MowatWilson syndrome: Facial phenotype changing with age: Study of 19 Italian patients and review of the literature. Am J Med Genet Part A 149A:417–426. Ghoumid J, Drevillon L, Alavi-Naini SM, Bondurand N, Rio M, Briand-Suleau A, Nasser M, Goodwin L, Raymond P, Yanicostas C, Goossens M, Lyonnet S, Mowat D, Amiel J, Soussi-Yanicostas N, Giurgea I. 2013. ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. Hum Mol Genet 22:2652–2661. Guerrini R, Dobyns WB. 2014. Malformation of cortical development: Clinical features and genetic causes. Lancet Neurol 13:710–726. K€a€ari€ainen H, Wallgren-Pettersson C, Clarke A, Pihko H, Taskinen H, Rintala R. 2001. Hirschsprung disease, mental retardation and dysmorphic facial features in five unrelated children. Clin Dysmorphol 10:157–163. Mowat DR, Croaker GD, Cass DT, Kerr BA, Chaitow J, Ades LC, Chia NL, Wilson MJ. 1998. Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: Delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet 35:617–623. Mowat DR, Wilson MJ, Goossens M. 2003. Mowat-Wilson syndrome. J Med Genet 40:305–310. Silengo M, Ferrero GB, Tornetta L, Cortese MG, Canavese F, D’Alonzo G, Papalia F. 2003. Pachygyria and cerebellar hypoplasia in GoldbergShprintzen syndrome. Am J Med Genet Part A 118A:388–390.
Spaggiari E, Baumann C, Alison M, Oury JF, Belarbi N, Dupont C, Guimot F, Delezoide AL. 2013. Mowat-Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum: Advocacy for standard autopsy. Eur J Med Genet 56:297–300. Squier W, Jansen A. 2014. Polymicrogyria: Pathology, fetal origins and mechanisms. Acta Neuropatholo Commun 2:80. Stutterd CA, Leventer RJ. 2014. Polymicrogyria: A common and heterogeneous malformation of cortical development. Am J Med Genet Part C Semin in Med Genet 166C:227–239. Yamada K, Yamada Y, Nomura N, Miura K, Wakako R, Hayakawa C, Matsumoto A, Kumagai T, Yoshimura I, Miyazaki S, Kato K, Sonta S, Ono H, Yamanaka T, Nagaya M, Wakamatsu N. 2001. Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features. Am J Hum Genet 69:1178–1185.
Polymicrogyria in a 10-Month-Old Boy with Mowat–Wilson Syndrome Susan B. Murray,1 Brooke B. Spangler,1,2 Benjamin M. Helm,1,2 and Samantha Schrier Vergano1,2* 1
Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia
2
Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, Virginia
Manuscript Received: 9 October 2014; Manuscript Accepted: 6 May 2015
Mowat-Wilson syndrome (MWS, OMIM# 235730) is a multiple congenital anomaly disorder characterized by intellectual disability, seizures, microcephaly, and distinct facial features. Additional findings include structural brain abnormalities, eye defects, congenital heart defects, Hirschsprung disease (HSCR), and genitourinary anomalies. It is caused by de novo heterozygous mutations or deletions of the ZEB2 gene on chromosome 2q21–q23. We report here on a 10-month-old boy with typical features of MWS who presented with the novel finding of polymicrogyria on brain magnetic resonance imaging. We also review the current literature regarding central nervous system anomalies in MWS. © 2015 Wiley Periodicals, Inc.
Key words: Mowat–Wilson syndrome; ZEB2; polymicrogyria; Hirschsprung disease
INTRODUCTION Mowat–Wilson syndrome (OMIM# 235730) was first reported in 1998 by Mowat et al., and was linked with either deletions or heterozygous single gene mutations of the ZEB2 gene on chromosome 2q21–q23. Since that time a multitude of cases have been reported in the medical literature with the consistent clinical findings of moderate to severe intellectual disability, microcephaly, seizures, and short stature [Mowat et al., 2003]. Characteristic facial features include hypertelorism, medially flared eyebrows, deep-set eyes, fleshy, up-turned ear lobes, a prominent, pointed nasal tip, and a pointed chin. Other anomalies include central nervous system abnormalities, congenital heart defects (CHD), and genitourinary anomalies (most commonly hypospadias) [Silengo et al., 2003; Silengo et al., 2004; Garavelli et al., 2009]. 57% of individuals have biopsy-proven (HSCR) and 26% have severe constipation without a pathologic diagnosis of HSCR [Garavelli and Mainardi, 2007]. We describe the case of a 10-month-old boy with who presented with typical clinical features of the disorder, including microcephaly, seizures, characteristic facial dysmorphisms, HSCR, hypospadias, and unilateral hydronephrosis. Along with a hypoplastic corpus callosum, a brain MRI was notable for diffuse polymicrogyria (PMG), which to our knowledge has not previously been reported with this syndrome.
© 2015 Wiley Periodicals, Inc.
How to Cite this Article: Murray SB, Spangler BB, Helm BM, Vergano SS. 2015. Polymicrogyria in a 10-month-old boy with Mowat–Wilson syndrome. Am J Med Genet Part A 167A:2402–2405.
CLINICAL REPORT The male proband was referred to the Medical Genetics clinic initially at 10 months of age for multiple congenital anomalies, including microcephaly, dysmorphic facial features, and hypospadias. He was the third child of this Caucasian couple and was born at 39 weeks gestation by repeat Cesarean. Consanguinity was denied. Prenatal ultrasounds were significant for moderate leftsided hydronephrosis which persisted postnatally. Microcephaly and mild hypospadias were noted at birth. Although he failed his newborn hearing screen, his initial newborn period was otherwise uncomplicated, and he was discharged home at 3 days of life. At one week of age, he was re-admitted to the hospital for diffuse diarrhea and failure to thrive. A head ultrasound obtained during this admission revealed abnormal echogenicities, and a subsequent MRI showed diffuse polymicrogyria, a thin corpus callosum, and simplified sylvian fissures (Fig. 2). A TORCH work-up, including a fundoscopic examination, was normal. An echocardiogram was obtained and showed a small atrial septal defect and mild pulmonic stenosis, which has persisted. The diarrhea resolved during this admission, although he continued to have problems with constipation; in retrospect, it is likely that the initial diarrhea was a result of overflow from stool impaction. Over the subsequent months, his family noted choking and wheezing after feeds, resulting in two additional hospitalizations. Conflict of interest: None. Correspondence to: Samantha Schrier Vergano, MD, FAAP, FACMG, Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, 601 Children’s Lane, Norfolk, VA 23507. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 26 May 2015 DOI 10.1002/ajmg.a.37171
2402
MURRAY ET AL. Home oxygen therapy was necessary at the time of his second discharge until 7 months of age. He was diagnosed with gastroesophageal reflux, and a laryngoscopy revealed tracheobronchomalacia and laryngomalacia. Audiology examination showed mild bilateral conductive hearing loss, for which tympanostomy tubes were placed at around 10 months. A sleep study revealed severe obstructive sleep apnea. An initial EEG was performed at a few months of life after concern for episodes of stiffening. This was reported as normal and the episodes were felt to be secondary to reflux. At about 7 months of age, he was noted to have staring spells; a repeat EEG showed generalized discharges, central discharges, photoparoxysmal discharges and intermittent occipital slowing, consistent with increased risk for both generalized and partial seizures. At the time of initial presentation to our Medical Genetics clinic, the proband was 10 months of age and was globally developmentally delayed, with gross, fine motor, social, and verbal milestones at the level of a 3–4 month-old infant. He could roll both directions but not sit unassisted or get to a sitting position. Fists remained clenched with no efforts to pick up objects. He did not consistently track with his gaze. He could smile and coo but not make any speech-like sounds. At 14 months of life a rectal biopsy was done in light of persistent constipation, and it confirmed partial colonic aganglionosis consistent with HSCR. Family history was significant for a history of a seizure disorder in the father which began at around age 20. Examination of brain
2403 imaging from the father after a recent trauma showed no abnormal gyral pattern. The proband’s 9-year-old brother also had seizures as an infant that resolved by six months of life; he is reported to have a brain MRI at birth that was also normal. This brother and the father are otherwise healthy without cognitive delays. There is another 3-year-old brother who has no history of seizures and is healthy. There is a paternal first cousin, once removed, with autism and intellectual disability of unknown etiology. The remainder of the family history was essentially otherwise noncontributory. On physical exam, the infant’s weight was 9.34 kg (13th centile), height was 72.5 cm (below the first centile), and head circumference was 42.5 cm (below the first centile and 50th centile for a 4-monthold). He was grossly microcephalic with bitemporal narrowing and a prominent supraorbital ridge, nasal bridge, and midface. Nasal tip was bulbous with columella below the nares. Ears were slightly lowset with a thickened crus and upturned earlobes bilaterally (Fig. 1). Philtrum was long and his upper lip was slightly tented. He was not able to track with his eyes, and he had notable spasticity of all four extremities with fists consistently clenched. Extremities were grossly normally formed. He had Tanner I male genitalia with mild hypospadias and testes descended bilaterally.
MATERIALS AND METHODS Approximately 3–5 ml of the proband’s peripheral blood was shipped at ambient temperature to Emory Genetics Laboratory
FIG. 1. The proband at age 18 months. (A) Left ear with classic “orecchietti pasta” formation to lobe. (B) Note relative microcephaly, deep-set eyes, and micrognathia. Arms held in flexion and wrists in fist formation.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2404
RESULTS A known, previously reported, nonsense mutation was detected in one copy of the ZEB2 gene; the mutation is denoted as c.2083C>T which leads to a premature stop codon in exon 8 (p.R695X).
DISCUSSION
FIG. 2. T2 weighted coronal (A) and axial (B) images of the proband demonstrating polymicrogyria in temporal, frontal, and parietal lobes.
(Decatur, GA) for ZEB2 gene sequencing. PCR was used to amplify the 9 coding exons and immediate flanking regions of the ZEB2 gene. The PCR products were sequenced in the forward and reverse directions. Intronic variants greater than 10 nucleotides from the exon/intron boundaries were not analyzed and variants greater than three nucleotides from the exon/intron boundary were not reported unless known to be pathogenic. Nucleotide numbering was based on GenBank accession number NM_014795.3; nucleotide one corresponds to the A of the start codon ATG (Fig. 2).
Our proband is a Caucasian male with multiple congenital anomalies including microcephaly, hypoplasia of the corpus callosum, seizures, global developmental delay, facial dysmorphisms characteristic of MWS, HSCR, hypospadias, and unilateral hydronephrosis. He also has diffuse polymicrogyria on brain MRI, which is notably absent from brain MRIs in two first-degree family members. He has a previously reported nonsense mutation in ZEB2 known to cause MWS. Studies of ZEB2 in mice have demonstrated that the gene is a member of the two-handed zinc-finger/homeodomain transcription factor family and that the protein that it encodes is important for neural crest development. In murine models, neurodevelopment relies on ZEB2 for differentiation and guidance of cortical neurons, and haploinsufficiency of its protein is thought to be the mechanism that underlies seizures in patients with MWS. The interaction of ZEB2 with SOX10, which encodes a protein that is critical in enteric nervous system development, is thought to explain the molecular basis of HSCR in MWS [Ghoumid et al., 2013]. The nonsense mutation detected in the proband was initially reported in four other cases of MWS by Yamada et al. [2001] and has been reported in numerous individuals since that time [Dastot-Le Moal et al., 2007]. Brain malformations in individuals with MWS are not uncommon; hypoplasia and agenesis of the corpus callosum are reported in up to 56% of individuals with MWS [Spaggiari et al., 2013]. Other reported anomalies include Chiari 1 malformation [Garavelli et al., 2009], cerebellar hypoplasia [Silengo et al., 2003; Silengo et al., 2004], ventriculomegaly [Adam et al., 2006], underdeveloped hippocampi [Kaariainen et al., 2001], and frontotemporal hypoplasia with temporal dysplasia [Cacheux et al., 2001]. Cortical malformations in the MWS literature include atrophy [Garavelli et al., 2003], and pachygyria and nodular subependymal heterotopia [Silengo et al., 2003; Silengo et al., 2004]. Polymicrogyria is a relatively common malformation of cortical development in which the cerebral cortex is notable for excessive folding and abnormal lamination. It is estimated to occur in approximately 20% of all cortical brain malformations [Stutterd and Leventer, 2014]. PMG has been attributed to both non-genetic and genetic causes, with multiple chromosomal loci and genes impacting a variety of cellular processes described in recent years. It has been associated with a number of genetic syndromes including 22q11.2 deletion, Zellweger, and Ehlers–Danlos [Guerrini and Dobyns, 2014; Squier and Jansen, 2014]. Non-genetic causes include intrauterine hypoxia and hypoperfusion, and infections such as congenital cytomegalovirus, syphilis, and varicella zoster. The clinical sequelae from PMG depend upon its underlying cause, associated syndromic features, and the extent and location of the PMG as well as the presence of any other intracranial abnormalities [Stutterd and Leventer, 2014].
MURRAY ET AL.
2405
The etiology and pathogenesis of this brain malformation remain subjects of active debate in the medical literature. It is suspected that PMG has a heterogeneous etiology with both environmental and genetic causes resulting in a similar phenotypic endpoint. The most current research, based on pathologic data, suggests that the anatomic change in most forms of PMG occurs after the majority of the neurons that will form the cerebral cortex have completed their migration from the periventricular region, thus classifying it as a “post-migrational” disorder [Stutterd and Leventer, 2014]. PMG has not previously been reported in association with MWS. Initial evaluations of the proband focused on the neuronal migration defect as the underlying cause of his other symptoms, possibly delaying the ultimate diagnosis. Although there are several individuals on the paternal side of the family with either a history of seizures or autism/intellectual disability, a review of their records and imaging did not indicate a heritable form of polymicrogyria or other disorder. Common non-genetic causes of PMG were not felt to be at play with our proband. Our patient’s specific mutation in the ZEB2 gene is a common pathogenic variant, and it has been reported in MWS patients without documented PMG [Dastot-Le Moal et al., 2007; Garavelli et al., 2009; Ghoumid et al., 2013]. It is worth noting that intracranial anomalies are likely underreported in MWS, as not all patients have had brain imaging [Garavelli et al., 2009]. The proband’s clinical picture is somewhat atypical for MWS in that he has diffuse spasticity and carries a diagnosis of spastic cerebral palsy involving all four extremities. While this is not characteristic of MWS, it is a relatively common finding in patients with PMG [Stutterd and Leventer, 2014]. The etiology of PMG in our patient is unclear and could well be derived from unidentified gene-gene interactions or non-genetic factors. Analysis of cerebral imaging in a larger subset of patients with MWS is needed to identify whether the presence of PMG is an isolated co-occurrence in our patient or a true association with MWS. Given the pathogenesis of MWS and the effects of haploinsufficiency of the ZEB2 gene product on neural crest development in murine models, the association of the two disorders is intriguing and could provide further insight into the etiology of PMG.
Dastot-Le Moal F, Wilson M, Mowat D, Collot N, Niel F, Goossens M. 2007. ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum Mutat 28:313–321.
ACKNOWLEDGMENTS
Silengo M, Ferrero GB, Wakamatsu N. 2004. Pachygyria and cerebellar hypoplasia in a patient with a 2q22-q23 deletion that includes the ZFHX1B gene. Am J Med Genet Part A 127A:109.
The authors wish to thank the proband and his family for their participation in this manuscript. Dr. Schrier Vergano is a member of the clinical advisory group for Ambry Genetics but has not received any additional funding or grants in support of this research. The remaining authors report no conflicts of interest.
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