Journal of Perinatology (2007) 27, 589–591 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Currarino syndrome as an etiology of a neonatal Escherichia coli meningitis

J Fleury1, G Picherot1, C Cretolle2, G Podevin3, A David4, J Caillon5,6, JC Roze7 and C Gras-le Guen6,7 1Clinique Me´dicale Pe´diatrique, Hoˆpital Me`re Enfant CHU Nantes, CHU Nantes, France; 2Service de Chirurgie Visce´rale Infantile et INSERM U781, Hoˆpital Necker-Enfants Malades, Paris, France; 3Service de Chirurgie Infantile, Hoˆpital Me`re Enfant CHU Nantes, CHU Nantes, France; 4Service de Ge´ne´tique Me´dicale, CHU Nantes, France; 5Laboratoire de Microbiologie, CHU Nantes, France; 6UPRES EA 3826, Faculte´ de Me´decine de Nantes, Nantes, France and 7Service de Ne´onatologie, Hoˆpital Me`re Enfant CHU Nantes, CHU Nantes, France

Magnetic resonance imaging (MRI) revealed a presacral mass with We report the case of a 29-day-old baby girl in whom Escherichia coli a probable neurenteric fistula, a tethered cord with low-lying meningitis led to the diagnosis of Currarino syndrome (CS) (OMIM medullary conus below the L3–L4 level and an intraspinal lipoma 176450), an autosomal-dominant associated with sacral (Figure 1). The cerebral MRI was normal. Currarino syndrome agenesis, anorectal malformation, presacral masses and (CS) was diagnosed (OMIM 176450) based on these observations. malformations. Her condition improved with antibiotics and early surgical A single-stage surgical treatment was performed with a posterior treatment. A familial study identified other genetically related individuals median sagittal approach 21 days after the beginning of with similar symptoms. antibiotherapy. The tethered cord was released, the presacral tumor Journal of Perinatology (2007) 27, 589–591; doi:10.1038/sj.jp.7211783 and the intra-spinal lipoma were excised, the dural sheath was Keywords: neonate; anorectal malformation; bacterial meningitis; closed and the region between the and the presacral mass Currarino syndrome; HLXB9 gene was repaired. Histological examination of the excised mass confirmed a mature . At 1 year of age, the girl had normal psychomotor development. Case report The follow-up was favorable, except for the persistence of chronic A 29-day-old baby girl was referred to our hospital due to a fever of constipation. 381C, anorexia and unusual behavior. Clinical examination A familial study was then conducted as some intrafamilial identified symptoms of neurological problems and shock, including correlation has been noted in half of CS cases, where autosomal- moaning and cutaneous hyperesthesia. A lumbar puncture revealed dominant inheritance and a broad inter- and intrafamilial high protein (8.38 g/l) and low glucose (0 g/l) levels. The phenotypic variability are observed. This study identified at least cerebrospinal fluid (CSF) was cloudy with 6740 cells/mm3 five members of the family with sacral anomalies, which had not containing 91% neutrophils. Culture of the fluid isolated been previously classified (Figure 2). Patient III2 had Escherichia coli K1, and the infant was then given ceftriaxone Streptococcus agalactae and Bacteroides meningitis revealing a (100 mg/kg/day) for 21 days. Recovery was observed after 2 days of neurenteric cyst and a presacral anterior meningocele. X-ray treatment. Improvement was confirmed by biochemical analysis revealed a sacral agenesis below the 4th vertebrae, and examination of the CSF. After 10 days of treatment, culture of the lumbosacral MRI confirmed the presence of an intraspinal lipoma. CSF isolated Bacteroides, which led to the addition of Despite surgical treatment, this individual continues to suffer from metronidazole (20 mg/kg/day) to the treatment regimen. severe constipation. Her son, patient IV1, has a sacrococcygeal A cutaneous mark in front of the right sacroiliac joint region agenesis, and surgery was performed for an anorectal was observed on the infant during hospitalization, prompting a malformation during the neonatal period. Radiological X-ray. The X-ray identified hemi-agenesis of the right examinations of patient II3 confirmed the presence of a sacral pieces with conservation of S1, indicating a sickle-shaped sacrococcygeal dysplasia and a presacral mass. Patient II2 was sacrum. Anorectal examination identified a rectal stenosis. treated in childhood for an anorectal malformation with perineal fistula, and she still suffers from chronic intestinal obstruction and Correspondence: Dr C Gras-le Guen, Ne´onatologie, Hoˆpital Me`re Enfant CHU Nantes, 38 bd fecal soiling. She also harbors a sacral agenesis, a bicornuate Jean Monnet, Cedex 1, Nantes 44093, France. E-mail: [email protected] uterus and urinary incontinence. Patient I2 has a sacral Received 19 February 2007; revised 23 April 2007; accepted 24 April 2007 malformation. The diagnosis of CS was confirmed after molecular Currarino syndrome and E coli meningitis J Fleury et al 590

Figure 1 Magnetic resonance imaging (MRI) revealed a presacral mass with a neuroenteric fistula, a tethered cord and an intraspinal lipoma. genetic analysis of patient IV2. Direct DNA sequencing of the three coding exons of the HLXB9 gene detected a heterozygous nonsense mutation (c644G>A, pTrp215X). This mutation is located in the Figure 2 Family pedigree illustrating the variable expression of Currarino first exon, and results in a 189-amino acids truncated HB9 protein syndrome (CS). Our patient, IV2, is the only one who presents the complete (the truncated protein is 214 amino acids long) that, if stably association of symptoms. Five family members present an incomplete CS and translated, lacks the homeodomain region that interacts with DNA. patient III3 must be a mutation carrier with a low penetrance.

practitioner must be prudent because of the absence of correlation Discussion between genotype and phenotype in this syndrome. The diagnosis of CS as a result of neonatal E. coli meningitis is Our case illustrates the incomplete penetrance of CS. Lynch uncommon.1,2 Moreover, diagnosis of a dominant familial disorder et al.8 observed that 4% of patients with a mutation in the HLXB9 is important, both to detect other affected family members and to gene were asymptomatic, with normal sacral X-ray imaging. administer more accurate genetic counseling. Patient III3, the father of the patient discussed in this study, CS is a genetic autosomal-dominant disorder. In 1981, harbors normal X-rays of the sacrum. G Currarino defined it as the association of a sacral agenesis, an The variable expression of this disease is well represented in our anorectal malformation and a presacral mass.2 In 1998, mutation family pedigree. Impairments associated with CS are frequent. First, in the HLXB9 gene at the chromosomal region 7p36 was identified bacterial meningitis can be the first symptom of neurological as being responsible for this phenotype.3–5 This gene encodes the malformation (7–11% of cases)9 and reveal the possibility of nuclear HB9, which plays a role in the early communication between the spinal canal and the presacral phases of embryogenesis. In case of HB9 protein dysfunction, it tumor.1,2 Therefore, as reported for patients III2 and IV2, the CSF is may lead to a defect in the dorsoventral separation in the caudal often polymicrobial and the digestive origin of the incriminated region of the embryo, particularly between the neural ectoderm germs is frequent. E. coli is a frequently isolated bacterium from and the digestive endoderm.6 About half of CS cases are sporadic. the CSF culture, but Bacteroides (patients IV2 and III2), Cytogenetic anomalies or de novo HLXB9 gene point mutations S. agalactae (patient III2) or Constellatus, Enterococcus faecalis cases are rare. It is likely that other genes, probably involved in the or Prevotella bivia can also be present.1 The onset of neurological same pathway, account for cases with no mutation of the HLXB9 complications in this syndrome can also be associated with a gene. The mutation c644G>A, pTrp215X has been previously tethered cord in approximately 63% of patients.10 , described in one case reported by Garcia-Barcelo et al.7 intra- or extraspinal lipomas (patients III2 and IV2) and Most familial cases of CS harbor a point mutation in the neurological symptoms can be observed as a result of the presacral HLXB9 gene. This makes prenatal diagnosis of CS possible, but the mass.

Journal of Perinatology Currarino syndrome and E coli meningitis J Fleury et al 591

Investigation into malformation of the urogenital tract (vesico- 3 Ross AJ, Ruiz-Perez V, Wang Y, Hagan DM, Scherer S, Lynch SA et al. A homeobox urethral reflux) is recommended, as it is sometimes responsible for gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet recurrent urinary tract infections9 and Mu¨llerian duplications.1,8 1998; 20: 358–361. The digestive system is often affected as severe constipation is the 4 Hagan DM, Ross AJ, Strachan T, Lynch SA, Ruiz-Perez V, Wang YM et al. Mutation 11 analysis and embryonic expression of the HLXB9 Currarino syndrome gene. Am J primary symptom of the disease (patients II2, III2 and IV2). Hum Genet 2000; 66: 1504–1515. In conclusion, we report here the first case of CS revealed by 5 Belloni E, Martucciello G, Verderio D, Ponti E, Seri M, Jasonni V et al. Involvement acute E. coli meningitis during the neonatal period. This discovery of the HLXB9 Homeobox gene in Currarino syndrome. Am J Hum Genet 2000; 66: led to the identification of five other familial cases. Complete CS is 312–319. rare, and this familial series provides evidence for differences in its 6 Gegg CA, Vollmer DG, Tullous MW, Kagan-Hallet KS. An unusual case of the complete Currarino triad: case report, discussion of the literature and the embryogenic expressivity. In those patients with suspected CS, a mutational implications. Neurosurgery 1999; 44: 658–662. analysis and a full workup of family members should be considered 7 Garcia-Barcelo M, So MT, Lau DK, Leon TY, Yuan ZW, Cai WS et al. Population to offer precise genetic counseling. differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome. Clin Chem 2006; 52: 46–52. 8 Lynch SA, Wang Y, Strachan T, Burn J, Lindsay S. Autosomal dominant sacral agenesis: Currarino syndrome. J Med Genet 2000; 37: 561–566. References 9 Kochling J, Karbasiyan M, Reis A. Spectrum of mutations and genotype-phenotype analysis in Currarino syndrome. Eur J Hum Genet 2001; 9: 599–605. 1 Guerin JM, Leibinger F, Raskine L, Ekherian JM. Polymicrobial meningitis revealing 10 Cretolle C, Zerah M, Jaubert F, Sarnacki S, Revillon Y, Lyonnet S et al. New clinical and an anterior sacral meningocele in a 23-year-old woman. J Infect 2000; 40: 195–197. therapeutic perspectives in Currarino syndrome. J Pediatr Surg 2006; 41: 126–131. 2 Currarino G, Coln D, Votteler T. Triad of anorectal, sacral, and presacral anomalies. 11 Samuel M, Hosie G, Holmes K. Currarino triadFdiagnostic dilemma and a combined Am J Roentgenol 1981; 137: 395–398. surgical approach. J Pediatr Surg 2000; 35: 1790–1794.

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