Distal 13q Deletion Syndrome and the VACTERLAssociation: Case Report, Literature Review, andPossible Implications

Laurence E. Walsh,1,2* Gail H. Vance,1 and David D. Weaver1

1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana2Department of Neurology, Section of Pediatric Neurology, Indiana University School of Medicine,Indianapolis, Indiana

We present a case of a child with del(13)(q31.1qter), VACTERL association, and pe-noscrotal transposition. Deletion of the dis-tal long arm of chromosome 13 is associatedwith variable phenotypes. These pheno-types are divided into three clusters; eachcluster represents a specific deleted seg-ment of 13q. Individuals with deletions of acritical region at 13q32 have multiple con-genital malformations that include compo-nents of the VACTERL association. Our pa-tient had all six manifestations of VACTERLassociation. In addition, he had completepenoscrotal transposition, a unique malfor-mation reported rarely in VACTERL asso-ciation and only twice previously in dele-tion of distal 13q. We reviewed all reportedcases of distal 13q deletions to date. Of these137 patients, 15 could be classified into theVACTERL association. Ours was the onlypatient with distal 13q deletion and allVACTERL association features and also theonly one with tracheoesophageal fistula.Neither holoprosencephaly nor the othercentral nervous system malformations thathave been seen in individuals with distal13q deletions were apparent in him. The pa-tient presented here appears to be uniqueamong individuals with distal 13q deletion.His cluster of malformations strengthensthe argument that distal 13q deletion is acause for VACTERL association, and thatthis causal relationship implies a syndromicform of VACTERL. In addition, this case andthose ascertained from the literature sug-gest that penoscrotal transposition should

be considered part of both the distal 13q-deletion syndrome and some forms ofVACTERL association. © 2001 Wiley-Liss, Inc.

KEY WORDS: chromosome pair 13; VATERassociation; VACTERL asso-ciation; penoscrotal transpo-sition

INTRODUCTION

Distal 13q deletions result in characteristic pheno-types. Common findings include prenatal growth retar-dation, microcephaly and other central nervous system(CNS) malformations, eye abnormalities, characteris-tic facial appearance, congenital heart defects, gastro-intestinal anomalies, vertebral, limb, and perineal de-fects, and varying degrees of mental retardation[Khoury et al., 1983]. Specific breakpoints are associ-ated with specific phenotypes, with distal deletions in-cluding the 13q31.3-q32 region resulting in the mostsevere extra-CNS malformations [Fryns et al., 1980;Brown et al., 1993, 1995].

The major findings in the VACTERL association in-clude vertebral anomalies, anal atresia, tracheo-esophageal fistula, esophageal atresia, urogenitalanomalies, and cardiac and limb defects, although di-agnosis requires the presence of only three [Czeizel andLudanyi, 1985; McMullen et al., 1996]. Phenotypicallydistinct syndromic and non-syndromic forms occur,e.g., VACTERL-hydrocephalus syndrome [Sujanskyand Leonard, 1983; Lurie and Ferencz, 1997]. Althoughthe etiology of the VACTERL association is unknown, anumber of possible etiological factors have been re-ported including various cytogenetic abnormalities,maternal, diabetes, Fanconi anemia, CCG repeat ex-pansion in the fragile X syndrome, and mitochondrialdisorders [Auchterlonie and White, 1982; Weaver et al.,1986; Giampietro et al., 1996; Damian et al., 1996].Although most patients with the VACTERL associa-tion have had normal chromosomal constitutions, a fewreports have been published of chromosomal abnor-malities in patients with the VACTERL association

*Correspondence to: Dr. Laurence Walsh, Department of Medi-cal and Molecular Genetics, IB130, 975 West Walnut Street, In-dianapolis, IN 46202–5251. E-mail: lewalsh@iupui.edu

Received 7 January 2000; Accepted 24 August 2000Published online 29 December 2000

American Journal of Medical Genetics 98:137–144 (2001)

© 2001 Wiley-Liss, Inc.

[Digilio et al., 1997]. None of these reports, however,has shown a relationship between distal 13q deletionand the VACTERL association, although the coinci-dence of the two has been mentioned [Quan and Smith,1972]. A rarely noted finding in the VACTERL associa-tion is penoscrotal transposition [Fryns et al., 1980;Schneider and Harms, 1987; Hall, 1992; Gershoni-Baruch and Zekaria, 1996]. The latter malformationalso has been reported previously in five children withdistal 13q deletions [MacKenzie et al., 1994; Parida etal., 1995; Bartsch et al., 1996; Boduroglu et al., 1998].

In this report, we describe an infant with the distal13q deletion syndrome, the complete VACTERL phe-notype, and penoscrotal transposition. We concludethat penoscrotal transposition as a genital abnormalitymay be part of the distal 13q deletion phenotype andthat VACTERL association, when associated with thisdeletion, probably represents a syndrome, and not anassociation. In this full expression of the VACTERLassociation phenotype, the cluster of abnormalitiesmay also represent an example of a polytopic field de-fect [Martınez-Frıas et al., 1998].

CASE REPORTThe propositus, E.H. (FN89766), was a 1,860-g, 39-

week-gestational age infant born by spontaneous vagi-nal delivery to a 20-year-old gravida 2, para 0 to 1, Ab1 African-American woman. The mother had prenatalcare from 8 weeks of gestation onward, denied illnessduring the pregnancy, and did not use tobacco, alcohol,or unusual medications. Ultrasound examinations at24 weeks of gestation did not visualize fetal thumbs norallow fetal gender assignment. The child had Apgarscores of 5 and 7 at 1 and 5 min, respectively. Mechani-cal ventilation was required initially but was weanedrapidly to continuous positive airway pressure withsupplemental oxygen. After discovery of a tracheo-esophageal fistula, the child was transferred to RileyHospital for Children for further management. The sig-nificant physical findings of the propositus follow: pre-natal growth retardation and microcephaly (all below−3 SD); flattened face with short palpebral fissures;flat, broad nasal root and bridge with hypoplastic alaenasi; short philtrum; down-turned mouth and narrow,high-arched palate; low-set apparently posteriorly ro-tated and cupped ears; webbed neck; small testes pal-pable in inguinal canal with complete penoscrotaltranspostion and perineal hypospadias; imperforateanus; absent thumbs with hypoplastic radii, cutaneoustoe 4–5 syndactyly; and hypotonia with diminishedspontaneous movements. Radiographs revealed incom-plete vertebral arch of T-3 and T-5, multiple notchedthoracic vertebrae, anterior placement of sixth ribs bi-laterally, fused left 10–11th ribs, and absent first rayswith hypoplastic radii. Echocardiogram showed a ven-tricular septal defect and patent ductus arteriosus.Barium studies confirmed tracheoesophageal fistulaand esophageal atresia as well as an anal fistula. Ab-dominal ultrasound and cystogram demonstrated nor-mal kidneys, but a simple urethra and the urachuscould not be identified. Head ultrasound revealed anormal-appearing brain. Significant findings can beseen in Figures 1 through 4.

The child was assigned male sex and underwentrepair of the tracheoesophageal fistula. He succumb-ed subsequently to recurrent pulmonary and sys-temic infections at age 2 months. Chromosomal analy-sis on the patient showed partial 13q deletion46,XY,del(13)(q31.1) (Fig. 5). Autopsy was refused. Pa-rental chromosomal analyses were normal.

Review of the family history revealed neither consan-guinity nor a family history of congenital anomalies.The mother electively had terminated her previouspregnancy.

DISCUSSION

The patient presented in this paper had numerousabnormalities including prenatal growth retardation,microcephaly, unusual facial features, vertebral de-fects, tracheoesophageal fistula, imperforate anus,cardiac septal defect, penoscrotal transposition, hypo-plastic radii, and absent thumbs. The patient alsowas found to have a partial deletion of the distal seg-ment of 13q.

A literature review indicated that Allderdice et al.initially characterized the 13q deletion syndrome in1969. These authors described 23 patients with either46,Dq- or 46,r(D) abnormalities, two of whom were

Fig. 1. Photograph of face of propositus displaying characteristic facialdysmorphisms of 13q deletion syndrome including prominent nasal rootand bridge, hypertelorism, epicanthal folds, and short palpebral fissures.

138 Walsh et al.

shown to have chromosome 13 deletions. Salient clini-cal features included psychomotor retardation, micro-cephaly with trigonocephaly, protruding upper inci-sors, micrognathia, large and malformed ears, broadprominent nasal bridge, ocular hypertelorism, mi-crophthalmos, hypoplastic or absent thumbs, and ano-genital anomalies [Allderdice et al., 1969]. Others havedelineated further the del 13q phenotype [Grace et al.,1971; Niebuhr and Ottosen, 1973; Nichols et al., 1979;Tranebjaerg et al., 1988; Roland et al., 1989; Brown etal., 1993, 1995]. Chromosomal mapping studies have

allowed refinement of the 13q deletion phenotypebased on cytogenetic breakpoints [Brown et al., 1995].Our patient fits this proposed genotype-phenotype cor-relation scheme [Niebuhr and Ottosen, 1973; Brown etal., 1993, 1995]. These studies indicate that deletion ofa 13q32 “critical region” appears to be necessary forexpression of the most severe phenotype. Interstitialdeletions distal to 13q14 that are also proximal to13q32 are associated with mild to moderate mental re-tardation, variable dysmorphic features, and growthretardation [Dean et al., 1991]. Interstitial 13q21 dele-tion has been reported in one family; the affected mem-

Fig. 3. Chest radiograph taken in first week of life demonstrating mul-tiple vertebral and rib anomalies. Fig. 5. Karyotype showing 46,XY,del(13)(q31.1)

Fig. 2. Photograph of patient’s perineum showing complete penoscrotaltransposition. Fig. 4. Cystourethrogram showing absent urachus and smooth feature-

less urethra.

Distal 13q Deletion 139

bers had normal phenotypes [Nielsen et al., 1977]. De-letions distal to 13q32 result usually in severe mentalretardation but without major malformations orgrowth retardation. Bottani et al. [1991] reported aboy with del(13)(q32.3q33.2) who had mental retarda-tion and minor abnormalities but who had no majormalformations.

Distal 13q deletion was noted in one of the patientsincluded in the original characterization of the VATERassociation [Quan and Smith, 1972]. Further connec-tion between 13q deletion and VATER/VACTERL as-sociation has not been reported. This is despite pub-lished cases of distal 13q deletion patients who, whilethey are not described as such, fulfill the criteria for theVACTERL association. Our literature review included142 patients with presumed distal 13q deletions, al-though 47 individuals did not have banded karyotypes[Adams, 1965; Allderdice et al., 1969; Bain and Gauld,1963; Bamforth and Lin, 1997; Bartsch et al., 1996;

Battin et al., 1988; Baud et al., 1999; Benn et al., 1983;Biles et al., 1970; Boduroglu et al., 1998; Bottani et al.,1991; Brondum-Nielsen et al., 1981; Brown et al., 1993;Brown et al., 1995; Carmichael et al., 1977; Carnevaleet al., 1984; Coco and Penchaszadeh, 1982; Coffin andWilson, 1970; Cossu et al., 1979; Couturier et al., 1985;Cuschieri et al., 1977; Dean et al., 1991; Emanuel et al.,1979; Faed et al., 1969; Fried et al., 1975; Fryns et al.,1974, 1980; Gerald et al., 1967; Gershoni-Baruch andZekaria, 1996; Goldsmith et al., 1993; Grace et al.,1971; Grindel et al., 1999; Grosse and Schwanitz, 1973;Guala et al., 1997; Hollowell et al., 1971; Hoo et al.,1974; Ikeuchi et al., 1974; Juberg et al., 1969; Jubergand Mowrey, 1984; Kiss and Osztovics, 1989; Kisten-macher and Punnett, 1970; Kondo et al., 1985;Kučerova et al., 1975; Lam et al., 1998; Lamontet al., 1989; Laurent et al., 1967; Lehrke et al., 1971;LeJeune et al., 1968; Luquet et al., 1999; MacIntyre etal., 1964; Magenis et al., 1976; Martin et al., 1982; Mc-

Fig. 6. Patients reported in the literature with 13q deletion and one or more features of the VACTERL association. aSerena-Lungarotti et al., 1979;Lamont et al., 1989; Coffin and Wilson, 1970; Teplitz et al., 1967; Battin et al., 1988; bAllderdice et al., 1969(2); Tolksdorf et al., 1969; Bartsch et al., 1996;cBrown et al., 1993, 1995; Hollowell et al., 1971; Towfighi et al., 1987; Varela and Sternberg, 1969; dBrown et al., 1993; Hoo et al., 1974; Lamont et al.,1989; MacIntyre et al., 1964; eBrown et al., 1995; Fryns et al., 1980; Allderdice et al., 1969; Pai et al., 1979; Nichols et al., 1979; Weisswichert andStogmann, 1979; Fryns, 1974; Grindel et al., 1999; fGrace et al., 1971; gYunis et al., 1981; hTefler et al., 1980; Tranebjaerg et al., 1988; iSerena-Lungarottiet al., 1979; Schmid et al., 1975; Bartsch et al., 1996; jAllderdice et al., 1969; Magenis et al., 1976; Vittu et al., 1989; Benn et al., 1983; kGershoni-Baruchand Zekaria, 1996; Martin et al., 1982; Borduroglu et al., 1998; lAdams, 1965; Carnevale et al., 1984; Faed et al., 1969; Carmichael et al., 1977; mBennet al., 1983; nBrown et al., 1995; oGrindel et al., 1999; pJuberg et al., 1969; Grindel et al., 1999; qLaurent et al., 1967, Sparkes et al., 1967; rBrown et al.,1995; sMartin et al., 1982; Bamforth and Lin, 1997; tWilroy et al., 1976; Bain and Gauld, 1963; Orbeli et al., 1971; Nishikawa et al., 1985; Opitz et al.,1969; uBenn et al., 1983(2); Biles et al., 1970; Goldsmith et al., 1993; vcurrent patient; wGuala et al., 1997.

140 Walsh et al.

Candless and Walker, 1976; Mikkelsen and Niebuhr,1969; Nichols et al., 1979; Niebuhr and Ottosen, 1973;Nielsen et al., 1977; Nishikawa et al., 1985; Noel et al.,1976; Opitz et al., 1969; Orbeli et al., 1971; Pai et al.,1979; Reisman et al., 1965; Rivera et al., 1985; Rolandet al., 1989; Salamanca et al., 1972; Schmid et al., 1975;Serena-Lungarotti et al., 1979, 1980; Sparks et al.,1967; Stathacopoulos et al., 1987; Stoll and Alembik,1998; Telfer et al., 1980; Teplitz et al., 1967; Tolksdorfet al., 1969; Toomey et al., 1978; Towfighi et al., 1987;Tranebjaerg et al., 1988; Turleau et al., 1978; Varelaand Sternberg, 1969; Vittu et al., 1989; Wang et al.,1962; Weisswichert and Stogmann, 1979; Wilroy et al.,1976; Yunis et al., 1981]. Of these 142 patients, 28patients had one major manifestation of VACTERL as-sociation; 23 had two manifestations, 12 had threemanifestations, and 5 had four signs (Fig. 6). Our pa-tient has all of the six VACTERL association charac-teristics, and is the only distal 13q deletion patientreported with tracheoesophageal fistula. This patient’sfindings are especially intriguing in light of the argu-ment of Weyerts et al. [1992] that VACTERL associa-tion may be subdivided into rostral and caudal pheno-types with tracheoesophageal abnormalities, upperlimb, and cardiac defects defining the former whereasgenital abnormalities are more common in the latter.

Penoscrotal transposition has been reported previ-ously in five individuals with distal 13q deletions [Bar-tsch et al., 1996; Boduroglu et al., 1998; Fryns et al.,1980; Gershoni-Baruch and Zekaria, 1996]. Our pa-tient also had penoscrotal transposition. Therefore,penoscrotal transposition should be included in thespectrum of the 13q deletion phenotype [Apold et al.,1976; Bartsch et al., 1996; Parida et al., 1995]. As notedby Boduroglu et al. [1998], distal 13q deletions reportedin association with penoscrotal transposition overlapin the region 13(q32.2q34). This suggests an importantrole for this region in genital development. Moreinteresting is the fact that our patient had the fullVACTERL association phenotype in association withpenoscrotal transposition. This cluster of findings over-laps the two groups delineated by Weyerts et al. [1992].If genital abnormalities are to be considered as a fea-ture of VACTERL association, this case is also consis-tent with Lurie’s contention that cases at the extremeof a spectrum disorder should display core features ofthat disorder [Lurie, 2000].

The findings in our patient, and those in the litera-ture, suggest that deletion of the 13q critical region(13q32) allows expression of a severe phenotype but theexpression may be modified by the allelic or othergenes. Imprinting has not been demonstrated for 13q.Furthermore, since the VACTERL association and theurorectal septum malformation sequence may be re-lated to a defect in mesoderm formation, the distal 13qregion may contain a gene(s) that influence mesoder-mal formation and migration [Quan and Smith, 1972;Khoury et al., 1983; Wheeler et al., 1997]. A defect inpolarization during embryogenesis caused by an as yetunrecognized homeobox gene cluster is also a possibleexplanation, and would predict defects related to de-rangements in both mesoderm and neural crest deriva-tives [Kostic and Capecchi, 1994]. On the other hand, a

contiguous gene deletion phenomenon has not been ex-cluded, and might explain the VACTERL/13q deletionphenotypic spectrum. Any of these mechanisms wouldbe consistent with the concept of VACTERL associationas manifestation of a polytopic field defect [Martınez-Frıas et al., 1998]. Such a conceptual framework mayprovide a biological link between presumed cause (thecytogenetic abnormality) and clinical features. As thegenes resident within the 13q32 critical region are elu-cidated, such a framework may allow discovery of thedevelopmental biology of this pattern of abnormalities.At the least, we suggest that when all of the cardinalfeatures of VACTERL association are present, theremay be an increased risk of a deletion including the13q32 region, and that the VACTERL association inthese situations represents a syndrome rather than anassociation.

Recently, Brown et al. [1998] have reported a gene at13q32 that is critical for normal development of thebrain and possibly of extra-CNS structures. Mutationsin this gene (ZIC2) are associated with holoprosen-cephaly with relatively mild facial features. Besidesthe patients reported by Brown et al. [1998], there arean additional eight patients previously reported withdistal 13q deletions and holoprosencephaly and 25patients with 13q deletions who have other CNS mal-formations (Table I). This suggests that the otherreported CNS malformations may be due to severaldifferent mechanisms. These may include milder vari-ants of ZIC2-associated holoprosencephaly, effects ofother genes, or epigenetic phenomena. All of these mal-formations can occur in the VACTERL association;occurrence of specific brain malformations such as ho-loprosencephaly, aqueductal stenosis, possibly XK-aprosencephaly, and callosal agenesis combined withcore features of the VACTERL association may suggesta syndromic condition rather than a simple associationof developmental abnormalities [Guala et al., 1997;Walsh et al., unpublished data]. The occurrence of bothCNS and extra-CNS malformations in deletions of dis-tal chromosome 13q32 suggests that this region con-tains a gene(s) that are crucial for normal developmentof both the brain and the body.

TABLE I. Distal 13q Deletion Cases Reported with CNSMalformations (Excluding Holoprosencephaly)

MalformationNumber of

cases

Anencephaly/hydranencephaly 5a–e

Callosal agenesis 7f–h,j,t

Neural tube defects 41–j,k

Ventriculomegaly 5l–n,u

Dandy-Walker malformation 1p

Atelencephaly 1q

Frontal gyral malformations 1f

Absent septum pellucidum 1s

aBenn et al., 1983; bBrown et al., 1993; cGershoni-Baruch and Zekaria,1996; dLam et al., 1998; eSchmid et al., 1975; fBaud et al., 1999; gTelfer etal., 1980; hWilroy et al., 1976; iBamforth and Lin, 1997; jMartin et al., 1982;kAllderdice et al., 1969; lSerena-Lungarotti et al., 1979; mRivera et al.,1985; nBattin et al., 1988; oVittu et al., 1989; pCarnevale et al., 1984;qTowfighi et al., 1987; rYunis et al., 1981; sJuberg et al., 1969; tGuala et al.,1997; uBoduroglu et al., 1998.

Distal 13q Deletion 141

ACKNOWLEDGMENTS

We thank Suzanne Merrell for assistance with thehalftone figure, Catherine Muesing for preparation ofthe karyotype, and Mona Harbaugh for her editorialassistance.

REFERENCESAdams MS. 1965. Palm-prints and a ring-D chromosome. Lancet 2:494–

495.

Allderdice PW, Davis JG, Miller OJ, Kliner HP, Warburton D, Miller DA,Allen FH, Abrams CAL, McGilvray E. 1969. The 13q- deletion syn-drome. Am J Hum Genet 21:499–512.

Apold J, Dahl E, Aarskog D. 1976. The VATER association: malformationsof the male external genitalia. Acta Pediatr Scand 65:150–152.

Auchterlonie IA, White MP. 1982. Recurrence of the VATER associationwithin a sibship. Clin Genet 21:122–124.

Bain AD, Gauld IK. 1963. Multiple congenital abnormalities associatedwith ring chromosome. Lancet 2:304–305.

Bamforth JS, Lin CC. 1997. DK phocomelia phenotype (von Voss-Cherstvoy syndrome) caused by somatic mosaicism for del(13q). Am JMed Genet 73:408–411.

Battin J, Seville F, Mullon MH, Mateille N. 1988. Del (13)(q31.1-qter) denovo chez une fille: effect de dosage genique pour les facteurs VII et Xde la coagulation. J Genet Hum 36:307–314.

Bartsch O, Kuhnle U, Wu LL, Schwinger E, Hinkel GK. 1996. Evidence fora critical region for penoscrotal inversion, hypospadias, and imperfo-rate anus within chromosomal region 13q32.2q34. Am J Med Genet65:218–221.

Baud O, Cormier-Daire V, Lyonnet S, Desjardins L, Turleau C, Doz F.1999. Dysmorphic phenotype and neurological impairment in 22 reti-noblastoma patients with constitutional cytogenetic 13q deletion. ClinGenet 55:478–482.

Benn PA, Warburton D, Byrne JM, Rudelli R, Shonhaut A, Yeboa K, Moo-tabar H, Hsu LYF. 1983. A fetus with a chromosome 13 ring and pla-centa with a chromosome 13 rod/ring mosaicism. Prenat Diagn 3:297–302.

Biles AR, Luers T, Sperling K. 1970. D1 ring chromosome in newborn withpeculiar face, polydactyly, imperforate anus, arrhinencephaly andother abnormalities. J Med Genet 7:399–401.

Boduroglu K, Alikasifoglu M, Tuncbilek E, Uludogan S. 1998. Ring chro-mosome 13 in an infant with multiple congenital anomalies and peno-scrotal transpostion. Clin Dysmorph 7:299–301.

Bottani A, Xie Y, Binkert F, Schinzel A. 1991. A case report of Hir-schsprung disease with a chromosome 13 microdeletion; del(13)(q32.3q33.2): potential mapping of one disease locus. Hum Genet87:748–750.

Brondum-Nielsen K, Bjorner H, Mikkelsen M. 1981. Clinical and psycho-logical follow-up of two children with the 13q- karyotype. Clin Genet20:380A.

Brown S, Gersen S, Anyane-Yeboa K, Warburton D. 1993. Preliminarydefinition of a “critical region” of chromosome 13 in q32: report of 14cases with 13q deletions and review of the literature. Am J Med Genet45:52–59.

Brown S, Russo J, Chitayat D, Warburton D. 1995. The 13q- syndrome: themolecular definition of a critical deletion region in band 13q32. Am JHum Genet 57:859–866.

Brown SA, Warburton D, Brown LY, Yu CY, Roeder ER, Stengel-Rutkowski S, Hennekam RC, Muenke M. 1998. Holoprosencephaly dueto mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet20:180–183.

Carmichael A, Addy DP, Shortland-Webb WR, Cameron H, Davies ICS.1977. 13q- syndrome family study. Arch Dis Child 52:972–974.

Carnevale A, Frias S, Alcantar R. 1984. Interstitial deletion of long arm ofchromosome 13. Ann Genet 27:49–52.

Coco R, Penchaszadeh VB. 1982. Cytogenetic findings in 200 children withmental retardation and multiple congenital anomalies of unknowncause. Am J Med Genet 12:155–173.

Coffin GS, Wilson MG. 1970. Ring chromosome D13. Am J Dis Child 119:370–373.

Cossu P, Diana G, Mameli M, Cardia S, Milia A, Floris G, Cao A. 1979. Acase of D13 ring chromosome. Hum Genet 46:111–114.

Couturier J, Morichon-Delvallez N, Dutrillaux B. 1985. Deletion of band13q21 is compatible with normal phenotype. Hum Genet 70:87–91.

Cuschieri A, Agius PV, Scheres JMJC. 1977. Partial deletion of the longarm of chromosome no. 13. Hum Genet 36:341–344.

Czeizel A, Ludanyi I. 1985. An aetiological study of the VACTERL-association. Eur J Pediatr 144:331–337.

Damian MS, Seibel P, Schachenmayr W, Reichmann, Dorndorf W. 1996.VACTERL with the mitochondrial np3243 point mutation. Am J MedGenet 62:398–403.

Dean JCS, Simpson S, Couzin DA, Stephen GS. 1991. Interstitial deletionof chromosome 13: prognosis and adult phenotype. J Med Genet 25:533–535.

Digilio MC, Giannotti A, Marino B, Guadagni AM, Orzalesi M, DallapiccolaB. 1997. Radial aplasia and chromosome 22q11 deletion. J Med Genet34:942–944.

Emanuel B, Zakai E, Moreau L, Coates P, Orrechio E. 1979. Interstitialdeletion 13q33 resulting from maternal insertional translocation. ClinGenet 16:340–346.

Faed M, Stewart A, Keay AJ. 1969. Chromosomal abnormalities in twocases with bilateral radial element defects. J Med Genet 6:342–346.

Fried K, Rosenblatt M, Mundel G, Krikler R. 1975. Ring chromosome 13syndrome. Clin Genet 7:203–208.

Fryns JP, Deroover J, Van Den Berghe H, Cassiman JJ, Goffaux P, LebasE. 1974. Malformative syndrome with ring chromosome 13. Humange-netik 24:235–240.

Fryns JP, Peeters R, Petit P, Van den Berghe H. 1980. New chromosomalsyndromes: III. The 13q deletion syndrome. Acta Pediatr Belg 33:261–264.

Gerald PS, Warner S, Singer JD, Corcoran PA, Umansky I. 1967. A ringchromosome and anomalous inheritance of haptoglobin type. J Pediatr70:172–179.

Gershoni-Baruch R, Zekaria D. 1996. Deletion (13)(q22) with multiple con-genital anomalies, hydranencephaly, and penoscrotal transposition.Clin Dysmorphol 5:289–294.

Giampietro PF, Haas BR, Lipper E, Gutman A, Zellers NJ, LaTrenta GS,Brooks SS, Matalon R, Kaul R, Ding X-H, Brown WT. 1996. Fragile Xsyndrome in two siblings with major congenital malformations. Am JMed Genet 63:396–400.

Goldsmith CL, Tawagi GF, Carpenter BF, Speevak MD, Hunter AGW.1993. Mosaic r(13) in an infant with aprosencephaly. Am J Med Genet47:531–533.

Grace E, Drennan J, Colver D, Gordon RR. 1971. The 13q- deletion syn-drome. J Med Genet 8:351–357.

Grindel SI, Sandlin C, Wood VE. 1999. Hand involvement in 13q deletionsyndrome. J Pediatr Orthoped 19:620–623.

Grosse KP, Schwanitz G. 1973. Ein neues syndrom durch chromosenstuck-verlust (13q-) Kasuistik und Zusammenstellung der symptomatik. KlinPadiat 185:468–473.

Guala A, Dellavecchia C, Mannarino S, Rognone F, Giglio S, Minelli A,Danesino C. 1997. Ring chromosome 13 with loss of the regionD13S317-D13S285: phenotypic overlap with the XK syndrome. Am JMed Genet 72:319–323.

Hall BD. 1992. Penoscrotal transposition and the VATER association. ClinRes 40:56A.

Hollowell JG, Littlefield LG, Dharmkrong-at A, Folger GM, Heath CW,Bloom GE. 1971. Ring 13 chromosome with normal haptoglobin inher-itance. J Med Genet 8:222–226.

Hoo JJ, Obermann U, Cramer H. 1974. The behaviour of ring chromosome13. Humangenetik 24:161–171.

Ikeuchi T, Sonta S, Sasaki M, Hujita M, Tsunematsu K. 1974. Chromo-some banding patterns in an infant with 13q- syndrome. Humangene-tik 21:309–314.

Juberg RC, Adams MS, Venema WJ, Hart MG. 1969. Multiple congenitalanomalies associated with a ring-D chromosome. J Med Genet 6:314–321.

Juberg RC, Mowrey PN. 1984. Interstitial del 13q associated with blind-ness and mental retardation. Am J Med Genet 17:609–613.

Khoury MJ, Cordero JF, Greenberg R, James LM, Erickson JD. 1983. Apopulation study of the VACTERL association: evidence for its etiologicheterogeneity. Pediatrics 71:815–820.

Kiss P, Osztovics M. 1989. Association of 13q deletion and Hirschsprung’sdisease. J Med Genet 26:793–796.

142 Walsh et al.

Kistenmacher ML, Punnett HH. 1970. Comparative behavior of ring chro-mosomes. Am J Hum Genet 22:304–318.

Kondo I, Shin K, Honmura S, Naskajima H, Yamamura E, Satoh H, Te-rauchi M, Usuki Y, Takita H, Hamguchi H. 1985. A case report of apatient with retinoblastoma and chromosome 13q deletion: assignmentof a new gene (gene for LCP1): on human chromosome 13. Hum Genet71:263–266.

Kostic D, Capecchi MR. 1994. Targeted disruptions of the murine Hoxa-6genes result in homeotic transformations of components of the verte-bral column. Mech Dev 46:231–247.

Kučerova M, Polıvkova Z, Pokorna M. 1975. Deletion of long armsof chromosome 13. Humangenetik 27:255–257.

Lam YH, Tang MH, Ng LK. 1998. 13q- in a fetus with ultrasonographicdiagnosis of exencephaly in the first trimester. Prenat Diagn 18:634–635.

Lamont MA, Fitchett M, Dennis NR. 1989. Interstitial deletion of distal13q associated with Hirschsprung’s disease. J Med Genet 26:100–104.

Laurent C, Cotton JB, Nivelon A, Freycon MT. 1967. Deletion partielle dubras long d’un chromosome du groupe D (13–15): Dq-. Ann Genet 10:25–31.

Lehrke R, Thelen T, Lehrke R. 1971. Syndrome associated with group Dchromosome deletions. Lancet 2:98–99.

LeJeune J, Lafourcade J, Berger R, Cruveiller J, Rethore MO, DutrillauxB, Abonyi D, Jerome H. 1968. Le phenotype (Dr). Etude de trois cas dechromosomes D en anneau. Ann Genet 11:79.

Luquet I, Favre B, Nadal N, Madinier N, Khau Van Kien P, Huet F,Nivelon-Chevallier A, Mugneret F. 1999. Two cases of terminal dele-tion of chromosome 13: clinical features, conventional and molecularcytogenetic analysis. Ann Genet 42:33–39.

Lurie IW. 2000. Association of amelia and anal atresia is separate fromVACTERL association. Clin Dysmorph 9:71.

Lurie IW, Ferencz C. 1997. VACTERL-hydrocephaly, DK-phocomelia, andcerebro-cardio-radio-reno-rectal community. Am J Med Genet 70:144–149.

MacIntyre MN, Hempel JM, Staples WI, Stenchever MA. 1964. A ringchromosome in a human male with congenital anomalies. Anat Rec148:386.

MacKenzie J, Chitayat D, McLorie G, Balfe JW, Pandit PB, Blecher SR.1994. Penoscrotal transposition: a case report and review. Am J MedGenet 49:103–107.

Magenis RE, Wyandt HE, Overton KM, McFarlane J. 1976. Parental originof a ring 13 chromosome in a female with multiple anomalies. HumGenet 33:181–186.

Martin NJ, Harvey PJ, Pearn JH. 1982. The ring chromosome 13 syn-drome. Hum Genet 61:18–23.

Martınez-Frıas M-L, Frıas JL, Opitz JM. 1998. Errors of morphogenesisand developmental field theory. Am J Med Genet 76:291–296.

McCandless A, Walker S. 1976. D13 ring chromosome syndrome. Arch DisChild 51:449–453.

McMullen KP, Karnes PS, Moir CR, Michels VV. 1996. Familial recurrenceof tracheoesophageal fistula and associated malformations. Am J MedGenet 63:525–528.

Mikkelsen M, Niebuhr E. 1969. A ring chromosome (46,XY,13r) occurringin a family with a D-D translocation, 13-, 14-, t(13q,14q). Ann Genet12:51–56.

Nichols WW, Miller RC, Hoffman E, Albert D, Weichselbaum RR, Nove J,Little JB. 1979. Interstitial deletion of chromosome 13 and associatedcongenital anomalies. Hum Genet 52:169–173.

Niebuhr E, Ottosen J. 1973. Ring chromosome D13 associated with mul-tiple congenital malformations. Ann Genet 16:157–166.

Nielsen U, Homma A, Christiansen F, Rasmussen P, Saldana-Garcia P.1977. Deletion long arm 13. Hum Genet 37:339–345.

Nishikawa A, Mitimori T, Matsura A, Imore A, Mori H, Takahashi M.1985. The 13q- syndrome with extensive intestinal atresia. Acta P{di-atr Scand 74:305–308.

Noel B, Quack B, Rethore MO. 1976. Partial deletions and trisomies ofchromosome 13; mapping of bands associated with particular malfor-mations. Clin Genet 9:593–602.

Opitz JM, Slumgaard R, Edwards RH, Inhorn SL, Muller K, de Venecia G.1969. Report of a patient with a presumed Dq- syndrome. Birth DefectsOrig Artic Ser 5:93–99.

Orbeli DJ, Lurie IW, Goroshenko Jr L. 1971. The syndrome associated withpartial D-monosomy. Humangenetik 13:296–308.

Pai GS, Thomas GH, Leonard CO, Ward JC, Valle DL, Pyeritz RE. 1979.Syndromes due to chromosomal abnormalities: partial trisomy 22, in-terstitial deletion of the long arm of 13, and trisomy 8. Johns HopkinsMed J 145:162–169.

Parida SK, Hall BD, Barton L, Fujimoto A. 1995. Penoscrotal transpositionand associated anomalies: report of five new cases and review of theliterature. Am J Med Genet 59:68–75.

Quan L, Smith DW. 1972. The VATER association: vertebral defects, analatresia, tracheoesophageal fistula with esophageal atresia, radial dys-plasia. Birth Defects Orig Artic Ser 8:75–78.

Reisman LE, Darnell A, Murphy JW. 1965. Abnormalities with ring chro-mosomes. Lancet 2:445.

Rivera H, Gonzalez-Flores SA, Rivas F, Sanchez-Corona J, Moller M,Cantu JM. 1985. Monosomy 13q32.3-qter: report of two cases. J MedGenet 22:142–145.

Roland B, Lowry RB, Robertson AS, Cox DM. 1989. An interstitial deletionof the long arm of chromosome 13. Clin Genet 35:276–281.

Salamanca F, Buentello L, Armendares S. 1972. Ring D1 chromosome withremarkable morphological variation in a boy with mental retardation.Ann Genet 15:183–186.

Schmid W, Muhlethaler JP, Briner J, Knechtli H. 1975. Ring chromosome13 in a polymalformed anencephalic. Humangenetik 27:63–66.

Schneider A, Harms D. 1987. Transposition of the external genitalia asso-ciated with the VACTERL association. Eur J Pediatr 146:95.

Serena-Lungarotti M, Calabro A, Mariotti G, Mastroiacovo PP, Proven-zano S, Dallapiccola B. 1979. Interstitial deletion 13q syndromes: areport on two unrelated patients. Hum Genet 52:269–274.

Serena-Lungarotti M, Mariotti G, Quarta C, Delogu A, Fiore C. 1980. Chro-mosome 13 deletion syndrome: report of a new case and discussion ofthe different etiologic patterns of retinoblastoma. Ophthalmologica181:245–250.

Sparks RS, Carrel RE, Wright SW. 1967. Absent thumbs with a ring D2chromosome: a new deletion syndrome. Am J Hum Genet 19:644–659.

Stathacopoulos RA, Bateman JB, Sparkes RS, Hepler RS. 1987. The Riegersyndrome and a chromosome13 deletion. J Pediatr Ophthal Strabism24:198–203.

Stoll C, Alembik Y. 1998. A patient with 13q- syndrome with mild mentalretardation and with growth retardation. Ann Genet 41:209–212.

Sujansky E, Leonard B. 1983. VACTERL association with hydrocephalus:a new recessive syndrome? Am J Hum Genet 35:119A.

Telfer MA, Clark CE, Casey PA, Cowell HR, Stroud HH. 1980. Long armdeletion of chromosome 13 with exclusion of esterase D from13q32→13qter. Clin Genet 17:428–432.

Teplitz RL, Miller D, Hansson KS, Rundall TS. 1967. A human ring Dchromosome associated with multiple congenital abnormalities. J Pe-diatr 70:936–941.

Tolksdorf M, Wiedmann H-R, Goll U. 1969. Ring D1 chromosome and mul-tiple malformations. Lancet 2:1009.

Toomey KE, Mohandas T, Sparkes RS, Kaback MM, Rimoin DL. 1978.Segregation of an insertional chromosome rearrangement in 3 genera-tions. J Med Genet 15:382–387.

Towfighi J, Ladda RL, Sharkey FE. 1987. Purkinje cell inclusions andatelencephaly in 13q- chromosomal syndrome. Arch Pathol Lab Med111:146–150.

Tranebjaerg L, Brøndum-Nielsen K, Tommerup N, Warburg M, MikkelsenM. 1988. Interstitial deletion 13q: further delineation of the syndromeby clinical and high resolution chromosome analysis of five patients.Am J Med Genet 29:739–753.

Turleau C, Seger J, Grouchy J, de Dore F, Job JC. 1978. Del (13)(q33).Exclusion de esterase D (ESD) de 13q33 et Q (sic) 34. Ann Genet 21:189–192.

Varela MA, Sternberg WH. 1969. Ring chromosome in two infants withcongenital malformations. J Med Genet 6:334–341.

Vittu G, Croquette MF, Donney A, Duminy FR, Couturier J, Cousin J.1989. Lethal polymalformative syndrome with 13q deletion secondaryto a maternal X; 13 translocation. J Genet Hum 37:141–147.

Distal 13q Deletion 143

Wang H-C, Melnyk J, McDonald LT, Uchida IA, Carr DH, Goldberg B.1962. Ring chromosomes in human beings. Nature 195:733–734.

Weaver DD, Mapstone CL, Yu P. 1986. The VATER association. Am J DisChild 140:225–229.

Weisswichert P, Stogmann W. 1979. Interstitial deletion of a chromosomeno. 13: a new syndrome? Klin Padiatr 191:318–324.

Weyerts LK, Jones MC, Mendoza A, Jones KL. 1992. VACTERR associa-tion and genital abnormalities. Proc Greenwood Genet Center 11:83–84.

Wheeler PG, Weaver DD, Obeime MO, Vance GH, Bull MJ, Escobar LF.1997. Urorectal septum malformation sequence: report of thirteen ad-ditional cases and review of the literature. Am J Med Genet 73:456–462.

Wilroy Jr RS, Summitt RL, Martens P, Gooch WM, Hood C, Wiser W. 1976.Partial monosomy and partial trisomy for different segments of chro-mosome 13 in several individuals of the same family. Birth DefectsOrig Artic Ser 12:161–167.

Yunis E, Zuniga R, Ramirez E. 1981. Retinoblastoma, gross internal mal-formations, and deletion 13q14-q31. Hum Genet 56:283–286.

144 Walsh et al.