Table V.

Specific conditions in which mutations have been identified that may cause features that overlap VACTERL association. The degree of overlap with “classic” VACTERL association (if such a term might be used) is highly variable, and certain conditions may frequently be readily recognizable. VACTERL-type features, either isolated or in combination have additionally been reported in a number of other conditions, and the differential diagnosis may extend further depending on specific characteristics present.

Condition	Associated gene(s)	Features in common with VACTERL association (in individuals with proven mutations)	Features not typically observed in conjunction with VACTERL association	Reference(s)
Alagille syndrome	JAG1, NOTCH2 (heterozygous)	Vertebral anomalies, cardiac anomalies, renal anomalies	Characteristic dysmorphic facies, hepatic anomalies including bile duct paucity and cholestasis, ophthalmologic anomalies (e.g., posterior embryotoxon), neurological anomalies	Li et al., 1997; Oda et al., 1997; Krantz et al., 1999; McDaniell et al., 2006; Kamath et al., 2012
Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome; Fuhrmann syndrome	WNT7A (homozygous/compound heterozygous)	Vertebral anomalies, genitourinary anomalies, limb anomalies	Pelvic and limb anomalies tend to be more severe than typically described in VACTERL association, and primarily affect the lower limbs	Woods et al., 2006; Lonardo et al., 2007; Kantaputra et al., 2010; Eyaid et al., 2011
Andersen syndrome	KCNJ2 (heterozygous)	Skeletal anomalies (including vertebral and limb anomalies), cardiovascular anomalies, renal anomalies	Characteristic dysmorphic facies, severe arrhythmias, hypokalemic periodic paralysis	Andelfinger et al., 2002; Tristani-Firouzi et al., 2002; Davies et al., 2005
Anopthhalmia-esophageal atresia-genital syndrome	SOX2 (heterozygous)	Tracheo-esophageal fistula, limb anomalies, genitourinary malformations	Specific ocular anomalies (anophthalmia/microophthalmia), neurocognitive impairment	Williamson et al., 2006
Baller-Gerold syndrome	RECQL4 (heterozygous)	Limb anomalies (radial ray), anorectal anomalies in some individuals	Craniosynostosis, skin anomalies	Van Meldergem et al., 2006
Beals syndrome	FBN2 (heterozygous)	Vertebral anomalies, cardiac anomalies, esophageal atresia, single umbilical artery	Contractures, arachnodactly, other GI atresia,	Wang et al., 1996
Cat-eye syndrome	Tetrasomy 22q11.1q11. 21 (typically supernumerary)	Anorectal malformations cardiac malformations, renal anomalies, genitourinary anomalies	Eye anomalies (e.g., coloboma, microphthalmia), ear anomalies, clefting	Rosias et al., 2001; Knijnenburg et al., 2012
Caudal regression syndrome	VANGL1 (heterozygous)	Vertebral malformations, anorectal malformations	Classic (including severe) neural tube defects	Kibar et al., 2007
Cenani-Lenz syndactyly syndrome	LRP4 (homozygous/compound heterozygous)	Renal anomalies, limb anomalies	Characteristic dysmorphic facies, limb malformations including syndactyly	Li et al., 2010
CHARGE syndrome	CHD7 (heterozygous)	Cardiac malformations, genitourinary anomalies; may also include TEF	Colobomata, choanal atresia, neurocognitive and growth impairment, ear anomalies, cranial nerve dysfunction, characteristic facial features	Vissers et al., 2004; Zentner et al., 2010
Ciliopathies: Bardet-Biedl syndrome; McKusick-Kaufman syndrome; Meckel-Gruber syndrome	Multiple genes, including MKKS (homozygous/compound heterozygous, though more complex models of inheritance have been described)	Cardiac malformations, renal anomalies, genitourinary malformations	Retinitis pigmentosa, obesity, neurocognitive impairment, characteristic polydactyly as part of limb malformations	Kaufman et al., 1972; Slavotinek and Biesecker, 2000; Smith et al., 2006; Deveault et al., 2011
Cornelia de Lange syndrome	NIPBL (heterozygou s); SMC1A (X-linked); SMC3 (heterozygou s) (mutations in the latter 2 genes may be less likely to be associated with VACTERL- like features)	Renal anomalies, limb anomalies	Characteristic facial appearance; characteristic limb anomalies	Krantz et al., 2004; Tonkin et al., 2004; Selicorni et al., 2005; Deardorff et al., 2007; Pié et al., 2010
Currarino syndrome	MNX1 (heterozygous)		Presacral mass (e.g., teratoma, lipoma), anterior meningocele	Ross et al., 1998; Hagan et al., 2000; Urioste et al., 2004; Wang et al., 2006
Diamond-Blackfan anemia	Multiple Ribosomal protein genes: RPL5, RPS7, RPS10, RPS11, RPS17, RPS19, RPS24, RPS 26, RPL35A (heterozygous)	Cardiac malformations, renal anomalies, limb anomalies, genitourinary anomalies	Dysmorphic facial features (including clefts), Hematologic anomalies, oncologic complications	Doherty et al., 2010; Vlachos and Muir, 2010
Diarrhea 3, secretory sodium, congenital, syndromic	SPINT2 (heterozygous)	Anal atresia, renal anomalies, limb anomalies	Congenital sodium diarrhea, ocular anomalies (including corneal erosions), choanal atresia	Heinz-Erian 2009
22q11.2 deletion syndrome (also known by other names, such as DiGeorge syndrome or velocardiofacial syndrome)	22q11.2 deletion (heterozygous)	Cardiac malformations, renal anomalies, numerous other VACTERL-type anomalies have been additionally described	Characteristic dysmorphic facies, specific palatal anomalies, learning difficulties, immune dysfunction, neuropsychiatric disturbances, hypocalcemia	Kobrynski and Sullivan, 2007
Duane radial ray syndrome; IVIC syndrome; Okihiro syndrome	SALL4 (heterozygous)	Anorectal malformations, renal anomalies, limb anomalies	Ocular anomalies (Duane syndrome), hearing impairment, hematologic anomalies	Al-Baradie et al., 2002; Kohlhase et al., 2002; Kohlhase et al., 2003
Fanconi anemia	Multiple genes (homozygous/compound heterozygous or X-linked); Testing is usually via chromosomal breakage studies	Limb (radial) anomalies, though any VACTERL association-related feature may occur	Skin pigmentation anomalies; hematologic anomalies	Alter et al., 2007; Auerbach 2009
Feingold syndrome	MYCN (heterozygous)	Gastrointestinal atresias, cardiac malformations, renal anomalies	Characteristic dysmorphic facies, syndactyly (toe), brachymesophalangy microcephaly, neurological impairment,	van Bokhoven et al., 2005; Marcelis et al., 2008
FOXF1 mutations	FOXF1 (heterozygous)	Vertebral anomalies, cardiovascular malformations, trachea-esophageal fistula, renal anomalies	Alveolar capillary dysplasia, additional GI anomalies (e.g., pancreatic anomalies)	Stankiewicz et al., 2009
Fraser syndrome	FRAS1 or FREM2 (homozygouss/compound heterozygous)	Cardiopulmonary anomalies, renal anomalies, genitourinary malformations	Crypophthalmos, syndactyly	McGregor 2003; Jadeja 2005; Van Haelst 2008
GDF6 mutations	GDF6 (heterozygous)	Vertebral malformations, renal anomalies, genitourinary anomalies	Ophthalmologic anomalies	Asai-Coakwell et al., 2009
Hand-foot-genital syndrome	HOXA13 (heterozygous)	Genitourinary malformations, limb anomalies	Limb anomalies including dysmorphic first digits	Stern et al., 1970; Mortlock and Innis, 1997; Goodman et al., 2000
Holt-Oram syndrome	TBX5 (heterozygous)	Cardiac malformations, limb anomalies	Cardiac conduction disease (also reported in VACTERL association)	Basson et al., 1997; McDermott et al., 2005
HOXD13 mutations	HOXD13 (heterozygous)	Anal atresia, cardiac malformations, vesicoureteric reflux	Fusion of distal interphalangeal joints	Garcia-Barcelo et al., 2008
Mitochondrial mutations	Mitochondrial DNA mutations (and/or clear biochemical evidence of mitochondrial dysfunction)	Individual or multiple component features	Signs/symptoms consistent with mitochondrial disease	Solomon et al., 2011a
Mullerian aplasia and hyperandrogenism	WNT4 (heterozygous)	Renal anomalies, genitourinary anomalies	Hyperandrogenism	Biason-Lauber et al., 2004
Opitz G/BBB syndrome	MID1 (X-linked); deletion 22q11.2 (heterozygous)	Anorectal malformations, cardiac malformations, tracheo-esophageal fistula, genitourinary malformations (hypospadias)	Hypertelorism, syndactyly	McDonald-McGinn 1995; Quaderi 1997; De Falco 2003
Pallister-Hall syndrome	GLI3 (heterozygous)	Anorectal malformations, renal anomalies, limb anomalies	Hypothalamic hamartoma, clefting (including bifid epiglottis), nail hypoplasia, postaxial polydactyly as limb anomaly	Kang et al., 1997; Killoran et al., 2000; Johnston et al., 2005
Robinow syndrome	WNT5A (heterozygous)	Vertebral anomalies, limb anomalies, genitourinary anomalies	Characteristic dysmorphic facial appearance, dental anomalies	Robinow et al., 1969, Vera-Roman 1973; Person et al., 2010
STAR syndrome; Toe syndactyly, telecanthus, and anogenital and renal malformations	FAM58A (X- linked)	Anogenital malformations, renal anomalies	Characteristic dysmorphic facial appearance, toe syndactyly	Unger et al., 2008
Thrombocytopenia-absent radius syndrome	RBM8A (Homozygous/compound heterozygous, typically involving 1q21.1 deletion in one allele)	Radial anomalies; many VACTERL-associated findings have been described	Unaffected thumbs; thrombocytopenia	Greenhalgh et al., 2002; Griesinger et al., 2005; Albers et al., 2012
Townes-Brocks syndrome	SALL1 (heterozygous)	Anorectal malformations, cardiac malformations, limb (radial) anomalies, renal anomalies, limb (radial) anomalies,	Dysmorphic ears, hearing impairment	Kohlhase et al., 1998; Powell and Michaelis 1999
Ulnar-Mammary syndrome	TBX3 (heterozygous)	Cardiac malformations, limb anomalies, genitourinary malformations	Apocrine and endocrine anomalies, characteristic ulnar anomalies as part of limb anomalies	Bamshad et al., 1997; Wollnik et al., 2002; Linden et al., 2009
VACTERL/VACTERL-H	ZIC3 (X-linked)	All features of VACTERL association	May include situs abnormalities, hydrocephalus	Wessels et al., 2010; Chung et al., 2011

GI: gastrointestinal; GU: genitourinary; H: hydrocephalus; TEF: tracheo-esophageal fistula