Aetiological Classification

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The frequent association of ARM with common chromosomal anomalies is well known (e.g. Down syndrome, trisomy 18, 13q-, cat-eye syndrome (CEM), or genetic syndromes such as Currarino syndrome, FG syndrome, VATER association and others [14, 17, 22, 35, 39, 42, 48, 75, 80, 82, 85, 95, 98, 99, 111, 115, 123]. Teratogenic effects of certain agents such as thalidomide, oestrogen and ethanol intake has also been well described [8, 61, 89].

Table 2.2 Systemic malformations associated with ARM. US Ultrasound, IVU intravenous urethrogram, MCU micturating cysto-urethrogram, MRI magnetic resonance imaging, ECG electrocardiogram


Incidence in literature (%)






Hoekstra, Ratan, Mittal

Vesicoureteric reflux



Hassink, Narasimharao, Rickwood, Ratan


3-18% (boys) 26-39% (girls)

Hoekstra, Metts, Cortes



X-ray, MRI

Hassink, Carson, Mittal, Ratan

Other skeletal



Hassink, Ratan, Mittal



X-ray, MRI

Rivosecchi, Walton, Ratan, Mittal



ECG, echocardiography

Mittal, Greenwood, Ratan



X-ray, biopsy

Ratan, Mittal, Hassink



Hassink, Ratan




2.4.1 Chromosomal Anomalies Associated with ARM

In a study of 1,846 babies with ARM [24], chromosomal anomalies were found in 11%, the most frequent form being perineal fistula. The frequencies of trisomy 21, 13, and 18 among babies with ARM were 15, 30, and 90 times higher, respectively, in comparison to neonates in the general population (Table 2.3).

2.4.2 Down Syndrome

The ARM occurs more frequently with Down syndrome than in the general population and there is a higher rate of deformities without fistula [11, 116]. In a study of 1,992 patients with ARM in Japan [30], Down syndrome was seen in 101 patients (5.1%), with no gender variation. The incidence of high, intermediate, and low types were 2.7%, 18.7% and 4.1%, respectively, showing clearly the statistical difference between the intermediate type and the others. Ninety-five percent (96 out of 101) of patients with Down syndrome had deformities without fistula, while only 3 patients had rectourethral fistula; the remaining 2 had a perineal fistula.

2.4.3 Cat-Eye Syndrome

CES is characterised by ARM, coloboma of the iris (total or rarely partial, unilateral or bilateral), colo-boma of the choroid and/or optic nerve, microphthalmia (usually unilateral) and variable external ear deformities ranging from unilateral auricular reduction defects to several tags, mostly with atresia of the external auditory canal. These anomalies can be associated with mental retardation in half of the cases; dysmorphic features are the leading signs for the diagnosis, including hypertelorism, downward-slanting palpebral fissures and low root of the nose. Congenital heart disease can also be associated with this syndrome, especially septal defects and anomalous pulmonary venous return, as can different forms of urinary tract malformations such as renal agenesis or hypoplasia, vesicoureteral reflux and bladder anomalies [7, 61, 105].

CES is usually associated with the cytogenetic finding of a supernumerary marker chromosome consisting of duplicated material of chromosome 22. Bisatellite and dicentric markers are usually found (idic(22)(pter^q11.2::q11.2^pter)) and thus results in tetrasomy of the p arm and a part of 22q11.2 [74, 105]. This chromosomal anomaly generally follows a de novo mutation, and the recurrence risk does not increase with subsequent pregnancies. However, in a few cases the anomaly may segregate from an affected parent. Mosaicism can be a frequent finding in blood samples of the affected index case and of his family members. This may draw attention to considerable intrafamilial variability of the phenotypic expression, and the potential recurrence risk for patients with a normal karyotype [105].

2.4.4 Genetic Syndromes Associated with ARM

Seven major syndromes have been considered in this chapter: Townes-Brocks syndrome (TBS), FG syndrome, Pallister-Hall syndrome (PHS), VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb anomalies) Association (VATER), sire-nomelia, caudal regression syndrome (CRS) and Cur-rarino syndrome. Townes-Brocks Syndrome

Otherwise known as renal-ear-anal-radial syndrome or Townes-Brocks-branchio-oto-renal-like syndrome,

Table 2.3 Some forms of chromosomal anomalies associated with ARM (from Cuscheri et al. 2002) [24]

Chromosomal anomalies

Number of cases out of 1,846 ARM patients

Trisomy 8 mosaic


Trisomy 13




Trisomy 21


Trisomy 22


Sex chromosome aneuploidy




Tetrasomy 12 p (Pallister-Killian)


Ring (13)


Deletion 5p


Extra fragment


Partial tri/monosomy


Other chromosome anomalies


this autosomal dominant syndrome was first described in 1972 [116]. It is estimated to have an incidence rate of 1:250,000 live births [70]. TBS has great variability among affected families [89], but in general the main characteristic features of TBS are: (1) ARM (imperforate anus and anal stenosis), (2) hand malformations in the form of preaxial Polydactyly with diverse thumb anomalies ranging from vestigial, broad, to triphalangeal thumb, and even distal ulnar deviation of the thumb and (3) external ear malformation (microtia, external auditory atresia, satyr ear with overfolding of the superior helix, preauricular pits and sensorineural deafness). Other associated anomalies are congenital heart malformations, mostly tetralogy of Fallot, ventricular septal defect, truncus arteriosus and genitourinary anomalies (which can include dysplastic kidneys, vesicoureteric reflux and hypospadias); mental retardation has been noted in variable degrees [89]. The major criteria for the diagnosis of TBS are the hands, ears and anus. In the presence of only two major criteria the diagnosis becomes less secure and may be taken in consideration only if: (1) they are accompanied by minor malformations such as cardiac and renal anomalies and deafness, (2) absence of atypical features (i.e. tracheoesophageal or vertebral anomalies), (3) presence of another affected individual in the family and (4) other affected persons in the family who have the missing major feature in the index case. In that case the clinical diagnosis can be confirmed by a mutational analysis of the causative gene SALL1. Failure to detect the mutation does not rule out the diagnosis since the detection rate is 64.3-83.3% of patients with "classical" TBS with hands, ears and anal malformations. SALL1 gene is the only known gene causing TBS [56, 58, 69]. TBS exhibits similar features to other syndromes, namely Goldenhaar, VACTERL or oculo-auriculo-vertebral [89]. SALL1 was mapped first to 16q12.1 by fluorescence in situ hybridisation [57]. Up to 29 mutations were reported in affected individuals with scattered mutations all over the gene [56]. However, it is still unknown whether certain forms of mutations in other parts of SALL1 would result in different pheno-types. Mutation analysis of SALL1 has confirmed that penetrance is complete in TBS [56]. Prenatal diagnosis can be performed by searching for mutations of the SALL1 gene in amniotic fluid and chorionic villus samples. In the case of absence of known mutations of SALL1 in affected families, prenatal diagnosis can be performed by high-resolution ultrasound between 18 and 22 weeks of gestation, by finding the thumb malformations since ARM can not be seen easily, while renal anomalies can be identified [56]. FG Syndrome

FG syndrome, which takes its name from the initials of the first described case [83], is characterised by mental retardation, and multiple congenital anomalies including large head, imperforate anus, congenital hypotonia and partial agenesis of corpus callo-sum). It can involve many body systems, including:

(1) the central nervous system (most markedly mental retardation, congenital hypotonia, convulsions, and sensorineural deafness) - the malformations that can be seen through imaging techniques are partial or total agenesis of the corpus callosum, hydrocepha-lus, megaloencephaly and neuronal migration defect;

(2) dysmorphic features: frontal bossing, macroceph-aly, hypertelorism, telecanthus, epicanthal folds and downward-slanting palpebral fissures; (3) severe con-tipation that can be associated with ARM; (4) genital malformations: cryptorchidism, hypospadias, hernia; (5) patients usually have fine, silky, and soft hair with an anterior upswept hairline and excessive number of hairwhorls; (6) ocular abnormalites in the form of squint and ptosis; (7) broad thumbs and halluces. This syndrome is X-linked recessive with a gene map locus on Xq12-q21.31. Pallister-Hall Syndrome

This is a rare, life-threatening disorder that is characterised by hypothalamic hamartoma (commonly leading to precocious puberty or panhypopituita-rism), polydactyly (central), imperforate anus, and respiratory tract anomalies (bifid epiglottis and/or other laryngeal anomalies) [37]. The mode of inheritance is autosomal dominant, with remarkably variable expression [10, 102]. PHS (together with Greig cephalopolysyndactyly), as a distinct and pleiotropic developmental anomaly, is caused by mutations in the gene GLI3, which is inherited in an autosomal dominant pattern [50, 121].

PHS disease tends to be expressed mildly in familial cases, while it takes a more dramatic course in sporadic cases. The estimate of recurrence risk and genetic counselling should be based on whether the index case is part of a familial condition. In this case the disease usually tends to repeat itself in successive generations of affected individuals, with a 50% recurrence risk. Incomplete penetrance is not reported and those who harbour the mutation usually manifest the disease, but with highly variable expression. However it is important to inform these families about the possibility of having a baby affected with PHS in a more severe or even milder form than that of the other individuals in the family. Regarding sporadic cases, in whom the disease tends to occur in a severe form and frequently with a higher mortality rate and reduced reproductive fitness, the recurrence risk can be that of the general population. However, the absence of cases with gonadal or germinal mosaicism does not mean that it can not exist, so the family should be informed about the substantial risk of recurrence [9]. VACTERL Association (VATER)

VACTERL is an acronym for vertebral anomalies (fusion, hypoplasia), ARM, cardiac malformations, tra-cheoesophageal fistula with or without atresia, renal anomalies (renal agenesis, hypoplasia or even cystic dysplasia) and limb anomalies (usually involving the radial ray such as radial or thumb hypoplasia, either uni- or bilateral). This term represents the expanded previous acronym of VATER, which stands for vertebral defects, anal atresia, tracheoesophageal fistula, and radial dysplasia, first reported by Quan and Smith [91]. VACTERL is believed to result from an early embryonic insult, more specifically of blas-togenic origin occurring during the first 4 weeks of embryogenesis, so the expected effects are primary, polytopic, developmental field defects [70]. This early embryonic event can lead to different defects in various body systems. Of the 416 patients with ARM described by Ratan et al. [93], the additional anomalies occurred in 58%, of whom 2, 3 and 4 additional malformations were observed in 50%, 29%, and 16% of cases, respectively. Only three patients showed the full picture of VACTERL. In another study of 140 patients with ARM, only 2 patients exhibited all of the characteristics of the association, but 44 patients had 3 or more of the components of VACTERL association besides the ARM [76].

This association is frequent and it is estimated to be 1:7,000-10,000 live births [21]. Almost all cases are sporadic and the recurrence risk is minimal. However, VATER with hydrocephalus represents a distinct entity, since an autosomal recessive mode of inheritance has been reported in several families [47, 119]. A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation and features of VATER association was recently reported [94]. Another form of VACTERL and hydrocephalus is thought to be X-linked recessive [32, 46, 65]. Chromosomal anomalies have been reported frequently in the literature in association with VAC-

TERL, these can be trisomy 18 or long arm deletion of chromosome 13 [1, 6, 43, 110]. Recently, a case of VATER with 9q+ was reported [2], similarly a case of interstitial deletion of the long arm of chromosome 6: del (6) (q13q15) in association with VACTERL association [122], and another male case with VACTERL association and a karyotype showing mosaicism for a supernumerary ring chromosome in 63% of all the metaphases of both the lymphocytes and fibroblasts. This ring chromosome belongs to chromosome 12 [20]. A patient affected with VACTERL has also been found to harbour a somatic point mutation in mitochondrial DNA obtained from kidney tissue [25]. Sirenomelia

Sirenomelia may represent one of the oldest diagnosed congenital deformities, since it was mentioned by the ancient Greeks. Sirenomelia manifests with fusion of the lower limbs at a varying level and degree, with inability to perform normal movements and rotation (apodia, monopodia and dipodia). Not only are limb anomalies found in this lethal phenomenon, but also ARM (variable forms, including cloacal anomalies), genital (absent or arrested development), renal (cystic kidneys, or agenesis as a common cause of death when bilateral), gastrointestinal tract malformation, skeletal (vertebral and rib anomalies), various upper-limb defects, congenital heart disease and more [61]. It has an estimated incidence rate of 1:60,000, and a male:female ratio of 2:7. Almost all cases are sporadic with recurrence risk similar to that of the general population [49]. It was originally believed that sirenomelia is a severe form of CRS; however it has since been suggested that it is rather the result of early embryonic vascular insult leading to ischaemia in the caudal portion of the foetus [5, 15, 117]. It is thought that in sirenomelia an aberrant vessel originating from the vitelline artery shunts the blood supply coming to the high abdominal aorta directly through the umbilical cord to the placenta. The result would be severe hypoperfusion of structures distal to the origin of that aberrant vessel, since this vessel steals the blood supply from the caudal region of the foetus; this vascular stealing phenomenon is thought to be responsible for the pathogenesis of si-renomelia [112]. Caudal Regression Syndrome

As the name implies, this syndrome is characterised by a heterogeneous group of caudal anomalies. It may include variable degrees of spinal column agenesis, ARM and genitourinary anomalies. Its effects are not restricted to the caudal part of the body; CRS can also be associated with pulmonary hypoplasia and congenital heart malformations [29]. The estimated incidence rate of CRS is 1:7,500 births, but some authors report a higher incidence of 1:200-1:1,000 [125], while Diel et al. [26] reports an incidence rate of 1:10,000-1:20,000. We believe that the difference in previously reported incidence rates is due to the various presentations of CRS and to the possibility of its association with other multisystemic malformations such as omphalocele, cloacal exstrophy, imperforate anus, and spinal deformities, and VACTERL [104].

Cama et al. [16] outlined some of the typical features of this syndrome: (1) cutaneous signs (such flattening of the buttock and shortening of the inter-gluteal cleft secondary to lumbosacral agenesis), (2) sacrococcygeal agenesis (partial or total), (3) skeletal deformities (vertebral, rib, or even lower-limb deformities, scoliosis with or without kyphosis, hip dislocation), (4) congenital heart defects (tetralogy of Fallot), (5) ARM, (6) genitourinary disorders (renal aplasia or dysplasia, whether unilateral or bilateral, vesicoureteral reflux, ureterocele, hypospadias and malformed external genitalia) and (7) pulmonary hypoplasia. ARM is considered a frequent finding with CRS: 27-48% of published CRS series of cases were associated with ARM [16, 96]. ARM can be present in CRS in different forms, whether mild or severe.

Nearly all the cases of CRS are sporadic, and the genetic background to the development of CRS is partially known [15, 113, 127]. CRS occurs in up to 1% of pregnancies of diabetic women, and up to 22% of CRS occurs in the offspring of mothers affected with diabetes mellitus type I or type II [118]. The risk seems to be greater for women who are insulin-dependent since it is estimated that they are 200-400 times more likely to have a child with CRS than non-diabetic women, reflecting the fact that CRS is one of the most characteristic abnormalities occurring in foetuses of diabetic women. A reasonable explanation of this combination is that the teratogenic cause underlying CRS in diabetes is hyperglycaemia [33]. To the best of our knowledge, the exact mechanism leading to CRS is not yet known; however, it has been proposed that before the 7th week of gestation, one or more processes of primitive streak migration, pri mary or secondary neurulation, or differentiation are compromised in the embryonic caudal parts [15, 113, 118, 127]. Currarino Syndrome

CS was first described as the triad of ARM, hemisa-crum and presacral mass [23]. The radiological aspect of the sacrum described by Currarino is the so-called "sickle-shaped sacrum", which is caused by the presence of a hemisacrum with preservation of the first sacral vertebra. This finding is pathognomonic for the diagnosis CS [103]. According to Cama [16], classification of sacral anomalies presents: (1) total sacral agenesis with normal or short transverse pelvic diameter, and the defect extending to include some lumbar vertebrae, (2) total sacral agenesis with intact lumbar vertebrae, (3) partial agenesis or hypodevel-oped sacrum (preserved S1), (4) hemisacrum and (5) coccygeal agenesis. Following this classification, CS has been characterised as a type 4 sacral anomaly. Different forms of ARM can be present in CS, such as rectourethral fistula, rectovestibular fistula and rectocloacal fistula [73]. It is estimated that 29% of ARM are associated with sacral anomalies [97]. The most frequent ARM in CS is ARM with perineal fistula [86]. The same anomaly was reported by some investigators as anorectal stenosis [84]. The presence of perineal fistula leads to difficulty in defecation, and constipation, which can be the leading symptom in the diagnosis of the disease [73]. The presacral mass can be an anterior meningocoele, teratoma, dermoid cyst, rectal duplication, a combination of these or another uncommon tumour with reported malignant forms [81, 114].

This disorder can be associated with other defects, such as urologic abnormalities including horseshoe, duplex, or dysplastic kidney, vesicoureteric reflux, duplex ureter or hypospadias. Gynaecological malformations may include bicornuate uterus, septate vagina and bifid clitoris. Thus, the term syndrome was applied correctly rather than triad [4, 67]. CS can be sporadic or familial, with an autosomal dominant mode of inheritance. It has variable expression (i.e. it can present with all or some of the previously mentioned anomalies), and incomplete penetrance, which means that some individuals have the affected genotype but with normal phenotype. In the biggest series in the literature, the female:male ratio is 1.7:1, with the possibility that the greater number of females is due to the coexistence of the gynaecologic or urologic problems, which are noticed more frequently in females. Moreover, 33% of cases maybe asymptomatic [67].

Previous studies suggest the importance of a locus on chromosome 7q39. This region was identified by linkage analysis to search for the causative gene for CS [3, 66]. The region 7q39 includes three genes; one of the best known is Sonic Hedgehog (SHH), a very important molecular factor in early embryogenesis in different body systems; its mutations are responsible for holoprosencephaly in humans [3]. SHH was excluded as a causative gene for CS by two thorough investigations performed by Seri et al. [107] and Vargas et al. [120]. The remaining two homeobox genes are also important for early development, namely EN2 and HLXB9. Further linkage analysis on affected families with sacral agenesis showed that the position of the causative gene was more towards the terminal end of the long arm of chromosome 7. This excluded more obviously the involvement of SHH and EN2, which are located more centromerically. EN2 was excluded since it is located upstream of SHH [101, 107]. The third candidate gene is HLXB9 (homeobox gene), which was found to be expressed in early development in human embryos and expressed specifically in the anterior horn region of the spinal cord [101]. HLXB9 is composed of three exons. A combination of DGGE, single-strand conformation polymorphism and direct DNA sequencing experiments were carried out. These studies demonstrated several mutations in the gene coding sequence and in intron-exon boundaries in both sporadic and familial cases, confirming the causative role of HLXB9 in this syndrome (Fig. 2.2) [4, 36, 101]. To the best of our knowledge, the known

(Genomic) 1 87

774 4131 4291 4891 5321

697 698 858 859



233 234 286 287 243

Fig. 2.2 Schematic representation of the structure of HLXB9 gene, showing the three exons, the homeodomain, the numbering according to genomic sequence, and nucleotide numeration according to cDNA sequence, and residues numeration. The arrows indicate the sites of discovered mutations along the gene mutations causing CS are in total 9 missense, 2 nonsense, 2 splicing, 7 frameshifts, and 6 hemizygous microdeletions. Since the loss of one copy of HLXB9 gene (haploinsufficiency) can lead to CS, as well as cases involving deletions of the region 7q35-tel, it is quite probable that CS is caused by loss-of-function mutations. The presence of polyalanine expansion with various triplet repeats in homeobox genes can lead to certain pathologic conditions, for example synpolydactyly, oculopharyngeal muscular dystrophy, and cleidocranial dysplasia [13, 34, 79]. This abnormal expansion was not found to determine CS, since they were found in both affected and control cases. In the study performed by Belloni et al. [4], the commonest allele in the heterozygous form for the general population was CGC11, accounting for 90.23% of the 100 total control chromosomes. Other cases observed were CGC12, CGC9 and CGC8, accounting for 1.7, 7.47 and 0.6%, respectively. Only one case was found with homozygous change in the polyalanine tract giving rise to the CGC9/CGC9 allelic combination. The sample was a "control" case, but a closer look and detailed investigations showed that the person lacked posterior arch fusion of the vertebrae and had left-sided scoliosis. The possible relationship between the length of the alanine fragment and the presence of sacral anomalies in either affected or control cases was also excluded in that study [4].

The same studies showed in some familial cases, that the mutation was found as well in asymptomatic patients with normal sacral X-ray giving the disease the characteristic of incomplete penetrance. HLXB9 mutations are not found in other forms of sacral agenesis and are found only in individuals with CS. However, HLXB9 mutations are not found in all patients who are diagnosed clinically; this may suggest the possibility of genetic heterogeneity or the presence of some non-genetic components influencing the occurrence of this anomaly, at least for sporadic cases. To the best of our knowledge, no further studies have proved the involvement of any other genes in sacral and anorectal development [104]. However Horn et al. [45] have reported four cases of minimal clinical expression of holoprosencephaly and CS due to different cytogenetic rearrangements affecting both SHH and HLXB9 at 7q36.3

Taking into consideration all of the previous data, we believe that genetic counselling is highly appreciated in any diagnosed case of CS. There is always the need for detailed physical examination and sacral X-ray to the parents to exclude minimal signs of the disease. Finding HLXB9 mutations in the index case necessitates the molecular genetic study of the parents,

Table 2.4 Examples of genetic syndromes with ARM as a feature. XR X-linked recessive, AD autosomal-dominant, AR autosomal-recessive


Prominent Features

Mode of inheritance

Locus or gene if known

Opitz G

Hypertelorism, hypospadias, swallowing difficulties.


MID 1 gene

Opitz Frias

The same features of Opitz




cryptophthalmos with other malformations, cryptophthalmos-syndactyly syndrome.




Hypoplastic alae nasi, deafness, pancreatic insufficiency, hypothyroidism.




Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies

Sporadic or AD



Ectrodactyly, ectodermal dysplasia, and cleft lip/palate




Hemifacial microsomia, cardiac, vertebral, and central nervous system defects

Sporadic or AD


Cardiac, thymic, hypocalcaemia, vertebral, others

Sporadic or AD

Chromosome 22 microdeletion


Hydrometrocolpus, Hirschsprung, hydronephrosis



even if they were asymptomatic, because of incomplete penetrance with possible subsequent extension of the study for further family members in the case of positive results. Since CS is autosomal dominant and the recurrence risk is 50%, the disease has both incomplete penetrance and variable expression. Prenatal diagnosis through ultrasound can only detect the presacral mass, which is not present in all cases, making the molecular diagnosis the most favourable method for diagnosing CS prenatally [67]. ARM can also be associated with many other syndromes, although in some cases it maybe not be a main characteristic feature (Table 2.4) (see Chap. 3).

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