Human Anorectal Malformations: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Cell Biology
Contributor:
Heiko Reutter

Anorectal malformations (ARM) represent a rare birth defect of the hindgut that occur in approximately 1 in 3000 live births. Around 60% of ARM occur with associated anomalies including defined genetic syndromes and associations with chromosomal aberrations. The etiology of ARM is heterogeneous, with the individual environmental or genetic risk factors remaining unknown for the majority of cases.

  • anorectal malformation (ARM)
  • de novo
  • heritability
  • fecundity
  • copy number variation (CNV)
  • birth defect

1. Introduction

Anorectal malformations (ARM) comprise a broad spectrum of birth defects, ranging from mild anal anomalies to complex cloacal malformations. The estimated birth prevalence is 1 in 3000 live births, with a male to female ratio of 1.7 [1][2][3][4]. Associated anomalies occur within approximately 60% of patients, most commonly involving the genitourinary tract, cardiovascular system, central nervous system and the skeletal system [4][5]. ARM may present as a feature of a defined genetic syndrome or in association with chromosomal aberrations [6][7]. In this respect, ARM may present non-syndromic (isolated) or syndromic (non-isolated). According to the case classification guidelines for the National Birth Defects Prevention Study [8], ARM patients with a chromosomal or single gene disorder, a defined clinical syndrome, mental retardation, and/or dysmorphisms have syndromic ARM. The clinical management of ARM is mainly reconstructive surgery and life-long symptomatic treatment (i.e., management of chronic constipation, incontinence, recurrent infections, and psychosocial support).

2. Established Genetic Factors in the etiology of ARM

Townes–Brocks syndrome (TBS; OMIM #107480) is characterized by ARM, thumb anomalies, renal anomalies, cardiac anomalies, dysplastic ears and hearing loss. TBS results from dominant variants in SALL1 that occur in 50% of patients de novo [9]. Interestingly, pathogenic de novo SALL1 variants most commonly affect the paternally derived chromosome (87.5%) without an obvious age effect [10]. In 2017, Webb et al. identified a DACT1 variant in a three-generation family with features overlapping with TBS, negative for variants in SALL1 [11]. In a re-sequencing study of 78 patients with ARM, no pathogenic DACT1 variants were discovered [12] and no additional patient with a DACT1 variant and a phenotype overlapping TBS has been reported since.

The Duane-radial ray syndrome (OMIM #607323) is an autosomal dominant disorder characterized by upper limb, ocular, and renal anomalies caused by variants in SALL4 . Less common features comprise sensorineural hearing loss and gastrointestinal anomalies, such as ARM. Pathogenic variants in SALL4 occur in 40%–50% de novo [13].

Currarino syndrome (CS; OMIM #176450) is characterized by the triad of a presacral mass, sacral anomalies and ARM [14]. Heterozygous variants in MNX1 have been identified in 92% of familial and 32% of sporadic cases [15]. The fraction of de novo MNX1 variants has not been systematically studied, but there are frequent reports of de novo occurrence [16][17][18][19]. Since CS presents with variable expressivity and pathogenic variants may have a reduced penetrance, it is not surprising that completely asymptomatic individuals with pathogenic MNX1 variants have been reported [20]. However, even if a patient appears to represent a sporadic case, screening of the parents for features of CS and genetic testing of the parents in the case of identification of a MNX1 variant in the patient is recommended [15].

The CHARGE syndrome (#214800) comprises coloboma, heart defect, choanal atresia, growth retardation, developmental delay, genital hypoplasia, ear anomalies (including deafness) and ARM. Heterozygous variants in CHD7 have been identified as causative. Pathogenic variants in CHD7 occur in the majority of cases de novo [21] and affect predominantly the paternal allele [22]. About 70% of these variants represent nonsense or frameshift variants [23].

3. Epidemiological Aspects—A De Novo Paradigm

Although ARM is usually sporadic, the occurrence of familial ARM affecting multiple generations suggested autosomal dominant inheritance in, at least, a subset of families [24]. In an epidemiological study in a cohort of 1606 ARM patients Falcone et al. reported an additional family member with ARM in 1.4% of patients [25]. Later, in a study with 327 ARM patients the risk of recurrence between siblings was calculated, with 1% supporting the figure from Falcone et al. [26]. However, the same study suggested a recurrence risk of ARM of approximately one in two live births (62%) for parent–offspring transmission. This finding supports the hypothesis of autosomal dominant inheritance for a subset of ARM patients.

Not even five decades ago, ARM have been associated with a significant mortality and morbidity. Especially the implicated mortality and the reduced fecundity in patients with ARM lead to allele loss. Although the evolutionary pressure would eliminate such deleterious alleles, the prevalence of ARM has been relatively stable between 1980 and 2019 according to data of the European Surveillance of Congenital Malformations (EUROCAT) network ( www.eurocat-network.eu , accessed on 28 July 2021) [27]. Since the human per-generation mutation rate is exceptionally high compared to other species, with an average newborn acquiring a total of 50 to 100 de novo variants [28], these variants may have severe phenotypic effects when they affect functionally important bases in the genome. The de novo occurrence of deleterious variants may explain a stable prevalence of disease in the human population. This paradigm is especially appropriate when the mutational target is large and includes many genes. Similar mechanisms have been shown for other disorders that compromise individual fecundity, such as mental retardation [29].

Due to the improvement of delicate surgical techniques, such as the definitive repair of ARM, sexual function can be preserved more often, resulting in more offspring of patients with ARM. This would lead to a higher burden of deleterious variants and ultimately lead to an increase in the prevalence of ARM. However, it remains to be seen how these factors will develop in the future.

4. Conclusions and Outlook

Several lines of evidence show different genetic factors to be involved in the development of ARM. These factors are heterogeneous and include chromosomal aberrations, copy number variants and single nucleotide variants. De novo variants contribute substantially to the epidemiologic disease burden. Similar to what has been shown for other genetic conditions associated with reduced fecundity, de novo variants may compensate for allele loss in patients with ARM.

Exploration and characterization of the complete genome will ultimately identify regulatory genetic elements that might also contribute to the formation of ARM. The identification of these de novo variations within these regulatory elements might complement the missing heritability among cases with ARM.

This entry is adapted from the peer-reviewed paper 10.3390/genes12091298

References

  1. Cuschieri, A. Descriptive epidemiology of isolated anal anomalies: A survey of 4.6 million births in Europe. Am. J. Med. Genet. 2001, 103, 207–215.
  2. Jenetzky, E. Prevalence estimation of anorectal malformations using German diagnosis related groups system. Pediatr. Surg. Int. 2007, 23, 1161–1165.
  3. Levitt, M.A.; Peña, A. Anorectal malformations. Orphanet J. Rare Dis. 2007, 2, 33.
  4. Stoll, C.; Alembik, Y.; Dott, B.; Roth, M.P. Associated malformations in patients with anorectal anomalies. Eur. J. Med. Genet. 2007, 50, 281–290.
  5. Cuschieri, A. Anorectal anomalies associated with or as part of other anomalies. Am. J. Med. Genet. 2002, 110, 122–130.
  6. Marcelis, C.; de Blaauw, I.; Brunner, H. Chromosomal anomalies in the etiology of anorectal malformations: A review. Am. J. Med. Genet. Part A 2011, 155, 2692–2704.
  7. Martuciello, G. Genetics of anorectal malformations. In Anorectal Malformations in Children; Holschneider, H., Hutson, J., Eds.; Springer: Heidelberg, Germany, 2006; pp. 31–48.
  8. Rasmussen, S.A.; Olney, R.S.; Holmes, L.B.; Lin, A.E.; Keppler-Noreuil, K.M.; Moore, C.A. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res. Part A Clin. Mol. Teratol. 2003, 67, 193–201.
  9. Kohlhase, J. Townes-brocks syndrome. In GeneReviews®; University of Washington: Seattle, WA, USA, 2016. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1445/ (accessed on 28 July 2021).
  10. Böhm, J.; Munk-Schulenburg, S.; Felscher, S.; Kohlhase, J. SALL1 mutations in sporadic Townes-Brocks syndrome are of predominantly paternal origin without obvious paternal age effect. Am. J. Med. Genet. Part A 2006, 140, 1904–1908.
  11. Webb, B.D.; Metikala, S.; Wheeler, P.G.; Sherpa, M.D.; Houten, S.M.; Horb, M.E.; Schadt, E.E. Heterozygous pathogenic variant in DACT1 causes an autosomal-dominant syndrome with features overlapping townes–brocks syndrome. Hum. Mutat. 2017, 38, 373–377.
  12. Draaken, M.; Prins, W.; Zeidler, C.; Hilger, A.; Mughal, S.S.; Latus, J.; Boemers, T.M.; Schmidt, D.; Schmiedeke, E.; Spychalski, N.; et al. Involvement of the WNT and FGF signaling pathways in non-isolated anorectal malformations: Sequencing analysis of WNT3A, WNT5A, WNT11, DACT1, FGF10, FGFR2 and the T gene. Int. J. Mol. Med. 2012, 30, 1459–1464.
  13. Kohlhase, J. SALL4-related disorders. In GeneReviews®; University of Washington: Seattle, WA, USA, 2015. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1373/ (accessed on 28 July 2021).
  14. Currarino, G.; Coln, D.; Votteler, T. Triad of anorectal, sacral, and presacral anomalies. Am. J. Roentgenol. 1981, 137, 395–398.
  15. Dworschak, G.C.; Reutter, H.M.; Ludwig, M. Currarino syndrome: A comprehensive genetic review of a rare congenital disorder. Orphanet J. Rare Dis. 2021, 16, 167.
  16. Ross, A.J.; Ruiz-Perez, V.; Wang, Y.; Hagan, D.M.; Scherer, S.; Lynch, S.A.; Lindsay, S.; Custard, E.; Belloni, E.; Wilson, D.I.; et al. A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat. Genet. 1998, 20, 358–361.
  17. Zu, S.; Winberg, J.; Arnberg, F.; Palmer, G.; Svensson, P.J.; Wester, T.; Nordenskjöld, A. Mutation analysis of the motor neuron and pancreas homeobox 1 (MNX1, former HLXB9) gene in Swedish patients with Currarino syndrome. J. Pediatr. Surg. 2011, 46, 1390–1395.
  18. Han, L.; Zhang, Z.; Wang, H.; Song, H.; Gao, Q.; Yan, Y.; Tao, R.; Xiao, P.; Li, L.; Jiang, Q.; et al. Novel MNX1 mutations and genotype-phenotype analysis of patients with Currarino syndrome. Orphanet J. Rare Dis. 2020, 15, 155.
  19. Köchling, J.; Karbasiyan, M.; Reis, A. Spectrum of mutations and genotype—Phenotype analysis in Currarino syndrome. Eur. J. Hum. Genet. 2001, 9, 599–605.
  20. Lynch, S.A.; Wang, Y.; Strachan, T.; Burn, J.; Lindsay, S. Autosomal dominant sacral agenesis: Currarino syndrome. J. Med. Genet. 2000, 37, 561–566.
  21. van Ravenswaaij-Arts, C.M.; Hefner, M.; Blake, K.; Martin, D.M. CHD7 Disorder; University of Washington: Seattle, WA, USA, 1993.
  22. Pauli, S.; von Velsen, N.; Burfeind, P.; Steckel, M.; Mänz, J.; Buchholz, A.; Borozdin, W.; Kohlhase, J. CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin. Genet. 2012, 81, 234–239.
  23. Zentner, G.E.; Layman, W.S.; Martin, D.M.; Scacheri, P.C. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am. J. Med. Genet. Part A 2010, 152A, 674–686.
  24. Schramm, C.; Draaken, M.; Tewes, G.; Bartels, E.; Schmiedeke, E.; Märzheuser, S.; Grasshoff-Derr, S.; Hosie, S.; Holland-Cunz, S.; Priebe, L.; et al. Autosomal-dominant non-syndromic anal atresia: Sequencing of candidate genes, array-based molecular karyotyping, and review of the literature. Eur. J. Pediatr. 2011, 170, 741–746.
  25. Falcone, R.A.; Levitt, M.A.; Peña, A.; Bates, M. Increased heritability of certain types of anorectal malformations. J. Pediatr. Surg. 2007, 42, 124–128.
  26. Dworschak, G.C.; Zwink, N.; Schmiedeke, E.; Mortazawi, K.; Märzheuser, S.; Reinshagen, K.; Leonhardt, J.; Gómez, B.; Volk, P.; Rißmann, A.; et al. Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance. Orphanet J. Rare Dis. 2017, 12, 180.
  27. EUROCAT. Prevalence Charts and Tables. Available online: https://eu-rd-platform.jrc.ec.europa.eu/eurocat/eurocat-data/prevalence_en (accessed on 27 July 2021).
  28. Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. USA 2010, 107, 961–968.
  29. Vissers, L.E.L.M.; De Ligt, J.; Gilissen, C.; Janssen, I.; Steehouwer, M.; De Vries, P.; Van Lier, B.; Arts, P.; Wieskamp, N.; Del Rosario, M.; et al. A de novo paradigm for mental retardation. Nat. Genet. 2010, 42, 1109–1112.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback