Database: OMIM
Entry: 600145
LinkDB: 600145
MIM Entry: 600145
  A number sign (#) is used with this entry because of evidence that some
  cases of caudal regression are caused by mutations in the VANGL1 gene
  Sacral defect with anterior meningocele (SDAM) is a form of caudal
  dysgenesis. It is present at birth and becomes symptomatic later in
  life, usually because of obstructive labor in females, chronic
  constipation, or meningitis. Inheritance is autosomal dominant (Chatkupt
  et al., 1994). Welch and Aterman (1984) gave a population frequency of
  Caudal dysgenesis syndrome and caudal regression syndrome are broad
  terms that refer to a heterogeneous constellation of congenital caudal
  anomalies affecting the caudal spine and spinal cord, the hindgut, the
  urogenital system, and the lower limbs. Approximately 15 to 25% of
  mothers of children with caudal dysgenesis have insulin-dependent
  diabetes mellitus (222100) (Lynch et al., 2000).
  See also Currarino syndrome (176450), a similar disorder caused by
  mutation in the HLXB9 gene (142994) on chromosome 7q36. Currarino
  syndrome classically comprises the triad of hemisacrum, anorectal
  malformation, and presacral mass. However, Currarino syndrome also shows
  phenotypic variability: Lynch et al. (2000) stated that there is
  variable expressivity of clinical features and that some patients with
  Currarino syndrome are asymptomatic. Kochling et al. (2001) found the
  complete triad of Currarino syndrome in only 8 of 23 patients with
  mutations in the HLXB9 gene, These reports suggest that some patients
  previously reported as having forms of sacral agenesis, including SDAM,
  may have had Currarino syndrome and vice versa.
  See also spina bifida (182940), which can be seen in some patients with
  sacral agenesis or caudal regression syndrome and may be etiologically
  Cohn and Bay-Nielsen (1969) described 7 females with anterior sacral
  meningocele and partial absence of the sacrum and coccyx. Symptoms
  included constipation and urinary incontinence. As 1 unaffected female
  appeared to have transmitted the disorder, the authors suggested
  X-linked dominant inheritance. Fellous et al. (1982) suggested autosomal
  dominant inheritance in the kindred reported by Cohn and Bay-Nielsen
  (1969). Welch and Aterman (1984) emphasized that the affected members of
  the kindred reported by Cohn and Bay-Nielsen (1969) had some degree of
  unilateral hemisacrum, and that there were no instances of surviving
  infants with sacral agenesis and no stillbirths. Welch and Aterman
  (1984) also suggested autosomal dominant inheritance in that family.
  Thierry et al. (1969) reported 5 affected males and 6 affected females.
  Aaronson (1970) reported 2 brothers and a sister with anterior sacral
  meningocele, anal canal duplication cysts, and covered anus. Kenefick
  (1973) reported a family in which 6 females and 3 males spanning 4
  generations had sacral agenesis associated with anterior sacral
  meningocele. Klenerman and Merrick (1973) reported anterior sacral
  meningocele in a woman, her father, and uncle. Say and Coldwell (1975)
  described the same anomaly in mother and 2 daughters.
  Thierry et al. (1969) and Gardner and Albright (2006) noted that the
  apparent female preponderance of sacral defect with anterior sacral
  meningocele may reflect ascertainment bias due to increased abdominal
  and vaginal examinations and to the gynecologic and obstetrical
  complications of the condition.
  Sacral agenesis and caudal regression syndrome may be attributed to
  maternal diabetes (Passarge and Lenz, 1966). Stewart and Stoll (1979)
  reported a family in which a diabetic woman gave birth to an affected
  girl and boy. Welch and Aterman (1984) suggested that caudal dysplasia
  due to maternal diabetes should be distinguished from familial forms of
  sacral dysgenesis.
  Finer et al. (1978) reported 2 male sibs with several congenital
  anomalies suggestive of the VATER association (192350) with prominent
  features of a caudal regression syndrome. The older infant had multiple
  cardiac abnormalities, including transposition of the great arteries and
  ventricular septal defect. Other features included imperforate anus,
  dislocated left hip, malformed sacrum, and hypoplasia of the lumbar
  vertebrae. The younger sib had suspected ventricular septal defect or
  patent ductus arteriosus, situs inversus of the abdominal viscera,
  hypoplasia of the lower limbs and pelvis, and absence of the sacrum and
  lower lumbar spine.
  Fellous et al. (1982) reported a 5-generation family with sacral
  agenesis and spina bifida. Abnormalities ranged from complete absence of
  the sacrum, with or without spina bifida aperta, to spina bifida
  occulta. Although many patients had isolated sacral agenesis, all those
  with spina bifida aperta had sacral agenesis. The condition appeared in
  a man with 4 children who were all affected, and thereafter, to varying
  degrees, in 17 of his 28 descendants. The authors suggested autosomal
  dominant inheritance.
  Chatkupt et al. (1994) reported a 5-generation family in which 17
  members had hemisacral defect with or without anterior meningocele.
  Inheritance was clearly autosomal dominant. One individual had only
  spina bifida occulta.
  Welch and Aterman (1984) classified congenital sacral anomalies into 4
  distinct clinical types: (1) a nonfamilial type associated with maternal
  diabetes showing complete absence of the sacrum and lower vertebrae and
  multiple congenital anomalies; (2) agenesis of the distal sacral or
  coccygeal segments; (3) hemisacral dysgenesis with presacral teratoma;
  and (4) hemisacral dysgenesis with anterior meningocele. Autosomal
  dominant inheritance was suggested for the latter 3 types. Cama et al.
  (1996) delineated 5 categories of sacral agenesis: (1) total sacral
  agenesis with some lumbar vertebrae missing; (2) total sacral agenesis
  without involvement of lumbar vertebrae; (3) subtotal sacral agenesis or
  sacral hypodevelopment; (4) hemisacrum; and (5) coccygeal agenesis
  (Belloni et al., 2000).
  Andersen et al. (1990) reported a family in which 5 members had anterior
  sacral meningoceles inherited in an autosomal dominant pattern.
  Gardner and Albright (2006) reported a mother and son with hemisacral
  defect and anterior meningocele. The child had associated lipoma,
  dermoid cyst, tethering of the spinal cord, and a syrinx in the conus.
  Although he had chronic constipation, he had no anorectal abnormalities.
  Duesterhoeft et al. (2007) reported 5 patients with caudal regression
  syndrome associated with an abdominal umbilical artery arising from the
  abdominal aorta inferior to the superior mesenteric artery. Additional
  variable features included sacral hypoplasia, urogenital anomalies, and
  gastrointestinal anomalies. One patient had a phenotype consistent with
  VACTERL (see 192350). Although none had fusion of the lower extremities,
  also known as sirenomelia, 3 had asymmetric lower limb defects including
  2 with fibular agenesis. The authors noted that there has been
  controversy in the literature regarding the relationship between caudal
  regression syndrome and sirenomelia. Based on their observations,
  Duesterhoeft et al. (2007) concluded that sirenomelia and caudal
  regression syndrome are part of a pathogenetic spectrum resulting from a
  primary deficiency of caudal embryonic mesoderm.
  The genetics of sacral agenesis was studied by Blumel et al. (1959) and
  Banta and Nichols (1969).
  Robert et al. (1974) observed 6 cases of sacro-coccygeal agenesis in 2
  families, one of which suggested irregular dominant inheritance and the
  other recessive inheritance.
  Gardner and Albright (2006) provided a review of the literature and
  noted that earlier reports of X-linked inheritance (e.g., Cohn and
  Bay-Nielsen, 1969) had been discounted.
  In a 5-generation family with autosomal dominant SDAM and spina bifida
  (see 182940), Fellous et al. (1982) found linkage to a locus on
  chromosome 6q near PGM3 (172100) (lod score = 1.85 at a recombination
  fraction of 0.087).
  Chatkupt et al. (1994) excluded linkage to HLA on chromosome 6p in a
  5-generation kindred with autosomal dominant SDAM.
  In a study of 144 patients with neural tube defects and 106 controls,
  Kibar et al. (2007) tested the hypothesis that mutations in the VANGL1
  gene (610132), a human homolog of a Drosophila gene that is required for
  establishing planar cell polarity in the developing eye, wing, and leg
  tissues, can cause neural tube defects. They identified a missense
  mutation (V239I; 610132.0001) in a 10-year-old Italian girl who had a
  severe form of caudal regression, type IV of sacral agenesis, according
  to the classification of Pang (1993). The girl also had
  lipomyeloschisis, anorectal malformation, hydromelia, and tethered
  spinal cord. The girl's mother showed no clinical signs of neural tube
  defect, but carried the same V239I mutation, which was absent in her
  parents; the proband's brother had a milder form of neural tube defect,
  dermal sinus. VANGL1 is a human homolog of a Drosophila gene that is
  required for establishing planar cell polarity in the developing eye,
  wing, and leg tissues. Kibar et al. (2007) found 2 other mutations in
  the VANGL1 gene in 2 patients with neural tube defects including
  myelomeningocele, hydrocephalus, and club feet (see 182940).
  1. Aaronson, I.: Anterior sacral meningocele, anal canal duplication
  cyst and covered anus occurring in one family. J. Pediat. Surg. 5:
  559-563, 1970.
  2. Andersen, C.; Tange, M.; Bjerre, P.: Anterior sacral meningocele
  occurring in one family: an autosomal dominantly inherited condition. Brit.
  J. Neurosurg. 4: 59-62, 1990.
  3. Banta, J. V.; Nichols, O.: Sacral agenesis. J. Bone Joint Surg.
  Am. 51: 693-703, 1969.
  4. Belloni, E.; Martucciello, G.; Verderio, D.; Ponti, E.; Seri, M.;
  Jasonni, V.; Torre, M.; Ferrari, M.; Tsui, L.-C.; Scherer, S. W.:
  Involvement of the HLXB9 homeobox gene in Currarino syndrome. (Letter) Am.
  J. Hum. Genet. 66: 312-319, 2000.
  5. Blumel, J.; Evans, E. B.; Eggers, G. W. N.: Partial and complete
  agenesis or malformation of the sacrum with associated anomalies. J.
  Bone Joint Surg. Am. 41: 497-518, 1959.
  6. Cama, A.; Palmieri, A.; Capra, V.; Piatelli, G. L.; Ravegnani,
  M.; Fondelli, P.: Multidisciplinary management of caudal regression
  syndrome (26 cases). Europ. J. Pediat. Surg. 6 (suppl. 1): 44-46,
  7. Chatkupt, S.; Speer, M. C.; Ding, Y.; Thomas, M.; Stenroos, E.
  S.; Dermody, J. J.; Koenigsberger, M. R.; Ott, J.; Johnson, W. G.
  : Linkage analysis of a candidate locus (HLA) in autosomal dominant
  sacral defect with anterior meningocele. Am. J. Med. Genet. 52:
  1-4, 1994.
  8. Cohn, J.; Bay-Nielsen, E.: Hereditary defects of the sacrum and
  coccyx with anterior sacral meningocele. Acta Paediat. Scand. 58:
  268-274, 1969.
  9. Duesterhoeft, S. M.; Ernst, L. M.; Siebert, J. R.; Kapur, R. P.
  : Five cases of caudal regression with an aberrant abdominal umbilical
  artery: further support for a caudal regression-sirenomelia spectrum. Am.
  J. Med. Genet. 143A: 3175-3184, 2007.
  10. Fellous, M.; Boue, J.; Malbrunot, C.; Wollman, E.; Sasportes,
  M.; Van Cong, N.; Marcelli, A.; Rebourcet, R.; Hubert, C.; Demenais,
  F.; Elston, R. C.; Namboodiri, K. K.; Kaplan, E. B.: A five-generation
  family with sacral agenesis and spina bifida: possible similarities
  with the mouse T-locus. Am. J. Med. Genet. 12: 465-487, 1982.
  11. Finer, N. N.; Bowen, P.; Dunbar, L. G.: Caudal regression anomalad
  (sacral agenesis) in siblings. Clin. Genet. 13: 353-358, 1978.
  12. Gardner, P. A.; Albright, A. L.: 'Like mother, like son:' hereditary
  anterior sacral meningocele: case report and review of the literature. :J.
  Neurosurg. 104 (2 suppl.): 138-142, 2006.
  13. Kenefick, J. S.: Hereditary sacral agenesis associated with presacral
  tumors. Brit. J. Surg. 60: 271-274, 1973.
  14. Kibar, Z.; Torban, E.; McDearmid, J. R.; Reynolds, A.; Berghout,
  J.; Mathieu, M.; Kirillova, I.; De Marco, P.; Merello, E.; Hayes,
  J. M.; Wallingford, J. B.; Drapeau, P.; Capra, V.; Gros, P.: Mutations
  in VANGL1 associated with neural-tube defects. New Eng. J. Med. 356:
  1432-1437, 2007.
  15. Klenerman, L.; Merrick, M. V.: Anterior sacral meningocele occurring
  in a family. J. Bone Joint Surg. Br. 55: 331-334, 1973.
  16. Kochling, J.; Karbasiyan, M.; Reis, A.: Spectrum of mutations
  and genotype-phenotype analysis in Currarino syndrome. Europ. J.
  Hum. Genet. 9: 599-605, 2001.
  17. Lynch, S. A.; Wang, Y.; Strachan, T.; Burn, J.; Lindsay, S.:
  Autosomal dominant sacral agenesis: Currarino syndrome. J. Med. Genet. 37:
  561-566, 2000.
  18. Pang, D.: Sacral agenesis and caudal spinal cord malformations. Neurosurgery   32:
  755-779, 1993.
  19. Passarge, E.; Lenz, W.: Syndrome of caudal regression in infants
  of diabetic mothers: observation of further cases. Pediatrics 37:
  672-679, 1966.
  20. Robert, J. M.; Pernod, J.; Bonnet, R.: L'agenesie sacro-coccygienne
  familiale. J. Genet. Hum. 22: 45-60, 1974.
  21. Say, B.; Coldwell, J. G.: Hereditary defect of the sacrum. Humangenetik 27:
  231-234, 1975.
  22. Stewart, J. M.; Stoll, S.: Familial caudal regression anomalad
  and maternal diabetes. J. Med. Genet. 16: 17-20, 1979.
  23. Thierry, A.; Archimbaud, J.-P.; Fischer, G.; Freidel, M.; Mansuy,
  L.: La meningocele sacree anterieure: revue de la litterature et
  presentation d'un cas. Neuro-chirurgie 15: 389-412, 1969.
  24. Welch, J. P.; Aterman, K.: The syndrome of caudal dysplasia:
  a review, including etiologic considerations and evidence of heterogeneity. Pedi  at.
  Path. 2: 313-327, 1984.
Clinical Synopsis:
     Autosomal dominant
     Constipation due to mass effect of meningocele
     Urinary retention due to mass effect of meningocele;
     Increased urinary frequency;
     Neurogenic bladder
     Anterior sacral hemidefect;
     'Scimitar' sign on X-ray;
     Sacral agenesis;
     Coccyx defects;
     Back pain
     [Central nervous system];
     Meningocele, anterior sacral;
     Cysts tend to enlarge with age;
     Lipoma, anterior sacral;
     Dermoid cyst;
     Neural tube defects may occur;
     Meningitis, recurrent;
     Back pain;
     Tethered spinal cord
     Prolonged labor;
     Obstructed labor
     Present at birth;
     Intrafamilial variability;
     Considered to be a manifestation of the caudal regression syndrome;
     Phenotypic overlap with Currarino syndrome (176450)
  Cassandra L. Kniffin - revised: 07/26/2006
Creation Date: 
  John F. Jackson: 6/15/1995
Edit Dates: 
  ckniffin: 07/26/2006
  Cassandra L. Kniffin - updated: 1/12/2009
  Victor A. McKusick - updated: 5/2/2007
  Cassandra L. Kniffin - reorganized: 8/1/2006
  Cassandra L. Kniffin - updated: 7/26/2006
Creation Date: 
  Victor A. McKusick: 10/12/1994
Edit Dates: 
  terry: 01/13/2011
  wwang: 2/16/2009
  ckniffin: 1/12/2009
  terry: 5/20/2008
  alopez: 5/10/2007
  terry: 5/2/2007
  carol: 8/1/2006
  ckniffin: 7/26/2006
  joanna: 3/18/2004
  terry: 12/18/1996
  mimadm: 9/23/1995
  carol: 10/24/1994
  carol: 10/12/1994
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