MIM Entry: 600145
#600145 SACRAL DEFECT WITH ANTERIOR MENINGOCELE
CAUDAL DYSGENESIS SYNDROME, INCLUDED;;
CAUDAL REGRESSION SYNDROME, INCLUDED;;
SACRAL AGENESIS, INCLUDED;;
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
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
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:
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:
8. Cohn, J.; Bay-Nielsen, E.: Hereditary defects of the sacrum and
coccyx with anterior sacral meningocele. Acta Paediat. Scand. 58:
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:
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:
18. Pang, D.: Sacral agenesis and caudal spinal cord malformations. Neurosurgery 32:
19. Passarge, E.; Lenz, W.: Syndrome of caudal regression in infants
of diabetic mothers: observation of further cases. Pediatrics 37:
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:
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.
Constipation due to mass effect of meningocele
Urinary retention due to mass effect of meningocele;
Increased urinary frequency;
Anterior sacral hemidefect;
'Scimitar' sign on X-ray;
[Central nervous system];
Meningocele, anterior sacral;
Cysts tend to enlarge with age;
Lipoma, anterior sacral;
Neural tube defects may occur;
Tethered spinal cord
Present at birth;
Considered to be a manifestation of the caudal regression syndrome;
Phenotypic overlap with Currarino syndrome (176450)
Cassandra L. Kniffin - revised: 07/26/2006
John F. Jackson: 6/15/1995
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
Victor A. McKusick: 10/12/1994