Syndrome with limb malformations as a major feature
-Rare developmental defect during embryogenesis
Syndromic anorectal malformation
-Rare abdominal surgical disease
-Rare developmental defect during embryogenesis
-Rare genetic disease
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 ... 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 0.14%. 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 related.
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 ... 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.
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 ... 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 heterozygous 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).
Orioli et al. (2011) performed a large epidemiologic study describing the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance ... Orioli et al. (2011) performed a large epidemiologic study describing the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance and Research, and were reported according to a single preestablished protocol. Cases were clinically evaluated locally and reviewed centrally. A total of 249 cases with sirenomelia were identified among 25,290,172 births, for a prevalence of 0.98 per 100,000, with higher prevalence in the Mexican registry. An increase of sirenomelia prevalence with maternal age less than 20 years was statistically significant. The proportion of twinning was 9%, higher than the 1% expected. Sex was ambiguous in 47% of cases, and no different from expectation in the rest. The proportion of cases born alive, premature, and weighing less than 2,500 grams were 47%, 71%, and 88%, respectively. Half of the cases with sirenomelia also presented with genital, large bowel, and urinary defects. About 10 to 15% of the cases had lower spinal column defects, single or anomalous umbilical artery, upper limb, cardiac, and central nervous system defects. There was a greater than expected association of sirenomelia with other very rare defects such as bladder exstrophy, cyclopia/holoprosencephaly, and acardia-acephalus.