Tetraamelia Syndrome 1
A number sign (#) is used with this entry because of evidence that tetraamelia syndrome-1 (TETAMS1) is caused by homozygous mutation in the WNT3 gene (165330) on chromosome 17q21. One such family has been reported.
DescriptionTetraamelia syndrome-1 is characterized by complete limb agenesis without defects of scapulae or clavicles. Other features include bilateral cleft lip/palate, diaphragmatic defect with bilobar right lung, renal and adrenal agenesis, pelvic hypoplasia, and urogenital defects (Niemann et al., 2004).
Genetic Heterogeneity of tetraamelia syndrome
Tetraamelia syndrome-2 (TETAMS2; 618021) is caused by mutation in the RSPO2 gene (610575) on chromosome 8q23.
Clinical FeaturesNiemann et al. (2004) reported a consanguineous Turkish family of Aramaic descent in which 4 of 8 sibs, 3 female and 1 male, were affected with tetraamelia and multiple other various anomalies. All 4 cases were diagnosed prenatally and were terminated by 20 weeks' gestation. In addition to absence of all 4 limbs, postmortem analysis of 3 fetuses showed multiple defects in each one, including cleft lip/palate, hypoplasia of the pelvis, malformed uterus, atresia of the urethra, vagina, and anus, and agenesis of the kidney, spleen, and adrenal glands. One fetus had a diaphragmatic defect with malposition of a bilobed right lung. Genetic analysis identified a mutation in the WNT3 gene (165330.0001).
Patients with Tetraamelia Syndrome without Molecular Diagnosis
Zimmer et al. (1985) reported a highly consanguineous Arab Moslem family in which 6 male infants had tetraamelia and hydrocephalus. All were severely affected with a malformed head and absence of upper and lower limbs. Postmortem examination of 1 affected fetus showed 12 left ribs, 11 right ribs, and complete absence of pelvic bones. All limbs were replaced with small, irregular soft tissue appendages. There was cleft lip, malformed mouth, no nose, no ears, and agenesis of the corpus callosum. Other features included bilateral left lung, patent ductus arteriosus, anal atresia, and empty scrotal sac with enlarged penis. Cytogenetic studies showed no abnormalities, including lack of the premature sister chromatid separation that had been observed in patients with Roberts syndrome (268300). Zimmer et al. (1985) concluded that the entity was distinct from Roberts syndrome, and postulated X-linked recessive inheritance, although autosomal recessive inheritance could not be excluded. In a follow-up of the family reported by Zimmer et al. (1985), Gershoni-Baruch et al. (1990) reported another affected male and noted that the phenotype was suggestive of Roberts syndrome, but the absence of the affected females suggested an X-linked disorder, best termed 'X-linked amelia.' However, Kosaki et al. (1996) suggested that the inheritance pattern in the family reported by Zimmer et al. (1985) and Gershoni-Baruch et al. (1990) may be autosomal recessive and proposed the term 'Zimmer phocomelia.'
Kosaki et al. (1996) reported a 46,XX fetus with tetraphocomelia. She also had absence of frontal bones and external ears, rudimentary nose, cleft palate, severe pulmonary hypoplasia with adenomatoid malformation, monolobated lungs, absence of thyroid, dysplastic kidneys, gallbladder, spleen, uterus, and ovaries, imperforate anus and vagina, and the presence of a phallus-like structure on an otherwise undefined perineum. The parents of this fetus were of Hispanic origin and nonconsanguineous. Kosaki et al. (1996) distinguished the condition from Roberts syndrome by the findings of severe craniofacial involvement, severe genital malformations, and pulmonary hypoplasia, which are not commonly observed in Roberts syndrome. Manifestations in this fetus were very similar to the cases reported by Zimmer et al. (1985). Multiple consanguinity in that family and the possibility that sex could be misinterpreted due to abnormal genitalia suggested that the actual inheritance of the defect in the original family (Zimmer et al., 1985) was autosomal recessive. Principal coordinate analysis was used to demonstrate that this condition was distinct from other phocomelia syndromes.
Rosenak et al. (1991) described amelia, severe lung hypoplasia, and aplasia of the peripheral pulmonary vessels in 2 fetuses of a nonconsanguineous Arab Moslem couple. The couple previously had an affected term female infant who died shortly after birth. The 2 fetuses were diagnosed by ultrasound and the pregnancies were terminated. One fetus had low-set ears and micrognathia. The other had apparent hydrocephaly and a left cleft lip in addition to the lung hypoplasia and abnormal pulmonary artery. The authors suggested that this represents a previously undescribed autosomal recessive malformation syndrome. Absence of premature centromere separation in chromosome studies excluded classic Roberts phocomelia syndrome.
Zlotogora et al. (1993) reported 2 additional families. In both instances, the parents of the affected children were Muslim Palestinian Arabs. No relationship was known between the 2 families and they originated from different areas; however, they had the same family name. The 2 families were not related to either of the parents of the patients reported by Rosenak et al. (1991), who originated from the same region as one of the families of Zlotogora et al. (1993). All the patients died soon after birth and were thought to have pulmonary hypoplasia. Cleft lip or hydrocephalus was found in some of the patients.
Krahn et al. (2005) reported 2 sibs, born of consanguineous Moroccan parents, with tetraamelia and severe lung hypoplasia. Both had complete absence of the limb bones with normal clavicles and scapulae in the second fetus. Karyotype was normal. The findings were similar to those reported by Rosenak et al. (1991). No mutations were identified in the coding exons of the WNT3 gene in the parents of the sibs.
Reviews
Bermejo-Sanchez et al. (2011) described the epidemiology of congenital amelia using data gathered from 20 surveillance programs on congenital anomalies, all International Clearinghouse for Birth Defects Surveillance and Research members, from all continents but Africa, from 1968 to 2006, depending on the program. Reported clinical information on cases was thoroughly reviewed to identify those strictly meeting the definition of amelia. Those with amniotic bands or limb-body wall complex were excluded. The primary epidemiologic analyses focused on isolated cases (about one-third) and those with multiple congenital anomalies (MCA) (two-thirds). A total of 326 amelia cases were ascertained among 23,110,591 live births, stillbirths, and, for some programs, elective terminations of pregnancy for fetal anomalies. The overall total prevalence was 1.41 per 100,000 (95% confidence interval 1.26-1.57). Only China, Beijing, and Mexico RYVEMCE had total prevalences, which were significantly higher than this overall total prevalence. Some underregistration could have influenced the total prevalence in some programs. Liveborn cases represented 54.6% of the total. Among monomelic cases (representing 65.2% of nonsyndromic amelia cases), both sides were equally involved, and the upper limbs (53.9%) were slightly more frequently affected. One of the most interesting findings was a higher prevalence of amelia among offspring of mothers younger than 20 years. Sixty-nine percent of the cases had MCA or syndromes. The most frequent defects associated with amelia were other types of musculoskeletal defects, intestinal defects, some renal and genital defects, oral clefts, defects of cardiac septa, and anencephaly.
MappingBy homozygosity mapping of a consanguineous Turkish family with tetraamelia, Niemann et al. (2004) assigned a disease locus to an 8.9-Mb region between D17S1299 and D17S797 on chromosome 17q21 (maximum lod score of 2.9).
Molecular GeneticsIn affected fetuses of a Turkish family with tetraamelia, Niemann et al. (2004) identified a homozygous nonsense mutation in the WNT3 gene (165330.0001).