DiagnosisClinical DiagnosisTetra-amelia is characterized by the (complete) absence of all four limbs (Figure 1). The diagnosis of tetra-amelia can be established clinically and is usually made on routine prenatal ultrasonography (Figure 2).FigureFigure 1. Postmortem radiograph of fetus with tetra-amelia syndrome demonstrating absence of all four limbs (without defects of scapulae and clavicles) FigureFigure 2. Prenatal ultrasonography showing fetus without limbs In the few families described to date, tetra-amelia was associated with craniofacial, urogenital, cardiopulmonary, nervous system, and skeletal malformations, in which instance the correct terminology should be tetra-amelia syndrome.TestingCytogenetic analyses, performed in some of the reported cases, showed normal karyotypes without ‘premature centromere separation’ (see Roberts syndrome).Molecular Genetic TestingGene. WNT3 is the only gene in which mutations are known to cause tetra-amelia syndrome in one family [Niemann et al 2004].Evidence for locus heterogeneity. Genetic heterogeneity of tetra-amelia syndrome is strongly suggested by Krahn et al [2005] and Sousa et al [2008], who described fetuses with tetra-amelia, agenesis of both lungs, cleft lip/cleft palate, and micrognathia in whom no mutations were identified in the coding exon regions of WNT3 and other candidate genes (see Molecular Genetics). Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Tetra-Amelia SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityWNT3Sequence analysisp.Gln83X
(c.247C>T) 2Unknown 3ClinicalDeletion / duplication analysis 4Deletion / duplication of one or more exons or the whole geneUnknown; none reported 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Only one family studied to date [Niemann et al 2004]3. Percentage of detectable mutations is unknown, as a WNT3 mutation has so far been demonstrated in only one family with tetra-amelia syndrome [Niemann et al 2004].4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No deletions or duplications of WNT3 have been reported to cause tetra-amelia syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm the diagnosis in a proband, sequence analysis of WNT3 can be performed; however, the mutation detection frequency is unknown because to date only one family with tetra-amelia syndrome has been reported to have a mutation in WNT3. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other disorders have been reported to be associated with mutations in WNT3. Eyaid et al [2011] described a WNT7A mutation in Al-Awadi/Raas-Rothschild/Schinzel (AA/RRS) syndrome and Fuhrmann syndrome.}

Natural HistoryIn addition to complete absence of all four extremities, phenotypic manifestations of tetra-amelia syndrome in affected individuals may include craniofacial, urogenital, cardiopulmonary, nervous system, and skeletal malformations. The following list is based on the findings in the affected individuals in the few families reported [Zimmer et al 1985, Gershoni-Baruch et al 1990, Rosenak et al 1991, Zlotogora et al 1993, Başaran et al 1994, Ohdo et al 1994, Niemann et al 2004, Krahn et al 2005, Sousa et al 2008].While the affected individuals in these families have all had similar findings, a mutation in WNT3 was only identified in the family reported by Niemann et al [2004]. With the exception of the family reported by Krahn et al [2005] and Sousa et al [2008], no molecular studies were undertaken in the other families. Therefore, in the absence of molecular genetic information to suggest subtypes of tetra-amelia syndrome, all reported cases are grouped together in this review. The findings in the family with a WNT3 mutation are compared in Table 2 with the findings in families in which no molecular studies were undertaken or no WNT3 mutation was identified.CraniofacialEyes. Microphthalmia, cataract, microcornea, coloboma, palpebral fusionEars. Absence of external ears (microtia), low-set earsNose. Single naris, choanal atresia, prominent nose, absence of noseMouth. Cleft lip/cleft palate, high and narrow palate, macrostomia, micrognathiaUrogenitalAgenesis of kidneyRudimentary ovary and salpinxPersistence of cloacaAtresia of vaginaAtresia of anusAtresia of urethraHypospadiasAbsence of external genitaliaAmbiguous genitaliaAbsence of scrotumIntra-abdominal location of testisCardiopulmonaryHypoplasia/aplasia of lungs, bilobular right lungHypoplasia/aplasia of pulmonary vesselsDiaphragmatic defectVentricular septal defectSmall right heart Mitral valve aplasiaSkeletalHypoplasia/absence of pelvic bonesAbsence of vertebraAbsence of ribCNSAgenesis of olfactory nervesAgenesis of optic nervesAgenesis of corpus callosumHydrocephalusOtherPolyhydramniosAbsence of nipplesGastroschisisAgenesis of suprarenal glandAgenesis of spleenTable 2. Clinical and Autopsy Findings in Families with Tetra-AmeliaView in own windowFindingStudyZimmer et al [1985], Gershoni-Baruch et al [1990]Rosenak et al [1991]Zlotogora et al [1993]Başaran et al [1994]Niemann et al [2004]Krahn et al [2005]Sousa et al [2008]Ragavan et al [2010]Tetra-amelia++++++++Cleft lip/cleft palate+++++++-Micrognathia−+−+−++-Ear malformationAbsent+−−−−−-Eye malformation+−−++−−-Nose malformationAbsent−−−+−−-Mouth malformation+−−−−−−-Heart malformation−−?+−−+-Pulmonary defects+Hypoplasia / aplasia?Aplasia++AplasiaHypoplasiaPulmonary arteries−Hypoplasia??−?Aplasia-Diaphragmatic defect−−?−+−−-Pelvic bonesHypoplasia / aplasia−?−Hypoplasia−−-Other skeletal defectsAbsent vertebrae and ribs−?−−−−-Renal malformation−−?−Agenesis−−-Genital malformation+−?++−−+Anal atresia+−−−+−−-Polyhydramnios+−−−−−−-Hydrocephalus++?−−−−-Other CNS defectsAgenesis of olfactory and optic nerves, corpus callosum−?−−−−-Cases −
total/autopsied7/23/25/02/14/32/21/11/1Data on the course of the disease or the prognosis are not available because the condition is rare. In nearly all reported cases, the pregnancy was terminated on diagnosis of tetra-amelia syndrome, or infants died shortly after birth as a consequence of other malformations such as pulmonary hypoplasia. Limb agenesis is generally compatible with life if adequate assistance is provided. The natural history of the disease is likely to be determined by extent and degree of associated manifestations.Note: An X-linked form of tetra-amelia, also termed "Zimmer phocomelia”, has been suggested for the family reported by Zimmer [Zimmer et al 1985, Gershoni-Baruch et al 1990] since all affected fetuses in this family were male connected only through female relatives. However, extensive consanguinity in this family and the fact that the gender may have been incorrectly assigned in some fetuses also suggested autosomal recessive inheritance [Gershoni-Baruch et al 1990]. (For more information see Differential Diagnosis, X-linked tetra-amelia.)

Differential DiagnosisMany of the associated phenotypic manifestations observed in tetra-amelia syndrome have also been observed in other syndromes. Limb deficiency as the hallmark of the disorder may occur in limb reduction syndromes different from tetra-amelia syndrome. In these syndromes, limb defects are variable and include phocomelia, amelia, and (rarely) tetra-amelia. The finding of several individuals with (complete) absence of all four extremities in a family is highly suggestive of tetra-amelia syndrome.Tetra-amelia with ectodermal dysplasia and lacrimal duct abnormalities (OMIM 273390), characterized by tetra-amelia, hypotrichosis, hypoplastic lacrimal ducts and sacs opening to the exterior, lack of lacrimal openings, upward slanting palpebral fissures, and bilateral preauricular pits. One of two affected sibs in the family described by Ohdo et al [1987] had complete absence of both lower limbs and the left upper limb, and hypomelia of the right upper limb with approximately 3 cm of humerus. The other affected sib had (complete) tetra-amelia [Ohdo et al 1987].X-linked tetra-amelia (Zimmer phocomelia) characterized by absence of all four limbs, absence/hypoplasia of pelvic bones, absence of vertebrae, absence of ribs, ‘bilateral’ left lung/hypoplasia of lungs, absence of nipples, cleft lip, microphthalmia, microcornea, cataract, coloboma, microcornea, absence of nose and external ears, and nonfusion of maxillae. Other findings include hydrocephalus, agenesis of olfactory nerves, agenesis of optic nerves, agenesis of the corpus callosum, empty scrotal sacs, anal atresia, and communication of rectum and urinary bladder [Zimmer et al 1985, Gershoni-Baruch et al 1990]. X-linked inheritance in this family has later been questioned since the gender of some fetuses may have been incorrectly assigned and because of the presence of multiple consanguinity in the family, indicating autosomal recessive inheritance [Kosaki et al 1996].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTetra-amelia syndrome is usually diagnosed prenatally. Based on the few published reports, assessment of the clinical manifestations in a fetus diagnosed with tetra-amelia syndrome by ultrasonography should include careful assessment of all organs and body structures that are known to be affected in tetra-amelia syndrome.Treatment of ManifestationsIn nearly all reported cases, the pregnancy was terminated on diagnosis of tetra-amelia syndrome or infants died shortly after birth as a consequence of other malformations including pulmonary hypoplasia. Data on the management of tetra-amelia syndrome therefore do not exist.It should be noted that (complete) absence of all extremities is principally not incompatible with life. Persons without extremities depend on extensive, life-long assistance with most daily activities. They would require specifically designed wheelchairs with assistive electronic technology and input control devices operated by head, chin, or tongue movements. Other individualized ambulatory devices may be indicated.Should individuals with tetra-amelia syndrome survive, management depends on the presence and severity of associated malformations and may involve multiple interdisciplinary surgical interventions and the support of several medical disciplines.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Tetra-Amelia Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDWNT317q21​.31Proto-oncogene protein Wnt-3WNT3 homepage - Mendelian genesWNT3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Tetra-Amelia Syndrome (View All in OMIM) View in own window 165330WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 3; WNT3 273395TETRAAMELIA, AUTOSOMAL RECESSIVEMolecular Genetic PathogenesisOne family with tetra-amelia syndrome with a mutation in WNT3 has been identified. However, genetic heterogeneity of tetra-amelia syndrome is suggested by Krahn et al [2005] and Sousa et al [2008]. Krahn et al [2005] described two sibs, born to a consanguineous family, with tetra-amelia and bilateral lung agenesis. Sousa et al [2008] reported a fetus with tetra-amelia, cleft lip/palate, bilateral lung agenesis with bilateral pulmonary artery agenesis and a small right heart. No mutation was identified by molecular analysis of the coding regions of WNT3 and of candidate genes HS6ST1, HS6ST3. Normal allelic variants. WNT3 is composed of five exons spanning 54.2 kb of genomic sequence; it encodes a transcript of 1506 nt (NM_030753.3). The 1068-nt open reading frame starts in exon 1 and terminates with a TAG stop codon in exon 4, encoding a protein of 355 amino acids.Pathologic allelic variants. The NM_030753.3:c.247C>T (p.Gln83X) substitution, identified in a single family with tetra-amelia syndrome, is the only causative mutation reported to date. The nonsense mutation at codon 83 creates a premature stop codon. The mutated transcript, unless rapidly degraded by nonsense-mediated RNA decay, is likely to result in a truncated protein of only 82 amino acids (including the signal peptide of 21 amino acids) instead of 355 amino acids of the mature peptide.Normal gene product. Proto-oncogene protein Wnt-3 (WNT3) is one of 19 members of the human WNT superfamily of highly conserved secreted signaling molecules that play key roles in embryonic development [Wodarz & Nusse 1998, Moon et al 2004]. Work in animal models supports the role of WNT3 signaling in the initiation of the formation of the apical ectodermal ridge, a transient structure in the embryonic limb bud critical for limb outgrowth.WNTs act as ligands for the frizzled family of transmembrane receptors. Intracellularly, WNT signals can be transduced through a β-catenin-dependent (= canonical) and a β-catenin-independent (non-canonical) WNT signaling. In the WNT/β-catenin pathway, absence of WNT ligand leads to degradation of β-catenin by the proteasome. Conversely, upon binding of WNT ligand to frizzled, degradation of β-catenin is decreased and it accumulates in the nucleus where it can activate transcription.Abnormal gene product. The p.Gln83X mutation leads either to rapid degradation by RNA surveillance mechanisms or to truncation of WNT3 at its amino terminus and is, in either case, likely to result in a null allele for WNT3. Loss of function of WNT3 in tetra-amelia syndrome supports the role of WNT3 as a limb-inducing gene in humans.