Clinical Diagnosis

Tetra-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).

Figure

Figure 1. Postmortem radiograph of fetus with tetra-amelia syndrome demonstrating absence of all four limbs (without defects of scapulae and clavicles)

Figure

Figure 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.

Testing

Cytogenetic analyses, performed in some of the reported cases, showed normal karyotypes without ‘premature centromere separation’ (see Roberts syndrome).

Molecular Genetic Testing

Gene. WNT3 has been shown to be associated with tetra-amelia syndrome in one family [Niemann et al 2004].

Other loci. Genetic heterogeneity of tetra-amelia syndrome is strongly suggested by Krahn et al [2005], who describe a new consanguineous family with tetra-amelia, agenesis of both lungs, cleft lip/cleft palate, and micrognathia. Sequence analysis of WNT3 (all exons and exon-intron boundaries), FGF10 (all exons and exon-intron boundaries), FGFR2 (exon 9), HS6ST1 (coding region), and HS6ST3 (coding region) did not identify a mutation in any of the genes.

Clinical testing

• Sequence analysis: Direct sequencing of genomic DNA of the entire WNT3 coding region (exons 1-4). 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].

Table 1. Summary of Molecular Genetic Testing Used in Tetra-Amelia Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
WNT3	Sequence analysis	p.Gln83X (c.366C>T) 2	Unknown	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Only one family studied to date [Niemann et al 2004]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To 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) Disorders

No other disorders have been reported to be associated with mutations in WNT3.

Natural History

In addition to complete absence of all four extremities, phenotypic manifestations of tetra-amelia syndrome in affected individuals may include craniofacial, urogenital, cardio-pulmonary, 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].

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]. No molecular studies were undertaken in the other families with the exception of the family reported by Krahn et al [2005], in which WNT3, FGF10, FGFR2, HS6ST1, and HS6ST3 were analyzed but no mutation was identified. 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.

Craniofacial

• Eyes. Microphthalmia, cataract, microcornea, coloboma, palpebral fusion

• Ears. Absence of external ears (microtia), low-set ears

• Nose. Single naris, choanal atresia, prominent nose, absence of nose

• Mouth. Cleft lip/cleft palate, high and narrow palate, macrostomia, micrognathia

Urogenital

• Agenesis of kidney

• Rudimentary ovary and salpinx

• Persistence of cloaca

• Atresia of vagina

• Atresia of anus

• Atresia of urethra

• Absence of external genitalia

• Absence of scrotum

• Intra-abdominal location of testis

Cardiopulmonary

• Hypoplasia/aplasia of lungs, bilobular right lung

• Hypoplasia of pulmonary vessels

• Diaphragmatic defect

• Ventricular septal defect

• Mitral valve aplasia

Skeletal

• Hypoplasia/absence of pelvic bones

• Absence of vertebra

• Absence of rib

CNS

• Agenesis of olfactory nerves

• Agenesis of optic nerves

• Agenesis of corpus callosum

• Hydrocephalus

Other

• Polyhydramnios

• Absence of nipples

• Gastroschisis

• Agenesis of supra-adrenal gland

• Agenesis of spleen

Data 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, multiple 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.)

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations have been established.

Penetrance

Based on the few reports, penetrance appears to be complete with respect to absence of the limbs and incomplete with respect to the associated malformations. Expressivity of the associated manifestations is highly variable.

Nomenclature

In all cases reported so far, tetra-amelia was associated with other malformations, as ‘tetra-amelia syndrome’. However, there is evidence that tetra-amelia may occur as ‘pure tetra-amelia’ (or ‘isolated tetra-amelia’) without other anomalies.

Prevalence

Tetra-amelia syndrome is an extremely rare disorder and has so far been described in only five families of different ethnic backgrounds (Arabic, Moroccan, Syrian-Aramaic). No estimates of prevalence and carrier frequency for tetra-amelia syndrome have been reported.

Parental consanguinity appears to account for at least some of the few cases reported to date.

Evaluations Following Initial Diagnosis

Tetra-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 Manifestations

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 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.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Tetra-amelia syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with tetra-amelia syndrome are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members and their reproductive partners is available on a clinical basis once the mutations have been identified in the proband.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at about ten to 12 weeks’ gestation. Although this testing can determine whether a fetus is homozygous for WNT3 disease-causing mutations, it may not be required as the accurate diagnosis of limb agenesis should be possible by ultrasonography at the time of CVS.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination is recommended to assess the fetus for the presence and degree of malformations in other organs and structures affected in tetra-amelia syndrome.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Literature Cited

1. Başaran S, Yuksel A, Ermis H, Kuseyri F, Agan M, Yuksel-Apak M. Tetra-amelia, lung hypo-/aplasia, cleft lip-palate, and heart defect: a new syndrome? Am J Med Genet. 1994;51:77–80. [PubMed: 8030673]
2. Gershoni-Baruch R, Drugan A, Bronshtein M, Zimmer EZ. Roberts syndrome or "X-linked amelia"? Am J Med Genet. 1990;37:569–572. [PubMed: 2260610]
3. Kosaki K, Jones MC, Stayboldt C. Zimmer phocomelia: delineation by principal coordinate analysis. Am J Med Genet. 1996;66:55–59. [PubMed: 8957512]
4. Krahn M, Julia S, Sigaudy S, Liprandi A, Bernard R, Gonnet K, Heuertz S, Bonaventure J, Chau C, Fredouille C, Levy N, Philip N. Tetra-amelia and lung aplasia syndrome: report of a new family and exclusion of candidate genes. Clin Genet. 2005;68:558–560. [PubMed: 16283889]
5. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5:691–701. [PubMed: 15372092]
6. Niemann S, Zhao C, Pascu F, Stahl U, Aulepp U, Niswander L, Weber JL, Muller U. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet. 2004;74:558–563. [PMC free article: PMC1182269] [PubMed: 14872406]
7. Ohdo S, Madokoro H, Sonoda T, Takei M, Yasuda H, Mori N. Association of tetra-amelia, ectodermal dysplasia, hypoplastic lacrimal ducts and sacs opening towards the exterior, peculiar face, and developmental retardation. J Med Genet. 1987;24:609–612. [PMC free article: PMC1050288] [PubMed: 3681906]
8. Ohdo S, Sonoda T, Ohba K. Natural history and postmortem anatomy of a patient with tetra-amelia, ectodermal dysplasia, peculiar face, and developmental retardation (MIM 273390). J Med Genet. 1994;31:980–981. [PMC free article: PMC1016707] [PubMed: 7534355]
9. Rosenak D, Ariel I, Arnon J, Diamant YZ, Ben Chetrit A, Nadjari M, Zilberman R, Yaffe H, Cohen T, Ornoy A. Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs. Am J Med Genet. 1991;38:25–28. [PubMed: 2012129]
10. Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1998;14:59–88. [PubMed: 9891778]
11. Zimmer EZ, Taub E, Sova Y, Divon MY, Pery M, Peretz BA. Tetra-amelia with multiple malformations in six male fetuses of one kindred. Eur J Pediatr. 1985;144:412–414. [PubMed: 4076260]
12. Zlotogora J, Sagi M, Shabany YO, Jarallah RY. Syndrome of tetraamelia with pulmonary hypoplasia. Am J Med Genet. 1993;47:570–571. [PubMed: 8256824]

Revision History

• 28 August 2007 (me) Review posted to live Web site

• 2 May 2007 (sn) Original submission