Clinical characteristics.

Tetra-amelia syndrome is characterized by the (complete) absence of all four limbs and anomalies involving the cranium and the face (cleft lip/cleft palate, micrognathia, microtia, single naris, choanal atresia, absence of nose); eyes (microphthalmia, microcornea, cataract, coloboma, palpebral fusion); urogenital system (renal agenesis, persistence of cloaca, absence of external genitalia, atresia of vagina); anus (atresia); heart; lungs (hypoplasia/aplasia), skeleton (hypoplasia/absence of pelvic bones, absence of ribs, absence of vertebrae), and central nervous system (agenesis of olfactory nerves, agenesis of optic nerves, agenesis of corpus callosum, hydrocephalus). Affected infants are often stillborn or die shortly after birth.

Diagnosis/testing.

The diagnosis of tetra-amelia syndrome can be established clinically and is usually made on routine prenatal ultrasonography. WNT3 is the only gene in which pathogenic variants are known to cause tetra-amelia syndrome. The variant detection frequency is unknown as only a limited number of families have been studied.

Management.

Affected infants are often stillborn or die shortly after birth. Management of (as yet unreported) persons who survive will depend on the presence and severity of associated malformations and require the support of several medical disciplines.

Genetic counseling.

Tetra-amelia syndrome is inherited in an autosomal recessive manner. 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. Heterozygotes (carriers) are asymptomatic. Prenatal testing by molecular genetic testing is possible if the pathogenic variants in WNT3 have been identified in an affected family member.

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 1.

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

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).

Testing Strategy

To confirm the diagnosis in a proband, sequence analysis of WNT3 can be performed; however, the variant detection frequency is unknown because to date only one family with tetra-amelia syndrome has been reported to have a pathogenic variant in WNT3.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants 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 pathogenic variants in the family.

Clinical Description

In 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 pathogenic variant are compared in Table 2 with the findings in families in which no molecular studies were undertaken or no WNT3 pathogenic variant 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
• Hypospadias
• Absence of external genitalia
• Ambiguous genitalia
• Absence of scrotum
• Intra-abdominal location of testis

Cardiopulmonary

• Hypoplasia/aplasia of lungs, bilobular right lung
• Hypoplasia/aplasia of pulmonary vessels
• Diaphragmatic defect
• Ventricular septal defect
• Small right heart
• 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 suprarenal 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, 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.)

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 [personal communication].

Note: Some reports in the literature that refer to "tetra-amelia" describe cases with different combinations of (di-, tri-) phocomelia/-amelia. These cases do not represent true tetra-amelia, which is defined by the (complete) absence of all four limbs.

Prevalence

Tetra-amelia syndrome is an extremely rare disorder and has so far been described in only five families of different ethnic backgrounds (Arab, 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.

Evaluation 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 in the US and EU Clinical Trials Register in Europe 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.

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. To date, no individuals with tetra-amelia syndrome have survived to reproduce.

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 possible once the pathogenic variants 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the WNT3 pathogenic variants have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for tetra-amelia syndrome are possible. Although such testing can determine whether a fetus is homozygous for WNT3 pathogenic variants, it may not be required as the accurate diagnosis of limb agenesis should be possible by ultrasonography.

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.

Molecular Pathogenesis

One family with tetra-amelia syndrome with a pathogenic variant 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 pathogenic variant was identified by molecular analysis of the coding regions of WNT3 and of candidate genes HS6ST1, HS6ST3.

Gene structure. WNT3 comprises 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The NM_030753.3:c.247C>T (p.Gln83Ter) substitution, identified in a single family with tetra-amelia syndrome, is the only causative variant reported to date. The nonsense variant 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 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 (= canonic) and a β-catenin-independent (non-canonic) 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.Gln83Ter variant 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.

Literature Cited

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• Gershoni-Baruch R, Drugan A, Bronshtein M, Zimmer EZ. Roberts syndrome or "X-linked amelia?". Am J Med Genet. 1990;37:569–72. [PubMed: 2260610]
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Revision History

• 7 March 2019 (ma) Chapter retired: extremely rare
• 2 August 2012 (me) Comprehensive update posted live
• 28 August 2007 (me) Review posted live
• 2 May 2007 (sn) Original submission