Tetraamelia Syndrome 2

A number sign (#) is used with this entry because of evidence that tetraamelia syndrome-2 (TETAMS2) is caused by homozygous mutation in the RSPO2 gene (610575) on chromosome 8q23.

Description

Tetraamelia syndrome-2 (TETAMS2) is characterized by rudimentary appendages or complete absence of the limbs, usually symmetric, as well as bilateral agenesis of the lungs. There are abnormalities of the pulmonary vasculature and dysmorphic features, including bilateral cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, and labioscrotal fold aplasia (Szenker-Ravi et al., 2018).

For a discussion of genetic heterogeneity of TETAMS, see 273395.

Clinical Features

Basaran et al. (1994) reported a Turkish family in which 2 sons, born of first-cousin parents, had tetraamelia, cleft lip/palate, bilateral agenesis of the lungs, and heart defects, including ventricular septal defect and mitral valve aplasia. The mode of inheritance was unclear.

Sousa et al. (2008) reported a fetus with tetraamelia, bilateral cleft lip/palate, and possible pulmonary hypoplasia identified by ultrasound at 20 weeks' gestation. The pregnancy was terminated. Physical examination confirmed the sonographic findings and also showed micrognathia and low-set ears. There was bilateral lung agenesis with bilateral pulmonary artery agenesis and a small right heart. Fetal x-ray confirmed the complete absence of limb bones and revealed normal clavicles, scapulae, and pelvis. No mutations were identified in the coding region of the WNT3 gene.

Szenker-Ravi et al. (2018) studied 4 families with tetraamelia and pulmonary aplasia, including the Turkish family originally described by Basaran et al. (1994) (family 2) and the Portuguese family previously reported by Sousa et al. (2008) (family 3). The proband of a consanguineous French family (family 4) was a 22-week female fetus with complete absence of upper limbs, rudimentary appendages of the lower limbs, bilateral cleft lip/palate, ankyloglossia due to short frenulum, microretrognathia, and bilateral lung agenesis. In a consanguineous Indian family (family 5), there were 3 affected fetuses, who showed phenotypic variability: 1 had complete absence of the upper limbs with rudimentary lower appendages, whereas the other 2 had absence of lower extremities below the knees, associated with rudimentary upper limbs in 1 case and asymmetric upper limb involvement in the other case, with complete absence of the left upper limb and hypoplastic right arm with absence of forearm and hand. Complete agenesis of both lungs was reported in 2 fetuses; other features included cleft lip/palate, severe microretrognathia, and ankyloglossia, as well as agenesis of branches of the pulmonary artery and hypoplastic pulmonary veins.

Molecular Genetics

By exome sequencing in 4 families with tetraamelia and bilateral pulmonary agenesis, including the Turkish family originally described by Basaran et al. (1994) and the Portuguese family previously reported by Sousa et al. (2008), Szenker-Ravi et al. (2018) identified homozygous truncating mutations in the RSPO2 gene (see, e.g., 610575.0001 and 610575.0002). In the Turkish family (family 2), the unaffected parents and 2 unaffected sibs were heterozygous for a Q70X substitution in RSPO2, but DNA was unavailable from the deceased affected individuals. In the Portuguese family (family 3), the affected fetus was shown to be homozygous for a 154-kb deletion within the RSPO2 gene, but the mutation status of the parents was not reported.