LRP4 mutations in bilateral renal agenesis with severe limb deficiencies

Introduction : Severe limb deficiencies have been reported in association with bilateral renal agenesis in several syndromes. Recently, truncating mutations in LRP4 have
been associated with a lethal autosomal recessive form of Cenani-Lenz syndrome (CLS). The objectives of our study was to delineate the phenotype of the third fetus, and through a search of syndromes, identify a group of disorders with overlapping phenotypes that may be allelic with CLS or due to mutations in the same pathway.
Results : A male fetus at 22 weeks’ gestation was found to have bilateral renal agenesis by ultrasound. The pregnancy was interrupted and autopsy and skeletal survey revealed shortening of forearms and legs below the knees, radioulnar synostosis, foreshortened triangular shaped tibia and fibula, and oligosyndactyly with disorganized metacarpals, metatarsals and phalanges. Bilateral renal agenesis, absent ureters and small bladder were confirmed. Additional features included downslanting palpebral fissures, high-arched palate, small mouth, low-set and posteriorly rotated ears, nuchal oedema, pulmonary hypoplasia, hypospadias and absent olfactory nerves. An autosomal recessive disorder was suspected, given a prior obstetric history of termination at 18 weeks for unilateral limb anomalies and cleft lip. Based on the aforementioned renal and limb anomalies, the lethal form of CLS was considered. Sequencing of LRP4 identified a paternally inherited variant (c.919+3G del) and a maternally inherited variant (c.4808T>A ;p.Ile1603Val). Both variants were rare in the general population and bioinformatically predicted to be damaging. We compared the phenotype with the two previously reported fetuses as well as with syndromes and disorders that may present prenatally with genitourinary anomalies plus acromesomelia of upper and lower limbs. We found significant overlap with a subset of cases of acro-renal-uterine-mandibular syndrome presenting with high-arched palate plus or minus micrognathia and microglossia, severe limb anomalies affecting the middle and distal segments, oligosyndactyly, renal agenesis, uterine anomalies and absence of olfactory nerves.
Conclusion : Based on the clinical features seen in three lethal cases of CLS, we propose that acro-renal-uterine-mandibular syndrome may be allelic with CLS or due to mutations in the molecular pathway involving LRP4.