RERE-Related Disorders

Clinical characteristics: RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.

Diagnosis/testing: The diagnosis of RERE-related disorders is established in a proband by identification of a heterozygous pathogenic variant in RERE by molecular genetic testing.

Management: Treatment of manifestations: Feeding difficulties may require the use of feeding therapy and/or thickened liquids; in severe cases, a nasogastric or gastrostomy tube may be considered. Seizure disorders, abnormal vision and/or strabismus, hearing loss, congenital heart defects, gastroesophageal reflux, genitourinary anomalies, scoliosis, congenital hip dysplasia, developmental delay, and behavioral problems are treated in the standard manner.

Surveillance: At least annual monitoring of developmental progress / educational needs and for scoliosis (until growth is complete). Annual (or as clinically indicated) ophthalmologic and audiologic evaluations. Routine follow up with a cardiologist and a urologist, as indicated for those who have anomalies involving these organ systems. Monitoring of seizure activity and behavioral issues as needed.

Genetic counseling: RERE-related disorders are inherited in an autosomal dominant manner and are typically caused by a de novo pathogenic variant. If the RERE pathogenic variant identified in the proband is not identified in one of the parents, the risk to sibs is low (~1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the pathogenic variant. Once the RERE pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.