SALL4-Related Disorders

Clinical characteristics: SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities.

1. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly).

2. AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly.

3. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).

Diagnosis/testing: The diagnosis of a SALL4-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in SALL4 identified by molecular genetic testing.

Management: Treatment of manifestations: Surgery as needed for strabismus from Duane anomaly, malformations of the forearms, and congenital heart defects; management of renal anomalies per nephrologist and/or urologist; antiarrhythmic medications or pacemaker for those with conduction defects or heart block; cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis; hearing aids as needed; consideration of growth hormone therapy for children with growth deficiency; treatment of pituitary hypoplasia per endocrinologist.

Surveillance: Ophthalmologic exam with frequency as recommended by ophthalmologist; monitor renal function in those with renal anomalies, even if renal function is normal initially; periodic renal ultrasound evaluation if renal position anomalies could cause obstruction; periodic echocardiographic surveillance may be recommended for individuals with certain congenital heart defects; in those at risk for conduction defects, EKG at least annually with consideration of annual Holter monitor in those with known conduction defects; at least annual blood counts in those with a history of thrombocytopenia and leukocytosis; audiologic evaluation as needed; assessment of growth and for signs and symptoms of pituitary hypoplasia at each visit.

Agents/circumstances to avoid: Drugs affecting the kidney if renal function is impaired, or the inner ear if hearing is impaired; certain medications may be contraindicated in those with arrhythmias.

Genetic counseling: SALL4-related disorders are inherited in an autosomal dominant manner. The proportion of cases caused by a de novo pathogenic variant is approximately 40%-50%. Each child of an individual with a SALL4-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant has been identified in an affected family member.