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.

• 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).
• 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.
• 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.

Suggestive Findings

SALL4-related disorders include a spectrum of phenotypes: Duane-radial ray syndrome (DRRS), or Okihiro syndrome; acro-renal-ocular syndrome (AROS); and SALL4-related Holt-Oram syndrome (HOS). A SALL4-related disorder should be suspected in individuals with clinical features of DRRS, AROS, or HOS.

DRRS clinical features

• Duane anomaly. Uni- or bilateral limitation of abduction of the eye associated with retraction of the globe and narrowing of the palpebral fissure on adduction. The abducens nucleus and nerve (cranial nerve VI) are absent and the lateral rectus muscle is innervated by a branch of the oculomotor nerve (cranial nerve III), which explains the aberrant ocular movements (see Duane Syndrome).
• Radial ray malformation. 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)
• Other features are variably present; see Clinical Characteristics.

AROS clinical features

• Radial ray malformations
• Renal abnormalities: mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, and bladder diverticula
• Ocular abnormalities: ocular coloboma and Duane anomaly

SALL4-related HOS clinical features

• Upper-extremity malformations: radial, thenar, and/or carpal bones, including preaxial polydactyly
• Congenital heart malformations: ventricular septal defects, atrial septal defects, and tetralogy of Fallot
• Cardiac conduction defects (less common than in TBX5-related HOS)
  Note: HOS is a heterogeneous phenotype in which 70% of affected individuals have pathogenic variants in TBX5; see Differential Diagnosis and Holt-Oram Syndrome for further clinical information on this condition.

Establishing the Diagnosis

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 (see Table 1).

Note: Identification of a heterozygous SALL4 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include single-gene testing (see Option 1) or use of a multigene panel (see Option 2) depending on the phenotype.

Clinical Description

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 [Al-Baradie et al 2002, Kohlhase et al 2002, Kohlhase et al 2003, Borozdin et al 2004a, Borozdin et al 2004b, Kohlhase et al 2005, Borozdin et al 2007].

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

Of 69 affected individuals from 23 families with a SALL4 pathogenic variant, 13% show the triad of Duane anomaly, radial ray malformation, and sensorineural hearing loss originally described for Okihiro syndrome; 45% have Duane anomaly and radial defects; and 21% have radial defects only. To date, more than 100 individuals with a pathogenic variant in SALL4 have been identified [Al-Baradie et al 2002, Kohlhase et al 2002, Kohlhase et al 2003, Borozdin et al 2004a, Borozdin et al 2004b, Kohlhase et al 2005, Borozdin et al 2007, Vanlerberghe et al 2019, van de Putte et al 2020, and others]. The following description of the phenotypic features associated with this condition is based on these reports.

Ocular. Duane anomaly is the most common ocular finding. Other ocular anomalies include iris, retinal, and choroidal colobomata, cataract, optic disc hypoplasia, and microphthalmia (structural eye anomalies are rare).

Musculoskeletal. Radial ray anomalies 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). Other reported upper-extremity anomalies include concomitant shortening of ulnae, syndactyly, radial clubhand, carpal bone anomalies, shortened humeri, and hypoplasia of deltoid muscles. Lower-extremity anomalies include talipes, clubfoot, tibial hemimelia, and syndactyly of toes. Fused vertebrae have also been reported.

Renal anomalies include mild malrotation, ectopia, crossed renal ectopia, horseshoe kidney, renal hypoplasia, renal agenesis, vesicoureteral reflux, and bladder diverticula.

Cardiac. Congenital heart malformations include ventricular septal defect, atrial septal defect, and tetralogy of Fallot. Cardiac conduction defects are also reported but are less common than in TBX5-related HOS.

Ears/hearing. Sensorineural and/or conductive deafness can occur. Ear anomalies include abnormal pinnae, slit-like opening of auditory canals, and small ears.

Gastrointestinal features can include anal stenosis and imperforate anus.

Characteristic facial features reported in some individuals include epicanthal folds, widely spaced eyes, depressed nasal bridge, and hemifacial microsomia.

Pituitary. Growth hormone deficiency, postnatal growth deficiency, pituitary hypoplasia

Development and cognition are normal.

Other

• Central nervous system. Neural tube defects (rare); meningomyelocele has been observed in two affected individuals [J Kohlhase, unpublished data].
• Mild thrombocytopenia and leukocytosis were reported in some affected individuals with one SALL4 pathogenic frameshift variant from one family. See IVIC syndrome (OMIM 147750).
• Isolated ventricular septal defects (VSD). Two SALL4 missense variants have been reported to be associated with isolated VSD [Wang et al 2010]. However, since neither of these missense variants affects amino acids with known functional domains, it is unclear if this phenotype is clearly associated with pathogenic variants in SALL4.

Genotype-Phenotype Correlations

Most SALL4 loss-of-function variants are private or have been observed in no more than three independent families. The phenotype of larger deletions (not extending into other genes) is not significantly different from that caused by almost all truncating single-nucleotide variants, and these are expected to result in nonsense-mediated mRNA decay.

The only clearly pathogenic missense variant identified to date in an individual with malformations (c.2663A>G, p.His888Arg) affects an essential coordinating amino acid and is associated with central midline defects (single upper incisor, pituitary hypoplasia, widely spaced eyes). It is predicted to result in an increase of DNA binding capacity [Miertus et al 2006].

The only truncating pathogenic variant predicted to escape nonsense-mediated mRNA decay is associated with extensive clinical variability and severe hemifacial microsomia in one affected member of the reported family [Terhal et al 2006].

Some pathogenic missense variants have been reported to result in a gain of function, and those variants have been reported to cause premature ovarian failure alone, without developmental disorder (see Genetically Related Disorders) [Wang et al 2019].

Penetrance

Penetrance is approximately 95% but may be lower for certain pathogenic variants.

In two reported families. An individual known (on the basis of pedigree position) to have the SALL4 pathogenic variant is unaffected; an individual with a proven SALL4 pathogenic variant shows no signs of a SALL4-related disorder [Hayes et al 1985, Kohlhase et al 2002]. In the latter family, however, the phenotype was mild in all individuals with the pathogenic variant (i.e., presenting with only thenar hypoplasia and Duane anomaly).

Of 69 family members known in 2004 to have a SALL4 pathogenic variant, only one (1.4%) was clinically unaffected [J Kohlhase, personal observation]. No further case of non-penetrance is known to the author.

Nomenclature

One of the earliest reports of Duane anomaly occurring together with radial ray defects is that of Ferrell et al [1966] (earlier reports are cited in OMIM). Further families were reported by Temtamy et al [1975] and Okihiro et al [1977]. Temtamy & McKusick [1978] named the syndrome Duane/radial dysplasia syndrome (DR syndrome, later modified to Duane-radial ray syndrome [DRRS]). The term "Okihiro syndrome" was first used by Hayes et al [1985].

The term "acro-renal-ocular syndrome" was used in 1984 to describe a family with autosomal dominant inheritance of thumb abnormalities, renal malformations, and ocular coloboma, ptosis, and Duane anomaly [Halal et al 1984].

Holt-Oram syndrome has also been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures.

Prevalence

The prevalence is unknown, partly because in many countries SALL4-related disorders have not been and are still not differentiated from HOS caused by pathogenic variants in TBX5, or from other heart-hand syndromes.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SALL4-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Drugs affecting renal clearance or the inner ear should be avoided in individuals with impaired renal function and/or hearing impairment.

Certain medications may be contraindicated in individuals with arrhythmias.

Evaluation of Relatives at Risk

Children of affected persons who are themselves not obviously affected should be tested for the pathogenic variant present in the family because individuals with a SALL4 pathogenic variant should undergo clinical evaluation for hearing problems, renal disease, eye disease, and heart defects.

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

SALL4-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with a SALL4-related disorder have an affected parent.
• A proband with a SALL4-related disorder may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with a SALL4-related disorder caused by a de novo pathogenic variant is approximately 40%-50% [J Kohlhase, unpublished data].
• Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include molecular genetic testing for the SALL4 pathogenic variant identified in the proband and/or physical examination, ophthalmologic examination for structural malformations of the eyes as well as eye movement disorders, examination of the limbs (x-rays of the forearms), examination of the heart, and ultrasound examination of the kidneys.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with a SALL4-related disorder may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or has a SALL4 pathogenic variant, the risk to the sibs is inheriting the pathogenic variant is 50%. The penetrance of SALL4-related disorders is approximately 95% in heterozygous individuals but may be lower for certain pathogenic variants (see Penetrance).
• If the SALL4 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SALL4 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for a SALL4-related disorder because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a SALL4-related disorder has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a SALL4 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

For a pregnancy known to be at increased risk for a SALL4-related disorder. Once the SALL4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Although such testing can determine whether or not the fetus has inherited the SALL4 pathogenic variant, it cannot predict which manifestations will be present or the severity of the manifestations. High-resolution ultrasound examination is therefore recommended to evaluate the fetus for phenotypic manifestations.

For a pregnancy not known to be at increased risk for a SALL4-related disorder. A SALL4 pathogenic variant may be detected for the first time in a family if radial malformations are detected on ultrasound examination as an incidental prenatal finding and prenatal genetic analysis reveals a SALL4 pathogenic variant. If a larger deletion is found, chromosomal microarray analysis may be used to determine if neighboring genes, in additional to SALL4, are included in the deletion (see Genetically Related Disorders).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SALL4 encodes sal-like protein 4 (SALL4), a C2H2 (Krüppel-like) zinc finger transcription factor of the SAL type [Kohlhase et al 2002]. SALL4 appears to be an essential developmental regulator. No embryonic or extra-embryonic endoderm stem cell lines can be established if Sall4 is missing. Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells [Wu et al 2006].

Apart from its role in embryonic and stem cell development, Sall4 is involved in malignant transformation. More than 1,000 putative Sall4 target genes were identified, including many known to have roles in stem cell self-renewal and blood differentiation [Yang et al 2008, Gao et al 2013]. Since human SALL4 is upregulated in some tumor types, especially hepatocellular carcinoma [Yong et al 2013], cancer-related targets are being sought. One direct target is ABCA3, encoding an ATP-binding cassette drug transport protein, which contributes to chemotherapeutic drug resistance [Jeong et al 2011].

Mechanism of disease causation. SALL4 pathogenic variants related to developmental disorders likely lead to haploinsufficiency or some degree of loss of SALL4 function, since all but two pathogenic variants responsible for malformation syndromes are expected to undergo nonsense-mediated decay, and deletions of the whole gene appear to result in the same phenotype [Borozdin et al 2004a, Kohlhase et al 2005].

One pathogenic variant, p.Arg905Ter, is expected to escape nonsense-mediated mRNA decay and to result in a truncated protein with one nonfunctional zinc finger domain [Terhal et al 2006].

Another pathogenic variant, p.His888Arg, exchanges one of the essential amino acids for zinc coordination in a zinc finger and is predicted to result in increased DNA binding of the respective zinc finger [Miertus et al 2006].

Missense variants reported to be causative for premature ovarian insufficiency have been reported to result in a gain of function [Wang et al 2019]. Carriers of such variants do not show any of the malformations that are characteristic for SALL4-related malformation syndromes, whereas female subjects affected by such syndromes have not been reported to suffer from ovarian dysfunction.

Acknowledgments

The author's research has received funding from the Wilhelm-Sander-Stiftung of Germany, a nonprofit organization funding medical research, and from the Deutsche Forschungsgemeinschaft.

Author Notes

SYNLAB Center for Human Genetics Freiburg

Revision History

• 17 March 2022 (sw) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis
• 19 January 2007 (me) Comprehensive update posted live
• 16 August 2004 (ca) Review posted live
• 1 March 2004 (jk) Original submission

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