Sall4-Related Disorders

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2021-01-18
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Summary

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, vesico-ureteral 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.

Diagnosis is based on clinical findings and presence of a heterozygous SALL4 pathogenic variant.

Management.

Treatment of manifestations: Surgery as needed for strabismus from Duane anomaly, malformations of the forearms, and congenital heart defects; antiarrhythmic medications or pacemaker for those with conduction defects or heart block; hearing aids as needed; consideration of growth hormone therapy for treating children with growth retardation.

Prevention of secondary complications: A cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis (SBE).

Surveillance: In those at risk for conduction defects, ECG at least annually with consideration of annual Holter monitor in those with known conduction defects; periodic echocardiographic surveillance may be recommended for individuals with certain congenital heart defects; routine monitoring of 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; at least yearly blood counts in those with a history of thrombocytopenia and leukocytosis.

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 diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

SALL4-related disorders include a spectrum of phenotypes previously thought to be distinct entities: Duane-radial ray syndrome (DRRS), or Okihiro syndrome; acro-renal-ocular syndrome (AROS) [Kohlhase et al 2003]; and SALL4-related Holt-Oram syndrome (HOS).

Duane-radial ray syndrome/Okihiro syndrome is established clinically in individuals with the following:

  • Duane anomaly, characterized by 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. Malformations 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 features that are variably present; see Clinical Characteristics.

Acro-renal-ocular syndrome is established clinically in individuals with the following:

  • Radial ray malformations
  • Renal abnormalities that can include mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesico-ureteral reflux, and bladder diverticula
  • Ocular abnormalities that can include ocular coloboma and Duane anomaly

SALL4-related Holt-Oram syndrome (HOS) is characterized by the following:

  • Upper-extremity malformations involving radial, thenar, and/or carpal bones, including preaxial polydactyly
  • Congenital heart malformations, including 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.

Molecular Genetic Testing

Gene. SALL4 is the only gene mutated in Duane-radial ray/Okihiro syndrome (DRRS), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS).

One genetic testing strategy is SALL4 sequence analysis, followed by deletion/duplication analysis if a pathogenic variant is not identified (Table 1).

An alternative genetic testing strategy is use of a multigene panel that includes SALL4 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included and the methods used in multigene panels vary by laboratory and are likely to change over time. (3) Panel testing should be considered only if the phenotype falls outside of the typical spectrum of SALL4-related disorders. (4) Panel testing may not detect larger deletions in the genes included.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in SALL4-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SALL4Sequence analysis 2≤80% 3
Deletion/duplication analysis 410%-15% 5, 6
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

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

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Borozdin et al [2004a], Borozdin et al [2007]

6.

FISH analysis detects deletions; however, given the relatively small size of the gene, FISH analysis may have a low yield / limited utility.

Clinical Characteristics

Clinical Description

In addition to the clinical features described in Diagnosis, the clinical manifestations of SALL4-related disorders may include the following:

  • Eyes. Microphthalmia (rare); iris, retinal, and choroidal colobomata; cataract; optic disc hypoplasia
  • Upper extremities. Concomitant shortening of ulnae, syndactyly, radial clubhand, shortened humeri, hypoplasia of deltoid muscles
  • Kidneys. Renal agenesis, crossed renal ectopia, position anomalies of kidneys
  • Ears/hearing. Sensorineural and/or conductive deafness, abnormal pinnae, slit-like opening of auditory canals, small ears
  • Heart. Atrial septal defect, ventricular septal defect, tetralogy of Fallot
  • Gastrointestinal. Anal stenosis, imperforate anus
  • Face. Epicanthal folds, widely spaced eyes , depressed nasal bridge, hemifacial microsomia
  • Lower extremities. Talipes, clubfoot, tibial hemimelia, syndactyly of toes
  • Spine. Fused vertebrae
  • Pituitary. Growth hormone deficiency, postnatal growth retardation, pituitary hypoplasia
  • Central nervous system. Neural tube defects (rare); meningomyelocele has been observed in two affected individuals [J Kohlhase, unpublished results].
  • Blood. Mild thrombocytopenia and leukocytosis; present in some individuals with SALL4 pathogenic variants [Paradisi & Arias 2007]; see Genetically Related Disorders.

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. In 82.6% of families, at least one person has Duane anomaly and in 48%, at least one person has hearing loss. Radial ray malformations have been found in all families with a SALL4 pathogenic variant and in 91.3% of individuals with a pathogenic variant. Sixty-five percent of individuals with a SALL4 pathogenic variant have Duane anomaly and 16% have hearing loss [data collected in 2004 from published reports and unpublished cases compiled by the Author].

Genotype-Phenotype Correlations

Most pathogenic 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 so far (c.2663A>G, p.His633Arg) 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].

Persons with Okihiro syndrome and developmental delay are likely to have a larger deletion including SALL4 and neighboring genes [Borozdin et al 2007]. Developmental delay/intellectual disability associated with a pathogenic variant within SALL4 has not been observed.

Penetrance

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

In two reported families [Hayes et al 1985, Kohlhase et al 2002]: either an individual known (on the basis of pedigree position) to have the SALL4 pathogenic variant is unaffected, or an individual with a proven SALL4 pathogenic variant shows no signs of a SALL4-related disorder. 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 are known to the author.

Anticipation

Apparent increased severity in successive generations is attributed to ascertainment bias.

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].

The term "Holt-Oram syndrome" has 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 Holt-Oram syndrome caused by pathogenic variants in TBX5 or from other hand-heart syndromes.

Differential Diagnosis

Holt-Oram syndrome. The main differential diagnosis is Holt-Oram syndrome (HOS) caused by pathogenic variants in TBX5. HOS is characterized by upper-limb malformations involving radial, thenar, or carpal bones; a personal and/or family history of congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum; and cardiac conduction defects. TBX5-related Holt-Oram syndrome and SALL4-related HOS have the same type of radial ray malformations, although preaxial polydactyly is almost exclusively associated with SALL4 pathogenic variants and is extremely rare in those with a TBX5 pathogenic variant (a single case is known to the author). The heart defects seen in those with SALL4-related disorders and HOS caused by pathogenic variants in TBX5 are similar [Borozdin et al 2004a] but ASD may be more common than VSD with mutation of TBX5, whereas the opposite may apply for SALL4. Pathogenic variants of both genes may result in more severe heart defects like tetralogy of Fallot, but cardiac conduction defects have been observed less commonly with SALL4 pathogenic variants than with TBX5 pathogenic variants. Individuals with typical radial ray malformations and a renal or urogenital malformation (especially position anomalies of the kidneys), but without Duane anomaly, are more likely to have a SALL4 pathogenic variant than a TBX5 pathogenic variant.

Townes-Brocks syndrome. This syndrome is characterized by a triad of dysplastic ears, imperforate anus, and triphalangeal thumbs/preaxial polydactyly [Powell & Michaelis 1999]. Townes-Brocks syndrome is associated with mutation of SALL1. In a few individuals, complete overlap exists between Okihiro syndrome and Townes-Brocks syndrome [Kohlhase et al 2002, Borozdin et al 2004a]. In these individuals, SALL4 molecular genetic testing should be considered if Duane anomaly is present and if SALL1 molecular genetic testing does not reveal a pathogenic variant. Because radial aplasia has not been observed in individuals with mutation of SALL1 [J Kohlhase, unpublished data], its presence points towards mutation of SALL4 even when all other features suggest Townes-Brocks syndrome.

Fanconi anemia. Individuals with radial ray malformations may also have Fanconi anemia. A range of additional features may be present, including other skeletal anomalies, heart defects, urogenital and renal anomalies, hypogonadism, ear anomalies, hearing loss, eye anomalies, imperforate anus, growth retardation, pigmentation anomalies, and developmental delay. Persons with Fanconi anemia often show blood cell count anomalies (a very rare finding in individuals with SALL4 pathogenic variants) and develop progressive bone marrow failure with pancytopenia. There is a significant risk for leukemia and solid tumors. Developmental delay is not a feature of SALL4-related disorders apart from rare persons with multigene deletions that include SALL4 [J Kohlhase, unpublished data], and Duane anomaly is not a feature of Fanconi anemia. Persons with radial ray anomalies and involvement of other organs who do not present with typical findings of Okihiro syndrome/AROS should be evaluated for Fanconi anemia by appropriate tests (i.e., chromosomal aberrations [breaks, radial figures] after cell cultivation in medium with DEB [diepoxybutane] and/or mitomycin C; see Fanconi Anemia for details).

Thrombocytopenia-absent radius (TAR) syndrome. Individuals with TAR syndrome have radial aplasia, but in contrast to SALL4-related disorders, the thumbs are never absent, although they may appear malformed. Thromobocytopenia does not typically occur in SALL4-related disorders; it may be only transiently detectable in TAR syndrome. Several other malformations may occur in TAR syndrome [Greenhalgh et al 2002]. RBM8A is the only gene in which biallelic pathogenic variants are known to cause TAR syndrome. One allele is typically inactivated by a minimally deleted region of 200 kb at chromosome band 1q21.1 (including RBM8A), which is distinct from the region involved in the 1q21.1 deletion/duplication syndrome [Klopocki et al 2007, Mefford et al 2008]. The second allele is hypomorphic (i.e., demonstrates partial loss of gene function in the noncoding region of R8BM8A) [Albers et al 2012].

Arthrogryposis-ophthalmoplegia syndrome. In this syndrome, Duane anomaly is associated with deafness, muscle wasting, and contractures, but not typical radial limb malformations. A SALL4 pathogenic variant was not identified in one of the few families reported [McCann et al 2005].

Wildervanck syndrome. The Wildervanck syndrome consists of congenital perceptive deafness, Klippel-Feil anomaly, and Duane anomaly. The disorder affects almost exclusively females. The cause of Wildervanck syndrome is unknown. SALL4 pathogenic variants have not been detected in some persons who meet the diagnostic criteria for Wildervanck syndrome [J Kohlhase, unpublished data].

Thalidomide embryopathy. From 1957 to 1962, malformed children were born to mothers who took the drug thalidomide for treatment of nausea and insomnia during pregnancy. Currently, thalidomide is prescribed to treat conditions such as multiple myeloma, HIV, and leprosy. Fetal abnormalities related to thalidomide administration during pregnancy include amelia, phocomelia, radial hypoplasia, external ear abnormalities (including anotia, microtia, micropinna), facial palsy, eye abnormalities (anophthalmos, microphthalmos, Duane anomaly, cranial nerve misrouting resulting in "crocodile tears"), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations also occur. Mortality at or shortly after birth is approximately 40% [Miller & Strömland 1999]. If an individual with a diagnosis of thalidomide embryopathy has a child with radial ray malformations similar to those seen in Holt-Oram syndrome and SALL4-related disorders and additional malformations (i.e., Duane anomaly or kidney defects), a SALL4 pathogenic variant is more likely to be found than a TBX5 pathogenic variant [Kohlhase et al 2003].

Testing strategy for individuals with typical radial ray malformations

  • Perform cardiac evaluation, ophthalmologic examination, and renal ultrasound examination in addition to a routine physical examination.
  • If no features typical of SALL4-related disorders are found, TBX5 molecular genetic testing is suggested as the first molecular test.
  • If other features typical of SALL4-related disorders are found, SALL4 molecular genetic testing is suggested as the first step.
  • If clinical overlap exists with Townes-Brocks syndrome, SALL1 molecular genetic testing should be the first test if the radial ray malformations do not include malformations of the radius itself; if malformation of the radius is present, SALL4 molecular genetic testing is suggested as the first molecular test.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SALL4-related disorder, the following evaluations are recommended:

  • Eyes. A complete eye examination by an ophthalmologist with special attention to extraocular movements and structural eye defects
  • Heart. Baseline evaluation by a cardiologist including an echocardiogram and an ECG. If suspected, more extensive evaluation for cardiac conduction defects may be needed especially when structural heart defects are present.
  • Kidneys. Renal ultrasound examination and routine laboratory tests for renal function
  • Hearing. See Hereditary Hearing Loss and Deafness Overview.
  • Endocrine. If growth retardation is present, consideration of evaluation for growth hormone deficiency
  • Blood. Baseline CBC to evaluate for thrombocytopenia and/or leukocytosis.
  • Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Duane anomaly. Severe strabismus may require eye surgery.

Radial ray malformations. Severe malformations of the forearms may require surgery, e.g., surgery to correct aplasia of the thumb by constructing a functional thumb (pollicization).

Heart defects. Cardiac surgery, if required for a congenital heart defect, is standard. A cardiologist can assist in determining the need for antiarrhythmic medications and surgery. Individuals with severe heart block may require pacemaker implantation.

Hearing deficits. Hearing aids may be required.

Growth retardation. Growth hormone therapy should be considered for treating affected children.

Prevention of Secondary Complications

A cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis (SBE).

Surveillance

In those with cardiac malformations or conduction defects:

  • ECG is indicated annually or more often in individuals diagnosed with a conduction defect, as well as in individuals at risk for developing a conduction defect.
  • ECG should be combined with annual Holter monitor in individuals with known conduction disease to assess progression.
  • Depending on the nature and significance of a known cardiac malformation, echocardiogram surveillance may be requested every one to five years by the managing cardiologist.

In those with renal anomalies:

  • Renal function should be monitored by routine laboratory parameters for renal function (ie, serum creatinine), even if no impairment of renal function is detected on initial examination. In the first years of life, renal function should be performed every six months or once per year. If renal function remains normal, the screening intervals may be extended.
  • Renal ultrasound should be repeated if renal position anomalies could cause obstruction. The frequency depends on the clinical situation.
  • In those affected individuals with thrombocytopenia and leukocytosis, blood counts should be monitored at least yearly. However, data are sparse on the natural history of thrombocytopenia in individuals with SALL4 pathogenic variants and so it is unknown at present if more severe complications may occur.

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

Although reduced penetrance does not appear to be associated with most SALL4 pathogenic variants, unaffected persons may consider molecular genetic testing prior to family planning. Children of affected persons who are themselves not obviously affected may be tested for the pathogenic variant present in the family because individuals with the 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 www.ClinicalTrialsRegister.eu 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.