Satb2-Associated Syndrome

Clinical characteristics.

SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited to absent speech, behavioral issues, and craniofacial anomalies. All individuals described to date have manifest developmental delay / intellectual disability, with severe speech delay. Affected individuals often have hypotonia and feeding difficulties in infancy. Behavioral issues may include autistic features, hyperactivity, and aggressiveness. Craniofacial anomalies may include palatal abnormalities (cleft palate, high-arched palate, and bifid uvula), micrognathia, and abnormal shape or size of the upper central incisors. Less common features include skeletal anomalies (osteopenia, pectus deformities, kyphosis/lordosis, and scoliosis), growth restriction, strabismus/refractive errors, congenital heart defects, genitourinary anomalies, and epilepsy. While dysmorphic features have been described in individuals with this condition, these features are not typically distinctive enough to allow for a clinical diagnosis of SAS.

Diagnosis/testing.

The diagnosis of SATB2-associated syndrome (SAS) is established in a proband by detection of one of the following:

• A heterozygous intragenic SATB2 pathogenic variant (61%)
• A heterozygous deletion at chromosome 2q33.1 that includes SATB2 (22%)
• An intragenic deletion or duplication of SATB2 (9%)
• A chromosome translocation with a chromosome 2q33.1 breakpoint that disrupts SATB2 (8%)

Management.

Treatment of manifestations: Treatment is symptomatic. Nutritional support for feeding difficulties and management by a cleft/craniofacial team for those with palatal anomalies early in life. Early referral for developmental support/special education; standard treatment for dental anomalies, sleep disturbance, skeletal anomalies, seizure disorders, genitourinary anomalies, strabismus and refractive errors, and congenital heart defects.

Surveillance: Evaluation of nutritional status, growth, and developmental progress at each visit; routine monitoring by a neurologist for those with epilepsy; annual sleep study in those with a history of sleep disturbance; evaluation for scoliosis/spine deformity at each visit and consideration of screening for osteopenia; routine evaluations by dentistry and ophthalmology.

Genetic counseling.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a de novo genetic event. In two families, parental mosaicism seemed likely (given recurrence of SAS in sibs and failure to detect the genetic alteration in parental blood samples).To date, individuals with SAS are not known to reproduce. Once an SATB2 intragenic pathogenic variant, a 2q33.1 deletion that includes SATB2, or a chromosome translocation affecting SATB2 has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

SATB2-associated syndrome (SAS) should be suspected in individuals with the following major features [Zarate & Fish 2017]:

• Significant neurodevelopmental disorders in all affected individuals
  • Infantile hypotonia and feeding difficulties (relatively common)
  • Subsequent developmental delay and severe speech delay (including, in some, absence of speech)
• Behavioral issues: autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies: cleft palate, bifid uvula, and high-arched palate
• Dental anomalies: prominent upper incisors and other anomalies

Some of the common features can be described using the acronym SATB2: severe speech anomalies; abnormalities of the palate, teeth anomalies, behavioral issues with or without bone or brain anomalies, and onset before age 2.

Establishing the Diagnosis

The diagnosis of SATB2-associated syndrome (SAS) is established in a proband by detection of one of the following: a heterozygous intragenic SATB2 pathogenic variant, a heterozygous non-recurrent deletion at 2q33.1 that includes SATB2, an intragenic deletion or duplication of SATB2 detectable by chromosomal microarray analysis (CMA), or a chromosome translocation with a 2q33.1 breakpoint that disrupts SATB2 (see Table 1).

Molecular genetic testing approaches can include a combination of CMA, a multigene panel, comprehensive genomic sequencing, and exome array.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many inherited disorders with developmental delay / intellectual disability overlap, many children with SAS are diagnosed by the following recommended genomic testing.

Note: Because the phenotype of SAS is indistinguishable from a wide range of other developmental disorders, most affected individuals with a 2q33.1 deletion are likely to be diagnosed using CMA and individuals with a pathogenic variant detectable by sequence analysis are likely detected by comprehensive genomic sequencing.

Clinical Description

SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited or absent speech, behavioral issues, and craniofacial anomalies.

The following clinical findings, based on published reports of 76 individuals with a molecularly confirmed diagnosis of SAS (47 male, 27 female, 2 where sex was not reported), are summarized in Table 2 [Van Buggenhout et al 2005, Leoyklang et al 2007, de Ravel et al 2009, Rosenfeld et al 2009, Urquhart et al 2009, Rifai et al 2010, Balasubramanian et al 2011, Rauch et al 2012, Mc Cormack et al 2013, Tomaszewska et al 2013, Döcker et al 2014, Gilissen et al 2014, Liedén et al 2014, Trakadis et al 2014, Kaiser et al 2015, Yu et al 2015, Zarate et al 2015, Boone et al 2016, Gregoric Kumperscak et al 2016, Lee et al 2016, Bengani et al 2017, Schwartz et al 2017, Zarate et al 2017].

Developmental delay / intellectual disability. While all known individuals with SAS have some degree of intellectual disability, more than half experience severe developmental delay / intellectual disability with absent speech [Zarate & Fish 2017]. For those with a heterozygous pathogenic variant within SATB2 (those who do not have a larger deletion of 2q33.1 that includes SATB2 and other genes), mean age at walking is 20.9 months (range 11-35) and at first word is 19.8 months (range 13-42), although some never achieve verbal communication [Zarate et al 2017].

Developmental regression and/or cognitive decline has been described only once in an adult female with an 8.6-Mb deletion of 2q32.2-q33.1 who progressed from mild to severe intellectual disability and from poor to absent speech between ages six and 12 years [Gregoric Kumperscak et al 2016].

Mild but nonspecific facial dysmorphism. In most reports of affected individuals, at least minor facial dysmorphic features have been reported. For those with pathogenic variants within SATB2, thin vermilion of the upper lip (20%) and long and smooth philtrum (17%) are the most consistent features (Figure 1 A-E) [Zarate & Fish 2017, Zarate et al 2017]. In those with larger 2q33.1 deletions, the most consistent features include prominent forehead or high anterior hairline (53%), thin vermilion of the upper lip (35%), low-set ears (29%), and/or long face (24%) (Figure 1 F-G) [Zarate & Fish 2017].

Figure 1.

Facial features of individuals with SATB2-associated syndrome caused by intragenic pathogenic variants in SATB2 (A-D), intragenic deletion of SATB2 (E), and large deletions that include SATB2 and other adjacent genes (F-G). Most consistently reported (more...)

Dental anomalies. While abnormal shape or size or the upper central incisors is the most common finding (36%), other dental issues can include crowding (36%), hypodontia (16%), delayed primary dentition (6%), and/or diastema (4%). Other issues reported by families include sialorrhea, malocclusion, and fused incisors [Zarate et al 2017].

Behavioral anomalies. A broad spectrum of behavioral findings described can include jovial or friendly personality, autistic tendencies, agitation or aggressive outbursts, hyperactivity, difficulties falling asleep or maintaining sleep, and sensory issues [Bengani et al 2017, Zarate et al 2017]. Two affected females were described to have Rett syndrome-like phenotypes with limited purposeful hand movements, stereotyped repetitive movements, and bruxism [Lee et al 2016]. Additional behavioral issues include high pain tolerance, obsessive tendencies, skin picking, and anxiety [Zarate et al 2017].

Skeletal anomalies. Pectus deformities, kyphosis/lordosis, and scoliosis have been described in several affected individuals. To date tibial and/or femoral bowing has been described in a few individuals, some with concurrent osteopenia [Zarate et al 2018]. Arachnodactyly, broad thumbs, clinodactyly, small hands/feet, and finger contractures have been infrequently reported.

While routine screening for osteopenia has not been conducted systematically, low bone mineral density or radiographic evidence of osteopenia has been documented to date in several affected individuals as early as age two years [Leoyklang et al 2007, Tegay et al 2009, Talkowski et al 2012, Liedén et al 2014, Rainger et al 2014, Zarate et al 2015, Boone et al 2016, Lee et al 2016, Zarate et al 2018]. Elevated alkaline phosphatase levels have been seen in some individuals with documented osteopenia [Boone et al 2016, Zarate et al 2018].

Craniofacial anomalies. Palatal abnormalities documented in 76% of individuals include cleft palate (50%), high-arched palate (23%), and bifid uvula (3%). Micrognathia, diagnosed in 42%, has not required surgical correction. The combination of craniofacial issues and hypotonia is the most likely explanation for the high frequency of feeding issues present during infancy and beyond.

Neuroimaging. Brain abnormalities, documented in half of affected individuals who underwent head MRI, include nonspecific findings such as enlarged ventricles (12%), agenesis of the corpus callosum (5%), and prominent perivascular spaces (5%). Of interest, abnormal myelination for age and/or non-progressive white matter abnormalities appear to be particularly common (26%) in those with pathogenic nonsense, frameshift, and missense variants [Zarate & Fish 2017, Zarate et al 2017]. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of SAS.

Other neurologic manifestations

• Hypotonia, particularly during infancy (42%)
• Clinical seizures (14%)
• EEG abnormalities without clinically recognizable seizures [Zarate et al 2017]
• Less common neurologic issues include gait abnormalities/ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).

Growth restriction. Pre- and postnatal growth restriction, sometimes with associated microcephaly, can be found in individuals with SAS, particularly in those with large deletions involving SATB2 and adjacent genes (71%).

Eye findings. Both strabismus (18%) and refractive errors (8%) have been described.

Cardiovascular. Septal defects have been reported in two affected individuals with large deletions involving SATB2 and adjacent genes. In one person, echocardiographic evaluation also revealed severe right ventricular volume overload and persistent pulmonary hypertension [Van Buggenhout et al 2005, Mc Cormack et al 2013].

Genitourinary. Small or undescended testicles, inguinal hernias, and hypospadias have been described in males with large deletions involving SATB2 and adjacent genes.

Ectodermal changes. Thin skin, reduced subcutaneous fat, and thin or sparse hair have been described in some affected individuals with large deletions involving SATB2 and adjacent genes.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for SATB2 pathogenic variants have been formally established to date; however, it has been suggested that genitourinary anomalies, cardiac defects, and ectodermal changes (other than dental) are more common (or exclusively present) in affected individuals with large deletions involving SATB2 and adjacent genes [Zarate & Fish 2017].

The number of reported individuals with SAS is still relatively small; genotype-phenotype correlations may emerge as more affected individuals are identified.

Nomenclature

The name Glass syndrome was suggested after a report of a male with a cytogenetically visible 2q32.2-q33.1 deletion that included SATB2 was published [Glass et al 1989]. SATB2 was subsequently identified as the gene associated with this syndrome [FitzPatrick et al 2003]. The designation of SATB2-associated syndrome (SAS) was recently proposed as a new clinically recognizable syndrome [Döcker et al 2014].

For SATB2 alterations, however, the existence of multiple designations for a fairly consistent phenotype ‒ regardless of the underlying pathomechanism ‒ has created some confusion particularly for families of affected individuals [Author, personal experience] such that separate social media support groups exist, one for individuals with deletions of SATB2 and another for individuals with pathogenic intragenic SATB2 variants. In this review, the authors have documented a consistent phenotype independent of the underlying SATB2 genetic alteration. When described, phenotypic differences appear to relate (with few exceptions) to differences in severity rather than in the system affected. Therefore, in an attempt to unify the nomenclature and reduce confusion, the authors support use of the term SATB2-associated syndrome.

Prevalence

The prevalence of SAS is not known. However, two recent studies have estimated the frequency of SAS in large cohorts of individuals with undiagnosed intellectual disability / developmental delay at 0.24%-0.3% [Bengani et al 2017, Zarate et al 2018].

Evaluations and Referrals Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SATB2-associated syndrome (SAS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended:

Treatment of Manifestations

Treatment is symptomatic; no specific therapy is available. The following are appropriate interventions [Zarate & Fish 2017].