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].
Table 2.
Summary of the Most Common Clinical Findings in 76 Individuals with SATB2-Associated Syndrome
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Finding | % of Affected Individuals 1 |
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Developmental delay / intellectual disability | 100% |
Speech delay | 95% |
Craniofacial dysmorphism | 89% |
Dental anomalies | 72% |
Behavioral issues | 55% |
Cleft palate | 50% |
Abnormal brain MRI | 49% |
Micrognathia | 42% |
Hypotonia | 42% |
Feeding difficulties | 39% |
Growth restriction | 34% |
Skeletal anomalies | 32% |
- 1.
Complete information was not available on some individuals.
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 () [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%) () [Zarate & Fish 2017].
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%)
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.