Behavioral issues with or without bone or brain MRI anomalies
A broad spectrum of behavioral issues has been reported, including pleasant personality, irritability, hyperactivity, sleep problems, sensory issues, stereotyped repetitive movements, and Rett syndrome-like phenotypes[3,7,22,27,28]. Nonspecific brain abnormalities detected by MRI are found in half of affected individuals, including ventricle enlargements, thin corpus callosum, enlarged perivascular spaces, and abnormal myelinization in white matter[7,22]. Some Pectus, finger, or spine deformities have been reported in a few affected individuals, some with concurrent osteopenia[8,22]. In our case, the patient slept less, and brain MRI indicated periventricular leukomalacia and poor myelinization, which is relatively common in subjects with a history of preterm or neonatal respiratory distress syndrome, and showed normal corpus callosum without obvious physical abnormalities (Figure 2B).
Age of onset before 2 years
Individuals with SAS fail to reach normal developmental milestones from infancy. Some other signs may exist from infancy, such as mild but nonspecific facial dysmorphism, hypotonia, feeding difficulties, clinical seizures, and abnormal muscle strength. Growth restriction, severe heart defects, small or undescended testicles, inguinal hernias, hypospadias, and thin skin or hair have been reported in several cases with large deletions including SATB2. In our case, the patient had short stature, though genetic analysis did not reveal large gene deletions.
According to the gene database for SAS (https://satb2gene.com/pros-molecular-data/), 194 variants have been identified, and single nucleotide variants causing a premature stop codon were the most frequent type (46%) followed by missense variants (25%), large deletions > 1 Mb (19%), and small deletions (12%). According to the published data, 120 unique variants have been identified in SATB2, and the most common ones were single nucleotide variants inducing the occurrence of a stop codon (42.5%), and next were the missense variants (25.8%). About 74.2% of missense variants are located in CUT1, CUT2, or homeodomain DNA protein domains. The mutation detected in our case (c.687C>A (p.Y229X)) is a nonsense point mutation that has not been reported previously and located in the CUTL domain.
The phenotypes are heterogeneous according to the fragment deletion size and locations of mutations in SATB2 . For example, abnormal myelination and/or white matter abnormalities were relatively common (26%) in patients with pathogenic nonsense, missense, and frameshift variants, while abnormalities in heart, testicles, skin, or hair were reported in patients with large fragment deletions[7,22]. In addition, even the same genotypes of p.R239* that have been detected in different individuals have phenotypes that were not identical (from Genotype-Phenotype database at https://satb2gene.com/pros-molecular-data/).
The reasons for the heterogeneous manifestations for SAS can be the complicated pathogenic involvements and functions of SATB2. SATB2 is a kind of matrix attachment region-binding transcription factor, with high levels of expression in the brain, including the cerebral cortex and spinal cord, and plays a role in central nervous system development. SATB2 haploinsufficiency can be the cause for intellectual disability. Mutant SATB2 protein appears functionally inactive because of the disrupted associations with chromatin or matrix[3,14]. The oligomerization of the N-terminal domain of SATB1, another SATB family protein, is critical for DNA-binding affinity. The truncated protein with left N-terminus and CUTL domain in a patient with a heterozygous nonsense mutation of c.715C>T (p.R239X) has been shown to localize to the nucleus and interferes with the normal activity of wild-type SATB2 protein by forming a dimer with wild-type SATB2. In our case, the mutation is near the reported mutation of c.715C>T (p.R239X), induces a stop codon at the end of the CUTL domain, and can leave an unaffected N-terminus and oligomerization domain of SATB2. This may disturb the DNA binding and gene regulation like the reported mutation of c.715C>T (p.R239X).
SATB2 is involved in transcription regulation and chromatin remodeling. SATB2 can activate UPF3B transcription, and defects in UPF3B in humans can induce cognitive deficits and craniofacial dysmorphisms. SATB2 regulates a transcriptional network of multiple key determinants for skeletal development by activating or repressing DNA bound protein or enhancing the activity of other DNA binding proteins. Three gene sets related to or regulated by SATB2 have been analyzed at different stages of development; the sets include many genes contributing to schizophrenia and educational attainment. Other research has shown that SATB2 interacts with different protein networks at developing and adult stages in the cortex, indicating that the SATB2 function shifts in the cortex over a lifetime. In the mouse, Satb2 regulates regionalization of the retrosplenial cortex by controlling Nr4a2 and Ctip2 during development, and loss of Satb2 in cortex and hippocampus contributed to abnormal behavior. Satb2 was involved in the specification of upper-layer neuron specification in the neocortex in mouse by regulating expression of specific genes. In the developing cerebral cortex, Satb2 regulated the formation of corticocortical connections by repressing the expression of Ctip2, which is a transcription factor involved in the extension of subcortical projections from cortical neurons[35,36].
The SATB2 function shift at different developmental stages and complex interactions with related proteins may be involved in the pathogenesis of variable manifestations in SAS patients.
Diagnosis for SAS can be quite challenging in infants with only DD, hypotonia, feeding difficulties, and palatal issues. Cerebral palsy may be considered at this time, especially for those who were preterm or had neonatal asphyxia, but nonprogressing motor developmental abnormalities during follow-up are the main characteristic of cerebral palsy. Leukodystrophy is usually the initial diagnosis for those with some neurological manifestations and abnormal findings in white matter on brain MRI and can occur at different ages, from newborn to adult. The initial clinical manifestation of leukodystrophies is often nonspecific, such as motor impairment, cognitive impairment, and seizures. Further diagnosis of leukodystrophies constitutes many kinds of rare heritable disorders and is challenging in most cases. Angelman syndrome and related disorders can be considered during infancy, which are characterized by severe cognitive disability, motor dysfunction, speech impairment, and hyperactivity, but inappropriate happy demeanor may help diagnose[20,39]. Dental and behavioral problems over time may indicate SAS during follow-up. KBG syndrome manifests dental abnormalities (macrodontia of upper central incisors), DD, and other characteristic features that help in diagnosis, including distinctive craniofacial features, such as triangular face, broadened nasal bridge, thin upper lip, and synophrys[20,40].
Today, next generation sequencing technologies, especially whole exome sequencing and whole genome sequencing, are available for clinical genetic diagnosis and differential diagnosis of heritable diseases, especially for distinct differential diagnosis. Cerebral palsy and leukodystrophy are clinical diagnoses, but the etiologies vary and are not fully known. Approximately one-third of cases do not have traditional risk factors, such as prematurity, hypoxic–ischemic injury, placental insufficiency, and prenatal infection, and genetic mutations may be involved in the pathogenesis of a substantial proportion of cases of cerebral palsy. Distinct diagnoses of leukodystrophies have significantly increased due to genetic diagnostic tests. Genetic testing of UBE3A for Angelman syndrome and ANKRD11 for KBG syndrome can help to differentiate the diseases from SAS[39,40].
No specific therapy or guidelines are available for SAS, and regular evaluations after diagnosis and treatment of symptoms are recommended. Specialists in different fields deal with sleep disturbances, seizures, feeding difficulties, behavioral issues, scoliosis, tibial bowing, and joint contractures, among others. Developmental support/special education is referred for DD/ID. Prompts for restructuring oral muscular phonetic targets and aggressive speech therapy (3 ×/wk) at 2-years-old have shown improvements in speech over time, and some communication devices, such as picture exchange communication system, may provide additional help for SAS patients.