Glass Syndrome

A number sign (#) is used with this entry because Glass syndrome (GLASS) is caused by heterozygous interstitial deletion on chromosome 2q32-q33. The disorder can also be caused by heterozygous mutation in the SATB2 gene (608148), which is within the Glass syndrome chromosome region.

Description

Glass syndrome is characterized by intellectual disability of variable severity and dysmorphic facial features, including micrognathia, downslanting palpebral fissures, cleft palate, and crowded teeth. Additional features may include seizures, joint laxity, arachnodactyly, and happy demeanor (summary by Glass et al., 1989; Urquhart et al., 2009; Rainger et al., 2014).

Clinical Features

Glass et al. (1989) reported a 16-year-old boy with severe mental retardation, microcephaly, and craniofacial dysmorphism associated with an interstitial deletion of chromosome 2q32.2-q33.1. He had no comprehensible speech and was totally dependent for all activities. Facial features included large beaked nose, ptosis, and cleft palate. He also had seizures and a striking scalloped skin pigmentation that did not follow Blaschko lines. Activity of isocitrate dehydrogenase (IDH1; 147700) was normal.

Van Buggenhout et al. (2005) reported 4 unrelated patients with interstitial deletions of chromosome 2q32-q33. Common clinical features included pre- and postnatal growth retardation, severe mental retardation, thin and sparse hair, persistent feeding difficulties, inguinal hernia, and broad-based gait. Facial features included high long face, high forehead, ptosis, dacrocystitis, high nasal bridge, small mouth, teeth abnormalities, micrognathia, and cleft or high-arched palate. Two patients had seizures, and 3 had spasticity and contractures. Three patients had a specific behavioral phenotype with hyperactivity and motor restlessness, chaotic behavior, and happy personality intermixed with periods of aggression and anxiety, sleeping problems and self-mutilation. Array CGH and FISH analysis showed that all patients shared an 8.1-Mb minimal deleted region. The cleft or high-arched palate most likely resulted from hemizygosity for the SATB2 gene (608148).

Rosenfeld et al. (2009) reported 3 unrelated patients with small heterozygous deletions of chromosome 2q33.1, ranging from 173.1 to 185.2 kb, that affected only the SATB2 gene. Parental samples from the mother were available for only 2 patients, and neither mother carried the deletion; parental samples were not available for the third patient. All patients had severe developmental delay, mental retardation, and tooth anomalies, but other features varied. Dentofacial anomalies included delayed primary dentition and micrognathia in 1 patient; cleft palate, crowded teeth, and small mandible in the second; and fused mandibular central incisors without cleft palate in the third. Two patients had behavioral abnormalities and mild dysmorphic features. Rosenfeld et al. (2009) concluded that haploinsufficiency for SATB2 is responsible for some of the clinical features associated with the 2q32-q33 deletion syndrome.

Urquhart et al. (2009) reported a girl with a de novo heterozygous 4.5-Mb microdeletion of chromosome 2q33.1. She had cleft soft palate, feeding problems, febrile seizures, and delayed psychomotor development with poor speech. She was mildly dysmorphic, with broad forehead, flat philtrum, small mouth, thin upper lip, missing lateral incisors, and relative macrocephaly, but ears were normal. She also had joint laxity, valgus foot deformity, broad toes and thumbs, brachydactyly, and contractures of the fourth and fifth fingers. She had a social disposition. Brain MRI showed nonspecific periventricular white matter abnormalities. The deleted region included the SATB2 gene.

Rifai et al. (2010) reported a 16-year-old girl, born of unrelated French Caribbean parents, with an interstitial 26.3-Mb deletion of chromosome 2q31.2-q33.2. She had prenatal and postnatal growth retardation, microcephaly, facial dysmorphism, cleft palate, camptodactyly, bilateral talipes equinovarus, severe intellectual disability, and ectodermal anomalies. Ectodermal anomalies included thin, atrophic skin, sparse, brittle, slowly growing hair, oligodontia with abnormally shaped teeth, normal sweating, and normal fingernails. These findings were consistent with a diagnosis of ectodermal dysplasia. The deletion resulted in hemizygosity for the HOXD gene (see, e.g., HOXD1; 142987) cluster and its regulatory elements, which may affect limb development. Haploinsufficiency of other genes such as COL3A1 (120180)/COL5A2 (120190), GTF3C3 (604888), CASP8 (601763), CASP10 (601762), and SATB2 may also influence the phenotype.

Balasubramanian et al. (2011) reported 7 unrelated patients with different interstitial deletions of chromosome 2q33.1. The phenotype was variable, but common features included delayed psychomotor development, feeding difficulties early in life, and dysmorphic facies. Dysmorphic features could be delineated into 2 groups: one with upturned nose and myopathic facies, and another with a prominent nose and downslanting palpebral fissures. However, variable features were reported, including slightly low-set ears, sparse hair, high forehead, tented upper lip, downturned mouth corners, hypertelorism, long or short philtrum, and micrognathia. Three had cleft palate, 4 had high-arched palate, and most had dental crowding. Four had digital anomalies, such as overlapping toes, 2 had joint laxity, and 5 had behavioral anomalies, ranging from inappropriate hugging to hyperactivity and aggression.

Leoyklang et al. (2007) reported a Thai man with isolated cleft palate, gum hyperplasia, slight micrognathia, generalized osteoporosis, and mental retardation. CT scan of the facial bones revealed multiple anomalies, including asymmetric mandibular hypoplasia, wide mandibular angles, anterior overbite of the upper teeth with marked anterior-pointing incisors, midline cleft palate, abnormal sinuses, short zygomatic arches, and flattened mandibular condylar heads. The patient also had profound mental retardation, seizures, and a jovial personality.

Docker et al. (2014) reported a 3-year-old girl with cleft palate, severely delayed speech, hypotonia, and mental retardation. Dysmorphic facial features included hypotonic face with hypersalivation, hypertelorism, downslanting palpebral fissures, long eyelashes, upturned nose with broad tip, microretrognathia, long philtrum, low-set and posteriorly rotated ears, and crowded teeth. She also had severe sleeping disturbances, restlessness/hyperactivity, and recurrent temper tantrums.

Rainger et al. (2014) reported a 33-year-old man with severe intellectual disability, aggressive behavior, and dysmorphic features, including small mouth, cleft palate, micrognathia, prominent nasal bridge, long nose, long columella, abnormal dentition, and arachnodactyly. Molecular studies identified a de novo heterozygous t(2;3)(q33.1;q26.33) translocation with the breakpoint on 2q33.1 within the PLCL1 (600597)-SATB2 gene desert.

Lieden et al. (2014) reported a 20-year-old man with delayed psychomotor development since infancy and moderate to severe intellectual disability with only a few spoken words. Neurologic features included impairment of fine and gross motor skills, mild hemiparesis, and spasticity with hyperreflexia. He had no seizures, and brain imaging was normal at age 3 years. Additional features included tall forehead, bushy eyebrows, prominent nose, cleft palate, narrow maxilla with malocclusion, oligodontia, and abnormally shaped teeth. He had a slender body habitus with bowing of the tibiae and osteoporosis. He had a happy demeanor without behavioral problems. The phenotype was similar to that observed in other patients with this disorder.

Kaiser et al. (2015) reported a 10-year-old German girl who presented at age 33 months with delayed psychomotor development, no speech development, sleeping problems, and feeding difficulties. Brain MRI showed pathologic myelination with increased signal intensity in the right parietooccipital region. At age 10 years, she had mild growth retardation, moderate to severe intellectual disability with nearly absent speech, and attended a school for disabled children. Mild dysmorphic features were also present, including narrow jaw with high palate and crowded teeth, short palpebral fissures, broad nose with broad nasal bridge, bulbous nasal tip and thick columella, short hands, mildly broad thumbs, and big toes. Her sleeping and feeding difficulties had improved.

Bengani et al. (2017) reported 20 previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants). Of the 19, all had neurodevelopmental impairment, 16 had absent/near absent speech, 17 had normal somatic growth, 9 had cleft palate, 12 had drooling, and 8 had dental anomalies. Sib recurrence due to gonadal mosaicism was seen in 1 family.

Inheritance

All patients with Glass syndrome have been shown to carry de novo heterozygous mutations in the SATB2 gene or de novo heterozygous deletions of chromosome 2q32-q33 (Leoyklang et al., 2013).

Cytogenetics

Brewer et al. (1999) reported 2 unrelated girls with cleft palate, facial dysmorphism, and mildly delayed development and learning difficulties associated with balanced, de novo cytogenetic rearrangements involving the same region of 2q. Molecular cytogenetic analyses localized both translocation breakpoints between markers D2S311 and D2S116 on chromosome 2q32. Facial features included prominent nasal bridge with underhanging columella, small mouth with distinctive upper lip, and long, slender fingers. FitzPatrick et al. (2003) determined that 1 of the breakpoints in the 2 girls reported by Brewer et al. (1999) localized to intron 2 of SATB2, and the other breakpoint was located 130 kb 3-prime to the SATB2 polyadenylation signal, within a conserved region of noncoding DNA. Whole-mount in situ hybridization to mouse embryos showed site- and stage-specific expression of SATB2 in the developing palate. Despite the strong evidence supporting an important role for SATB2 in palatal development, mutation analysis of an additional 70 unrelated patients with isolated cleft palate did not reveal any coding region variants.

Rainger et al. (2014) reevaluated 1 of the patients reported by Brewer et al. (1999) and FitzPatrick et al. (2003) at age 24 years. She had long thin face, micrognathia, and arachnodactyly. She had significant intellectual disability and required constant supervision. Rainger et al. (2014) also reevaluated a father and son with cleft palate, micrognathia, microstomia, and oligodontia (OFC13; 613857) previously reported by Ghassibe-Sabbagh et al. (2011). Ghassibe-Sabbagh et al. (2011) had identified a translocation in these patients, t(1;2)(p34;q33), that interrupted the FAF1 gene (604460) on chromosome 1p34; they did not think that the 2q breakpoint contributed to the phenotype. However, Rainger et al. (2014) found that the 2q33 breakpoint in this family was about 896-kb centromeric to the SATB2 gene and likely interrupted SATB2 cis-regulatory elements. Rainger et al. (2014) suggested that the phenotypes in the patients reported by Brewer et al. (1999) and Ghassibe-Sabbagh et al. (2011) resulted from SATB2 haploinsufficiency.

By oligonucleotide-based array CGH analysis in 7 patients with chromosome 2q33.1 deletion syndrome, Balasubramanian et al. (2011) determined that the interstitial deletions ranged in size from 35 kb to 10.4 Mb. The smallest deletion was entirely within the SATB2 gene (chr2:199,877,238-199,911,975). Four other deletions also included the SATB2 gene, suggesting that haploinsufficiency for this gene is responsible for many of the features. However, 2 deletions did not include the SATB2 gene and did not overlap, indicating that other genes proximal and distal to SATB2 contribute to the phenotype.

Using comparative genomics, Rainger et al. (2014) identified 3 different functional enhancing cis-regulatory elements (CREs) in the gene desert between the PLCL1 and SATB2 genes, 3-prime to SATB2. Sites within these 3 CREs were shown to bind SOX9 (608160) in cells derived from a mouse embryonic pharyngeal arch. Studies in zebrafish showed that CRE2 could drive SATB2-like expression in the embryonic craniofacial region. The findings suggested that the translocation breakpoints identified in patients with craniofacial defects disrupt the long-range cis regulation of SATB2 by SOX9, resulting in functional haploinsufficiency of SATB2.

Molecular Genetics

In a Thai man with isolated cleft palate, gum hyperplasia, slight micrognathia, generalized osteoporosis, and mental retardation, Leoyklang et al. (2007) identified a de novo heterozygous nonsense mutation in the SATB2 gene (R239X; 608148.0001).

Docker et al. (2014) identified a de novo heterozygous R239X mutation (rs137853127) in a 3-year-old girl with cleft palate, severely delayed speech, hypotonia, and mental retardation. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Mutant mRNA was present in the patient's cells, suggesting that it does not undergo nonsense-mediated mRNA decay. Docker et al. (2014) concluded that the SATB2 gene is essential for normal craniofacial patterning and cognitive development.

In a 20-year-old man with Glass syndrome, Lieden et al. (2014) identified a de novo heterozygous intragenic duplication of the SATB2 gene (608148.0002). The duplication was found by array CGH analysis; functional studies and studies of patient cells were not performed.

In a 10-year-old girl with Glass syndrome, Kaiser et al. (2015) identified a de novo heterozygous intragenic duplication of the SATB2 gene (608148.0003), predicted to result in haploinsufficiency. The patient was born of unrelated parents and conceived via intracytoplasmic sperm injection.

Bengani et al. (2017) reported 19 different SATB2 mutations, of which 11 were loss-of-function and 8 missense (e.g., 608148.0004-608148.0006). SATB2 nuclear mobility was mutation-dependent. The clinical features in individuals with missense variants were indistinguishable from those with loss-of-function variants. Bengani et al. (2017) found that when mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.