Natural History of the SATB2-Associated Syndrome: case report and literature review

RESUMO

INTRODUÇÃO: Historically, the phenotype related to alterations in the Special AT-rich Sequence Binding Protein 2 gene (SATB2) have been initially denominated “the Glass Syndrome” after the report of one patient with a deletion on chromosome 2q32.2q33.1.(1) Microdeletions, duplications and translocations encompassing SATB2 were subsequently reported in the literature suggesting that haploinsufficiency might be responsible for the 2q32q33 microdeletion syndrome, which is characterized by learning difficulties, growth retardation, dysmorphic features, thin/sparse hair, feeding difficulties, and cleft or high palate.(2) Until 2014, two individuals were reported with the same nonsense mutation c.715C>T (p.Arg239*) in the SATB2 gene.(3,4) Small duplication and four deletions restricted to SATB2 gene were also described.(2,5-12) Based on these reports, a clinical entity named SAS (SATB2-Associated Syndrome) was proposed and it is characterized by severe developmental delay/intellectual disability, abnormalities in craniofacial patterning including micrognathia, dental and palatal abnormalities, behavioral problems, and subtle dysmorphic features.(4,13) Other findings described later include skeletal anomalies and osteopenia/osteoporosis.(13,14)

OBJETIVOS: We describe the natural hystory of a 25-year-old male with SATB2-Associated Syndrome due to a de novo heterozygous nonsense mutation: c.715C>T (p.Arg239*) who was identified within a multicentric etiologic study of Syndromic Oral Clefts.

MÉTODOS: (Clinical report)

RESULTADOS: Clinical Report: The proband is a 25-year-old man, the only child of healthy and nonconsanguineous parents. He was born after an uneventful gestation at 39 weeks. Physical examination after delivery showed a hypotonic newborn with a cleft palate. At the age of three months, he started supportive therapies as he maintained general hypotonia, and neurological and motor development were delayed. He was referred for genetic evaluation at 6 years of age with the following symptoms: axial hypotonia, delayed development of fine motor skills, and behavioral anomalies. Neuropsychological assessment revealed absence of speech with a difficulty in global comprehension and processing. He had skull and facial asymmetry, a triangular face with a high anterior hairline, deeply set eyes and prominent orbital ridges, synophrys, strabismus, dental anomalies (prominent incisors and dental crowding) and mandibular prognathism. Skeletal deformities included thoracic scoliosis, pectus excavatum, lower limb asymmetry, and valgus deformity of the right knee. Echocardiogram showed mitral and tricuspid regurgitation and a discrete right ventricular dilation. Renal and lower urinary tract ultrasounds were normal. At the age of 13 years old, the patient started using risperidone in order to control his aggressiveness and agitation. The latest physical examination was accomplished at the age of 25 years and unraveled a low stature and weight for his age (stature: 164 cm (5th percentile) and weight: 53kg (less than 3rd percentile)), an adequate head circumference (57cm (50th percentile)) and the same dysmorphism described earlier, including facial and skeletal anomalies. He has moderate intellectual disability, but psychometric testes were not performed. In spite of maintaining absence of speech, he was able to communicate by gestures and to comprehend simple commands. He has never presented seizures. During the follow-up, he was investigated by GTG-banding karyotype, fluorescence in situ hybridization with the TUPLE1 probe, and chromosomal microarray analysis, all with normal results. Subsequently, whole exome sequencing demonstrated a heterozygous pathogenic variant in the SATB2 gene, a predicted loss-of-function variant c.715C>T (p.Arg239*).

CONCLUSÃO: Review of the literature has identified cleft palate to be more frequent in patients with a c.715C>T (p.Arg239*) mutation than other mutations causing SAS. Given the more widespread use of next-generation sequencing in diagnostics, variants in SATB2 are being more frequently identified and this approach is important to improve our knowledge on clinical phenotypes, pathogenesis, natural history, and therefore management of SAS. Since our patient is 25 years old, the case herein reported contributes to a better characterization of the evolution of this genetic condition in addition to a better delineation of the genotype-phenotype correlation in SAS.

BIBLIOGRAFIA: 1. Glass IA, Swindlehurst CA, Aitken DA, et al. Interstitial deletion of the long arm of chromosome 2 with normal levels of isocitrate dehydrogenase. J Med Genet. 1989;26:127-130. 2. Balasubramanian M, Smith K, Basel-Vanagaite L, et al. Case series: 2q33.1 microdeletion syndrome-further delineation of the phenotype. J Med Genet. 2011;48:290-298. 3. Leoyklang P, Suphapeetiporn K, Siriwan P, et al. Heterozygous nonsense mutation SATB2 associated with cleft palate, osteoporosis, and cognitive defects. Hum Mutat. 2007;28:732-738. 4. Docker D, Schubach M, Menzel M, et al. Further delineation of the SATB2 phenotype. Eur J Hum Genet. 2014;22:1034-1039. 5. Van Buggenhout G, Van Ravenswaaij-Arts C, MC Mass N, et al. The del(2)(q32.2q33) deletion syndrome defined by clinical and molecular characterization of four patients. Eur J Med Genet. 2005;48:276-289. 6. Mencarelli MA, Caselli R, Pescucci C, et al. Clinical and molecular characterization of a patient with a 2q31.2-32.3 deletion identified by array-CGH. Am J Med Genet A. 2007;143A:858-865. 7. de Ravel TJ, Balikova I, Thiry P, et al. Another patient with a de novo deletion further delineates the 2q33.1 microdeletion syndrome. Eur J Med Genet. 2009;52:120-122. 8. Urquhart J, Black GC, Clayton-Smith J. 4.5 Mb microdeletion in chromosome band 2q33.1 associated with learning disability and cleft palate. Eur J Med Genet. 2009;52:454-457. 9. Rosenfeld JA, Ballif BC, Lucas A, et al. Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome. PLoS One. 2009;4:e6568. 10. Cocchella A, Malacarne M, Forzano F, et al. The refinement of the critical region for the 2q31.2q32.3 deletion syndrome indicates candidate genes for mental retardation and speech impairment. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1342-1346. 11. Ferreira SI, Matoso E, Venancio M, et al. Critical region in 2q31.2q32.3 deletion syndrome: report of two phenotypically distinct patients, one with an additional deletion in Alagille syndrome region. Mol Cytogenet. 2012;5:25. 12. Kaiser AS, Maas B, Wolff A, et al: Girl with developmental delay, nearly absent speech and oligodontia: First case of an intragenic SATB2 duplication. Med Genet. 2013; 25:125. 13. Zarate YA, Perry H, Ben-Omran T, et al. Further supporting evidence for the SATB2-associated syndrome found through whole exome sequencing. Am J Med Genet A. 2015;167A:1026-1032. 14. Zarate YA, Smith‐Hicks CL, Greene C, et al. Natural history and genotype‐phenotype correlations in 72 individuals with SATB2‐ associated syndrome. Am J Med Genet A. 2018;176:925-935.

PALAVRA-CHAVE: natural history, whole-exome sequencing, cleft palate, SATB2.