Neonatal Sotos Syndrome: A Novel Frameshift Mutation of the NSD1 Gene Associated with Neonatal Encephalopathy Presenting without Overgrowth

Abstract

Sotos syndrome type I is one of the more common genetic overgrowth disorders. It presents classically with macrocephaly, distinctive facial gestalt, and acromegalic features, along with neonatal complications including hypotonia, feeding difficulties, and hypoglycemia with other minor feature inconstancies. The phenotypical overlap of features of this syndrome, more so in neonatal age, thwarts an easy diagnosis. In this case report, a neonate of a nonconsanguineous marriage to a multigravida mother with insignificant obstetric history, presented primarily with respiratory difficulty, central hypotonia, and hypoglycemia. Sparse hair, tall forehead, pointed chin, and lax skin were accompanied by persistent encephalopathy and refractory myoclonic jerks. However, the quintessential features of pre- and postnatal overgrowth were lacking, making the line of diagnosis difficult. On neuroimaging, atypical diffuse pachygyria was found. Clinical exome sequencing revealed heterozygous single base pair deletion in exon 21 of the NSD1 gene on chromosome 5q35, resulting in an unreported frameshift and premature truncation of the protein 19 amino acids downstream to codon 2065, confirming the genetic diagnosis of autosomal dominant Sotos syndrome 1. The neonate later succumbed to death after withdrawal of ventilatory support.

Keywords

Sotos syndrome - central hypotonia - persistent encephalopathy

Publication History

Received: 28 May 2022

Accepted: 02 August 2022

Article published online:
15 September 2022

• References

• 1 Sotos JF, Dodge PR, Muirhead D, Crawford JD, Talbot NB. Cerebral gigantism in childhood: a syndrome of excessively rapid growth and acromegalic features and a non-progressive neurologic disorder. N Engl J Med 1964; 271: 109-116
• 2 Tatton-Brown K, Cole TRP, Rahman N. Sotos syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al. Seattle, WA: GeneReviews(R) 1993. Accessed September 5, 2021, at: http://www.ncbi.nlm.nih.gov/books/NBK1116/
• 3 Noreau DR, Al-Ata J, Jutras L, Teebi AS. Congenital heart defects in Sotos syndrome. Am J Med Genet 1998; 79 (04) 327-328
• 4 Tatton-Brown K, Rahman N. The NSD1 and EZH2 overgrowth genes, similarities and differences. Am J Med Genet C Semin Med Genet 2013; 163C (02) 86-91
• 5 Cole TRP, Hughes HE. Sotos syndrome: a study of the diagnostic criteria and natural history. J Med Genet 1994; 31 (01) 20-32
• 6 Tatton-Brown K, Douglas J, Coleman K. et al; Childhood Overgrowth Collaboration. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet 2005; b 77 (02) 193-204
• 7 Waggoner DJ, Raca G, Welch K. et al. NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory. Genet Med 2005; 7 (08) 524-533
• 8 Cohen Jr MM. Mental deficiency, alterations in performance, and CNS abnormalities in overgrowth syndromes. Am J Med Genet C Semin Med Genet 2003; 117C (01) 49-56
• 9 Schaefer GB, Bodensteiner JB, Buehler BA, Lin A, Cole TR. The neuroimaging findings in Sotos syndrome. Am J Med Genet 1997; 68 (04) 462-465
• 10 Aoki N, Oikawa A, Sakai T. Serial neuroimaging studies in Sotos syndrome (cerebral gigantism syndrome). Neurol Res 1998; 20 (02) 149-152
• 11 Hersh JH, Cole TR, Bloom AS, Bertolone SJ, Hughes HE. Risk of malignancy in Sotos syndrome. J Pediatr 1992; 120 (4 Pt 1): 572-574
• 12 Tatton-Brown K, Rahman N. Clinical features of NSD1-positive Sotos syndrome. Clin Dysmorphol 2004; 13 (04) 199-204