ESPE Abstracts

Introduction: Coffin-Siris Syndrome (CSS) is a rare multisystem genetic disorder which arises from genetic abnormalities within genes encoding for the SWI/SNF complex (ARID1A, ARID1B, DPF2, SMARCA4, SMARCB1, SMARCA2, SMARCE1). Endocrinopathies have been associated with CSS, including idiopathic short stature, hyperinsulinism, obesity, growth hormone deficiency, and cryptorchidism. Here, we describe the endocrine features of a series of children with SWI/SNF-associated CSS.

Methods: Case note review of eight children with CSS caused by pathogenic variants in the SWI/SNF complex attending a tertiary endocrine centre (ARID1B n=6; ARID1A n=1; DPF2 n=1).

Results: Of the six children with ARID1B variants, one has confirmed growth hormone deficiency (GHD) with pituitary hypoplasia (ARID1B, c.1518dupC, p.Gly507fs) and one has short stature, bilateral undescended testes, and a hypoplastic corpus callosum. Two others do not have endocrinopathies but have abnormal pituitaries and/or septo-optic dysplasia (ARID1B, c.4063C>T, p.Gln1355*; ARID1B c.5993_5994del, p.Glu1998Glyfs*3). The fifth child has a normal pituitary gland, polycystic ovarian syndrome, insulin insensitivity, and anosmia (ARID1B, c.3862+1G>A). The sixth has no endocrine nor pituitary abnormalities (ARID1B, c.5345del, p.Ser1782Ilefs*8). The child with the ARID1A variant (c.1213C>T, p.Gln405*) has septo-optic dysplasia with no endocrinopathies. The child with the DPF2 variant (c.894_904+6del; p.Cys298Trpfs*) has delayed puberty, GHD, and anterior pituitary hypoplasia. All of these variants are novel, have not been associated previously with CSS, and are predicted pathogenic in in silico prediction models.

Discussion: CSS exhibits a complex, multisystem phenotype. Here we expand the spectrum of SWI/SNF-associated CSS to include pituitary endocrinopathies, anterior pituitary hypoplasia, and midline brain abnormalities on the septo-optic dysplasia spectrum. This is consistent with the phenotype seen in mice heterozygous for Arid1b loss-of-function variants. We describe novel variants in CSS-related genes, emphasising the genetic heterogeneity of this condition. The SWI/SNF complex modulates chromatin structure and carries key roles in transcription and cell differentiation, which may explain the aberrant pituitary development seen in a subset of patients with CSS.