Endocrine Abstracts

Introduction: Coffin-Siris Syndrome (CSS) is a rare multisystem genetic disorder which often arises from genetic abnormalities within genes encoding for the SWI/SNF complex (ARID1A, ARID1B, DPF2, SMARCA4, SMARCB1, SMARCA2, SMARCE1). Endocrine abnormalities previously associated with this disorder include idiopathic short stature, hyperinsulinism, obesity, growth hormone deficiency, and cryptorchidism. We describe the endocrine features and associated radiological findings of a series of children with SWI/SNF-associated CSS.

Results: A total of eight children with CSS caused by pathogenic variants in the SWI/SNF complex attend our tertiary endocrine centre (ARID1B n=6; ARID1A n=1; DPF2 n=1). 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, Gln405*) has septo-optic dysplasia with no endocrinopathies. The child with the DPF2 variant (c.894_904+6del; p.Cys298Trpfs*38) has delayed puberty, GHD, and anterior pituitary hypoplasia.

Discussion: CSS exhibits a complex, multisystem phenotype. We expand the spectrum of SWI/SNF-associated Coffin-Siris syndrome 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 Arib1b loss-of-function variants. 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.