An emerging, recognizable facial phenotype in association with mutations in GLI‐similar 3 (GLIS3)

Abstract

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non‐autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico‐medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI‐similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low‐set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

“…2A), have been linked to a wide range of pathologies. Patients with loss-of-GLIS3-function mutations most consistently develop a syndrome referred to as neonatal diabetes and congenital hypothyroidism (NDH) and have a greatly reduced life span of a few days to several years [13, 42–48]. Abnormalities associated with GLIS3 mutations can extend to intrauterine growth retardation (IUGR), developmental delay, development of polycystic kidneys, congenital glaucoma, hepatic cholestasis, osteopenia, atrial septal defects, and minor facial dysmorphisms.…”

“…Mutations in human GLIS3 that cause loss of function, are extremely rare and were first described in several NDH patients from Saudi Arabia and France and subsequently in a few other patients [13, 42–47]. Genetic mutations in GLIS3 include deletions encompassing exons 4–8, and several larger deletions covering regions >100 kb that include exons 1–3 and part of intron 3, and large parts of the upstream regulatory region (Fig.…”

“…Studies demonstrating that loss of GLIS3 function in humans and mice causes neonatal diabetes indicated a regulatory role for GLIS3 in pancreatic β cells [1, 4, 5, 13, 22, 28, 42–50]. The development of hyperglycemia and hypoinsulinemia in GLIS3 deficiency was found to be related to aberrant pancreatic β cell generation and insulin production suggesting that GLIS3 may have a role in the regulation of pancreas development.…”

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

“…Homozygous mutations in GLIS3 have been reported to cause infancy-onset diabetes, congenital primary hypothyroidism, and mild facial dysmorphism [1, 56]. These facial features were analyzed in detail for seven patients and include eye (elongated palpebral fissures), ear (low-set), nose (upturned; depressed nasal bridge), and mouth (long philtrum; thin dark border of the upper lip) characteristics [57]. Liver fibrosis and polycystic kidneys have been reported rarely [58].…”

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

“…These include craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, choanal atresia, sensorineural deafness and exocrine pancreatic insufficiency (Dimitri et al 2011(Dimitri et al , 2015. They further described facial dysmorphism including bilateral low-set ears, depressed nasal bridge, elongated and upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in some patients (Dimitri et al 2016). Notably, one patient with compound heterozygous mutations in GLIS3 (p.Arg589Trp/exons 1-11 del) presenting with neonatal diabetes, but not congenital hypothyroidism or renal cysts, survived to adulthood.…”