A novel heterozygous GLI2 mutation in a patient with congenital urethral stricture and renal hypoplasia/dysplasia leading to end-stage renal failure

Abstract

Glioblastoma 2 (GLI2) is a mediator of Sonic hedgehog signaling pathway that plays an important role in development of the central nervous system and limbs. Heterozygous GLI2 mutations have been associated with postaxial polydactyly, various pituitary dysfunction, and holoprosencephaly-like phenotype. Herein, we report a Japanese boy who presented with isolated growth hormone deficiency with ectopic posterior pituitary, postaxial polydactyly, atrioventricular septal defect, intellectual disability and dysmorphic facial features including mid-facial hypoplasia. The patient was also complicated with congenital urethral stricture with megacystis, hydronephrosis, and renal hypoplasia/dysplasia, which led to end-stage renal failure by the age of 8 years. Trio-whole-exome sequencing showed a novel de novo heterozygous frameshift mutation in GLI2 (c.3369delG, p.Met1123Ilefs*7) in the patient. This is the first report of possible association between GLI2 mutation and the phenotype of congenital anomalies of the kidney and urinary tract, and subsequent end-stage renal failure. Further studies on the urogenital phenotype in patients with GLI2 mutations may clarify a role of GLI2 in embryonic development of the urinary tract.

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the <i>GLI2</i> Gene

“…The clinical spectrum of mutations in GLI2 may vary from asymptomatic individuals to polydactyly, functional and structural abnormality in the pituitary gland, facial dysmorphism, Culler-Jones syndrome, HPE-like syndrome, and frank HPE ( 4 , 8 ). In addition, renal problems such as renal hypoplasia/dysplasia, urethral stricture and cardiac problems such as ASD/VSD have been reported in patients with GLI2 mutations ( 4 , 8 ). HPE is the most common anterior brain anomaly and HPE is characterized by incomplete separation of cerebral hemispheres and underdeveloped midbrain structures.…”

“…HPE presents with a more severe clinical spectrum with additional midline structural abnormality and forebrain cleavage defects. To date, about 25 different pathogenic GLI2 mutations have been identified ( 4 ). Heterozygous GLI2 mutations can be inherited in an autosomal dominant fashion or de novo (51% maternal, 40% paternal, and 9% de novo ) ( 5 ).…”

“…GH: Growth hormone, TSH: thyroid stimulating hormone, ACTH: adrenocorticotropic hormone, N/A: not available and structural abnormality in the pituitary gland, facial dysmorphism, Culler-Jones syndrome, HPE-like syndrome, and frank HPE(4,8). In addition, renal problems such as renal hypoplasia/dysplasia, urethral stricture and cardiac problems such as ASD/VSD have been reported in patients with GLI2 mutations(4,8).…”

Truncating and zinc‐finger variants in GLI2 are associated with hypopituitarism

“…We analyzed the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants, including the three reported here, for common findings (Figure 2) (Babu et al, 2019; Bertolacini et al, 2012; Culler & Jones, 1984; Demiral et al, 2020; Elizabeth et al, 2020; Elward et al, 2020; Flemming et al, 2013; França et al, 2010; Kremer Hovinga et al, 2018; Martín‐Rivada et al, 2019; Rahimov et al, 2006; Roessler et al, 2003; Shirakawa et al, 2018; Solomon et al, 2012; Vishnopolska et al, 2021). Hypopituitarism affected 58% (33/57) of the individuals.…”

Unique near-complete deletion of GLI2 in a patient with combined pituitary hormone deficiency and post-axial polydactyly

“…GLI2 is located on chromosome 2q14.2 and consists of a 6.8 kb coding sequence that extends 13 exons and encodes a 1586 amino acid protein [11]. GLI2 is the primary mediator in the Sonic Hedgehog (Shh) signaling pathway which is crucial for the formation of central nervous system midline and pituitary development [12].…”