Clinical Characteristics

Pituitary anomalies
Hypopituitarism may manifest as a deficiency of a single pituitary hormone, such as isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). Symptoms related to the hypopituitarism may include abdominal pain, decreased appetite, short stature, delayed bone age, diabetes insipidus, slowed growth and sexual development, cryptorchidism and small penis

In patients with GLI2 mutations, there is frequent anterior pituitary hormone deficiency. For patients with heterozygous truncating GLI2 mutations, the phenotype frequently included growth hormone (GH) deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging (MRI) and postaxial polydactyly. For patients with heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, the posterior pituitary was also ectopic, but none had polydactyly.

Of note, only two individuals with a non-truncating variant had polydactyly and one of them was the sole individual with preaxial polydactyly—all others with polydactyly had postaxial polydactyly.

Facial features
More than half of patients with GLI2 mutations with available clinical descriptions of facial features, were described as being normal or non-dysmorphic. Of those with dysmorphic features reported, although not universal, the patients had a specific well-defined combination of facial features. Many of them had features of mild midface hypoplasia (13/101, 13%), cleft lip/palate (16/101, 16%) and/or hypotelorism (4/101, 4%).

Neuroanatomical anomalies
After an extensive review of more than 400 patients, Bear et al. (2014) concluded that frank HPE resulting from pathogenic GLI2 mutations is rare. The absence of forebrain abnormalities in patients with GLI2 mutations, as opposed to those with SHH mutations, might be related to the maintained activity of GLI3 in the former.
The most severe neuroanatomical finding reliably reported appears to be agenesis of the genu of the corpus collosum, along with an abnormal cerebral periventricular venous system and abnormal gyri. Callosal anomalies are frequently described in HPE, but in HPE, they occur in conjunction with additional evidence of midline non-separation.
Patients with HPE with GLI2 variants were described as demonstrating typical facial features, with more severe facial features correlating with more severe brain abnormalities. These facial features include cyclopia, hypotelorism, proboscis, single nostril, flat nasal bridge, cleft lip and/or palate, iris coloboma and single central incisor.


  • The c.2064delC/p.Ser690Alafs*5 (S690Afs*5) mutation was identified in a 20‐year‐old girl with hexadactyly, choanal atresia, hypopituitarism, and cerebellar atrophia. This mutation occurred de novo.
  • The c.596dupG/p.Ala200Argfs*151 (A200Rfs*151) mutation was identified in a boy with nasal pyriform aperture atresia and was inherited from his asymptomatic mother.
  • The c.790C>T/p.Arg264* (R264*) mutation was identified in a 2‐year‐old girl with isolated solitary median maxillary central incisor and was inherited from her asymptomatic mother.
  • The c.4761G>C/p.*1587Tyrext*46 (*1587Y) mutation was found in a 16‐year‐old boy with hypopituitarism, solitary median maxillary central incisor, and choanal atresia. It was inherited from his asymptomatic mother.
  • The c.2237G>A/p.Trp746* (W746*) mutation was identified in a male fetus aborted because of lobar HPE, premaxillary agenesis, hexadactyly, pituitary hamartoma, and short femur. Moreover, his karyotype revealed a mosaic fragility on chromosome 3 (3p24.1, so very far from TDGF1). This mutation was not inherited from his mother, and DNA from the father was unavailable.

Bertolacini et al. (2012) reported 6 unrelated Brazilian patients with variable manifestations resulting from a heterozygous mutation in the GLI2 gene. The phenotype ranged from isolated cleft lip/palate with polydactyly, to branchial arch anomalies, to semilobar holoprosencephaly. Some patients had marked involvement of the temporomandibular joint and derivatives of the first branchial arch. Only 1 patient had neurodevelopmental delay. Three of the mutations were inherited from a mother with very mild manifestations, and one mutation occurred de novo.