Culler-Jones Syndrome

A number sign (#) is used with this entry because Culler-Jones syndrome (CJS) is caused by heterozygous mutation in the GLI2 gene (165230) on chromosome 2q14.

Mutation in the GLI2 gene also causes holoprosencephaly-9 (HPE9; 610829), or HPE-like features, which may be considered at the severe end of the spectrum of features associated with GLI2 mutations.

Description

Culler-Jones syndrome (CJS) is an autosomal dominant disorder characterized by hypopituitarism, mainly growth hormone deficiency, and/or postaxial polydactyly. The phenotype is highly variable, and some patients may have midline facial defects and developmental delay. The disorder shows incomplete penetrance and variable expressivity (summary by Franca et al., 2010).

Clinical Features

Culler and Jones (1984) reported a boy (patient 2) with hypopituitarism and bilateral postaxial polydactyly. He had bilateral cryptorchidism and microphallus. Brain imaging showed an empty sella. His father and older brother had postaxial polydactyly, but no hormone deficiencies. In a follow-up of the family reported by Culler and Jones (1984), Roessler et al. (2005) noted that the proband's older brother with postaxial polydactyly had a son with panhypopituitarism and bilateral postaxial polydactyly. Brain MRI showed aplasia of the pituitary. His endocrine problems responded well to hormone replacement.

Franca et al. (2010) reported a large 4-generation Brazilian family with variable manifestations of polydactyly and pituitary anomalies. The proband was a 7-year-old girl who presented with growth failure and severely delayed psychomotor development associated with early-onset seizures. Endocrine work-up showed severe pituitary hormone deficiencies resulting in short stature (-5.4 SD), delayed bone age, hypogonadotropic hypogonadism, and low thyroid-stimulating hormone. Brain MRI showed a hypoplastic anterior pituitary, an ectopic posterior pituitary, and diminished brain size with asymmetry of the cerebral hemispheres, but no HPE-like abnormalities. She also had a high-pitched voice and bilateral postaxial polydactyly. There were no midline facial defects. Family screening identified 8 maternal relatives with postaxial polydactyly, 3 of whom had growth hormone deficiency associated with anterior pituitary hypoplasia and an ectopic posterior pituitary. One of the relatives with growth hormone deficiency had deficiency of several pituitary hormones. Two additional smaller families were also reported. A 12-year-old boy was born with cleft lip and palate, flat nasal bridge, and cryptorchidism. He later was found to have short stature due to growth hormone deficiency and partial ACTH deficiency. Brain imaging showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe; there were no signs of HPE. The proband of the third family had severe developmental delay with seizures, hypopituitarism of multiple hormones associated with a hypoplastic anterior pituitary, and ADH deficiency with diabetes insipidus associated with lack of a posterior pituitary on brain imaging. In the latter 2 cases, the parents transmitting the mutations were clinically unaffected.

Franca et al. (2013) screened 41 Brazilian patients with isolated growth hormone deficiency and 136 Brazilian patients with combined pituitary hormone deficiency (CPHD) for variants in the GLI2 gene. Eighteen different heterozygous variants were identified in 24 patients, including 1 with isolated GH deficiency and 23 with CPHD. Two patients also had diabetes insipidus, indicating deficiencies of both the anterior and posterior pituitary lobes. Brain imaging showed an ectopic posterior pituitary lobe in 16 patients and an undetectable posterior lobe in 4. None of the patients had signs of HPE, midline facial defects, or polydactyly. Functional studies of the identified GLI2 variants were not performed. Franca et al. (2013) concluded that patients with CPHD and an ectopic posterior pituitary lobe, with or without polydactyly or midline facial defects, are candidates for GLI2 study.

Bear et al. (2014) screened a large cohort of approximately 400 individuals with HPE spectrum disorders, including those with pituitary deficiencies, for variations in the GLI2 gene, and combined these data with patients with GLI2 variants collected from the published literature. Variants were identified in 112 individuals from 65 kindreds, including 30 individuals (27%) who had not previously been reported. Forty-three individuals had truncating mutations, whereas the rest had missense variants of unknown significance; functional studies of the variants were not performed. Only 1 of the 43 patients with truncating mutations had frank HPE (this patient was previously reported by Bertolacini et al., 2012). Most (67%) of the 112 patients with GLI2 variants studied by Bear et al. (2014) were described as having normal facial features or were nondysmorphic. Individuals with truncating mutations were more likely to have pituitary anomalies and/or polydactyly compared to those with variants of unknown significance. Those with truncating mutations also tended to have a common facial phenotype, with midface hypoplasia, cleft lip/palate, and hypotelorism. Bear et al. (2014) concluded that there is a well-defined phenotype in individuals with pathogenic GLI2 mutations, which does not typically include HPE. Rather, the phenotype includes anterior pituitary anomalies and postaxial polydactyly, although not all individuals with predicted pathogenic mutations have both findings.

Inheritance

The transmission pattern of Culler-Jones syndrome in the family reported by Culler and Jones (1984) and Roessler et al. (2005) was consistent with autosomal dominant inheritance and incomplete penetrance.

The transmission pattern of CJS in the families reported by Franca et al. (2010) was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity.

Molecular Genetics

In affected members of a 3-generation family with variable manifestations of CJS, originally reported by Culler and Jones (1984), Roessler et al. (2005) identified a heterozygous truncating mutation in the GLI2 gene (165230.0008).

In affected members of 3 unrelated families with variable manifestations of hypopituitarism and postaxial polydactyly without signs of HPE, Franca et al. (2010) identified 3 different heterozygous frameshift or truncating mutations in the GLI2 gene (see, e.g., 165230.0008 and 165230.0009). Franca et al. (2010) suggested that the incomplete penetrance and highly variable expressivity observed in this phenotype result from a complex pattern of inheritance combining multiple environmental and genetic factors, such as variants at other loci or digenic inheritance.