CDON gene contributes to pituitary stalk interruption syndrome associated with unilateral facial and abducens nerve palsy

Abstract

The relationship between congenital defects of the brain and facial anomalies was proven. The Hedgehog signaling pathway plays a fundamental role in normal craniofacial development in humans. Mutations in the sonic hedgehog (SHH) signaling gene CDON have been recently reported in patients with holoprosencephaly and with pituitary stalk interruption syndrome (PSIS). This study’s aim was an elucidation of an 18-year-old patient presenting PSIS, multiple pituitary hormone deficiency, and congenital unilateral facial and abducens nerve palsy. Additionally, bilateral sensorineural hearing loss, dominating at the right site, was diagnosed. From the second year of life, growth deceleration was observed, and from the age of eight, anterior pituitary hormone deficiencies were gradually confirmed and substituted. At the MRI, characteristic triad for PSIS (anterior pituitary hypoplasia, interrupted pituitary stalk and ectopic posterior lobe) was diagnosed. We performed a comprehensive genomic screening, including microarrays for structural rearrangements and whole-exome sequencing for a monogenic defect. A novel heterozygous missense variant in the CDON gene (c.1814G > T; p.Gly605Val) was identified. The variant was inherited from the mother, who, besides short stature, did not show any disease symptoms. The variant was absent in control databases and 100 healthy subjects originating from the same population. We report a novel variant in the CDON gene associated with PSIS and congenital cranial nerve palsy. The variant revealed autosomal dominant inheritance with incomplete penetrance in concordance with previous studies reporting CDON defects.

CDON Mutation Related to Nose Deformity with Variable Expression in Holoprosencephaly in an Iranian Family: A Case Report

“…A new CDON missense mutation (c.1814G > T; p. Gly605Val) is related to PSIS, and congenital cranial nerve palsy has been identified. In accordance with earlier research revealing CDON abnormalities, the variation exhibited autosomal dominant inheritance with partial penetrance ( 27 ). With a missing or inadequate columella, philtrum, and/or pro-labium, the nasal complex is hypoplastic.…”

The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis

“…Finally, mutations in PTCH1, PTCH2 ( 177 ), GPR161 , HHAT and CDON have been found in PSIS patients ( 86 , 178 , 179 ). PSIS is characterized by a combination of three specific findings on magnetic resonance imaging, which are an interrupted pituitary stalk, an absent or ectopic posterior pituitary and anterior pituitary hypoplasia.…”

“…PSIS is characterized by a combination of three specific findings on magnetic resonance imaging, which are an interrupted pituitary stalk, an absent or ectopic posterior pituitary and anterior pituitary hypoplasia. Besides these characteristics, PSIS is also associated with other midline and ophthalmic abnormalities and variable endocrine disorders such as hypoglycemia, growth failure, or CPHD ( 86 , 178 , 179 ).…”