Truncating and zinc-finger variants in GLI2 are associated with hypopituitarism.

Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low-risk variants. Four Zn-finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn-finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2-related phenotypic variability. The most prevalent phenotypic feature is post-axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.

C-reactive protein in the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome.

AIMS: To evaluate levels of C-reactive protein (CRP) during febrile episodes in children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). METHODS: All CRP values during typical episodes of fever in children diagnosed with PFAPA during a 3 years period were retrospectively registered. RESULTS: In 16 children with PFAPA, a total of 87 CRP values were registered during 38 episodes of fever. The mean of the maximum CRP during each episode was 185 mg/L (SD: 69.4, range: 45-322). Values of CRP were elevated throughout the whole period of fever, with higher values on days 2-4 compared to day 1. CONCLUSION: Levels of CRP are substantially increased during febrile episodes in children with PFAPA. High levels of CRP may suggest a role for immunological mechanisms in PFAPA, and may raise the suspicion of PFAPA when measured in children with periodic fever of unknown origin.