Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

Perceived utility of parent-generated family health history as a health promotion tool in pediatric practice.

OBJECTIVES: The purpose of this study was to describe how pediatric providers collect and use family health history (FHH) and their perceptions about My Family Health Portrait (MFHP) as a pediatric health promotion and disease prevention tool. STUDY DESIGNL: A random sample of 148 pediatric providers was invited to participate in a semistructured qualitative interview. Transcripts were reviewed by 2 coders, and interrater reliability was determined. RESULTS: In all, 21 providers were interviewed. All participants collected FHH at new visits and when patients presented with a symptom or complaint. Most providers believed that collecting FHH of chronic disease benefits the pediatric population. Time was the most commonly cited barrier to FHH collection; collecting FHH prior to the office visit was the most frequently cited facilitator. Providers believed that the use of MFHP would improve FHH collection and allow targeted education and preventive recommendations. Respondents also identified logistical and other issues that must be resolved to integrate MFHP into clinical practice. CONCLUSION: This research suggests that pediatric primary care presents many opportunities to collect and discuss FHH and that providers are optimistic about the clinical use of a parent-generated FHH collection tool. Future research should assess parent perspectives about the use of MFHP.