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.

Analysis of genotype-phenotype correlations in human holoprosencephaly.

Since the discovery of the first gene causing holoprosencephaly (HPE), over 500 patients with mutations in genes associated with non-chromosomal, non-syndromic HPE have been described, with detailed descriptions available in over 300. Comprehensive clinical analysis of these individuals allows examination for the presence of genotype-phenotype correlations. These correlations allow a degree of differentiation between patients with mutations in different HPE-associated genes and for the application of functional studies to determine intragenic correlations. These early correlations are an important advance in the understanding of the clinical aspects of this disease, and in general argue for continued analysis of the genetic and clinical findings of large cohorts of patients with rare diseases in order to better inform both basic biological insight and care and counseling for affected patients and families.

Total Hip Lithiasis: A Rare Sequelae of Spilled Gallstones.

Laparoscopic cholecystectomy is a surgical treatment for acute cholecystitis or symptomatic cholelithiasis. One potential complication, the spillage of gallstones into the peritoneal cavity, can form a nidus for infection and may be associated with hepatic, retroperitoneal, thoracic, and abdominal wall abscesses. We report a case of a patient presenting with a right iliopsoas abscess and an infected right hip prosthesis status postlaparoscopic cholecystectomy. A CT demonstrated that the acetabular shell was overmedialized and perforated through the medial wall. The patient was taken to the operating room for explantation of components. A collection of gallstones was identified deep to the acetabulum during the explantation. The case highlights the importance of avoiding overmedialization of the acetabular component, which can provide a direct route for infection into the hip joint.

Elevated circulating TGF-ß is not the cause of increased atherosclerosis development in biglycan deficient mice.

BACKGROUND AND AIMS: Vascular biglycan contributes to atherosclerosis development and increased biglycan expression correlates with increased atherosclerosis. However, mice deficient in biglycan have either no reduction in atherosclerosis or an unexpected increase in atherosclerosis. Biglycan deficient mice have systemically elevated TGF-ß, likely due to lack of sequestration of TGF-ß in the extracellular matrix. The purpose of this study was to determine if prevention of TGF-ß elevations in biglycan deficient mice affected atherosclerosis development. METHODS: Biglycan deficient mice were crossed to Ldlr deficient mice. Diabetes was induced via streptozotocin and all mice were fed a high cholesterol diet. Diabetic biglycan wild type and biglycan deficient Ldlr deficient mice were injected with the TGF-ß neutralizing antibody 1D11 or the irrelevant control antibody 13C4. RESULTS: Biglycan deficient mice had significantly elevated plasma TGF-ß levels, which was further increased by diabetes, and significantly increased atherosclerosis. There was a significant correlation between TGF-ß concentrations and atherosclerosis. However, despite nearly complete suppression of plasma TGF-ß levels in mice treated with the TGF-ß neutralizing antibody 1D11, there was no significant difference in atherosclerosis between mice with elevated TGF-ß levels and mice with suppressed TGF-ß levels. CONCLUSIONS: The increased atherosclerosis in biglycan deficient mice does not appear to be due to elevations in TGF-ß.