Familial stenosis of the pulmonary artery branches with a JAG1 mutation.

Although most congenital heart defects are isolated abnormalities of embryonic development, with little genetic contribution, a small number are components of syndromes. In such cases, an accurate diagnosis has important implications for individual prognosis and familial genetic counseling. Alagille syndrome (AGS) is a dominantly inherited multisystem developmental disorder, which primarily affects the liver, heart, eyes, skeleton, and face. In recent years, the identification of the AGS gene has drawn attention to the existence of subclinical carriers, and broadened the spectrum of phenotypical variation associated with this syndrome. The authors present a case of mother and son with benign stenosis of the pulmonary artery branches. Subtle facial aspects suggested the diagnosis of AGS, which was confirmed by molecular analysis. Relevant clinical investigations and diagnostic implications are discussed.     

DiGeorge anomaly in a patient with isochromosome 18p born to a diabetic mother

The DiGeorge anomaly (DGA) is an etiologically heterogeneous developmental field defect in which cardiovascular malformations, hypocalcemia, thymic hypoplasia, and characteristic dysmorphisms are major clinical features. The 22q11.2 deletion is the most common single etiology of DGA, although a number of other chromosomal abnormalities and teratogens, including maternal diabetes, have been implicated as well. We present a patient, born to a diabetic mother, with interrupted aortic arch type B (IAA-B), neonatal hypocalcemia, thymic hypoplasia, and dysmorphic features including microcephaly, thick, overfolded helices, and anteriorly-placed anus. Cytogenetic studies showed the presence of a marker chromosome, identified by fluorescence in-situ hybridization (FISH) as an isochromosome 18p [i(18p)]. We did not detect a 22q11.2 deletion by FISH using a cosmid probe corresponding to locus D22S75. The patient is the first example of either DGA or IAA-B in a patient with i(18p). We review the genetic abnormalities associated with DGA, and discuss the potential contributions of maternal diabetes and i(18p) in our patient.     

ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis

Epidemiological studies suggest links between cholesterol metabolism and Alzheimer's disease (AD), with hypercholesterolemia associated with increased AD risk, and use of cholesterol-lowering drugs associated with decreased risk. Animal models using cholesterol-modifying dietary or pharmacological interventions demonstrate similar findings. Proposed mechanisms include effects of cholesterol on the metabolism of amyloid-beta (Abeta), the protein that deposits in AD brain. To investigate the effect of genetic alterations in plasma cholesterol on Abeta pathology, we crossed the PDAPP transgenic mouse model of AD-like cerebral amyloidosis to apolipoprotein AI-null mice that have markedly reduced plasma cholesterol levels due to a virtual absence of high density lipoproteins, the primary lipoprotein in mice. Interestingly and in contrast to models using non-physiological high fat diets or cholesterol-lowering drugs to modify plasma cholesterol, we observed no differences in Abeta pathology in PDAPP mice of the various apoAI genotypes despite robust differences in plasma cholesterol levels between the groups. Absence of apoAI also resulted in reductions in brain but not cerebrospinal fluid cholesterol, but had no effect on brain apolipoprotein E levels. These and other data suggest that it is perhaps the level of brain apolipoprotein E, not cholesterol per se, that plays a primary role in brain Abeta metabolism.     

Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance

Alagille syndrome is an autosomal dominant disorder affecting multiple organ systems, predominantly the liver, heart, skeleton, eye, face, and kidney. The phenotype in Alagille syndrome is highly variable both within and between families. We report monozygotic twins with Alagille syndrome concordant for a mutation in Jagged1 but discordant for clinical phenotype. The twins' monozygosity was confirmed by molecular testing. A de novo splice site mutation was identified in exon 6 (1329 + 2T --> G) in both children. Both twins display a severe form of Alagille syndrome; however, one twin has a severe pulmonary atresia with mild liver involvement, while the other has tetralogy of Fallot and severe hepatic involvement, which has required liver transplantation. Potential mechanisms for phenotypic variability among monozygotic twins are discussed. This is the first reported case of discordance in phenotype in monozygotic twins with Alagille syndrome. This case implies that genotypic variations alone do not explain the clinical variability seen in Alagille syndrome and supports the contributory role of nongenetic factors in phenotype determination.     

Clinical significance of suprascapular nerve mobilization

The anatomy of the suprascapular nerve is important to surgeons when focal nerve lesions necessitate surgical repair. Recent experience with a patient who had a complete suprascapular nerve lesion in the retroclavicular region (combined with axillary and musculocutaneous nerve lesions) is presented to illustrate that successful direct nerve repair is possible despite resection of a neuroma. Specifically, we found that neurolysis and mobilization of the suprascapular nerve and release of the superior transverse scapular ligament provided the necessary nerve length to achieve direct nerve repair after the neuroma was removed. A combined supraclavicular and infraclavicular approach to the suprascapular nerve provided excellent visualization, especially in the retroclavicular region. Postoperatively, the patient recovered complete shoulder abduction and external rotation with the direct repair, an outcome uncommonly achieved with interpositional grafting. Based on our operative experience, we set out to quantify the length that the suprascapular nerve could be mobilized with neurolysis. Mobilization of the nerve and release of the superior transverse scapular ligament generated an average of 1.6 cm and 0.7 cm of extra nerve length respectively, totaling 2.3 cm of additional usable nerve length overall. The ability to expose the suprascapular nerve in the retroclavicular/infraclavicular region and to mobilize the suprascapular nerve for possible direct repair has not been previously emphasized and is clinically important. This surgical approach and technique permits direct nerve repair after resection of a focal neuroma in the retroclavicular or infraclavicular region, thus avoiding interpositional grafting, and improving outcomes.