Myocardial fat overgrowth in Proteus syndrome.

Proteus syndrome (PS) is a rare, mosaic disorder with asymmetric and distorting overgrowth of the skeletal system, skin, and adipose tissues. Cardiac abnormalities are rare in this syndrome and only two prior cases have been reported. Many patients with PS followed at our institution underwent transthoracic echocardiograms for preoperative evaluation or as work-up for associated pulmonary disease. Some were noted to have prominent, focal echodense areas in the myocardium. We further investigated cardiac findings in a cohort of children and adult patients with PS. Patients with abnormal echocardiograms were referred for cardiac magnetic resonance imaging, Holter monitoring, and exercise treadmill testing. Twenty children and adults with PS, age 24 months to 50 years old, underwent transthoracic echocardiograms. Seven patients (35%) had focal bright echodense areas within the myocardium suggesting fatty infiltration. The majority of patients had significant involvement of the interventricular septum. The cardiac characteristics of all patients with fatty infiltration on transthoracic echocardiograms were compared to Proteus patients without these findings. There were no significant differences in chamber sizes, mass, systolic or diastolic function. No increased risk of conduction defects or arrhythmias was found. This study shows that abnormal fat overgrowth is a common finding in the myocardium in patients with Proteus syndrome; however, it is not associated with functional derangements or arrhythmias. Further evaluation of a larger number of Proteus patients is needed in order to determine the frequency and prognosis of cardiac involvement. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for approximately 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (for example, deletions and duplications) in the human genome, which result in gene copy number variations (CNVs). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. METHODS AND RESULTS: This study identified duplications on chromosomes 5 or X using genome wide array comparative genomic hybridisation (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and craniofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. CONCLUSIONS: The results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new "reverse genomics" trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic aetiology.

OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases.

OEIS complex refers to a combination of defects consisting of omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. Possible embryologic mechanisms proposed for these findings have included: a single defect of early blastogenesis or a defect of mesodermal migration during the primitive streak period. Fourteen cases with OEIS complex and related malformations were reviewed for demographic features, prenatal and family histories, and clinical, radiological and pathological findings including the frequency and types of associated anomalies. The pathogenetic mechanisms causing OEIS complex and related malformations, such as anorectal and spinal defects, are discussed. The findings in these cases illustrate the spectrum of defects that can occur in the embryologic development of the cloaca and the urorectal septum. Differences in the timing and extent of mesenchymal ingrowth as well as cloacal membrane rupture may account for these variable findings. A developmental field defect involving the intraembryonic mesoderm suggests a possible etiologic role for homeobox genes, such as HLXB9 with mutations, resulting in anorectal and spine abnormalities, or retinoic acid receptors. OEIS complex with its mostly sporadic occurrence suggests etiologic heterogeneity with a possible role for environmental and genetic causes.

Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss.

We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.

Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes.

We report three unrelated patients with small terminal deletions involving 1p36.22-->pter that occurred de novo and compare our patients to the 10 previously reported cases. Although our patients have an identical cytogenetic deletion, patients 1 and 2 share similar clinical features that differ substantially from patient 3. Our patients confirm the existence of two characteristic phenotypes in 1p36.22-->pter deletion. Both phenotypes share some dysmorphic features, but are differentiated by characteristics of growth failure versus macrosomia. In addition, we report the new finding of cardiomyopathy and hydrocephalus in the phenotype associated with growth failure. It is possible that different phenotypic subgroups may exist because of differences in the parental origins of the deleted chromosome or of variations in undetectable amounts of genetic material.