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.

Cerebro-hepato-renal syndrome. Report of a case with histochemical and ultrastructural observations.

A new case of the cerebro-hepato-renal syndrome is being reported. The neuropathologic changes consisted of developmental abnormalities of cerebral and cerebellar cortex and of the inferior olives. In addition, there were metabolic changes in the central nervous system, indicated by an accumulation of lipid within histiocytes of free in gray and white matter, deficiency in myelination and gliosis of the white matter, and marked proliferation of protoplasmic astrocytes in the gray matter. A unique feature of this case was the presence of numerous clusters of lipid-filled macrophages and occasional cholesterol crystals in the molecular layer of the cerebellum. The histochemical reactions and ultrastructural appearances of the lipid deposits are suggestive of accumulation of several different types of lipids.

Bilateral congenital subdural cysts associated with porencephaly and CSF-subdural fistula. A report of two cases.

Tow infants had bilateral congenital subdural cysts associated with encephaloclastic porencephaly and a CSF-subdural fistula. The cysts occupied 80% to 90% of the crainal cavity. There was severe atrophy and malformation of the underlying brain, suggesting that its development had been disturbed at an early stage of gestation. The clinical and radiologic findings were indistinguishable from those of hydranencephaly.

Lipoprotein disorder, cirrhosis, and olivopontocerebellar degeneration in two siblings.

Two siblings had olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. This condition was distinct from other cerebellar atrophies and ataxias and was not due to malabsorption or malnutrition. Cerebellar degeneration progressed rapidly during the first year of life, and both children died from intercurrent infections and surgical complications at 11 and 17 months. Stereotyped clinical and pathologic findings in the two patients suggest a previously unreported genetic metabolic disorder affecting the liver and the CNS.

Coincident DiGeorge anomaly and renal agenesis and its relation to maternal diabetes.

We describe 2 cases of DiGeorge anomaly with bilateral renal agenesis-one, who also had hemivertebrae, in an infant of an insulin-dependent diabetic mother (IDDM). In a review we identified 2 other instances of this combination, both in IDDMs. The currently accepted notion that DiGeorge anomaly and renal agenesis are developmental field defects, coupled with their coincidence in IDDM, suggests that this combination is an association.

Weaver syndrome with neuroblastoma and cardiovascular anomalies.

We report on an infant with Weaver syndrome, neoplasia and cardiovascular anomalies. Stage 4S neuroblastoma underwent spontaneous resolution. Three neoplasms have been reported in Weaver syndrome: another stage 4S neuroblastoma [Muhonen and Menezes, 1990: J Pediatr 116:596-599], an ovarian endodermal sinus tumor [Derry et al., 1999: J Med Genet 36:725-728], and a sacrococcygeal teratoma [Kelly et al., 2000: Am J Med Genet 95:492-495]. No case was associated with cardiovascular anomalies. Our patient had VSD and PDA, and although several other patients with Weaver syndrome have had cardiovascular anomalies, they were shown not to have neoplasia.

Internal vascular access for hemodialysis in children weighing less than fifteen kilograms.

An arteroarterial femoral graft using expanded polytetrafluoroethylene is described which has been successfully for vascular access in young children having small peripheral vessels. This graft allows high flow and favorable patency for dialysis without the complications of arteriovenous shunting or the risks associated with an external hemodialysis device. This graft has been used successfully for outpatient dialysis in children weighing as little as 9 kg and may be a useful adjunct in long-term dialysis of patients for whom more conventional means of vascular access are not acceptable.

Discussion and management of late failures in reconstructive procedures involving the abdominal aorta.

Review of fifty-eight late failures of 326 procedures performed for revascularization of the abdominal aorta over the past six years showed a low overall operative mortality of 9 per cent. Secondary vascular procedures directed at the aorta itself or at its graft substitute proved more effective in relieving symptoms and restoring flow than did secondary procedures directed at more distal problems in the lower extremities. The aortofemoral graft in conjunction with profundaplasty proved to be the most effective means of restoring flow to the lower extermity after graft occlusion in a previous aortoiliac or aortofemoral graft.

Placental emboli from a fetus papyraceous.

A syndrome in monozygotic twins that consists of a macerated twin fetus (fetus papyraceous) and a live-born twin with various anatomical defects has been described. The etiology is thought to be placental transfer of emboli or thromboplastic material through vascular shunts. Thromboplastic material precipitates disseminated intravascular coagulation (DIC) in the fetus, with a resultant hypercoagulable state due to relative fetal antithrombin III deficiency. Two cases of this syndrome will be discussed. The case of a live-born twin with intestinal atresia, who developed in utero with a fetus papyraceous, is reported. Emboli were demonstrated in vascular shunts of the diamniotic-monochorionic placenta. The hypothesis of intestinal atresia as a result of a vascular accident is reviewed. Another case involving a live-born twin with congenital skin defects, who developed in utero with a fetus papyraceous, is also reported. The skin defects were a congenital disruption from fetal DIC with resultant hypercoagulable state. Several other manifestations of the placental emboli syndrome will be discussed and the vascular etiology of the disruptions explained.

Postoperative aneurysms of the heart. Case report and review of the literature.

A postoperative left ventricular pseudoaneurysm is reported in a seven-year-old after closure of an atrial septal defect and repair of partial anomalous venous drainage. A discussion of the etiology and clinical presentation of post operative aneurysms are presented. Cardiac aneurysms of both the true and false variety have been commonly reported following myocardial infarction, blunt and penetrating trauma and infectious processes such as tuberculosis and syphilis. As the frequency of open heart correction of congenital and acquired lesions increases, the incidence of post-operative pseudoaneurysm of heart can also be expected to increase. The diagnosis of this entity in the postoperative period is often difficult and may lead to delay in detection and correction. The clinical presentation and subsequent course of false anurysm differs from the more common true aneurysm to an extent which should be recognized by both cardiologists and cardiac surgeons. A case of left ventricular pseudoaneurysm after open heart repair of an atrial septal defect is reported and a clinical profile which may be helpful in the earlier recognition of this entity is presented.

Primordial cyst versus keratocyst.

The term primordial cyst was introduced in 1945 to identify the odontogenic cyst formed from enamel organ before calcification occurred as part of a classification based on development, structure, and radiographic appearance. The term odontogenic keratocyst was introduced in 1956 to describe cysts of the jaw exhibiting keratinization of their lining. Periodontal, dentigerous, primordial, residual, and gingival cysts may exhibit keratinized linings and can properly be identified as odontogenic keratocysts on the basis of their histologic appearance but may also be identified by their "developmental" designation. There is no justification for considering odontogenic keratocyst as a synonym for primordial cyst.

DiGeorge's or the III-IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis.

Six new cases of the III-IV pharyngeal pouch syndrome were encountered at autopsy among 897 consecutive pediatric autoposies. All occurred in patients with conotruncal cardiac anomalies. The anatomic characteristics of the heart defect suggest a possible mechanism for the pathogenesis of this developmental anomaly. It is postulated that premature involution of the thyroidea ima artery, which is the principal embryonic blood source to the 3rd and 4th pharyngeal pouches and the ultimobranchial body, may be the critical event in the embryogenesis of the syndrome. Hemodynamic alterations in the course of anomalous morphogenesis of conotruncal anomalies may favor premature involution of certain vessels including the left 4th aortic arch and the thyroidea ima. Deficiencies of thymus, parathyroid glands and ultimobranchial tissue ("C" cells) may be the consequence of vascular deprivation during embryogenesis. These cases are discussed with regard to the proposed mechanism of pathogenesis and the influence of varying quantities of thymus upon peripheral lymphoid tissue. Both embryologic and clinical data support the possibility of a deficiency of ultimobranchial tissue. The range of minor and inconstant anomalies seen in patients with this syndrome is presented.