Marfan syndrome associated aortic disease in neonates and children: a clinical-morphologic review.

BACKGROUND: Marfan syndrome (MFS) is a multisystem connective tissue disorder that can lead to aortic dilation requiring aortic root replacement. Neonatal MFS (nMFS) is a rare and severe form of MFS compared to classic MFS (cMFS). Aortic root histology in MFS is thought to demonstrate predominantly medial degeneration (MD) of a translamellar mucoid extracellular matrix accumulation (MEMA-T) vs. the intralamellar mucoid extracellular matrix accumulation (MEMA-I) seen in other aortopathies. The objective of this study was to describe the clinical and histopathologic features of nMFS and cMFS patients undergoing aortic root replacement. METHODS: Children with MFS who underwent aortic root replacement between 2000 and 2012 at a single institution were included. Medical records including clinical details, aortic dimensions (Z scores), and histology including MD type were obtained. Statistics were descriptive with univariate analysis of age at surgery and type of MD. RESULTS: Eleven patients, 3 (27%) with nMFS, were included. Root dilation at time of surgery was greater in nMFS compared to cMFS (Z=12.8 vs. 7.6, P=.005), and nMFS patients were younger at time of surgery (7.3 vs. 18.8 years, P=.002). Histology in the nMFS group demonstrated MEMA-I in one and no MD in two. In the cMFS group, there were three with MEMA-T, four with MEMA-I, and one with both types. CONCLUSION: In summary, nMFS has earlier root dilation often in the absence of MD. Both forms of MD were present in our cohort, and there was no correlation between age at surgery and type of MD.

Two cases of Scimitar syndrome associated with multiple congenital skeletal anomalies and lacking abnormalities by genomic microarray analysis.

Scimitar syndrome is a congenital anomaly occurring in approximately 1/50,000 births, consisting of partial anomalous pulmonary venous return, right lung hypoplasia, and several associated defects. The condition generally has significant morbidity and mortality, but the underlying cause is poorly understood. In this report, we describe 2 autopsy cases of Scimitar syndrome associated with multiple skeletal anomalies and attempt to characterize possible genetic abnormalities in this condition. In light of these findings, we discuss the embryology and direct timing during development of the anomalies associated with this syndrome.

Heart failure due to "disappearing" aortic valve in hypoplastic left heart syndrome.

We present the unusual case of a "disappearing" aortic valve in an infant with hypoplastic left heart syndrome (mitral and aortic stenosis) that underwent Norwood palliation at birth and subsequently a Glenn operation. Angiographic images at the time of operation showed no apparent insufficiency of the native aortic valve. Over the course of 14 months following operation, the patient developed significant cardiomegaly with a workup revealing severe native aortic valve insufficiency. Following orthotopic heart transplantation, examination of the explanted heart revealed a complete absence of native aortic valve leaflets.

Molecular inversion probe array for the genetic evaluation of stillbirth using formalin-fixed, paraffin-embedded tissue.

Array comparative hybridization has been used successfully to identify genomic alterations in stillbirth material; however, high DNA quantity and quality requirements may limit its utility in some fetal samples. Molecular inversion probe (MIP) array analysis of FFPE stillbirth autopsy samples circumvents the challenges associated with karyotype and short-term fetal cell culture, requires limited DNA input, and allows for retrospective evaluation of fetal loss. We performed MIP analysis on archival FFPE autopsy tissue to identify underlying genetic abnormalities not previously detected using traditional cytogenetic methods. Archival FFPE stillbirth cases (≥20 weeks gestation) were identified with the following characteristics: i) the phenotype suggested underlying genomic alterations; ii) the karyotype was either normal or not available and there were no other known genetic abnormalities; or iii) previous microarray testing was not performed. Genomic DNA (75 ng) was processed onto a 330,000-feature MIP array. Twenty-seven of 29 (93.1%) FFPE samples had passing MIP quality control scores. Abnormalities were seen in 3 of 27 (11%) archival samples (deletion of 17q12, trisomy 18, and a case of 4qter duplication and 13qter deletion arising from an unbalanced 4q;13q translocation), which, if identified at the time of autopsy, may have changed the course of medical management. This study highlights the benefits of using MIP array analysis for identification of genomic alterations in FFPE stillbirth autopsy tissue.

Effect of ventriculotomy on right-ventricular remodeling in hypoplastic left heart syndrome: a histopathological and echocardiography correlation study.

The objective of this study was to compare histopathological changes in hypoplastic left heart syndrome right ventricles (RV) of patients undergoing Sano and modified Blalock-Taussig (MBT) shunt and correlate them with echocardiographic findings. Myocardial tissue samples were obtained from hearts with Sano or MBT shunts after transplantation or at autopsy. Histologic sections were reviewed manually and by automated digital image analysis. Velocity vector imaging was performed on echocardiogram images obtained before transplant or death. All of these parameters were compared between the Sano and MBT shunt cohorts. A total of 14 specimens (7 Sano and 7 MBT shunt) were studied. Median age at transplant/death of Sano and MBT shunt cohorts was 11 (range 2-41) and 8 months (range 2-200), respectively. All Sano specimens had a scar at ventriculotomy site, and the mean scar area was 6.2 ± 3.3 cm(2). Compared with remote RV free wall, myocardium bordering the scar showed increased fibrosis (34 ± 16 % vs. 28 ± 14 %, p = 0.04) and thinning (0.8 ± 0.9 vs. 5.3 ± 0.8 mm; p < 0.001), which did not regress with time. The Sano ventriculotomy site showed significantly decreased velocity, strain, and strain rate compared with the corresponding contralateral segment. No focal scarring or regional hypokinesia was seen in the MBT shunt cohort. This is the first study to demonstrate histopathological features of ventriculotomy-associated RV myocardial scarring and myocardial thinning. The scarred ventriculotomy site showed decreased segmental myocardial deformation after Norwood with Sano shunt.

Premature closure of the foramen ovale secondary to congenital aortic valvular stenosis in a stillborn.

Premature closure of the foramen ovale is a rare and deleterious condition that can occur as an isolated defect or in association with other congenital and cardiovascular anomalies. We report on the pathologic findings in a 22-week stillborn male fetus with premature closure of the foramen ovale, severe aortic valve stenosis, cardiomegaly, intact atrial and ventricular septa, hypoplasia of the ascending aorta, and hypoplastic aortic arch with a preductal coarctation ridge. To the best of our knowledge, this is only the second report on this rare constellation of complex congenital cardiac defects.

Lethal osteogenesis imperfecta-like condition with cutis laxa and arterial tortuosity in MZ twins due to a homozygous fibulin-4 mutation.

This case report involved male infants of a size consistent with the estimated gestational age of 31 weeks. The mother of the twins was a 27-year-old, G4P3 woman with limited prenatal care who presented for cesarean delivery. Resuscitation efforts were initiated and continued until the infants became asystolic. Postmortem radiographs showed innumerable fractures of the limbs, ribs, and skull in various states of healing with callus formation; hence, the fractures were of prenatal origin. Despite the fractures, the growth of the long bones was not impaired. The radiographic findings were initially thought to represent osteogenesis imperfecta type IIC. However, there were also vascular anomalies not explained by this phenotype. Grossly, all arteries were elongated, thickened, and tortuous. The carotids, descending aorta, and iliac arteries were redundant to such an extent that they produced corkscrew patterns. There was also cutis laxa with loose, redundant skin over the entire body. Collagen genes did not show any mutations; however, when it was suggested Fibulin-4 be studied because of overlap with the condition described by Dasouki and colleagues in 2007, a homozygous premature stop codon mutation was found in that gene.

Unilateral sclerocornea and tracheal stenosis: unusual findings in a patient with Goldenhar anomaly.

The Goldenhar anomaly (GA) is a heterogeneous field defect of uncertain cause and wide variability of expression, characterized by facial phenotypes, usually asymmetric and unilateral, accompanied by various combinations and gradations of cardiac, skeletal, renal, and central nervous system defects. We report the pathologic findings in a 5-month-old boy with GA, tracheal stenosis, and left unilateral sclerocornea. To the best of our knowledge this is the first description of sclerocornea in a patient with GA.

Cervical ribs are more prevalent in stillborn fetuses than in live-born infants and are strongly associated with fetal aneuploidy.

This study was undertaken to determine the prevalence of cervical ribs in stillborn fetuses undergoing autopsy at our institution and to search for significant associations with cervical ribs. European studies have reported an increased prevalence of cervical ribs in patients with childhood cancer and in stillborn fetuses. We reviewed data from autopsies performed at Primary Children's Medical Center, Utah, between 2006 and 2009 on 225 stillborns (≥20 weeks) and 93 deceased live-born infants (<1 year). Digital fetal radiographs in anterior-posterior and lateral views had been taken of each subject. Chi-square analysis and general linear models were used for statistical analysis of the data. The overall prevalence of cervical ribs was higher in stillborns than in live-borns who died in the first year (43.1% vs 11.8%). Karyotypes were available for 93 (41.3%) of the stillborns. Of those, cervical ribs were present in 33 of 76 (43.4%) stillborns with normal karyotype and in 13 of 17 (76.4%) stillborns with aneuploidy. Females with unavailable karyotypes were more likely to have cervical ribs than those with normal karyotypes (P  =  0.0002). This greater likelihood was not observed in males. Among the stillborns with normal karyotypes, we found no statistically significant association with gender or gestational age at fetal death. There was also no statistically significant association between congenital anomalies and the presence of cervical ribs. Our findings support the hypothesis that cervical ribs are markers for disadvantageous developmental events occurring during blastogenesis and have been subject to strong negative selection during evolution.

Pulmonary atresia with intact atrial and ventricular septums, unroofed coronary sinus, and absent aortocoronary arterial connections.

A stillborn fetus with pulmonary valvar atresia and intact atrial and ventricular septums also had absence of coronary arterial connections from the aorta and an unroofed coronary sinus. A left superior caval vein drained to the dilated coronary sinus. The left coronary artery was anomalously connected to the proximal branch of the right pulmonary artery, and a fistula from the right ventricle supplied the right coronary artery.