Perinatal and infant outcome of fetuses with prenatally diagnosed hyperechogenic kidneys.

OBJECTIVE: Hyperechogenic kidneys are a relatively rare antenatal finding, which can generate significant parental anxiety due to uncertain prognosis. We report on the perinatal and infant outcomes of a large cohort of fetuses with antenatally diagnosed hyperechogenic kidneys. METHODS: This was a retrospective analysis of all cases diagnosed prenatally with hyperechogenic kidneys between 2002 and 2017 in a large tertiary fetal medicine unit. Hyperechogenicity was defined as kidney parenchyma with greater echogenicity than that of the liver. Pregnancy, pathological and postnatal outcomes were collected from hospital and general practitioner records up to 1 year of age. Abnormal renal outcome was defined as elevated creatinine beyond 6 months of age, hypertension requiring medication or major kidney surgery, such as nephrectomy. Severe abnormal renal outcome was defined as the need for dialysis or kidney transplant at any stage. RESULTS: Three-hundred and sixteen fetuses with hyperechogenic kidneys were identified at a mean gestational age of 21 (range, 13-37) weeks. The majority of cases (97%) had bilateral hyperechogenic kidneys. In the 265 cases with available follow-up data, other associated renal tract abnormalities were identified prenatally in 36%, concomitant extrarenal structural abnormalities in 39% and abnormal karyotype in 15% of cases. Of the 316 included cases, 139 did not survive, including 105 terminations of pregnancy, five intrauterine deaths and 29 early neonatal deaths. Only 4.3% (6/139) of these fetuses had isolated hyperechogenic kidneys while 28.1% (39/139) had associated multiple renal tract abnormalities alongside hyperechogenic kidneys and over two-thirds (67.6%; 94/139) had concomitant extrarenal abnormalities. Of the 177 cases that survived beyond 1 month of age, outcome data were available in 126. Of these, based on the antenatal findings, 60 (47.6%) cases had isolated hyperechogenic kidneys, 56 (44.4%) had associated renal structural abnormalities and 10 (7.9%) had additional extrarenal abnormalities. Considering renal outcome alone, kidney function was abnormal in 13 (21.7%), 10 (17.9%) and 0 (0%) infants in these three groups, respectively, although concurrent pathology clearly affected global outcome in the more complex cases. Neonatal mortality of 1.6% was observed in the isolated renal hyperechogenicity group. The presence of oligohydramnios or abnormal renal volume was not associated significantly with abnormal renal function (odds ratio (OR), 2.32 (99% CI, 0.54-10.02) and OR, 0.74 (99% CI, 0.21-2.59), respectively) in this group. CONCLUSIONS: Hyperechogenic kidneys are often complicated by associated renal tract and extrarenal abnormalities, aberrant karyotype and genetic disease, and these factors have a greater effect on overall outcome than does kidney echogenicity. The renal outcome of fetuses with isolated hyperechogenic kidneys is good generally, with over 70% of cases having normal renal function postpartum. Importantly, for prognostic counseling, all of the fetuses in this non-selected series with isolated hyperechogenic kidneys and normal amniotic fluid levels had normal renal outcome in infancy. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes.

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.

Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report.

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.

An inducible intestinal epithelial cell-specific NHE3 knockout mouse model mimicking congenital sodium diarrhea.

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.

Clinical, molecular, and pathological findings in a Neu-Laxova syndrome stillborn: A Brazilian case report.

Neu-Laxova syndrome (NLS) is a lethal genetic multiple congenital anomaly syndrome of unknown prevalence representing the severe spectrum of serine biosynthesis defects associated with PHGDH, PSAT1, or PSP gene mutations. The purpose of this study was to describe clinical/molecular and pathologic features of a NLS case caused by novel heterozygous missense variant in PHGDH gene identified in his consanguineous parents.

Outcomes of hypoplastic left heart syndrome: analysis of National Inpatient Sample Database 1998-2004 versus 2005-2014.

Neonates with hypoplastic left heart syndrome (HLHS) were identified from the National Inpatient Sample dataset for the years 1998-2014. These patients were stratified into two chronological groups, past group (1998-2005) and recent group (2006-2014). A total of 20,649 neonates with HLHS were identified. Of them, 9179 (44.5%) were born in the past group and 11,470 (55.5%) in the recent group. Median birth weight was significantly less in the recent group (2967 g vs. 3110 g, p = 0.005). The patients in the recent group had more patients with low birth weight ( < 2.5 kg) and prematurity (8.7% vs 7.6% and 12.7% vs. 4.3%., respectively). In addition, recent group had more comorbidities including chromosomal anomalies, total anomalous pulmonary venous return, and kidney anomalies (5.6% vs. 3.6%, 2.3% vs. 1.7%, and 5.6% vs. 3.6%, respectively, p < 0.001); these were associated with a higher rate of extracorporeal membrane oxygenation utilization (9.2% vs. 4.5%, p < 0.001). Consequently, median length of stay was longer in the recent group (8 vs. 6 days, p < 0.001).Conclusion: Despite the higher frequency of comorbidities in recent group, the mortality rates decreased by 20% (from 25.3% to 20.6%, p < 0.001). Balloon atrial septostomy was performed less frequently in the recent group (23.3% vs. 16.1%, p < 0.001).What is known:• Hypoplastic left heart syndrome has the highest mortality among congenital cardiac defects during the first year of life.• Limited studies on patients' comorbidities and mortality rates trends over last two decades.What is new:• The study utilized a national database to compare in-hospital mortality and length of stay between the two time periods 1998-2005 and 2006-2014.• The recent group had more comorbidities (prematurity, chromosomal anomalies, total anomalous pulmonary venous return, and kidney anomalies), and there was higher rate of ECMO and longer length of stay, while mortality rates decreased by 20%.

Does prenatal counseling for pregnancies complicated by multiple fetal abnormalities concord with postnatal outcomes?

OBJECTIVE: In pregnancies complicated by multiple fetal abnormalities, our objective was to determine the degree of concordance between prenatal prognosis and postnatal outcomes. METHOD: Retrospective cohort study of pregnancies with multiple fetal abnormalities referred to the Fetal Concerns Center of Wisconsin (FCCW) from 2015 to 2018. We reviewed records for anomalies, given prognostic severity, and postnatal outcomes. Prognostic severity was categorized as "likely mortality," "severe impairment," "moderate," and "mild" based on predetermined criteria. RESULTS: In 85 pregnancies with multiple fetal abnormalities, 48% were given a prognosis of "likely mortality," and 19% were given a prognosis of "severe impairment." In pregnancies that were continued after being counseled as "likely mortality," this outcome was concordant in all but one case, despite medical interventions. In pregnancies counseled as "severe impairment," the more common outcome was mortality or severe impairment in 88% of cases and survival with severe impairment in 33% of cases. Postnatal outcomes were concordant with prenatal severity in 68% of the cases, more severe in 20% of the cases, and less severe in fewer than 5% of cases. CONCLUSION: Prenatal predictions about severe outcomes are usually true in pregnancies complicated by multiple abnormalities. In cases of outcome discordance, outcomes tend to be more severe than predicted.

The Correlation Between Severity of Postoperative Hypocalcemia and Perioperative Mortality in Chromosome 22q11.2 Microdeletion (22q11DS) Patient After Cardiac-Correction Surgery: A Retrospective Analysis.

OBJECTIVES: The aim of our study was to elucidate the association between severity of postoperative hypocalcemia and the prognosis of the patients with 22q11DS. METHODS: Data retrospectively were collected from 23 children with 22q11DS who underwent cardiac correction surgery. Area under the receiver operating characteristic curve (AUC) and diagnostic odds ratio were calculated to determine the tendency of perioperative mortality rate, according to the minimum levels of serum calcium and the duration of hypocalcemia. A novel risk assessment system for perioperative mortality was established according to these valid parameters. RESULTS: The death group had lower minimum levels of serum calcium and longer duration of hypocalcemia. The AUC of minimum levels of serum calcium was 0.912 (95% CI: 0.753-1; P = .003) and qualified its high accuracy for perioperative mortality. The AUC of duration of hypocalcemia was 0.804 (95% CI: 0.561-1; P = .03) and qualified its moderate accuracy. The tendency analyses also indicated the correlation between these two parameters and perioperative mortality. Based on the cut-off values from ROC analysis, a novel risk assessment system for perioperative mortality was established according to these two parameters. The patients with the lowest serum calcium level <0.885 mmol/L or duration of the hypocalcemia > 90.33 hours would be sorted into a high-risk group; others were divided into a low-risk group. The diagnostic odds ratio for this assessment system was 143(95% CI: 5.13-3982.52). No significant difference was found with regard to patient age, weight, preoperative serum total calcium, cardiopulmonary bypass (CPB) time, and aortic cross-clamp time between the high- and low-risk groups. CONCLUSIONS: The minimum levels of serum calcium and duration of hypocalcemia were valid predictors for preoperative mortality of 22q11DS patients.

Five-year survival of infants with major congenital anomalies: a registry based study.

AIM: To determine survival of infants with major congenital anomalies (CA) and assess the effect of co-existing anomalies and gestational age. METHODS: All liveborn infants with major CA born in New South Wales (NSW), Australia, 2004-2009 were identified from the NSW Register of Congenital Conditions. Deaths were identified via record linkage to death registrations and five-year survival was estimated using Kaplan-Meier methods. RESULTS: There were 8521 liveborn infants with CA of whom 617 (7.2%) died within the first five years of life. Half of deaths occurred in the first week of life. The overall five-year survival rate was 92.8% (95%CI: 92.2-93.3) and 83.2% (95%CI: 79.0-87.4) for syndromes, 83.4% (95%CI: 80.9-85.9) for multiple, 85.1% (95%CI: 82.6-87.5) for chromosomal, 95.3% (95%CI: 94.8-95.8) for isolated and 96.2% (95%CI: 94.3-98.1) for non-Q chapter anomalies. Five-year survival for chromosomal, syndromes and sub-groups was higher for isolated compared with multiple anomalies ranging from 77.5% to 98.9% and 68.6% to 89.5%, respectively. Survival was lower for preterm (79.4%; 95%CI: 77.5-81.4) than for term infants (95.8%; 95%CI: 95.3-96.3). CONCLUSION: Nine in ten infants with major CA survive up to five years, although there is variability in survival across CA groups. Survival of infants with major congenital anomalies has improved in recent years.

Predictors of mortality in neonates with giant omphaloceles.

INTRODUCTION: This analysis performed a review of giant-omphaloceles to determine the predictors of mortality. EVIDENCE ACQUISITION: PubMed and KoBson databases were searched for terms "giant," "omphalocele," and "mortality." Primary end points included mortality correlation with gestational age (GA), birth weight (BW), eviscerated organs, associated anomalies and management. To calculate mean and median values IBM SPSS v. 23.0 was used. EVIDENCE SYNTHESIS: After de-duplication and review search revealed 42 articles of which 23 met the inclusion criteria with 396 giant-omphaloceles for this analysis. Median gestational age (GA) was 36 weeks for all neonates (range 21-41); 21 neonates were reported as premature with median GA 33.5 (range 21-36). Overall median birth weight (BW) was 3100 g (range 1100-4100 g). The diameter of abdominal wall defect was 4-15 cm with the average size of 7.6 cm except for non-giant giant omphaloceles (N.=7) where the defect was measuring between 2.7 and 4 cm. Amniotic sac contents beside intestines included liver (N.=154), stomach (N.=11), spleen (N.=2), pancreas (N.=1), gallbladder (N.=5), and 5 giant omphaloceles were reported to contain only liver; sac was ruptured in 22. Giant omphaloceles were associated with a variety of other anomalies, most often with cardiac anomalies (N.=93; 23.4%) and pulmonary hypoplasia and/or pulmonary hypertension (N.=39; 9.8%). Management included conservative treatment N.=264 (66.6%), primary closure (N.=17; 4.3%), staged closures (N.=98; 24.7%) primary or staged closure (N.=17; 4.3%). The most frequent complication was sepsis (N.=52). There were 90 (22.7%) lethal outcomes, 6 lethal outcomes in neonates even before final closure could be achieved and 12 in prematures. Leading cause of mortality was sepsis (N.=51; 56.6%), the cause of lethal outcome was not reported in 8 cases. CONCLUSIONS: Giant-omphaloceles have a lethal outcome in one-fifth of neonates. Predictors of mortality included pulmonary hypoplasia and respiratory failure with prematurity and ruptured sacs implicated within this group. Sepsis was the independent iatrogenic factor in mortality.

Mortality in Joubert syndrome.

Joubert syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about mortality in affected individuals. Identifying the timing and causes of death will allow for development of healthcare guidelines for families and providers and, thus, help to prolong and improve the lives of patients with JS. We evaluated information on 40 deceased individuals with JS to characterize age and cause of death. We compared this population with 525 living individuals with JS to estimate associations between risk of death and extra-neurological features. Genetic causes were examined in both groups. Mean age of death in this cohort was 7.2 years, and the most prevalent causes of death were respiratory failure (35%), particularly in individuals younger than 6 years, and kidney failure (37.5%), which was more common in older individuals. We identified possible associations between risk of death and kidney disease, liver fibrosis, polydactyly, occipital encephalocele, and genetic cause. This work highlights factors (genetic cause, extra-neurological organ involvement, and other malformations) likely to be associated with higher risk of mortality in JS, which should prompt increased monitoring for respiratory issues, kidney disease, and liver fibrosis.

FAM111A mutations result in hypoparathyroidism and impaired skeletal development.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.

Clinical presentation and survival in a population-based cohort of infants with gastroschisis in Utah, 1997-2011.

Typically gastroschisis is considered an isolated birth defect; however, other major malformations are reported to occur in 5-35% of cases depending on inclusion criteria. This study evaluated the associated malformations, small for gestational age, and survival among a clinically well-characterized population-based gastroschisis cohort, delivered from 1997-2011. We used data from Utah's statewide population-based surveillance system, which monitors major structural birth defects among all pregnancy outcomes (i.e., live births, stillbirths, pregnancy terminations, and miscarriages). Of the initial 387 gastroschisis cases, we excluded 51 (13.2%) for the following reasons: inadequately described or macerated fetuses, part of a specific malformation complex or sequence (limb-body wall complex, amniotic band sequence, or a severe form of abdominoschisis), leaving a study sample of 336 clinically confirmed cases. Gastroschisis was isolated non-syndromic in 284 cases (84.5%). One case was syndromic (trisomy 16; 0.3%) and the remaining 51 (15.2%) were classified as multiple: one unrelated major malformation (27; 52.9%); two or more unrelated major malformation or one major with multiple minor anomalies or mild malformations (6; 11.8%); ≥ one distinctive minor anomaly or mild malformation (13; 25.5%); amyoplasia (5; 1.5%). Of the liveborn infants, 63.3% were preterm (delivered at <37 weeks of gestation) and 21.8% were small for gestational age (SGA). SGA was more common in males (38.8%) than females (16%) (P = 0.008). Overall first year survival was high (95.6%); however, preterm infants with congenital intestinal atresia had the highest mortality (13.8%). The high proportion of isolated cases (84.5%) in gastroschisis is similar to that observed in many other phenotypes and not unique to gastroschisis. Because one in every six infants with gastroschisis had a major unrelated malformation, additional malformations should be sought in every newborn with gastroschisis. Infant mortality was low overall but still a significant concern in affected preterm infants with associated congenital intestinal atresia.

Long-term survival for infants born with orofacial clefts in Western Australia.

BACKGROUND: Only two population-based studies have reported survival beyond 15 years for individuals with orofacial clefts (OFC), and only for individuals with isolated OFC. Compared with the general population, long-term survival was similar for individuals with cleft lip only, and lower for individuals with cleft palate only. Results for those born with isolated cleft lip and cleft palate were inconsistent. METHODS: Using linked population-based health data, including a congenital anomaly register with active surveillance and diagnoses up to 6 years, we compared survival at 1, 5, and 20 years for infants born 1980 to 2010 with, and without OFC. RESULTS: Of the 8112 live born infants in the cohort, 186 died before 20 years; most (81%) died during infancy. Compared with infants without OFC, infants born with all types of isolated OFC ± additional minor anomalies had similar infant survival (around 99%), but we found lower survival for infants with all cleft types and an additional major anomaly (66-84%). From 1 to 5 years, only infants with cleft palate only and an additional major anomaly had lower survival (97%) compared with children without OFC (99.9%). From 5 to 20 years, children with all cleft types, with or without additional major anomalies had similar survival to children without OFC (98-100%). CONCLUSION: Parents with a child diagnosed with an OFC ± additional minor anomalies only can be reassured that the OFC does not influence survival rates in infancy, or long-term. Infant survival was lower only for children with OFC and additional major anomalies.

Prenatal and postnatal markers of severity in congenital diaphragmatic hernia have similar prognostic ability.

OBJECTIVES: The purpose of this study was to compare prenatal versus postnatal markers of congenital diaphragmatic hernia (CDH) severity at a single fetal-care center. METHODS: A retrospective study was performed of patients having a complete prenatal evaluation and surgical repair (n = 55). Observed-to-expected lung-to-head ratio (o/eLHR), observed-to-expected total lung volume (o/eTLV), liver position (LP), a predictive dependent variable from logistic regression of o/eLHR and liver position (o/eLHR + LP), and diaphragmatic defect size per the CDH Study Group A-D classification were plotted into receiver-operating characteristics (ROC) curves. Survival and need for extracorporeal membrane oxygenation (ECMO) were primary outcomes. RESULTS: Survival was 69%, and ECMO utilization was 56%. Distribution was 80% left-sided defects. In the survival ROC curve, the area under the curve (AUC) for o/eLHR was 0.73, o/eTLV 0.74, LP 0.73, o/eLHR + LP 0.78, and defect size 0.84 (p = 0.23). The ROC curve for ECMO support showed o/eLHR had an AUC of 0.82, o/eTLV 0.89, LP 0.79, o/eLHR + LP 0.87, and defect size 0.90 (p = 0.19). The AUCs were similar when only left-sided CDH was analyzed. CONCLUSIONS: These data suggest that prenatal evaluation was equivalent to the postnatal diaphragmatic defect classification for predicting survival and need for ECMO in CDH patients.

Interstitial 1p32.1p32.3 deletion in a patient with multiple congenital anomalies.

Interstitial deletions encompassing chromosome bands 1p32.1p32.3 are rare. Only nine unrelated patients with partially overlapping 1p32.1p32.3 deletions of variable size and position have been reported to date. We report on a 17-month-old boy with choanal atresia, hearing loss, urogenital anomalies, and microcephaly in whom an interstitial de novo deletion of 6.4 Mb was detected in 1p32.1p32.3 (genomic position chr1:54,668,618-61,113,264 according to GRCh37/hg19). The deleted region harbors 31 RefSeq genes. Notable genes in the region are PCSK9, haploinsufficiency of which caused low LDL cholesterol plasma levels in the patient, and DAB1, which is a candidate gene for cognitive deficits, microcephaly, and cerebral abnormalities such as ventriculomegaly and agenesis of the corpus callosum. Choanal atresia, microcephaly, and severe hearing loss were previously not known to be associated with 1p32 deletions. Our reported patient thus broadens the spectrum of clinical findings in this chromosome region and further facilitates genotype-phenotype correlations. Additional patients with overlapping deletions and/or point mutations in genes of this region need to be identified to elucidate the role of individual genes for the complex clinical manifestations.

Performance of prenatal diagnosis in esophageal atresia.

OBJECTIVE: The aim of this study was to evaluate the performance of prenatal diagnosis of esophageal atresia (EA) and its associated abnormalities. METHODS: We conducted a retrospective study from a pediatric database of EA managed postnatally in a single center. Prenatal data included ultrasound and magnetic resonance imaging parameters including amniotic fluid (AF) volume, stomach visualization, AF biochemistry, and associated malformations. Postnatal data included type of EA, mortality, and postnatal diagnosis of associated malformations. RESULTS: One hundred twenty-two cases were included. The diagnosis was suspected prenatally in 39/122 (32%) cases. Polyhydramnios was noted in 64/122 (52.4%), and the stomach was not visualized or small in 39 (32%). There was 14 (11.5%), 2 (1.6%), 101 (82.8%), 5 (4.1%), and 0 (0%) types I, II, III, IV, and V, respectively. EA was suspected prenatally in 12/14 (85.7%) in type I and in 27/108 (25%) in cases with tracheoesophageal fistula (II + III + IV + V). Magnetic resonance imaging was performed in 28 cases, which confirmed EA in 19/28 (sensitivity 67.8%). AF biochemistry was performed in 17 cases, which confirmed EA in 15/17 (sensitivity 88.2%) cases. Of the 69 syndromic associations, 41/69 (59.4%) cases were detected prenatally. Associated malformation was a strong predictor of postnatal death [19/69 vs 3/53, odds ratio 6.33 (1.76; 22.75), p < 0.01]. CONCLUSION: Prenatal diagnosis of EA remains challenging. MRI and AF biochemistry may prove useful in the diagnosis of EA. Prenatal ultrasound and MRI examination should also focus on associated anomalies. © 2015 John Wiley & Sons, Ltd.

Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal.

BACKGROUND: The T gene (brachyury gene) is the founding member of the T-box family of transcription factors and is vital for the formation and differentiation of the mesoderm and the axial development of all vertebrates. RESULTS: We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies, and the identification and characterisation of their underlying genetic defect. Given the consanguineous nature and the similarity of the phenotypes between the three families, we performed homozygosity mapping and identified a common 4.1 Mb homozygous region on chromosome 6q27, containing T, brachyury homologue (mouse) or T. Sequencing of T in the affected individuals led to the identification of a homozygous missense mutation, p.H171R, in the highly conserved T-box. The homozygous mutation results in diminished DNA binding, increased cell growth, and interferes with the normal expression of genes involved in ossification, notochord maintenance and axial mesoderm development. CONCLUSIONS: We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.

Restrictive Atrial Septum Defect Becomes a Risk Factor for Norwood Palliation of Hypoplastic Left Heart Syndrome Only When It Is Combined with Mitral or Aortic Atresia.

BACKGROUND: Restrictive atrial septal defect (ASD) is described as risk factor for Norwood procedure because of elevated pulmonary resistance. We hypothesized that it invariably could not cause pulmonary hypertension, unless it was combined with mitral valve or aortic valve atresia. We investigated how restrictive ASD influenced survival of patients with hypoplastic left heart syndrome (HLHS) who underwent Norwood operation. PATIENTS AND METHODS: A total of 118 HLHS patients who underwent surgery between January 2005 and December 2012 were grouped into three groups. Group 1 included 31 patients with restrictive ASD combined with mitral or aortic atresia; Group 2 composed of 12 patients with restrictive ASD and mitral and aortic stenosis; Group 3 (n = 75) had no ASD restriction. Survival was determined for each group. Multivariate analysis was conducted to test risk factors for mortality. RESULTS: Mean follow-up was 26.3 ± 24.1 months. Survival was 78.7% ± 4.2% at 30-month interval and onward after Norwood procedure for the whole cohort; it was 43.8% ± 10.0%, 91.7% ± 8.0%, and 77.3% ± 5.0% for Group 1, 2, and 3, respectively. The difference was significant between Group 1 and Group 2 and 3: p < 0.001. Survival was similar for Group 2 and Group 3: p = 0.45. Combination of restrictive ASD and mitral or aortic atresia was found to be the sole risk factor for early and late mortality (odds ratio: 3.5, 95% confidence interval: 1.8-7.1, p < 0.001). CONCLUSION: Restrictive ASD only affects survival of HLHS patients following Norwood procedure if it is associated with mitral or aortic atresia.