Objective. To present any congenital anomalies with respect to tumor necrosis factor (TNF) antagonists reported to the US Food and Drug Administration (FDA) to determine if there are common findings. Methods. A review of the FDA database of reported adverse events with etanercept, infliximab, and adalimumab from 1999 through December of 2005 was performed. Key words for congenital anomalies were employed as search tools. Duplicate reports were eliminated. Any concomitant medicines were recorded. Results. Our review of > 120,000 adverse events revealed a total of 61 congenital anomalies in 41 children born to mothers taking a TNF antagonist. Of these mothers, 22 took etanercept and 19 took infliximab. There were no reports in women taking adalimumab. The most common reported congenital anomaly was some form of heart defect. Twenty-four of the 41 (59%) children had one or more congenital anomalies that are part of vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limp abnormalities (VACTERL) association. There were 34 specific types of congenital anomalies in total, and 19 (56%) of those are part of the VACTERL spectrum. Nine of these 19 (47%) types of VACTERL anomalies were observed statistically significantly more than historical controls (p Conclusion. A seemingly high number of congenital anomalies that are part of the VACTERL spectrum have been reported. These congenital anomalies are occurring at a rate higher than historical controls. This commonality raises concerns of a possible causative effect of the TNF antagonists.

https://www.jrheum.org/content/jrheum/36/3/635.full.pdf

A Safety Assessment of Tumor Necrosis Factor Antagonists During Pregnancy : A Review of the Food and Drug Administration Database

To the Editor:

In a recent article, Gorospe et al.1 describe the occurrence of a leukoencephalopathy, commonly called megalencephalic leukoencephalopathy with subcortical cysts (MLC), in an Asian-Indian group, the Agarwals. They describe the clinical and MRI findings in the patients and report on the founder mutation in the MLC1 gene, responsible for the disease in this community, which is an insertion of a cytosine-residue (C-residue) in a stretch of six C-residues in exon 2.

The authors refer to …

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation

PURPOSETo provide information about neonatal experiences for newborns with full trisomy 18 (t18).SUBJECTSMothers of 21 newborns with full t18 (13 survivors; 8 who died prior to mothers' participation in the study).DESIGNMixed method, descriptive, online survey.METHODSSubjects completed an on

Neonatal experiences of newborns with full trisomy 18.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive inherited neurological disorder characterized by macrocephaly, deterioration in motor functions and cerebellar ataxia. In Israel the disease is found in an increased frequency among Libyan Jews. The disease is caused by mutations in the MLC1 gene, which encodes a putative CNS membrane transporter. We describe three novel mutations (p.G59E, p.P92S, and 134_136insC) in seven MLC families. One of these mutations, p.G59E, was found in the vast majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the p.G59E mutation, revealed a carrier rate of 1/40 compared with an expected carrier rate of 1/81. Several explanations could account for this difference the most likely one is an admixture of the Libyan Jewish population.

Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.

Objective The purpose of this study was to investigate the role of second-trimester sonographic examination in the prenatal diagnosis of trisomy 13. Methods Of 22,150 fetal chromosome analyses, 28 fetuses with trisomy 13 were found between 1990 and 2004. Sonographic findings of this aneuploidy were analyzed in this study. Results The average maternal age was 32.4 years; the average gestational age was 19.5 weeks. There was an 89.3% (n = 25) total prevalence of sonographic abnormalities in fetuses with trisomy 13 in this series. Major (structural) malformations were seen in 23 cases (82.1%), whereas minor anomalies were detected on sonography in 16 cases (57.1%). Although in 2 fetuses 1 minor anomaly was the only sonographic sign of trisomy 13, other cases with minor anomalies (87.5% [n = 14]) were multiplex malformations, in which combinations of major and minor anomalies were detected on sonography. The most frequently seen structural abnormalities were central nervous system and facial anomalies (64.3% [n = 18]). Among central nervous system anomalies, ventriculomegaly and holoprosencephaly were seen most frequently. Cardiovascular anomalies were detected in 53.6% (n = 15) of the fetuses with trisomy 13. This high frequency underlines the importance of echocardiography in diagnosing this aneuploidy. Among minor anomalies, increased nuchal translucency (21.4%) and echogenic bowel (17.9%) were the most common findings. Conclusions Second-trimester sonographic examination is capable of showing anomalies that are characteristic of trisomy 13; thus, the scan can indicate whether fetal karyotyping is advisable. Incorporation of careful assessment of the fetal cardiovascular system by sonography certainly increases the detection rate of trisomy 13.

https://onlinelibrary.wiley.com/doi/pdf/10.7863/jum.2006.25.4.429

Prenatal Diagnosis of Trisomy 13 Analysis of 28 Cases

Vacuolating megalencephalic leucoencephalopathy with subcortical cysts (VL) is a newly described, inherited leucodystrophy (MIM 604004). Clinically, the disease is characterised by accelerated head growth beginning in the first year of life and resulting in extreme macrocephaly and mild delays in gross motor milestones. In most cases, these early manifestations are followed by evolution of pyramidal symptoms and signs, cerebellar ataxia, epilepsy, and in older patients dystonia and athetosis.1 Cognitive function is relatively spared in most patients. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) shows diffuse cerebral white matter swelling with progressive cystic-like changes, prominent in the frontotemporal regions, with preservation of grey matter structures.1,2 Pathological specimens from VL patients showed splitting of the myelin sheaths between the lamellae consistent with an oedematous process, with sparing of the exons.3 Although progressive in nature, VL is characterised by a relatively mild clinical course compared to the severity of the neuroradiological findings.4,5 About 70 cases of the disease have been described in different ethnic groups. The molecular basis of this disorder remains unknown. The inheritance is autosomal recessive and the disease gene was recently mapped to a 3 cM interval between D22S1161 and the telomere of chromosome 22q.6 Linkage was established in a group of 13 Turkish families all originating from rural areas of central and south eastern Anatolia. No shared alleles or shared haplotypes were detected between the Turkish families.

Six of the seven families included in this study (fig 1) have been described in detail by Ben Zeev et al .7 Families 1, 2, 4, and 6 are of Libyan Jewish origin and family 3 is of Turkish Jewish origin. …

https://jmg.bmj.com/content/jmedgenet/39/1/54.full.pdf

A common ancestral haplotype in carrier chromosomes from different ethnic backgrounds in vacuolating megalencephalic leucoencephalopathy with subcortical cysts.

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A common ancestral haplotype in carrier chromosomes from different ethnic backgrounds in vacuolating megalencephalic leucoencephalopathy with subcortical cysts.