HOLT-ORAM SYNDROME: RARE CASE SERIES

The upper limb malformations in association with congenital heart defects occurring as autosomal dominant disorder are seen in Holt-Oram syndrome. It is a very rare disorder which can be detected with early prenatal ultrasound checkups. Here we are reporting two cases of holt-oram syndrome

Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse

Tamoxifen is an estrogen receptor (ER) ligand with widespread use in clinical and basic research settings. Beyond its application in treating ER-positive cancer, tamoxifen has been co-opted into a powerful approach for temporal-specific genetic alteration. The use of tamoxifen-inducible Cre-recombinase mouse models to examine genetic, molecular, and cellular mechanisms of development and disease is now prevalent in biomedical research. Understanding off-target effects of tamoxifen will inform its use in both clinical and basic research applications. Here, we show that prenatal tamoxifen exposure can cause structural birth defects in the mouse. Administration of a single 200 mg/kg tamoxifen dose to pregnant wildtype C57BL/6J mice at gestational day 9.75 caused cleft palate and limb malformations in the fetuses, including posterior digit duplication, reduction, or fusion. These malformations were highly penetrant and consistent across independent chemical manufacturers. As opposed to 200 mg/kg, a single dose of 50 mg/kg tamoxifen at the same developmental stage did not result in overt structural malformations. Demonstrating that prenatal tamoxifen exposure at a specific time point causes dose-dependent developmental abnormalities, these findings argue for more considerate application of tamoxifen in Cre-inducible systems and further investigation of tamoxifen’s mechanisms of action.

Hand and Upper Limb Malformations in Italy: A Multicentric Study

Background: Although hand and upper limb malformations are quite frequent, up to now very few reports have been published on epidemiology. The aim of this study is to evaluate the number of infants who presented with hand and upper limb malformations from 2010 to 2015 in Italy. Methods: A retrospective analysis of a pediatric population presenting with hand and upper extremity malformations was carried out, gathering reports achieved from eight Italian Centers of pediatric hand surgery. Other factors such as gender, date and region of birth, family distribution of malformations and associated syndromes, were analysed. Results: Out of 3,100,421 live births, 765 children presented with hand and upper limb malformations. The incidence was 2,5/10,000 live births with a predominance of males and the right side. Radial polydactyly was the anomaly with the highest percentage, closely followed by simple syndactyly, simbrachidactyly and complex syndactyly. Less common conditions were the triphalangic thumb, thumb in palm, proximal radioulnar synostosis and Sprengel deformity. Inheritance of and familial predisposition to those malformations was recorded in 25 cases, while 84 children presented with syndromes related to hand anomalies. Conclusions: In conclusion the incidence of hand and upper extremity malformations in Italy is lower than that registered in other countries. The retrospective nature of the study combined with the fact that some defects frequently evade pediatric hand surgeon consultations are some possible limitations of the study. However, our data confirmed that, in spite of the decrease in the birth rate in Italy, the trend of congenital hand disorders maintained a stable trend. We aim to integrate this study with a prospective analysis and to involve the institutional health authorities in other countries so as to register the correct incidence of hand and upper extremity defects.

Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients

Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. Mutation in the NIPBL gene accounts for nearly 60% of the cases. This study reports the clinical and genetic findings of three cases of CdLS from unrelated Chinese families. Clinically, all the three cases were classified as classic CdLS based on the cardinal (distinctive facial features and limb malformations) and suggestive (developmental delay, growth retardation, microcephaly, hirsutism, etc.) manifestations. SNP array detected a novel de novo heterozygous microdeletion of 0.2 Mb [arr[GRCh37]5p13.2(36848530_37052821) × 1] that spans the first 43 exons of NIPBL in the fetus with nuchal translucency thickening in case 1. Whole-exome sequencing in family trios plus Sanger sequencing validation identified a de novo heterozygous NIPBL c.5566G>A (p.R1856G) mutation in the fetus with intrauterine growth retardation in case 2 and a novel de novo heterozygous NIPBL c.448dupA (p.S150Kfs*23) mutation in the proband (an 8-month-old girl) in case 3. The cases presented in this study may serve as references for increasing our understanding of the mutation spectrum of NIPBL in association with CdLS.

Genome sequencing in families with congenital limb malformations

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

Split Hand/Foot Malformation with Long Bone Deficiency: A Report of Two Female Siblings

Spilt Hand/Foot Malformation with Long-bone Deficiency (SHFMLD) is a rare heterogeneous group of limb malformations characterised by absence/hypoplasia and/or median cleft of hands and/or feet associated with long bone abnormalities, most frequently tibia. This case report described two sisters with congenital limb defects born to healthy consanguineous parents. The six-year-old girl did not had both radii and the left fibula. There was a cleft in the left hand and the right foot. She had one digit in her right upper limb, but did not have the left foot. The four-year-old girl had short four limbs, bilateral tibial aplasia with single digit in all limbs. Both parents were normal, and no other similar cases was reported in the family. According to the authors' best knowledge, these two cases are the first published cases in Yemen with the SHFMLD, but they need a genetic study to determine their genetic profile.

Fibular Aplasia, Tibial Campomelia, Oligo-Syndactyly Syndrome and Probable Femur Fibula Ulna Syndrome- Case Reports

One in two thousand neonates suffer from congenital limb deficiencies. Fibular hemimelia, a birth defect, has an estimated incidence of 5.7 to 20 cases per 1 million births. Fibular Aplasia, Tibial Campomelia and Oligo-Syndactyly (FATCO) syndrome is one such which is a triad of fibular hemimelia (aplasia/hypoplasia of fibula), tibial campomelia (bending of tibial bone) and oligo syndactyly. It is a syndrome of unknown genetic basis and inheritance. Very few cases on this condition have been reported so far. This article reports two cases on this condition, wherein the babies had considerable variability of limb malformations. The first is a newborn with FATCO, and the second is a two-month-old male infant with FATCO associated with right focal femoral deficiency. In view of paucity of the cases, there is a need to report every case which may help in creating awareness and a standardised management approach.

An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage

Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal recessive loss-of-function mutation of the establishment of cohesion (ESCO) 2 acetyltransferase. ESCO2 is an essential gene that targets the DNA-binding cohesin complex. ESCO2 acetylates alternate subunits of cohesin to orchestrate vital cellular processes that include sister chromatid cohesion, chromosome condensation, transcription, and DNA repair. Although significant advances were made over the last 20 years in our understanding of ESCO2 and cohesin biology, the molecular etiology of RBS remains ambiguous. In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS.