Radial Ray Defects Research Articles

EP22.08: Bilateral radial ray defect and postnatal follow‐up: a case report

EP22.08: Bilateral radial ray defect and postnatal follow‐up: a case report

INDIAMAN-20 (INstant DIAgnosis of 20 Major ANomalies) protocol: application of IOTA diagnostic strategy to fetal anomalies.

To compile a list of instant diagnoses of major fetal anomalies, and to present their sonographic descriptors and test them in a retrospective series of fetuses with congenital anomalies managed at our center. The first step was to identify major anomalies that meet the following criteria: (1) can be diagnosed directly and unequivocally on the basis of a set of descriptors evident on a single sonographic view; (2) are among those more commonly diagnosed in utero; (3) represent major lethal or life-threatening malformations or anomalies for which no or only palliative surgery can be performed. For each of these anomalies, a sonographic descriptor was produced. The second step was to test the descriptors of the instant diagnoses in all cases with these anomalies evaluated since January 2000 in our Fetal Medicine Unit, retrieved from our electronic database. For each congenital anomaly-sonographic descriptor pair we then evaluated the presence vs absence of an unequivocal relationship between anomaly and descriptor, assessing: whether a particular descriptor in a set reference plane identified unequivocally the anomaly, i.e. the same descriptor could not be found in any other malformation; and whether a particular anomaly presented the corresponding descriptor in all cases. Finally, we evaluated whether the sonographic descriptors could be applied in all trimesters or only selectively, considering the natural history of the 20 instant diagnoses. Of the 20 instant diagnoses, five involved the central/peripheral nervous system (exencephaly/anencephaly, alobar/semilobar holoprosencephaly, cephalocele, open spinal dysraphism, complete agenesis of corpus callosum), five involved the heart (hypoplastic left heart syndrome, complete atrioventricular septal defect, severe Ebstein's anomaly, critical aortic stenosis, transposition of the great arteries), five involved the abdominal wall (left-sided congenital diaphragmatic hernia, exomphalos, gastroschisis, body-stalk anomaly) or gastrointestinal tract (duodenal atresia), and five involved the remaining systems (three urinary (autosomal recessive polycystic kidney disease, multicystic dysplastic kidney, lower urinary tract obstruction), two skeletal (transverse limb defect, radial ray defect)). All of the descriptors were found to identify unequivocally the related malformations, whereas four of the malformations were not associated with their reference descriptors in every case. For example, congenital diaphragmatic hernia (left-sided) presented without the stomach in the thorax in 42/93 (45.2%) cases. Due to the natural history of the condition, not all signs were recognizable in the first trimester, some becoming evident only from the second trimester onwards. We have defined sonographic descriptors that enable an unequivocal instant diagnosis for a list of 20 major congenital anomalies: the 'INDIAMAN-20' (INstant DIAgnosis of Major ANomalies) protocol. We believe that using this approach may facilitate focused training of less experienced operators and that it may be incorporated into artificial intelligence and deep learning protocols, further boosting the instant prenatal recognition of these lethal or life-threatening malformations. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Radial Ray Anomaly with Associated Ventricular Septal Defect - Case Report with Review of Literature.

Ultrasound examination is used for the assessment of abnormal findings on prenatal screening. Radial ray defect can be screened by using ultrasonography. Abnormal findings can be detected quickly by having the understanding of the etiology, pathophysiology and embryology. It is a rare congenital defect that may be isolated or associated with other anomalies including Fanconi's syndrome and Holt-Oram syndrome. We report the case of a 28-year-old woman (G2P1L1) who presented for routine antenatal ultrasound at 25 weeks 0 days according to the last menstrual period. The patient did not have any level-II antenatal anomaly scan done. An ultrasound was performed, and the gestational age according to the ultrasound scan was 24 weeks and 3 days. In this paper, we present a brief review of embryology and critical practical points, and report a rare case of radial ray syndrome with associated ventricular septal defect.

Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling

LEF1 encodes a transcription factor acting downstream of the WNT-β-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 variants. High-throughput sequencing was employed to delineate the genetic underpinnings of the disease. Cellular consequences were characterized by immunofluorescence, immunoblotting, pulldown assays, and/or RNA sequencing. Monoallelic variants in LEF1 were detected in 11 affected individuals from 4 unrelated families, and a biallelic variant was detected in an affected individual from a consanguineous family. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Depending on the type and location of LEF1 variants, the inheritance of this novel Mendelian condition can be either autosomal dominant or recessive. Our functional data indicate that 2 molecular mechanisms are at play: haploinsufficiency or loss of DNA binding are responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants is associated with a severe phenotype. Transcriptomic studies reveal an alteration of WNT signaling. Our findings establish mono- and biallelic variants in LEF1 as a cause for a novel syndrome comprising limb malformations and ectodermal dysplasia.

A denovo mutation of SALL4 in a Chinese family with Okihiro syndrome.

Okihiro syndrome is an autosomal dominant condition characterized by Duane anomaly and radial ray defects. The present study aimed to analyze the clinical manifestations of a patient with Okihiro syndrome and perform genetic testing on the proband and his family to determine the biological pathogenesis. Clinical data were collected from the proband and his family and genomic DNA was extracted from peripheral blood. Whole exome sequencing was performed by high-throughput sequencing and mutation sites of the proband and his parents were validated by Sanger sequencing. The proband was diagnosed with Okihiro syndrome, which is characterized by bone abnormality in the arms and hands (radial ray malformation, absence of thumbs) and sensorineural hearing loss. A pathogenic heterozygous c.3060delG variant was identified in exon 4 of spalt-like transcription factor 4 (SALL4) gene in the proband. This is a frameshift mutation that changes increases the length of SALL4 protein from 1,053 to 1,076 amino acids. The variant was classed as a de novo mutation because the parents of the proband showed no variation at this site. This variant is not included in the ClinVar database and, to the best of our knowledge, has not previously been reported. The de novo heterozygous c.3060delG variant was the molecular pathological cause of Okihiro syndrome in the present study and expanded the database of known SALL4 variants.

Prenatal Diagnosis of Radial Ray Defect Associated with Fanconi Anemia: a Case Report

AbstractFanconi anemia (FA) is a rare genetic disorder with multisystem involvement. Confirmatory genetic testing is possible by diagnostic clues on examination of the proband within the differential diagnosis. We describe a fetus with radial ray defect in a primigravida. Cytogenetic testing for breakages confirmed Fanconi anemia as the etiology. Molecular testing by next generation sequencing did not reveal a point change in any of the twenty-one genes known to be associated with FA. A confirmed fetal autopsy phenotype and the cytogenetic report allowed for the identification of a homozygous deletion of exon 4–6 in the FANCC gene on re-analysis of the molecular dataset. This case exemplifies the utility of a step wise approach to the diagnosis of prenatally diagnosed radial ray defects and the importance of genetic counseling and prenatal testing.

The Classification of VACTERL Association into 3 Groups According to the Limb Defect.

Summary:The VACTERL association (VA) is defined as the nonrandom co-occurrence of 6 anomalies: vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula (TE), Renal defects (R), and Limb anomalies (L). The current communication presents an argument that patients with VA should be classified into three district groups based on their limb defects: VACTERL1: patients with normal limbs; VACTERL2: patients with limb anomalies other than radial ray defects of the upper limbs; and VACTERL3: patients with radial ray defects of the upper limbs. The author will demonstrate that the rationale behind the L1-3 classification in patients in VA is based on the embryogenesis of the 6 affected anatomical areas in VA. The pathogenesis of VACTERL1 is secondary to perturbations of Sonic Hedgehog (SHH) interactions. SHH signaling is known to have a major role in the normal development of the vertebrae, ano-rectal area, heart, tracheo-esophageal area, and kidney. However, SHH is not involved in the development of the radial ray; hence, patients present with no limb defects. The pathogenesis of VACTERL2 is variable depending on the type of gene mutation. The pathogenesis of VACTERL3 is related to errors in a group of proteins (namely, the proteins of the TBX5-SALL4-SALL1 loop and the FGF8-FGF10 loop/ pathway). These proteins are essential for the normal development of the radial ray and they interact in the development of the other anatomical areas of VA including the heart and kidney. Hence, VACTERL3 patients present with radial ray deficiency.

Anticancer Agent Gefitinib and Congenital Anomalies

AbstractCongenital abnormalities caused by human teratogenic drugs account for less than 1% of total congenital abnormalities. We report the first case of multiple anomalies associated with antenatal exposure to the anticancer agent Gefitinib. The patient conceived while she was on tablet Gefitinib 250 mg once a day for stage IV adenocarcinoma of lungs. The first scan done at 29 weeks 2 days showed liquor amnii on the upper limit of normal, single umbilical artery, left sided congenital diaphragmatic hernia, ventriculoseptal defect and left radial ray defect. The patient had a preterm delivery after one week and she refused autopsy. It is important to advise patients regarding contraception while undergoing chemotherapy as there is an increased risk of drug induced fetal malformations.

VP04.05: Associated anomalies and outcome in cases of absent ductus venosus diagnosed at 11–13+6 weeks' scan

To determine the incidence of associated anomalies and outcomes in absent ductus venosus in pregnant women undergoing the nuchal translucency scan (NT) at 11-13+6. A retrospective case record-based study of prospectively collected data from pregnant women attending NT scan at a single centre in western India. The assessment included measurement of NT, evaluation of nasal bone (NB), ductus venosus (DV), tricuspid regurgitation (TR), according to the Fetal Medicine Foundation protocols. The detailed anatomical evaluation was done in all patients. When the DV was not seen, the umbilical vein was traced to evaluate it's joining with systemic veins. The incidence of absent ductus venosus and the association with anomalies were determined. The cases where the pregnancy was continued, were followed up in postnatal life. The records of 2884 first trimester ultrasound examination from December 2016 to December 2019 were analysed. Absent ductus venosus was detected in 10 (0.35 %, 95 % CI: 0.19, 0.64) pregnant women . Eight (80.00 %) women were primigravida. Seven (70 %) had a normal NT thickness. Five (50.00 %) of these 10 fetuses had associated cardiac anomalies and one had radial ray defect. One fetus had bilateral jugular sacs, absent NB and increased NT which was confirmed as trisomy 21 after amniocentesis. In 9 cases the umbilical vein was opening in inferior vena cava, while in 1 case it was opening in iliac vein. All seven abnormal pregnancies were terminated. The remaining three fetuses with isolated absent DV were followed, one fetus had intrauterine demise at 29 weeks. The other two were born normal. One of these babies died at 6 months of age because of pneumonia. The other baby is normal till date. No postnatal sonography was done in these two live-born children. Assessment of DV during NT scan is very important. Absent DV is associated with cardiac, extracardiac and chromosomal abnormalities. Absent DV is associated with adverse outcome. Absent DV may be present even with a normal NT.

Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations

Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum.We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.

Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia

Fanconi anemia is a rare chromosome instability disorder with a highly variable phenotype. In the antenatal and neonatal periods, the diagnosis is usually suggested by the presence of typical congenital abnormalities such as intrauterine growth retardation, microcephaly and radial ray defects. We report a newborn female with a prenatal diagnosis of Fanconi anemia, complementation group O (FANCO). Antenatal ultrasounds identified symmetrical intrauterine growth retardation, complex heart defect as well as brain anomalies, overlapping fingers and cleft lip and palate. Imperforate anus was detected after birth. Compound heterozygous RAD51C variants c. [571+5G > A]; [c.935G > A] were detected by prenatal whole exome sequencing and cellular hypersensitivity to DNA interstrand crosslinking agents (DEB, MMC) was confirmed after birth. With only one previously described homozygous RAD51C variant to date, our findings expand the phenotypic spectrum of FANCO and suggest it should be part of the antenatal differential diagnosis for trisomy 13 and 18, due to the presence of atypical findings such as cleft lip and palate, holoprosencephaly, growth restriction and overlapping fingers.

First Trimester Detection of Heart-Hand Syndrome

AbstractHeart-hand syndrome is a heterogenous group of congenital disorders characterized by upper limb anomalies and congenital heart defects. We report the antenatal scan findings in a 14 week fetus in which bilateral radial ray defect was detected along with cardiac malformations at routine first trimester aneuploidy scan. The cardiac malformations were pulmonary atresia with ventricular septal defect. This was confirmed by clinical and pathological correlation. There are few case reports of early prenatal detection of this syndrome at 14 weeks.

Large Cryptic Derivative Chromosome 8 Detected by SNP Chromosomal Microarray

Large Cryptic Derivative Chromosome 8 Detected by SNP Chromosomal Microarray

Streamlining NGS Workflows Using Cancer Samples by the Application of Tthe DNA Integrity Number (DIN) from the Genomic DNA Screentape Assay

Streamlining NGS Workflows Using Cancer Samples by the Application of Tthe DNA Integrity Number (DIN) from the Genomic DNA Screentape Assay

Bilateral Radial Ray Defects: An Atypical Presentation of 16p11.2 Microdeletion Syndrome

Bilateral Radial Ray Defects: An Atypical Presentation of 16p11.2 Microdeletion Syndrome

RECQ4 selectively recognizes Holliday junctions.

The RECQ4 protein belongs to the RecQ helicase family, which plays crucial roles in genome maintenance. Mutations in the RECQ4 gene are associated with three insidious hereditary disorders: Rothmund-Thomson, Baller-Gerold, and RAPADILINO syndromes. These syndromes are characterized by growth deficiency, radial ray defects, red rashes, and higher predisposition to malignancy, especially osteosarcomas. Within the RecQ family, RECQ4 is the least characterized, and its role in DNA replication and repair remains unknown. We have identified several DNA binding sites within RECQ4. Two are located at the N-terminus and one is located within the conserved helicase domain. N-terminal domains probably cooperate with one another and promote the strong annealing activity of RECQ4. Surprisingly, the region spanning 322-400aa shows a very high affinity for branched DNA substrates, especially Holliday junctions. This study demonstrates biochemical activities of RECQ4 that could be involved in genome maintenance and suggest its possible role in processing replication and recombination intermediates.

Radial Ray Defect

A 24 days old male neonate presented to the University of Gondar Hospital with deformity at the right wrist joint since birth. Physical findings were deformity of the wrist joint with lateral deviation of fingers and absent thumb. Plain radiographs of the wrist joint showed absent radius and bones of the thumb which suggest the diagnosis of radial ray defect. Radial ray defect is a rare congenital defect that may be isolated or associated with other anomalies. This is a rare case of radial ray defect which has no association with other anomalies.

RECQL4 Regulates p53 Function In Vivo During Skeletogenesis

RECQ DNA helicases play critical roles in maintaining genomic stability, but their role in development has been less well studied. Rothmund-Thomson syndrome, RAPADILINO, and Baller-Gerold syndrome are rare genetic disorders caused by mutations in the RECQL4 gene. These patients have significant skeletal developmental abnormalities including radial ray, limb and craniofacial defects. To investigate the role of Recql4 in the developing skeletal system, we generated Recql4 conditional knockout mice targeting the skeletal lineage. Inactivation of Recql4 using the Prx1-Cre transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human RECQL4 patients. These Prx1-Cre(+) ;Recql4(fl/fl) mice as well as Col2a1-Cre(+) ;Recql4(fl/fl) mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of Trp53 in these Recql4 mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between Recql4 and Trp53, and p53 activation as an underlying mechanism for the developmental bone abnormalities in RECQL4 disorders. Our findings show that RECQL4 is critical for skeletal development by modulating p53 activity in vivo.

Delineation ofEFTUD2Haploinsufficiency-Related Phenotypes Through a Series of 36 Patients

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

Chromosomal instability and molecular mutations in multi spectrum disease of Fanconi anemia

Fanconi anemia (FA; MIM no. 227650), the most commonly inherited bone marrow disorder, has an overall prevalence of 1–5 per million and an estimated carrier frequency of 1:200-300 in most populations. Demonstrating either an autosomal or X-linked recessive mode of inheritance, FA is characterized by childhood progressive bone marrow failure and predisposition to acute myelogenous leukemia, older patients are at increased risk for squamous cell carcinomas of the head, neck, and genitourinary tract. Congenital abnormalities are present in approximately 70% of FA patients and may include radial ray defects, cafe´ au lait spots or hypopigmentation, short stature, microphthalmia, malformations of kidneys, gastrointestinal tract, and heart, mental retardation, and hearing defects. Because of the high degree of phenotypic variability exhibited by FA patients, diagnosis may be difficult on the basis of clinical manifestations alone. Because FA patient-derived lymphocytes and fibroblasts exhibit hypersensitivity to DNA crosslinking agents such as diepoxybutane (DEB) and mitomycin C (MMC), resulting in a high rate of chromosomal breakage and radial formation, analysis on the basis of this hypersensitivity has been routinely used to confirm clinical diagnosis. Molecular diagnosis of FA has been challenging because of the genetic heterogeneity associated with the disease. To date, 15 FA gene products (FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N, O and P) have been identified and they constitute the FANC pathway, which is thought to function in preventing genome instability. The FA core complex comprises FAAP24, FAAP100, and 8 FA proteins (FANCA, B, C, E, F, G, L, and M) and mediates DNA-damage-induced or replication-stress induced monoubiquitylation of FANCD2 and FANCI. Monoubiquitinated FANCD2 and FANCI translocate to chromatin and function in DNA repair at least partially by recruitment of FAN1 nuclease. Cloning of the FANC genes has provided a means, via complementation group analysis, to routinely pinpoint the patient’s specific FA gene harboring the mutations, thus greatly simplifying subsequent molecular analysis. Although retroviral-mediated complementation analysis of FA patient-derived cells is commonly used to identify the patient’s genetic subtype as a prerequisite for mutation screening, such analysis has not been formally validated for clinical use. Previous studies have considered Fanconi complementation Group A (FA-A) assignments, but none have performed comprehensive sequencing to verify complementation assignment and/or evaluated complementation assignments performed using retroviral-mediated rescue as evidenced by correction of MMC and DEB-induced chromosome breakage and radial formation. Among all complementation groups, FAA accounts for the majority of FA patients (60–65%) followed by FAC (10%) and FAG (9%). Mutations in the gene for complementation group FA-A (FANCA; MIM no. 607139) confer autosomal recessive inheritance and account for approximately 66% of all FA cases. The FANCA gene is mapped to chromosome 16q24.3,11 spans approximately 80 kb of genomic DNA (gDNA), and consists of 43 exons. With more than 200 different mutations described thus far, the FANCA mutation spectrum is very heterogeneous. Because of the presence of a large number of Alu repeat sequences within the FANCA gene, large intragenic deletions involving multiple exons have been reported to account for more than 40% of all FANCA mutations. First time we have carried out a molecular study in the Indian population. We have studied FA by chromosomal breakage study using mitomycin C (MMC) and diepoxybutane (DEB) induction and FANCD2 monoubiquitination by western blotting to understand gene defects in FA pathway. The complementation analysis was done by retroviral transfection. The molecular study was carried out by Multiplex Ligation-dependent Probe Amplification (MLPA) and direct sequencing of FANCA, C, G, E, F, L, and M genes. The complementation analysis results showed different spectrum as compared to world literature. Our study revealed FA-A and E gene defects in 69% cases and followed by FANCE gene defect. The molecular analysis showed the large deletions in 11 patients and FANCA gene mutations were in 12 FA patients. Out of 12 mutations 5 mutations (c.3678 C>G, p.Ser 1226 X, c.3993G>A p.Leu 1331 Pro, c.1274 C>G p.Glu 425 His, c.2630 C>G p.Ser 877 X) found to be novel mutations. In our series the single nucleotide polymorphisms (SNP); Exon9,c.796A>G(p.Thr266Ala), Exon16,c.1501G>A(p.Gly501Ser), Exon26, c.2426G>A(p.Gly809Asp), of FANCA gene also observed in 23 patients, and these polymorphisms in disease association was reported in FA database, however, it needs to be established in Indian population. Interesting finding of our study is the existence of FANCE mutation in Indian population, and the same was reported rarely in other places of the world. The study also highlighted the uncharacterized FA patients, which may associated with new genes in Indian population and these patients should be studied molecularly and genotype-phenotype correlation need to be established, which helps in better understanding and management of the disease.