Radial Ray Anomalies Research Articles

RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront

PurposeDiamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. RPL26 (ribosomal protein L26) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition. MethodsPatients carrying heterozygous RPL26 variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34+ cells were studied by flow cytometry, and RPL26 expression by qRT-PCR and immunoblotting. ResultsWe report on 8 affected patients from 4 families. Detailed phenotyping reveals that RPL26 is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that RPL26 haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes. ConclusionWe confirm RPL26 as a DBS gene and expand the phenotypic spectrum of the gene and the disease.

Cytogenetic analysis of fanconi anemia patients: An hospital based study

: Fanconi anemia is a rare genetic disorder caused by mutations in genes whose protein products are involved in replication, cell cycle control and DNA repair and is associated with a very high frequency of bone marrow failure and many other manifestations including, but not restricted to, severe birth defects.The diagnosis of FA is confirmed by a specific test known as chromosomal breakage study, a differential technique in which clastogenic substances, such as DEB (diepoxy butane) or MMC (mitomycin C), lead to sections of the chromosome being deleted, added, or rearranged.In this retrospective study, peripheral blood smears of patients with Aplastic Anemia were analyzed to diagnose Fanconi Anemia.: A total of 135 cases of Aplastic anemia were analyzed and screened by chromosomal breakage analysis for ruling in/out Fanconi anemia.: A total of 9 (6.66%) out of 135 patients showed a significant increase in the number of chromosomal breaks in comparison to their control. An analysis of the variable clinical manifestations was also done and correlated to the diagnosis of Fanconi Anemia. : This study throws light on the importance of cytogenetic analysis as being the most classical test for FA which involves detection of chromosomal breakage or aberrations in metaphase spreads. This relatively inexpensive assay may be useful for screening patients for whom FA is in the differential diagnosis, such as those with radial ray anomalies, short stature, hypogonadism, or café au lait spots, or for population-based FA incidence studies.

The incidence and spectrum of congenital hand differences in patients with Fanconi anaemia: analysis of 48 patients.

We analysed the spectrum of congenital hand differences in a cohort of patients with Fanconi anaemia (FA). Data of 48 FA patients at the National Cancer Institute were reviewed focusing on age at diagnosis, type and severity of limb difference and any potential association with other known clinical anomalies that are part of the FA phenotype, specifically VACTERL-H and PHENOS. Twenty-eight patients had an upper limb difference, which always included thumb hypoplasia. Twenty-three patients had bilateral upper limb differences, including varying combinations and severities of thumb hypoplasia, radial dysplasia and thumb duplication. Patients with a limb difference were diagnosed at a younger age (<2years: 15/28 with limb anomaly versus 4/20 without a limb anomaly). However, 7/28 with limb anomalies, usually thumb hypoplasia, were not diagnosed until after 6years of age. This study demonstrates the broad spectrum of radial ray anomalies within the FA phenotype along with the possibility of either unilateral or bilateral upper limb differences and adds further merit to consideration of screening for FA in all cases of radial ray anomaly.Level of evidence: II.

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.

Prenatal diagnosis of complex phenotype in a 13-week-old fetus with an interstitial multigene deletion 20q13.13.-q13.2 by chromosomal microarray

We report the first trimester three-dimensional ultrasonographic findings in a 13-week-old fetus with complex phenotype and a de novo 4.7 Mb multigene deletion encompassing chromosome region 20q13.13-q13.2 detected by chromosomal microarray. Fetal sonography detected radial-ray anomalies in the form of bilateral absence of thumbs and the left club hand deformity. The presence of single atrioventricular canal instead of the atrial septal defect typical for Holt-Oram syndrome pointed us to rather suspect the SALL4 related diseases. Central nervous system anomaly in the form of enlarged lateral brain ventricles with choroid plexus shifted backwards was not previously reported as a part of SALL4 related disorders. The pregnancy was terminated at 14 + 3 weeks of pregnancy and the autopsy confirmed ultrasonographic findings. Deleted region included 38 genes, where only SALL4, ADNP and KCNB1 heterozygote pathogenic variants were described to be cause of syndromic forms. Radial ray anomalies are common part of clinical picture of SALL4 related disorders. Despite the lack of prenatally described cases, we hypothesized that maldevelopment of lateral brain ventriculomegaly could be very early sonographic sign of disturbed ADNP expression causing Helsmoortel-Van der Aa syndrome, but in some extent also of KCNB1 related early-onset epileptic encephalopathy. Furthermore, the possible dosage-dependent influence of recessive genes located in this region cannot be also excluded. The use of genome-wide technologies enables the detection of subtle chromosomal imbalances and more precise familial genetic counseling regarding actual and future pregnancies.

Heart‐hand syndrome IV: a second family with LMNA‐related cardiomyopathy and brachydactyly

Clin Genet 2017: 91: 499–500 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/cge.12870 Letter to the Editor Heart-hand syndrome IV: a second family with LMNA-related cardiomyopathy and brachydactyly To the Editor: Heart-hand syndromes (HHS) include the most com- mon type – HHS I: Holt–Oram syndrome (congenital heart disease and radial ray anomalies) and several rare types – HHS II: Tabatznik syndrome (arrhythmias and brachytelephalangy), HHS III: Spanish type (arrhyth- mia and brachydactyly type C), and a potential HHS IV: Slovenian type [arrhythmia, dilated cardiomyopa- thy (DCM), and brachydactyly] (1, 2). TBX5 for HHS I: Holt–Oram syndrome and LMNA for HHS-Slovenian type (due to a cryptic splice-site mutation) are the only two genes found to contribute to HHS (1–3). We report a second HHS IV family due to a previ- ously reported LMNA mutation (p.Arg335Trp). All pro- cedures were approved by the UCI institutional review board. Written informed consent was obtained for all participants. The proband, who recently died at age 57, had DCM and ‘small hands.’ His family had Ger- man and Irish ancestry and multiple individuals born with ‘small hands’ and later developed heart disease. Eleven individuals were classified as affected or unaf- fected for heart disease (4) and hand anomalies (Fig. S1 and Table S1, Supporting Information). Characteriza- tion of the hands and feet for the proband (III-6) and his affected first-cousin (III-11) revealed small hands with short digital rays (Fig. 1a). Hand radiographs showed shortened digital rays with no carpal anomalies (Fig. 1b), and metacarpophalangeal pattern (MCPP) profile analy- sis (5) revealed a consistent wavy pattern with brachy- dactyly of all tubular bones with marked shortening of the first and third distal phalanges, second middle phalanx and first proximal phalanx (Fig. 1c). For both patients, the feet were normal in appearance with normal radiographs (not shown). In addition, there were no signs of myopathy or lipodystrophy. To identify the causative variant(s) for the cardiac and/or limb phenotypes, exome sequencing for the proband was conducted (4). The results included 14 giga- bases of data from 164 million reads, 91% of mapped reads to hg19, and 134X average read coverage of each exon. To identify high-priority candidate variants from 10,395 variants predicted to impact the protein, we focused on variants located in candidate genes associated with cardiomyopathy, arrhythmia, ion channels, or limb anomalies (Table S2). Ten candidates were identified (Table S3) and validated by Sanger sequencing. Fam- ily studies to determine co-segregation identified LMNA c.1003C>T, p.Arg335Trp [RefSeq NM_170707.3], a heterozygous C>T missense variant in exon 6 as the pri- mary mutation for both the cardiac and limb phenotypes (Figs S2 and S3). With similar cardiac and skeletal features as the HHS-Slovenian family (2), we provide further evidence for a fourth type of HHS due to a LMNA mutation. In both families, the cardiac features are typical for LMNA-related cardiac disease (2), and the skeletal fea- tures evaluated by MCPP profile analysis displayed a similar wavy pattern with brachydactyly affecting all the tubular bones of the hands with more severely affected first and third distal phalanges and first proximal pha- lanx (2). Differences between the families were noted. Patients in the Slovenian family presented in the fourth to fifth decades with cardiac disease (2) while patients in our family often presented younger: daughter (IV-13) with syncope at age 12, nephew (IV-16) with cardio- genic shock at age 27, and sister with sudden death at age 23. Differences in skeletal features included severe foot involvement as short or absent phalanges, short metatarsal bones, and IV–V syndactyly in the Slovenian family (2) while our family showed no significant foot abnormalities. Patients with LMNA c.1003C>T (p.Arg335Trp) and cardiac disease have been published; however, limb anomalies were not reported (ClinVar: Variation ID:36473 and Leiden Open Variation Database DB-ID LMNA_00127). This includes a heterozygous patient with atrial fibrillation, hypertriglyceridemia, mus- cle weakness, and acro-osteolysis. LMNA-associated acro-osteoylsis has been seen in autosomal recessive mandibuloacral dysplasia (OMIM 248370). The more severe involvement of the distal phalanges seen in both families and acro-osteolysis seen in other LMNA patients suggests an increased susceptibility of the distal limb elements to disturbances in LMNA dosage. The reasons for the clinical variability are not known. In the Slovenian family, a heterozygous cryptic splice-site mutation LMNA c.1609-12T>G was found; expression studies showed abnormal mRNA splicing and a truncated Lamin A/C protein with 14 new amino acids at the C-terminus (p.E536fsX14) consistent with © 2016 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Hereditary Predispositions to Myelodysplastic Syndrome.

Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SBS), hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA) and significantly increased risks for MDS and/or acute myeloid leukemia (AML) in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes.

The VACTERL Association as a disturbance of cell fate determination.

Cases diagnosed as the VACTERL Association are heterogeneous, and can involve other associations arising from different developmental processes with midline effects. However, these often lack the classic radial ray anomalies that help make VACTERL distinct. A more specific association can be delineated based on teratogenic disturbances affecting vulnerabilities associated with the establishment of cell fate through positional information, with two basic weaknesses: (i) The midline, where topological properties such as reduced lateral information should make information losses more likely; (ii) Increased distal sensitivity at the end of a morphogen gradient in the limbs, where both duplications and deficiencies can arise from similar disturbances. Vertebral, cardiac, anal-rectal, and tracheo-esophaeal findings are primary midline derivatives. While the kidneys are bilateral, they can be influenced by the midline, although there may also be effects on the ureteral buds as distal structures. The pre-axial area is the most distal in limb development, giving radial/tibial deficiencies and duplications. Alternatively, spina bifida and orofacial clefts originate from bilateral structures that are less likely to be affected by problems with midline determination, explaining the rarity of these disorders with VACTERL. Suggested human genetic models typically involve the midline, but lack radial findings, and true Mendelian forms are rare. However, developmental genes such as Sonic Hedgehog may have a pathogenetic role without being causal.

Fanconi’s anaemia and unilateral thumb polydactyly – Don’t miss it

Fanconi's anaemia (FA) is a rare, life threatening inherited syndrome. Patients usually present late in the first decade of life with aplastic anaemia or acute myeloid leukaemia. FA children are also at high risk of solid organ tumours, anogenital squamous cancers, and endocrinopathies. These patients can present with unilateral radial abnormalities including thumb duplication. Hand surgeons can help achieve early diagnosis and improved survival in this group by early referral for screening. In a retrospective study of 202 children with radial ray anomalies seen over a 20 year period seven children had FA. Of these seven with FA, four had bilateral thumb hypoplasia and three had unilateral thumb anomalies--two unilateral thumb hypoplasias and one thumb duplication. The three children with unilateral anomalies were diagnosed late, presenting with bone marrow failure. All three have subsequently died following late bone marrow transplants. This study highlights the link between unilateral radial anomalies, including thumb duplication and FA and the importance of early genetic referral for diagnosis and surveillance.

Outcome of Oesophageal Atresia Beyond Childhood

Esophageal atresia; Esophageal dysmotility; Esophagitis; Gastresophageal reflux; Long-term outcome; Metaplasia The overall survival rate of patients with esophageal atresia (OA) has increased significantly during the last decades, and today exceeds 90% of all patients. 1 Today, practically all patients without concomitant severe malformations survive, and the very high mortality of very low birth weight patients and patients with severe cardiac malformation has decreased significantly. Many surviving patients, however, continue having functional problems, especially from their gastrointestinal tract and respiratory system after the initial postoperative period. 2 The overall impact of these problems on the long-term outcome of OA patients is not fully understood. Moreover, it is unclear what impact postnatal postoperative, usually relatively long hospitalization time, and repeated anesthesias for anastomotic dilations in many patients may have on later psychosocial well-being of the patients. There are a limited number of reports concerning longterm outcome of patients with OA. The eventual quality of life appears to be good in most adults. 3,4 This assumption is

CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome

<i>CHN1</i> mutations are not a common cause of sporadic Duane's retraction syndrome

Mardini–Nyhan association (lung agenesis, congenital heart, and thumb anomalies): Three new cases and possible recurrence in a sib—Is there a distinct recessive syndrome?

In 1985, Mardini and Nyhan described three patients from consanguineous families with unilateral complete/partial lung agenesis, congenital cardiac defects, and ipsilateral thumb anomalies. Although there have been many reports of lung agenesis with other malformations, especially hemifacial microsomia and radial ray anomalies, very few demonstrate this triad of defects. We describe three patients with the Mardini-Nyhan association which may represent a distinct entity, although this remains uncertain at present. A fourth patient is also described, the sister of one of the other patients, with complex congenital cardiac disease and bilateral lung lobation abnormalities. This is the first reported incidence of a possible recurrence within a family and suggests, together with the consanguinity observed by Mardini and Nyhan, that recessive inheritance should be considered in genetic counseling for this disorder.

A clinical algorithm of prenatal diagnosis of Radial Ray Defects with two and three dimensional ultrasound

To review the antenatal diagnosis of Radial Ray Defects (RRD) in a tertiary referral fetal medicine unit & to set out a clinical algorithm to aid assessment and management. All cases of RRD isolated or associated with other anomalies notified to NorCAS between 2000 and 2005 were identified. Outcome information was obtained from paediatric records and histopathology and cytogenetics in cases of pregnancy interruption. Thirty five cases were referred, 17 cases were excluded including skeletal dysplasia (16). An antenatal diagnosis was made in 61% (11/18) - isolated limb reduction defects, Trisomy 18, TAR, fetal valproate syndrome, Roberts syndrome. Of the rest, 3 had a cordocentesis with normal chromosome fragility tests (VACTERL association, Goldenhar syndrome and Acrofacial dysostosis) and 4 declined testing (2 TOP with Cornelia de Lange, 2 ongoing pregnancies diagnosed postpartum with Fanconi anaemia and VACTERL association). The challenge of radial ray anomalies is to combine clinical and ultrasound expertise with input from clinical genetics, ultrasound and molecular testing. Our clinical algorithm encourages targeted sonography including 3D views for subtle face, ear and hand anomalies, providing a useful tool to diagnose the underlying condition, crucial for appropriate obstetric management and prognosticating for future pregnancies.

Pulmonary agenesis—vascular airway compression and gastroesophageal reflux influence outcome

Pulmonary agenesis (PA) is a rare malformation that can be isolated or associated with other anomalies. We report 3 cases of left-sided PA having ipsilateral renal agenesis, facial, and radial ray anomalies. Patients presented in infancy with nonspecific respiratory symptoms and were diagnosed to have PA on chest radiograph and computed tomographic scan. Bronchial compression, by dilated pulmonary artery and associated severe gastroesophageal reflux, aggravated respiratory symptoms and required surgical intervention. The relevant literature is briefly reviewed.

A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation

The SALL4 gene encodes a putative zinc finger transcription factor and is located on chromosome 20q13.13-13.2. Mutations in SALL4 have been identified in patients with Okihiro syndrome, which is characterized by radial ray anomalies associated with a Duane anomaly. Here, we report an unusual family in which affected persons show an extremely variable phenotype consistent with either Okihiro syndrome, hemifacial microsomia, or isolated Duane anomaly. A novel nonsense mutation in the SALL4 gene was detected in all affected family members and obligate carriers. This mutation is located in exon 3, only 29 bp 5' of the most 3' intron, and would therefore be expected to escape the nonsense mediated mRNA decay pathway, which might explain the phenotypic variability and mild degree of limb involvement.

Should chromosome breakage studies be performed in patients with VACTERL association?

The VACTERL association is characterized as a non-random pattern of defects including at least three of the following cardinal features: vertebral anomalies, anal atresia, cardiovascular malformations, tracheoesophageal fistula, renal and limb anomalies, and is postulated to be a very heterogeneous disorder. These defects can also be seen as part of the Fanconi anemia (FA) spectrum. Although VACTERL with hydrocephaly has clearly been associated with FA, the indication for chromosome breakage studies is not clear in VACTERL without hydrocephaly. We report on three unrelated patients with the VACTERL phenotype and the confirmed diagnosis of FA. Together with the data of 13 similar cases extracted from a European genotype-phenotype correlation study for FA and those from the four reported cases of the literature, we show that (i) in a series of individuals proven to have FA, 5% (13/245) also have the VACTERL phenotype, (ii) all have radial ray anomalies and 12 of these 13 subjects show at least 1 other feature of FA (café au lait spots, growth retardation, microcephaly, dysmorphism), and (iii) the VACTERL phenotype appears to be over represented in the FA complementation groups D1, E, and F. Since the diagnosis of FA is important for genetic counseling and early therapeutic intervention in patients, we conclude that chromosomal breakage studies should be performed, not only in cases of VACTERL with hydrocephaly, but also in cases VACTERL with radial-ray anomalies and especially if the individual has additional FA associated manifestations such as skin pigmentation abnormalities, growth retardation, microcephaly, or microphthalmia.

110th ENMC International Workshop: The congenital cranial dysinnervation disorders (CCDDs): Naarden, The Netherlands, 25–27 October, 2002

A multi-disciplinary group of 13 clinicians and researchers from six countries convened for the first time to study a group of congenital neuromuscular diseases characterized by abnormal eye, eyelid, and/or facial movement. This group of diseases includes Duane syndrome, congenital fibrosis of the extraocular muscles (CFEOM), Möbius syndrome, horizontal gaze palsy, congenital ptosis and congenital facial palsy. Although these disorders were previously referred to in the literature under various terms, including ‘congenital fibrosis syndromes’, we have now chosen to refer to them as the ‘congenital cranial dysinnervation disorders’ or CCDDs. This name reflects our belief that these disorders result from developmental errors in innervation of the ocular and facial muscles. Thus far, members of the consortium have identified ten CCDD genetic loci and two CCDD disease genes (PHOX2A mutated in CFEOM2 and SALL4 mutated in Duane syndrome with radial ray anomalies). A CCDD classification scheme and an International CCDD Consortium have been established. The goals of the Consortium are to foster continuing research into the genetic basis of these disorders by identifying new families and affected individuals and by the sharing of genetic resources. Future studies of the CCDD genes should enhance our understanding of the pathophysiology and treatment of these disorders.

Duane Radial Ray Syndrome (Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Member of the SAL Family

Duane syndrome is a congenital eye movement disorder characterized most typically by absence of abduction, restricted adduction, and retraction of the globe on attempted adduction. Duane syndrome can be coinherited with radial ray anomalies as an autosomal dominant trait, referred to as "Okihiro syndrome" or "Duane radial ray syndrome" (DRRS). We ascertained three pedigrees with DRRS and mapped their disease gene to a 21.6-cM region of chromosome 20 flanked by markers D20S888 and D20S102. A new member of the SAL family of proposed C(2)H(2) zinc finger transcription factors, SALL4, falls within the region. Mutation analysis of SALL4 in the three pedigrees revealed one nonsense and two frameshift heterozygous mutations. SALL4 represents the first identified Duane syndrome gene and the second malformation syndrome resulting from mutations in SAL genes and likely plays a critical role in abducens motoneuron development.

Patterns of acrorenal malformation associations.

Limb and urinary tract defects have frequently been reported to occur together as components of a single acrorenal field defect or in many multiple malformation syndromes. However, the concordance of such anomalies has rarely been studied on a population basis or the relationships between specific limb and renal defects defined. This paper documents the patterns of acrorenal associations seen in over 1,500,000 infants born in Hungary in 1975-1984. In all, 1 in 1,800 infants had a limb deficiency and 9% of these (75 cases) had a urinary tract anomaly. Urinary tract anomalies were most commonly seen with radial ray defects, micromelia and amelia. The commonest recognized patterns were VACTERL association and the cloacal exstrophy and caudal regression sequences. Chromosomal and single gene defects also occurred. Numerical taxonomic techniques delineated six main clusters of patients. Important groupings included micromelia with renal agenesis, split hand/foot with hydronephrosis, and radial ray anomalies with VACTERL defects. The radial ray groups differed in the nature of the VACTERL anomalies seen and with respect to laterality, symmetry, and non-VACTERL anomalies. There was a strong association of bilateral limb defects with bilateral renal anomalies and unilateral with unilateral. Ipsilateral defects tended to occur in typical VACTERL cases, while contralateral defects tended to occur with additional non VACTERL midline anomalies. Although renal and limb anomalies are associated, in almost all cases malformations in other systems are also present. The precise nature of the malformation patterns seen appear to reflect differences in the nature and magnitude of the underlying dysmorphogenetic processes as well as the timing of their effects.