De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association

The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies: vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant de novo copy number variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the patients'' parents. Three de novo CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising one (SPATA17), two (CAPN10, GPR35), and three (EPPK1, PLEC, PARP10) genes, respectively. Pre-existing data from the literature prompted us to choose GPR35 and EPPK1 for mouse expression studies. Based on these studies, we prioritized GPR35 for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest GPR35 to be involved in the development of the VATER/VACTERL phenotype. Follow-up of GPR35 and the other genes comprising the identified duplications is warranted.     

Genetic factors in esophageal atresia,tracheo-esophageal fistula and the VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster,and review of the literature

Esophageal atresia with/without tracheo-esophageal fistula is a relatively common malformation, occurring in around 1 in 3500 births. In around half of cases, additional malformations are present, forming either a syndrome of known genetic aetiology, or a recognised association, of which the VACTERL association (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal and Limb malformations) is the most recognised. Recently, microdeletions of the FOX gene cluster at 16q24.1, comprising four genes, FOXF1, MTHFSD, FOXC2 and FOXL1, were reported to cause a phenotype resembling VACTERL association, with vertebral anomalies, gastro-intestinal atresias (esophageal, duodenal and anal), congenital heart malformations, and urinary tract malformations, as well as a rare lethal developmental anomaly of the lung, alveolar capillary dysplasia. This article reviews these new data alongside other genetic causes of syndromic esophageal atresia, and also highlights information from relevant mouse models, particularly those for genes in the Sonic Hedgehog pathway.     

Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association

VACTERL association, a relatively common condition with an incidence of approximately 1 in 20,000 -35,000 births, is a non-random association of birth defects that includes vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-esophageal fistula (TE), renal anomalies (R) and limb malformations (L). Although the?etiology is unknown in the majority of patients, there is evidence that it is causally heterogeneous. Several studies have shown evidence for inheritance in VACTERL, implying a role for genetic loci. Recently, patients with component features of VACTERL and a lethal developmental pulmonary disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), were found to harbor deletions or mutations affecting FOXF1 and the FOX gene cluster on chromosome 16q24. We investigated this gene through direct sequencing and high-density SNP microarray in 12 patients with VACTERL association but without ACD/MPV. Our mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX?gene cluster on chromosome 16q24 in the studied patients. Possible explanations for these results include the etiologic and clinical heterogeneity of VACTERL association, the possibility that mutations affecting this gene may occur only in more severely affected individuals, and insufficient study sample size.     

Another observation with VATER association and a complex IV respiratory chain deficiency

The VATER association of vertebral anomalies (V), anal atresia (A), esophageal atresia and/or tracheo-esophageal fistula (TE), radial and renal anomalies (R) is a common congenital association of unknown origin with probably heterogeneous causes. Here, we report on a girl presenting with pre- and postnatal growth retardation, esophageal atresia, vertebral and costal anomalies and a unilateral radial defect, consistent with the diagnosis of VATER association. In the first month of life, she presented with failure to thrive, severe episodes of hypoglycemia, liver dysfunction and high levels of lactate, which prompted us to perform metabolic screening. A complex IV respiratory chain deficiency (RCD) was diagnosed on a liver biopsy. The respiratory chain defect was not observed in skin fibroblasts. No mtDNA point mutation or deletion was identified. The girl is now 9 years old and has a normal mental development but persistent feeding difficulties and moderate hyperlactatemia. To our knowledge, this is the second report of VATER association with mitochondrial disorder. In a previous report, a VACTERL association was observed in a girl with the mitochondrial A3243G point mutation. The association of VATER phenotype with a mitochondrial disorder may be coincidental but could also suggest that the presence of multiple malformations is the result of the antenatal expression of RCD.     

VATER non‐random association of congenital malformations: Study based on data from four malformation registers

This study was undertaken to find a strict, unbiased epidemiological delineation of the VATER non‐random association of congenital malformations and, based on registry information, to identify a group of probable VATER association infants suitable for etiological analyses. Information on 5,260 infants with multiple malformations was collected from four large registers of congenital malformations. Data were analyzed using a statistical method in which various putative confounders were controlled for. Our results indicate the existence of a distinct group of malformations corresponding to the VATER association: esophageal atresia, anal atresia, upper preaxial limb reduction defects, and costo‐vertebral malformations. A subdivision into an upper and a lower group of VATER association was indicated, with heart malformations associated with the upper group and kidney malformations associated with the lower group. Restricting the inclusion criteria for VATER association to the above mentioned core malformations, few infants seem to belong to the VATER association, thus limiting the possibilities of carrying out etiological analyses. A relatively large number of infants may belong to a family of related conditions among which VATER association is a subgroup. In the search for risk factors, a strict definition of the VATER association is needed in order to not dilute the study material with irrelevant cases. The present study provides such strict inclusion criteria. © 2001 Wiley‐Liss, Inc.     

VATER/VACTERL association: clinical variability and expanding phenotype including laryngeal stenosis.

Vertebral abnormalities and anorectal and tracheoesophageal defects are the main manifestations in the VATER/VACTERL association. Radial defects vary from radial aplasia to thumb duplication. Heart and renal defects are reported with lower frequency. Additional malformations, such as the laryngeal stenosis described in the present patient, may expand the phenotype of the association. The wide spectrum of congenital abnormalities confirms the high clinical variability of VATER/VACTERL association which seems to be due to a disruption of blastogenesis.     

Sacrococcygeal dysgenesis association

In the malformation analysis of 445 patients ascertained only for a sacrococcygeal malformation, a new phenotype, the sacrococcygeal dysgenesis association (SDA), was delineated in 34%. In addition, sirenomelia patients were found in 12%, the VATER association in 27%, and 27% could not be classified. Heterogeneity in the patients with sacrococcygeal malformations was identified by the differences found in their associated malformations. SDA patients have a relatively small average number (3.3) of anomalies per patient as compared with 9.3 in sirenomelia and 6.2 in VATER patients. SDA abnormalities occurred to a significant degree only in 6 of 20 designated malformation categories (vertebral, rib, pelvic, lower limb, central nervous system [CNS], renal) in contrast to 17 in VATER and 18 in sirenomelia patients. The SDA vertebral malformation pattern also differed from that of VATER/sirenomelia patients as did the high sacrococcygeal agenesis: dysgenesis ratio and low thoracolumbar vertebrae and/or rib hypersegmentations. Most significantly, SDA patients had a large number of CNS anomalies and CNS-related dysfunctions of the urinary and distal intestinal tracts but no anatomic urinary or intestinal tract malformations. This contrasted sharply with the markedly increased occurrences of anatomic abnormalities in these body regions of the sirenomelia and VATER patients. Demographic data such as patient survival, twinning and, particularly, the high (28%) incidence of maternal diabetes in the SDA further support its differentiation from VATER/sirenomelia patients.     

PHAVER syndrome: An autosomal recessive syndrome of limb pterygia,congenital heart anomalies,vertebral defects,ear anomalies,and radial defects

We have studied 2 sibs with vertebral, radial, congenital heart, and ear defects. The second patient also had limb pterygia and meningomyelocele. The abnormalities in these two sibs are seen in the VATER association; however, distinguishing these cases from the VATER association are the findings of pterygia, meningomyelocele, and probable autosomal recessive inheritance. We propose the acronym PHAVER syndrome for limb pterygia, heart defects, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects. This represents an new autosomal recessive disorder with phenotypic variability. © 1993 Wiley-Liss, Inc.     

Vertebral hypersegmentation in a case of the VATER association

Associations are statistical clusterings of malformations not known to be polytopic field defects, sequences, or syndromes. The VATER association is a nonrandom association of malformations including vertebral, anal, cardiovascular, tracheoesophageal, genitourinary, and limb defects. The caudal “dysplasia” sequence of lumbosacral vertebral defects, genitourinary abnormalities, and imperforate anus overlaps the VATER association. The cloacal membrane agenesis sequence is a pattern of malformations resulting in the absence of anal, genital, and urinary orifices with associated malformations in surrounding structures. We report on a 37-week gestation liveborn male with oligohydramnios deformations, tetralogy of Fallot, “H-type” tracheoesophageal fistula, duodenal atresia, imperforate anus, urethral atresia, undescended testes, absent right kidney with a small dysplastic left kidney, a “cloacal-like” abnormality of the bladder and distal bowel, and thoracic and lumbar vertebral hypersegmentation. This patient has manifestations of the VATER association, the caudal dysplasia sequence, and the cloacal membrane agenesis sequence. We propose that some of his defects may represent a malformation sequence secondary to excessive embryonic flexion resulting from vertebral hypersegmentation.     

Vertebral hypersegmentation in a case of the VATER association.

Associations are statistical clusterings of malformations not known to be polytopic field defects, sequences, or syndromes. The VATER association is a nonrandom association of malformations including vertebral, anal, cardiovascular, tracheoesophageal, genitourinary, and limb defects. The caudal "dysplasia" sequence of lumbosacral vertebral defects, genitourinary abnormalities, and imperforate anus overlaps the VATER association. The cloacal membrane agenesis sequence is a pattern of malformations resulting in the absence of anal, genital, and urinary orifices with associated malformations in surrounding structures. We report on a 37-week gestation liveborn male with oligohydramnios deformations, tetralogy of Fallot, "H-type" tracheoesophageal fistula, duodenal atresia, imperforate anus, urethral atresia, undescended testes, absent right kidney with a small dysplastic left kidney, a "cloacal-like" abnormality of the bladder and distal bowel, and thoracic and lumbar vertebral hypersegmentation. This patient has manifestations of the VATER association, the caudal dysplasia sequence, and the cloacal membrane agenesis sequence. We propose that some of his defects may represent a malformation sequence secondary to excessive embryonic flexion resulting from vertebral hypersegmentation.     

Twelve new patients with 13q deletion syndrome: Genotype–phenotype analyses in progress

13q deletion is characterized by a wide phenotypic spectrum resulting from a partial deletion of the long arm of chromosome 13. The main clinical features are mental retardation, growth retardation, craniofacial dysmorphy and various congenital defects. Only one recent Italian study was aimed at determining genotype–phenotype correlations among 13q deletions from a group of mainly live born children, using array-CGH and FISH.In order to improve the molecular characterization of 13q monosomy, 12 new patients (9 foetuses and 3 children) were collected based on a cohort of holoprosencephaly (HPE) linked to ZIC2 gene deletion and/or patients with 13q deletion diagnosed by standard karyotype. First, quantitative gene screening using MLPA (Multiplex Ligation dependent Probe Amplification) was performed to look for ZIC2 gene deletion and then, CGH array analysis was carried out using the Agilent Human Genome CGH microarray 4 × 44K (Agilent Technologies, Santa Clara, USA).All the foetuses had severe cerebral midline malformations associated with a deletion including the ZIC2 gene. We report one patient with Steinfeld phenotype linked to this chromosomal anomaly, and suggest that some of the associations between cerebral midline malformation and limb defects might be related to 13q deletion.Further candidate genes are suspected to explain the malformations associated with cerebral anomalies in the hypothesis of a contiguous gene syndrome: SPRY2 in 13q31.1 is implicated in lens cell proliferation and differentiation for congenital cataract; GPC5 in 13q32 is mainly expressed in the mesenchyme of the developing limb bud for upper limb anomalies.     

Oesophageal atresia,related malformations,and medical problems: A family study

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF. Am. J. Med. Genet. 85:31–37, 1999. © 1999 Wiley-Liss, Inc.     

Feingold syndrome: clinical review and genetic mapping

Feingold syndrome is characterized by autosomal dominant inheritance of microcephaly and limb malformations, notably hypoplastic thumbs, and clinodactyly of second and fifth fingers. Syndactyly frequently involves the second and third, as well as the fourth and fifth toes. Approximately one in three Feingold syndrome patients have esophageal or duodenal atresia or both. Anal atresia has been reported in a single case. At least 79 patients in 25 families have been reported. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Vertebral anomalies, cardiac malformations, and deafness have been noted in a minority of patients. Here, we report a patient with hydronephrosis of one kidney and cystic dysplasia of the other, necessitating nephrectomy. The overall pattern of malformations in Feingold syndrome shows considerable overlap with the VATER/VACTERL association. The gene for Feingold syndrome maps to 2p23-p24, but remains to be identified. Comparison of the pattern of anomalies that occurs in the Feingold syndrome in humans and malformations that are present in mice with mutations of genes in the sonic hedgehog signaling pathway suggest, that the elusive Feingold syndrome gene may involve this signaling pathway as well.     

Mandibulofacial dysostosis,microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome?

Zhang Y, Dai Y, Liu Y, Ren J. Mandibulofacial dysostosis, microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome? The acrofacial dysostoses (AFDs) are a heterogeneous group of disorders involving craniofacial dysostosis and limb anomalies. Depending on the type of limb defects, two major groups have been defined: Nager syndrome with predominant preaxial anomalies and Miller syndrome with postaxial malformations. Genomic copy number variation, a common type of genomic variability, can influence gene expression by disrupting coding sequences, perturbing long‐range gene regulation, or altering gene dosage, and these effects could contribute to phenotypic variations or disease risk. We present a distinct AFD case with mandibulofacial dysostosis, microtia and limb malformations but without limb defects, which may represent a new form of AFD. To investigate the etiology of the phenotype, whole genomic high‐resolution array comparative genomic hybridization analysis was carried out, revealing two cryptic duplications, 1p36.33 and 1q21.3‐q22 duplications. Two genes, VWA1 and PYGO2, contained in the two duplications, respectively, are likely to be the candidate genes for the phenotype of our patient.