Hedgehog in the human: a possible explanation for the VATER association

Foregut malformations are relatively common anomalies, occurring in 1 in 2000-5000 live births. The adriamycin-induced rat model of the VATER association has provided a means of studying the morphogenesis of a variety of major congenital structural abnormalities similar to those seen in humans with VATER association. The secreted glycoprotein, Sonic hedgehog (Shh), may act as an endodermal signal that controls gut and lung patterning. Mice with targeted deletion of Shh have foregut defects that are consistent with those produced by administration of adriamycin. It is possible that mutations induced by adriamycin may result from the breakdown of the Shh signalling pathway.     

The Vater association in a newborn infant of a diabetic mother

Concerning the case history of an infant of diabetic mother, the authors analyse the possible relationship between a VATER association and a poorly controlled diabetes mellitus in the early weeks of pregnancy. Caudal regression syndrome, the most frequently observed malformation noted in infants of diabetic mothers and VATER association are the results of an "AXIAL MESODERMAL DYSPLASIA". Furthermore, the factors causing VATER association occur before the seventh week of pregnancy like those responsible for the anomalies observed in infants of diabetic mothers. It is possible that a poorly controlled diabetes mellitus before conception and in the early weeks of pregnancy could favour the appearance of VATER association.     

Amelia,hypoplasia of iliac bone,and absence of ischium and ramus pubis in the VATER association

A 1-day-old female presented with hypoplasia of the iliac bone and absence of the ischium and ramus pubis in the VATER association. To our knowledge, these skeletal anomalies have not been previously reported with the VATER association. Offprint requests to: M. Pul     

Central nervous system malformations and the VATER association

Four patients with findings compatible with the VATER association having a malformation of the central nervous system requiring neurosurgical intervention are reviewed. Each patient has a different neurosurgical lesion, one of which has not been hitherto described as occurring with the other anomalies of the association. We suggest that all patients with the VATER association be evaluated carefully for malformations having neurosurgical implications.     

Oesophageal atresia and the CHARGE association

We report two boys with oesophageal atresia and the CHARGE association, both of whom eventually died from the effects of their cardiac anomalies. It is important to distinguish the CHARGE association from the VATER association because the former collection of anomalies conveys a much gloomier prognosis than the latter. Offprint requests to: A. Valente     

The contribution of the adriamycin-induced rat model of the VATER association to our understanding of congenital abnormalities and their embryogenesis

 The adriamycin-induced rat model of the VATER association has provided a means of studying the morphogenesis of a variety of major congenital structural abnormalities similar to those seen in humans with the VATER association. Most interest has been centered on the foregut, where the model has clarified some aspects of the development of esophageal atresia (EA), tracheal agenesis, and other communicating bronchopulmonary foregut malformations. It has demonstrated aberrations in the nerve supply to the esophagus in EA and allowed the study of tracheomalacia. A relationship between an abnormal notochord, foregut abnormalities, and vertebral defects has been shown, and the model has reignited interest in the role of the notochord as a regional organizer of axial development. The normal temporospatial characteristics of apoptosis during fore- and hindgut development is disturbed in this model, resulting in abnormal morphology. The indications are that this model will continue to clarify the processes that lead to many of the structural congenital abnormalities that are seen in infants born with the VATER association. Accepted: 19 January 2000     

Monozygotic twins concordant for tracheo-esophageal fistula and discordant for the VATER association

Monozygotic female twins were concordant for tracheo-esophageal fistula (TEF); and one twin also manifested other anomalies in the VATER association, including agenesis of the female reproductive tract. Review of the literature discloses a familial tendency for recurrence of TEF and a high concordance rate in monozygotic twins, indicating a significant genetic influence for the isolated anomaly. In the case of the VATER association, the sporadic occurrence of affected individuals and discordance in twins implicates the effect of non-genetic factors.     

MONOZYGOTIC TWINS CONCORDANT FOR TRACHEO-ESOPHAGEAL FISTULA AND DISCORDANT FOR THE VATER ASSOCIATION

Abstract. Monozygotic female twins were concordant for tracheo-esophageal fistula (TEF); and one twin also manifested other anomalies of the VATER association, including agenesis of the female reproductive tract. Review of the literature discloses a familial tendency for recurrence of TEF and a high concordance rate in monozygotic twins, indicating a significant genetic influence for the isolated anomaly. In the case of the VATER association, the sporadic occurrence of affected individuals and discordance in twins implicates the effect of non-genetic factors.     

Tracheal agenesis in infants with VATER association

Four newborns had tracheal agenesis and numerous features of the VATER (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia) association. Forty-two additional reported cases of tracheal agenesis have been reviewed to establish whether this defect usually occurs in association with other VATER abnormalities. Since tracheal agenesis usually is accompanied by other VATER-associated defects and since similar abnormalities in embryological mechanisms and timing are implicated, according to current theories of development, we propose that tracheal agenesis should be considered a component of the VATER association.     

The expanded spectrum of limb anomalies in the VATER association

The radiographs of 230 children who had undergone neonatal surgery for imperforate anus and/or esophageal atresia/tracheoesophageal fistula were reviewed. Of the 31 children with limb anomalies thus detected, the 24 who had no radiologic or laboratory evidence of chromosomal abnormality form the basis of this report. In 16 children the limb anomalies fell within the commonly described spectrum of the VATER association. In the other 8 children and in 3 of the children with typical VATER limb anomalies additional anomalies were encountered: Sprengel deformity [2], hypoplasia of the humerus [3], radioulnar synostosis [1], midline anomalies of the hand [1], absence of the pubis, femur, tibia, and fibula and two rays of the foot [1], and other foot deformities. Subtle anomalies of the hand were common and included: clinodactyly, syndactyly, shortening of the middle phalanx of the fifth digit, and rotary malposition of the digits.     

中国人直肠肛门畸形1262例分析

目的 了解中国人直肠肛门畸形基本状况及合并其他畸形的情况,为临床治疗提供参考资料。方法 １９８７￣１９９２年中国出生缺陷监测网以医院为基础在全国对孕２８周至产后７天的围产儿进行监测,对监测出的１２６２例直肠肛门畸形患儿进行流行病学分析。结果 中国人直肠肛门畸形的发病率为２．８１／万,全国各地发生率无显著差异,且发生率呈下降趋势。单发直肠肛门畸形５３１例,多发７３１例,其中尸解３０３例,直肠肛门畸形     

Association of ambiguous genitalia with VATER anomalies and its significance in management

Tracheo-oesophageal fistula, oesophageal atresia, and imperforate anus are known to be associated with renal anomalies — the VATER complex. The occurrence of ambiguous genitalia with this collection of anomalies has not previously been highlighted. We report two cases occurring 15 years apart; both had renal agenesis and neither was salvagealble from a renal or pulmonary viewpoint. Preoperative ultrasound examination of the renal tract should be performed in all babies born with the VATER complex and ambiguous genitalia; this will prevent unnecessary surgery.     

Surgical management of renal tract problems

The majority of renal tract problems in childhood are congenital in origin with an overall incidence of 2–4 per 1000 live births. Some anomalies may occur in isolation e.g. posterior urethral valves; whilst others may be part of a more complex spectrum of anomalies e.g. duplex or horseshoe kidney in VACTERL or VATER association. Prenatal screening has highlighted an increasing number of children with renal tract anomalies which may require paediatric specialist involvement in the immediate postnatal period. Most congenital renal tract problems are managed by paediatric urologists and paediatric surgeons with a special interest in urology.The aim of this review is to highlight the most common renal tract disorders of childhood and to discuss their aetiology, clinical presentation, investigation and surgical management.     

The VATER association. Analysis of 46 patients

Evaluation of 46 patients with the VATER association indicates that in addition to the major defects seen in this association, numerous other abnormalities occur at lesser frequency. Four of the defects that are not usually associated with the VATER association, namely, inguinal hernias, small intestinal malformations, choanal atresia, and cleft lip and/or palate, were seen at a relatively high frequency in this patient population. Two children possessed defects found in both the VATER and CHARGE associations. The spectrum of defects in the 46 patients in this study also is compared with that in 186 cases derived from the literature.     

Etiological Heterogeneity in Sirenomelia

Two babies with sirenomelia are described. Case 1, one of twins, showed the full sirenomelia sequence in conjunction with atelencephaly and cebocephaly. Case 2 had malformations consistent with a diagnosis of the VATER association. Review of the literature indicates that the basic defect in sirenomelia and the VATER association lies in the formation and differentiation of mesodermal tissue and that sirenomelia, the VATER association, and monozygotic twinning show a complex etiological interrelationship.     

Etiological heterogeneity in sirenomelia

Two babies with sirenomelia are described. Case 1, one of twins, showed the full sirenomelia sequence in conjunction with atelencephaly and cebocephaly. Case 2 had malformations consistent with a diagnosis of the VATER association. Review of the literature indicates that the basic defect in sirenomelia and the VATER association lies in the formation and differentiation of mesodermal tissue and that sirenomelia, the VATER association, and monozygotic twinning show a complex etiological interrelationship.     

Is urorectal septum malformation sequence a variant of the vertebral defects,anal atresia,tracheo-oesophageal fistula,renal defects and radial dysplasia association? Report of a case and a review of the literature

The urorectal septum malformation sequence (URSMS) consists of multiple systems anomalies including ambiguous genitalia, the absence of a perineal opening, an imperforate anus, and urogenital, colonic and lumbosacral anomalies. We describe a 3-day-old female infant with characteristic URSMS and review its clinical manifestations, outcomes and putative pathogenesis. We also compare its characteristics with those of the vertebral defects, anal atresia, tracheo-oesophageal fistula, renal defects and radial dysplasia (VATER) association. Conclusion:Although defects of the urorectal septum malformation sequence and the vertebral defects, anal atresia, tracheo-oesophageal fistula, renal defects and radial dysplasia association overlap, we believe that they are separate entities. Differentiating the urorectal septum malformation sequence from vertebral defects, anal atresia, tracheo-oesophageal fistula, renal defects and radial dysplasia association is helpful to develop appropriate clinical investigations and search for the aetiology and pathogenesis of these diseases.     

Familial occurrence of the VATER/VACTERL association

The acronym VATER/VACTERL association is used to describe the non-random co-occurrence of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheo-esophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We report a familial case of VATER/VACTERL association in which both the index case and her maternal uncle displayed four major component features of the disorder. A systematic literature search identified 12 previously described familial cases. However, on comparison, both members fulfilled the diagnostic criteria for VATER/VACTERL association only in one instance, and ours is the second such report. Although, a SNP array-based analysis identified no causal genomic alteration, the findings in the present family suggest that genetic factors are implicated in the development of the disorder.     

The Vater association: malformations of the male external genitalia.

Eight cases with the VATER association of malformations are presented. Maliformations of the external genitalia were found in 3 out of 7 male patients. Two of them presented with a bifid scrotum and a caudally displaced, dysplastic penis. Two patients had been exposed to progestin in early pregnancy and one of them had hyposadias and testicular atrophy. It is suggested that malformations of the male external genitalia might be part of malformations found in the VATER association.     

The CHARGE association

The CHARGE association includes a group of several malformations, and always a coloboma and/or choanal atresia. We present 8 cases of this syndrome, 5 complete and 3 incomplete forms. Prognosis at term seems severe, considering the visceral malformations (namely cardiac) and the cerebral handicap often associated. In most cases the CHARGE association is a sporadic event; however, one cannot exclude the possibility that certain forms follow a Mendelian pattern of inheritance. The mechanisms leading to this association have not yet been elucidated: it is probably due to migration abnormalities of the neural crests as in the VATER association of Di George syndrome.