Brief clinical and laboratory observation

Syndrome of imperforate anus, abnormalities of hands and feet, satyr ears, and sensorineural deafness

Hirschsprung disease (HD) and anorectal malformations (ARMs) result from alterations in hindgut development. It has long been recognized that both recur in families and thus result, at least in part, from genetic factors. Progress in the understanding of the genetic basis of HD has been made by the application of findings from genetic animal models of altered enteric nervous system development to human beings. Several genes have been shown to be important for human enteric nervous system development, and current work is progressing to identify genetic interactions that may explain the variable phenotype of HD. By contrast, understanding of the genetic factors underlying ARMs is much less developed. We and others have shown that genetic factors play an important role in the pathogenesis of ARMs, and many mouse genetic models suggest molecular pathways that may be altered in ARMs.

En 1972, Townes y Brocks describen una familia en la que un padre y 7 hijos mostraban ano imperforado, pulgares trifalángicos, fusión de metatarsos, dedos supernumerarios, sordera neurosensorial y anomalías en las orejas. Los rasgos fundamentales eran los ligados a alteraciones de la mano, oído y ano, transmitidos bajo un patrón autosómico dominante. En el presente trabajo presentamos varios miembros de una misma familia con similares alteraciones, y a los que, después de aunar los datos clínicos, diagnosticamos con el síndrome de Townes-Brocks

In nineteen seventy two Townes and Brocks reported on a family in which the father and seven children showed anal atresia, triphalangeal thumb, metatarsal synostosis, extra fingers, neurosensorial deafness and ear abnormalities. The main traits were those related to hand, ear and anus alterations, transmited under a dominant autosomal pattern. In this paper we present several members of the same family with similar alterations who finally were diagnosed of Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5′ of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Le syndrome de Townes-Brocks (TBS) est une entité rare se transmettant sur le mode autosomique dominant dont l'expressivité clinique marquée par des malformations ancrectales, des pavillons des oreilles et des extrémités, est en fait variable.

Observations. - Deux observations sont rapportées. La première ne présente pas de malformation anorectale mais un syndrome de Pierre-Robin avec atrésie de l'oesophage. La deuxième observation associe à la classique triade une tétralogie de Fallot qui a été rapportée seulement une fois dans la littérature.

Conclusions. - Ces deux observations confirment la fréquente variabilité clinique de ce syndrome expliquant les difficultés diagnostiques en l'absence d'un marqueur spécifique.

Background. - Townes-Brocks syndrome (TBS) is a rare autosomal dominant entity mainly characterized by ano-rectal, ear and extremities abnormalities which variable clinical expression.

Case reports. - The first case had ear and extremities, but not anorectal, abnormalities; a Pierre-Robin sequence with esophageal atresia was also observed. The second case had the classical triad of abnormalities also associated with tetralogy of Fallot wich has been only once reported in the literature.

Conclusions. - Both cases are other examples of the frequent clinical variability observed in this syndrome explaining diagnostic difficulties in the absence of a specific marker.

Goldenhar syndrome (oculoauriculovertebral dysplasia) is associated with anomalies in multiple organ systems. Renal abnormalities have also been reported with the complex, but the incidence of associated genitourinary malformations has not been defined.

We have reviewed our experience with 28 children with Goldenhar syndrome evaluated during the past twelve years. Twenty children underwent imaging evaluation of the urinary tract and 14 (70% of those imaged) children had urinary tract anomalies.

The majority of anomalies presented as an incidental finding on a screening ultrasound (8 patients) or during cardiac catheterization (2 patients). Two children presented with urinary tract infection, 1 child presented with renal failure, and another was diagnosed antenatally. The genitourinary anomalies included the following: ectopic and/or fused kidneys (8 patients), renal agenesis (7), vesicoureteral reflux (5), ureteropelvic junction obstruction (2), ureteral duplication (2), and multicystic kidney (1 patient). Four children have undergone surgical intervention.

Our experience in children with Goldenhar syndrome suggests that the incidence of genitourinary anomalies is higher than previously reported. A screening ultrasound in the neonatal period allows for early intervention in those children with significant urologic abnormalities.