Syndromic anorectal malformation associated with Holt–Oram syndrome, microcephaly, and bilateral corneal opacity: a case report

Malformation syndromes associated with ARM are very rare. In a retrospective review of 103 consecutive patients with ARMs and their associated anomalies over a 22-year period, Cho et al. [2] observed malformation syndromes in only three patients. These consisted of cat eye syndrome, Opitz syndrome, and Potter syndrome type 1. By contrast, after a retrospective investigation of 317 children with ARMs from 1968 to 2001, Berger et al. [5] found associated syndromes in 26 children. The observed syndromes included Down syndrome (trisomy 21), OEIS (omphalocele-exstrophy-imperforate anus-spinal defects) complex, Currarino’s syndrome (sacral dysgenesis or agenesis, presacral tumor, and ARM), cat eye syndrome (numeric aberration of chromosome 22, pre-auricular fistula or auricular appendix, and cardiac malformation), radial aplasia x-linked syndrome (esophageal atresia type IIIb and bilateral radial aplasia), Johanson–Blizzard syndrome, Casamassima–Morton–Nance syndrome, and ROCA-Wiedemann syndrome (retardation of growth and development, ocular ptosis, cardiac defect, and anal atresia) [5]. In all they identified 18 syndromes in 26 children with ARMs. A VACTERL (vertebral, anorectal, cardiac, tracheal, esophageal, renal, and limb) association of anomalies commonly occurs with ARM. A VACTERL association is said to exist when three or more of these anomalies occur together with ARM [2, 3, 5].

Nevertheless, none of these reports found an ARM occurring in association with HOS. To the best of our knowledge, and based on a limited MEDLINE search, the occurrence of ARMs in association with HOS has not been previously reported, though more than 200 cases of the syndrome have been published in the literature [6].

HOS is an autosomal dominant disorder characterized by congenital cardiac and forelimb anomalies with a prevalence of 0.95 per 100,000 live births [7]. The underlying genetic defect is located on the long arm of chromosome 12 (12q²). Mutations in the TBX3 and TBX5 genes give rise to a wide range of phenotypes typical of HOS. These genes play a vital role in cardiac and skeletal development [7]. Mutations in these two T-box genes on chromosome 12q2 give an embryologic basis for the prevalence of atrial septal defects and VSDs in patients with HOS [8].

There is wide variability in the expression of both the cardiac and upper limb anomalies. While all patients with HOS have upper limb malformations, 85–95 % have cardiac anomalies [6]. Skeletal abnormalities mainly affect the upper limbs bilaterally, the radial ray predominantly, and the thumb particularly [6]. Thumb defects may be triphalangeal, hypoplastic, or complete absence [6]. Newbury-Ecob et al. [9] found cases in which the thumbs were normal. In our index case, both thumbs were completely absent. Poznanski et al. [10] demonstrated that carpal abnormalities were more specific for HOS than are changes in the thumb. Unfortunately, the radiographs of the upper extremities of our patient did not capture the skeletal details of her hand and we have lost the opportunity of repeating the radiographic examination because of her death. Skeletal involvement of the long bones of the upper limbs is also often bilateral and varied. It includes hypoplasia or complete absence of the radius as well as hypoplasia of the ulnar or even the humerus or both [7, 9, 10]. In our index case, there was complete absence of both her radial bones with deformity of her ulnar bones.

Almost every type of cardiac anomaly has been reported in HOS [11, 12]. However, secundum-type atrial septal defects (ASD) and VSDs are the most common [11, 12]. Our index patient had a pansystolic murmur that, on evaluation with echocardiography, was diagnosed as a VSD. Very rarely, some patients with HOS present with ocular defects [9], similar to the bilateral microphthalmia and bilateral corneal opacity in our patient. In addition, our patient also had microcephaly.

A diagnosis of HOS, therefore, usually requires the presence of cardiac malformations, conduction defects, and/or radial ray abnormalities in an individual, or the presence of radial ray abnormalities with or without cardiac malformation or conduction defects in those with a family history of HOS [13]. The fact that our patient’s parents, close relatives, and siblings who died from unrelated causes did not have abnormalities of the upper limbs and heart possibly makes this a case of sporadic rather than familial HOS.

The relationship between ARM and HOS is unknown. However, it has been observed that organs that originate from mesodermal tissues are often subject to malformations in children with ARM because of the embryopathology [5]. Similarly, the relationship between HOS and nephroblastoma is poorly understood and is a subject for further investigation. This relationship may be related to the mutations on the T-box genes that give rise to the embryologic defects in HOS.

Similar to most congenital anomalies, HOS can be diagnosed prenatally using three-dimensional sonography to depict the characteristic upper limb malformations. The radius and ulna can be seen easily at 13–16 weeks, while most cardiac anomalies except ASD and small VSD are clearly visible on US screening for anomalies at 18–20 weeks [14]. Therefore, a detailed sonography will reveal an abnormal four-chamber view of the heart and abnormalities of both hands and forearms that are consistent with bilateral radial agenesis [15]. Unfortunately, although US scans were performed at 5 and 8 months’ gestation, the anomalies in our index patient were not diagnosed.