Ophthalmo-acromelic syndrome: Report and review

INTRODUCTION

Anophthalmia with anomalies of hands and feet as a distinct syndrome was first described by Waardenburg in 1935 (MIM 206920) [Waardenburg et al., 1961]. Only 25 additional cases have been reported so far [Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Traboulsi et al., 1984; Le Merrer et al., 1988; Al Gazali et al., 1994; Quarrell, 1995; Şaylı et al., 1995; Suyugül et al., 1996; Mégarbané et al., 1998]. In 1988, Le Merrer et al. proposed the name “ophthalmo-acromelic syndrome” for this condition. In addition to acromelic limb abnormalities, clinical eye findings range from mild microphthalmia to true anophthalmia. Internal abnormalities have not been reported previously. In this report we present a new case of ophthalmo-acromelic syndrome and review the literature. Our case also has interruption of the inferior vena cava with azygos continuation.

CLINICAL REPORT

The patient, a 2-day-old boy, was referred to our department because of bilateral anophthalmia and limb anomalies. He was born at 40 weeks of gestation to a 26-year-old G7P2A4 mother and a 27-year-old father by caesarian section because of fetal distress. The parents were healthy and are of Turkish ancestry. They were reportedly distant relatives. The mother had a history of four previous miscarriages and was diagnosed with cervical insufficiency. Two previous sons were born prematurely and died on the first day of life because of respiratory problems secondary to prematurity. They were not noted to have any structural abnormalities. This pregnancy was uneventful. There was no history of teratogen exposure or maternal illnesses. The patient's birth weight, length, and head circumference measured 2,995 g (25th–50th centile), 49 cm (50th centile), and 33 cm (25th centile), respectively. His Apgar scores were 8 at 1 min and 9 at 5 min. He had normal eyelids, eyelashes, and eyebrows but had no ocular bulbs. The palpebral fissures were somewhat short and down-slanted, but the eyelids were not adherent. The ears were in a normal position, relatively large, and had prominent antihelices. The other striking facial findings included a short nose with wide nostrils, a prominent philtrum, and mild retrognathia (Fig. 1A). His palate was intact. His 5th fingers were short and curved on both hands. He also had flexion contractures of his 3rd and 4th fingers. There were four toes on each foot with normal appearance of the toes and nails (Fig. 1B). No murmur was heard on heart examination. The neck, abdomen, genitalia, and neurological status were normal.

Radiographs of hands and feet showed synostosis at the base between the 4th and 5th metacarpal bones and abnormally positioned phalanges of the 5th fingers (Fig. 2). There were four metatarsal bones with corresponding phalanges on both feet.

The ocular globes were not observed on orbital computed tomography (CT), but the remnants of optic nerves were noted. No brain abnormalities were noted on cranial CT. Abdominal ultrasonography did not show any abnormalities. A two-dimensional echocardiography showed absence of the inferior vena cava at the level of the liver, independent drainage of the hepatic veins to the right atrium, and a dilated azygos vein, which was connected to the superior vena cava without any other abnormalities of the heart (Fig. 3).

The patient had physiological hyperbilirubinemia during the first week of life. The results of his liver enzymes, complete blood count, urinalysis, thyroid panel, and karyotype were within normal limits.

DISCUSSION

In 1935 Waardenburg reported four affected individuals with anophthalmia and limb malformations from two sibships [Waardenburg et al., 1961]. In one family, two sisters had unilateral anophthalmia, fusion of the 4th and 5th metacarpals, and a lacked toe. Their brother had similar limb abnormalities but no anophthalmia. All three had normal intelligence. In the second sibship there was a girl with the same limb findings but bilateral anophthalmia and mental retardation. Because the parents in both of the families were consanguineous, Waardenburg proposed autosomal recessive inheritance. Although 25 additional patients have been reported, the clinical spectrum described by Waardenburg has not changed dramatically. The clinical findings of 30 patients including our case are shown in Table I.

Thirty patients, 22 familial [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Traboulsi et al., 1984; Le Merrer et al., 1988; Şaylı et al., 1995; Suyugül et al., 1996] and 8 sporadic [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Al Gazali et al., 1994; Quarrell, 1995; Suyugül et al., 1996; Mégarbané et al., 1998], have been reported in 16 families. The most likely inheritance pattern appears to be autosomal recessive. All of the familial cases were in the same generation, and there was no example of vertical transmission. Five of the eight multiplex families included both affected males and females [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Traboulsi et al., 1984; Le Merrer et al., 1988]. In one family, two sisters were affected [Suyugül et al., 1996]. In two families, there were two affected brothers [Pallotta and Dallapiccola, 1984; Şaylı et al., 1995], one of set being twins [Pallotta and Dallapiccola, 1984]. Consanguinity was noted in 87% of the families, supporting autosomal recessive inheritance [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Traboulsi et al., 1984; Le Merrer et al., 1988; Al Gazali et al., 1994; Şaylı et al., 1995; Suyugül et al., 1996]. Karyotypes were normal in 12 cases including our case [Traboulsi et al., 1984; Le Merrer et al., 1988; Al Gazali et al., 1994; Quarrell et al., 1995; Şaylı et al., 1995; Suyugül et al., 1996; Mégarbané et al., 1998].

The reported families have thus far come from a limited number of ethnic backgrounds. Our family is the fourth family reported from Turkey [Şaylı et al., 1995; Suyugül et al., 1996]. Five families originated from Arabic countries [Traboulsi et al., 1984; Le Merrer et al., 1988; Al Gazali et al., 1994; Mégarbané et al., 1998]. Two families were reported from another Mediterranean country, Italy [Pallotta and Dallapiccola, 1984]. Two families were reported from continental America, although their ethnicity was not indicated [Richieri-Costa et al., 1983].

Anophthalmia occurred in 87% of the reported individuals [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Traboulsi et al., 1984; Le Merrer et al., 1988; Quarrell, 1995; Şaylı et al., 1995; Suyugül et al., 1996; Mégarbané et al., 1998]. Coloboma of the iris and choroid was noted in the apparently normal eye in one patient who had unilateral anophthalmia [Waardenburg et al., 1961]. In all of the cases, eyelids, eyebrows, eyelashes, and orbits were normal except for some shortness of the palpebral fissures and smallness of the bony orbits. Among the four patients without anophthalmia, two had only limb findings and were sibs of the index cases [Waardenburg et al., 1961; Traboulsi et al., 1984]. The third patient in this group had bilateral severe microphthalmia instead of anophthalmia [Le Merrer et al., 1988], and the fourth patient had only unilateral mild microphthalmia and limb findings [Al Gazali et al., 1994]. Identification of the optic nerve in anophthalmia reflects an arrest in differentiation at later stages and is called secondary anophthalmia [Richieri-Costa et al., 1983]. Imaging studies with CT or magnetic resonance imaging showed the presence of optic nerve remnants in eight patients, including our case [Richieri-Costa et al., 1983; Traboulsi et al., 1984; Şaylı et al., 1995; Suyugül et al., 1996; Mégarbané et al., 1998]. However, in four patients the optic nerve was not seen in the bony orbit [Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Le Merrer et al., 1988]. Cranial imaging studies did not show any structural brain abnormalities when performed in 10 patients [Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Traboulsi et al., 1984; Al Gazali et al., 1994; Şaylı et al., 1995; Suyugül et al., 1996; Mégarbané et al., 1998]. These findings suggest that the eyes might be affected throughout the developmental process in the ophthalmo-acromelic syndrome, which results in a broad spectrum of abnormalities ranging from unilateral or bilateral true anophthalmia to mild unilateral microphthalmia to normal eyes. The ophthalmo-acromelic syndrome would not be an extremely rare disease if the variability of the eye findings were appreciated.

Foot malformations have been noted in 27 of the 30 patients [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Traboulsi et al., 1984; Le Merrer et al., 1988; Al Gazali et al., 1994; Quarrell, 1995; Şaylı et al., 1995; Suyugül et al., 1996; Mégarbané et al., 1998]. The most common and distinctive abnormality was the presence of only four toes bilaterally. A wide gap between the 1st and 2nd toes has also been noted in most cases. Joint laxity, club foot, valgus deformity, hypoplastic fibula, bowed tibia, and hip dislocation were observed in some cases in addition to the other findings [Richieri-Costa et al., 1983; Le Merrer et al., 1988; Suyugül et al., 1996]

Both hands were affected in 22 of the 30 cases [Waardenburg et al., 1961; Richieri-Costa et al., 1983; Traboulsi et al., 1984; Le Merrer et al., 1988; Al Gazali et al., 1994; Suyugül et al., 1996; Mégarbané et al., 1998]. Basal synostosis of the 4th and 5th metacarpals, as seen in Figure 2, was the most distinctive abnormality. Camptodactyly affecting the 2nd through 5th fingers was noted in several cases.

None of the reported patients had significant intrauterine growth retardation. Birth weight ranged between 2,500 and 4,200 g with a mean of 2,900 g. However, in eight patients at an age ranging from 6 to 11 years, height and weight measurements were below the 5th centile of normal growth curves [Pallotta and Dallapiccola, 1984; Şaylı et al., 1995; Suyugül et al., 1996]. Microcephaly was not noted in these children.

Two patients were stillborn infants and the diagnosis was made based on history [Traboulsi et al., 1984]. Six patients died between 3 months and 3 ½ years of age with diagnoses of infectious gastroenteritis, fever, malnutrition, anemia, pneumonia, and failure to thrive [Richieri-Costa et al., 1983; Traboulsi et al., 1984; Le Merrer et al., 1988].

Four male and four female patients were noted to have mental retardation in 17 fully reported cases [Waardenburg et al., 1961; Pallotta and Dallapiccola, 1984; Le Merrer et al., 1988; Suyugül et al., 1996]. Mental retardation was severe in these children with significantly delayed motor, cognitive, and speech development [Waardenburg et al., 1961]. Mental retardation frequency may be overestimated since either some reported patients were too young to assess developmental delay or sufficient information was not available in some of the reports.

Most of the patients had a distinctive facial appearance with prominent forehead, flat maxillary regions, a flat nasal bridge, and flared nostrils. Apparently low-set, posteriorly angulated, over-developed ears with thick lobules were noted in some patients [Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984]. Retrognathia, high palate, large incisor teeth, rugated tongue, long philtrum, and thin lips were described in some of the patients [Richieri-Costa et al., 1983; Pallotta and Dallapiccola, 1984; Al Gazali et al., 1994; Suyugül et al., 1996]. Cleft lip was noted in one patient [Traboulsi et al., 1984] and cleft palate in another with sensorineural hearing loss [Le Merrer et al., 1988].

No internal organ abnormalities have been described to date. Nevertheless, only three patients had renal ultrasounds and/or echocardiography [Traboulsi et al., 1984; Al Gazali et al., 1994; Mégarbané et al., 1998]. Our patient was found to have infrahepatic interruption of the inferior vena cava with azygos continuation. This entity is often associated with complex cyanotic cardiovascular defects and abnormalities of cardiac situs. It may also be associated with polysplenia [Garris et al., 1980]. In this condition, the azygos vein is enlarged because it carries the blood returning from the abdomen and lower limbs and may present as a mediastinal structure. If the hepatic and prerenal segments of the embryonic inferior vena cava fail to unite, persistence of the midportion of the right supracardinal vein leads to azygos continuation [Mori et al., 1996]. This finding in our patient points out that the abnormal embryonic development is not confined only to the limbs and eyes in the ophthalmo-acromelic syndrome. We recommend consideration of evaluation for internal abnormalities.