American Journal of Medical Genetics 14:l51-157 (1983)

Radial Ray Aplasia and Renal Anomalies in Father and Son: A New Syndrome

Shaul Sofer, Jacob Bar-Ziv, and Dvorah Abeliovich

Department of Pediatrics (S. S.), Department of Pediatric Radiology (J. B.-Z.), Cytogenetics Laboratory (D. A.), Soroka University Hospital, Faculty of Health Sciences, and Ben-Gurion University of the Negev, Beer-Sheba, Israel

We describe a father and his son with bilateral absence of radius and thumb. Both have short stature, external ear malformation, and renal anomaly. In the son a high frequency of chromosome breaks in lymphocytes was found.

We compare this familial syndrome to Fanconi anemia and other radial ray aplasia syndromes and conclude that we are dealing with a different entity, which apparently is inherited as a dominant trait.

Key words: radial ray aplasia, renal anomaly, single kidney, ectopic kidney, chromosome breaks, short stature, external ear malformation, dominant trait

INTRODUCTION

Absence of radius and thumb is a rare congenital defect. Its frequency among live births has been estimated at 1:30,000 [Birch-Jensen, 19491. Some cases are genetically caused while others are sporadic [Birch-Jensen, 1949; Dodson, 19561. The radial ray defect may be an isolated defect or associated with other anomalies. Some of the well-known combinations are genetic syndromes, such as Fanconi anemia (FA) and Holt-Oram syndrome, while others, like the VATER association [Haarman, L e n , and Peterson, 1975; Quan and Smith, 19731 are apparently nongenetic.

We report a father and his son with radial ray aplasia, short stature, external ear malformation, and renal anomalies as a hitherto unpublished autosomal dominant syndrome.

Received for publication October 19, 1981; revision received February 9, 1982.

Address reprint requests to Dr. Dvorah Abeliovich, The Cytogenetics Laboratory, Soroka Medical Center, Beer-Sheba 84-101, Israel.

0148-7299/83/1401-011$03.0001983 Alan R. Liss, Inc.

152 Sofer, Bar-Ziv, and Abeliovich

CASE REPORT

The propositus (VI-I, Fig. 1) is a male, first child of a 26-year-old gravida 1, para 1, healthy mother. The father (V-11) is 28 years old and known to have bilateral congenital absence of radius and thumb (Fig. 2B). Both parents are of Jewish- Moroccan origin with no consanguinity.

VI-I was born at term after an uneventful pregnancy and labor. The mother was healthy and no medication was administered during pregnancy. The birth weight was 2,650 gm and the Apgar score was 10 at 1 and 5 min. Immediately after birth it was noted that both infant’s thumbs were missing and that the hands were clubbed and radially deviated at a right angle to the forearms (Fig. 2A). In addition, there was a mild malformation of the right auricle (Fig. 2C).

The child was followed for 2% yr. His psychomotor development was normal. Growth was delayed and height and weight did not exceed the 3rd centile.

The father (V-11, Fig. 1), a 28-year-old man, is 155 cm tall and of normal intelligence. He was known to have bilateral aplasia of the radius and thumb, and he has had several operations on hands and forearms. At the time of examination after his son’s birth, he had a mild external malformation of the right ear similar to that of his son (Fig. 2D).

Radiological Study The roentgenograms of the upper limbs of VI-I confirmed the complete absence

of radius and thumb on both sides (Fig. 3). Intravenous urography showed crossed renal ectopia of the left kidney. The radiographs of the father’s upper limbs showed the same type of anomalies. The intravenous urogram of the father showed a single left kidney.

I

II

111

IV

V

VI

Fig. 1 . The pedigree of the family (ID, infant death).

Radial Ray Aplasia and Renal Anomalies 153

Fig. 2.A) The son at the age of 1 wk (VI-I); B) the father (V-11) at 28 yr old; C) external ear of the son (VI-I); D) extended ear of the father (V-11).

154 Sofer, Bar-Ziv, and Abeliovich

Fig. 3. Radiograph of the upper limbs of son (VI-I). There is complete absence of the radius and thumb; mild bowing of the ulna and club hand in both sides. The second metacarpals and index fingers are hypoplastic.

Laboratory Examinations

and blood counts were normal in father and son.

Cytogenetic Studies

Chromosomes in peripheral blood lymphocytes were analyzed using AT medium (GIBCO, Grand Island, NY) for short-term culture. The induction of chromosome breaks by diepoxybutane (DEB) was performed according to the method of Auerbach et a1 [ 198 13. We analyzed cells for DEB-induced chromosome breakage in the patient (VI-I), his parents, a healthy 2-year-old male control, and an obligatory FA hetero- zygote (Mother of an FA patient). A normal karyotype was established in all subjects. An increased number of spontaneous chromosome breaks and gaps, including one quadriradial configuration (Fig. 4), was found in the lymphocytes of the son in three repeated studies at the age of 1 wk, 7 mo, and 2% yr (Table I). The mean chromosome break rate per cell was seven times higher than that of his parents and of a healthy control (t = 4.0, P < 0.01). At 2% yr we studied the effect of DEB on chromosomes. The results are summarized in Table 11. There was an overall increase in chromosome breaks ( x2-3), but in the FA heterozygotes it was more pronounced ( X 9). Quadri- radial configurations that are typical of FA patients and carriers were noted only in the FA heterozygote.

Results of routine laboratory studies including urinalysis, renal function tests,

Radial Ray Aplasia and Renal Anomalies 155

Fig. 4. Types of chromosome breaks in lymphocytes of the son (VI-I). a) chromosome gap; b),f) chromatid gaps; c) quadriradial; d) chromatid break; e) chromosome break.

TABLE I. Chromosome Breakage in Lymphocytes of Patient VI-I at Different Ages

Type of breaks Mean Age of Number of Quadri- chromosome patient cells CSC? CSB CTG, CTB, radial breakdcell

1 wk 55 4 2 I 1 0.29 7 mo 30 3 5 1 0.40 2% yr 50 2 4 0.16 Control 0.04 Total 135 3 6 I I 2 1 0.28

SD' = 0.0096

"CSG, chrornosomc gap; CSB, chromosome break: CTG, chromatid gap; CTB. chromatid break.

Family Study The father (V-11) had had five sibs (Fig. 1); except for two twin brothers who

died in infancy, all are reported to be normal and healthy. The infant's paternal grandparents were examined, including with an intravenous pyelogram, and were found to be normal. The maternal grandparents are first cousins once removed. All members of that family are normal and healthy.

DISCUSSION

Aplasia or hypoplasia of the radial ray can occur per se or as part of certain syndromes of genetic or nongenetic origin [Arias et al, 1980; Nilsson, 1960; Pruzan- ski, 19641. Some of the syndromes are autosomal dominant (the Holt-Oram [Pruzan- ski, 19641 or the IVIC [Arias et al, 19801 syndrome) or recessive (FA [Nilsson, 19601 TAR [Landing, 19751 syndrome traits. The defect varies from a mild thumb anomaly to complete absence of the whole radial ray [Birch-Jensen, 1949; Dodson, 19561. In the family presented, the severe upper limb defect was transmitted from father to son with roughly equal severity. Both had an associated renal anomaly: in the father, it was a solitary kidney, while in the son it was crossed fused ectopy. In both of them an external ear anomaly was also present. The association between radial ray and

156 Sofer, Bar-Ziv, and Abeliovich

TABLE 11. The Effect of DEB on the Occurrence of Chromosome Breaks

Mean number of chromosome breakskell

DEB-induced Quadriradial Spontaneous (0.1 1 L g w configuration

Patient (2 % yr) 0.16 0.46 -

Father 0.06 0.13 - Mother .06 0.33 - Control (2 yr) 0 0.16 - FA heterozygote 0.06 0.53 +

renal anomalies is known in several syndromes [Quan and Smith, 1973; Arias et al, 1980; Nilsson, 1960; Rohz, 1949; Siegler, Larson, and Buehler, 19801. In FA 27% of homozygotes have a renal anomaly, half being a solitary kidney. While crossed renal ectopy is occasionally present [Nilsson, 1960; Buchem, Samson, and Nieweg, 1954; Minagi and Steinbach, 19661, other similarities to the FA syndrome, present in our cases, are short stature and chromosome breaks [Bloom et al, 19661, found in VI- I while absent in V-II. We do not know whether the chromosome breaks are a part of the syndrome and why they are expressed differently in father and son. FA individuals have pancytopenia that does not exist in our patients. Since pancytopenia can appear later in life we cannot be sure concerning the child, but concerning the father, it is known that pancytopenia can appear at the beginning of the 3rd decade [Rohz, 1949, Cowdell, Phizackerley, and Dyke, 1955; McCabe, Lange, and Crosby, 19571. Yet, there is no report of a FA patient who developed the anemia after age 28.

To rule out the diagnosis of FA, we studied the clastogenic effect of DEB [Auerbach et al, 19811. DEB is known to induce chromosome breaks in FA homozy- gotes and heterozygotes at a higher rate than in other cell types, and it specifically induces complex chromatid exchanges , producing quadriradials and triradials. Not even one such configuration was noted in the propositus or his parents. The number of chromosome breaks after DEB treatment was lower than in FA cells. Therefore, we excluded the diagnosis of FA. In the VATER association [Quan and Smith, 19731, radial ray and renal anomalies are part of the syndrome, but these syndromes, to the best of our knowledge, are sporadic and have never been described as a genetic entity. Although thalidomide embryopathy can lead to both radial ray and renal defects [Warkany, 19711, this possibility is obviously excluded in our cases. In the acrorenal syndrome of Dieker [Curran and Curran, 1972; Dieker and Opitz, 19691, the upper limb malformations do not include the radial ray.

A familial ray defect in association with renal disease was described by Siegler, Larson, and Buehlev [1980] in two sibs. The otherwise negative family history sug- gests a recessive mode of inheritance. In the family presented by us, the most likely mode of inheritance is autosomal dominant. Therefore, we assume that, although both syndromes may be closely related pathogenetically, they are different entities.

Recently a new autosomal dominant syndrome was described [Arias et al, 19801. The IVIC syndrome includes mainly radial ray hypoplasia, hearing impairment, ex- ternal ophthalmoplegia, and thrombocytopenia. It has been suggested that 2-5% of the cases of the IVIC syndrome have urogenital anomalies too. Arias et a1 [1980] theorized that the common pathogenetic pathway common to all syndromes sharing radial ray defect lies in faulty collagen metabolism, whether the syndrome is geneti- cally controlled or not.

Radial Ray Aplasia and Renal Anomalies 157

Reviewing the published reports we could not find any similar familial case, and therefore we suggest that we are dealing with a new genetic syndrome character- ized by symmetrical radial aplasia and absent thumbs, renal anomalies in the form of solitary kidney or crossed fused ectopy, external ear anomaly, and by short stature, but without hematological disorders, although possibly with chromosome breaks. It is most likely autosomal dominant, although other interpretations are possible.

ACKNOWLEDGMENTS

We are indebted to Annalie Tal and Alina Levy for their excellent technical assistance.

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