Acrofacial dysostoses

American Journal of Medical Genetics 33:318-322(1989)

Acrofacial Dysostoses M. Le Merrer, M. Cikuli, J. Ribier, and M. L. Briard Clinique et Unite de Recherche de Genetique Medicale, INSERM U.12, Hhpital des Enfants Malades, Paris, France A female baby was born with phocomelia, bilateral cleft lip and palate, marked micrognathia, malar hypoplasia, absence of lower eyelids, and absence of external ears. Radiological examination showed hypoplastic pectoral and pelvic girdles, short humeri and femora, with absence of forearms and legs, and oligodactyly of upper limbs. Her mother has triphalangism of the left thumb and a hypoplastic right thumb with stiff metacarpophalangeal joint. She also has downward-slanting palpebral fissures, malar hypoplasia, and deepset eyes. This observation offers an opportunity to revisit the acrofacial dysostoses syndromes, including Nager-Reynier syndrome, GeneeWiedeman syndrome, and lethal forms.

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WORDS: Nager-Reynier syndrome, Miller syndrome, radial hypoplasia, dominant autosoma1 inheritance, variable expression ~~~~~~

INTRODUCTION Two acrofacial syndromes are usually distinguished. Both are characterized by mandibulofacial dysostosis of varying degrees; but in the syndrome described by Nager and de Reynier [1948] the radius is involved, and the ulna is involved in the syndrome described by Miller et al. [1979]. Miller [1979] proposed the term postaxial acrofacial dysostosis syndrome (POADS), but Lewin and Opitz [ 19861 ascribed the first observations on this condition to Genke [1969] and Wiedemann [1973] and proposed the term Genee- Wiedemann syndrome. CLINICAL REPORT A 25-year-old woman had had 3 spontaneous abortions before delivering a t 38 weeks a 2,450 g girl, with phoco-

melia and facial malformations (Fig. 1).Pregnancy had been induced with gonadotropin and maintained with ethynyl estradiol. The infant had a bilateral cleft lip, marked micrognathia, malar hypoplasia, absence of lower eyelids, and aplasia of the auricles, i.e., very severe mandibulofacial dysostosis. The head circumference was 37 cm. The upper limbs were short, and the hands had a hooked appearance: 2 fingers were fused on the right and 3 on the left hand; the arm was severely deficient. The feet seemed well formed with 5 toes turned inwards. The lower limbs were only a few centimeters long. Radiographs showed complex bone anomalies with involvement of pectoral and pelvic girdles (Figs. 2, 3): the scapulae had the shape of a halberd with no glenoid cavity. The humeri were very short, luxated at the level of the shoulder, with the distal end club-shaped like a bludgeon. The forearm bones were absent and the wrist articulated directly with the humerus. The right hand consisted of 2 metacarpal bones prolonged with 2 fingers, one of which had 3 phalanges; on the other hand there were 3 rudimentary fingers. The ilia and the ischiopubic rami were severely hypoplastic. The acetabula were absent, and the femora, which were luxated, were also hypoplastic and thin; they articulated directly with the tarsus. The toes and the metatarsal bones were turned inwards. The infant died in the first minutes of life. Autopsy could not be performed; culture failure prevented chromosome analysis. Parents had normal chromosomes. During genetic counselling it was noted that the mother had triphalangism of the left thumb and hypoplasia of the right thumb (Fig. 4). The metacarpophalangism articulations were stiff. She also had slight downward-slanted palpebral fissures, malar hypoplasia (Fig. 5), and deep-set eyes. Micrognathia was evident. The palate was highly arched. The ears were normal but apparently slightly low-set. The lower limbs seemed quite normal. She was the eldest of 4 children born to young parents with no abnormalities.

DISCUSSION

Received for publication March 21, 1988; revision received January 25, 1989. Address reprint requests to Martine Le Merrer, M.D., Clinique Robert Deb& H6pital des Enfants Malades, 149 rue de S h e s , 75743 Paris cedex 15, France.

0 1989 Alan R. Liss. Inc.

This family demonstrates the variability of an acrofacia1 syndrome which seems to be dominantly inherited. The Nager syndrome is a mandibulofacial dysostosis with radial hemimelia of varying severity. Both girls and boys are affected (13 boys and 19 girls in the published cases). Most of these cases are sporadic. Neidhart [ 19681

Acrofacial Dysostoses

Fig. 1. Severe acrofacial dysostosis, with limb defect.

and Walker [ 19741 have reported affected first cousins. However, the increased paternal age in the sporadic cases of Marden et al. [1964], Bowen and Hasley [1974], and Lowry [ 19771 and the mild form reported in a first cousin by Klein et al. [1970] and in several ascendants in the family studied by Weinbaum et al. [1981], with fatherto-son-transmission, all argue in favor of dominant inheritance with variable expression [Pfeiffer and Stoess, 19831. In the present case the mother of the child can be diagnosed as having a mild form of the Nager syndrome. The Genee-Wiedemann syndrome [Miller et al., 1979; Fineman, 19811 differs from the preceding by preferential involvement of ulna and fibula with inconstant involvement of radius. Seven of the 8 cases first published had at least a short radius or a radioulnar synostosis, and in 3 cases the thumb was abnormal, as was reported in more recent cases [Opitz and Stickler, 1987; Opitz, 1987al. There is also a more-or-less marked facial dysostosis, and the auricles are cup-shaped. Gen6e case [1969], which according to Lewin and Opitz [ 19861, was the first of this syndrome to be reported, adds to what is essentially a postaxial acrofacial dysostosis other skeletal abnormalities such as hemivertebrae, and dysplasia of the coxofemoral articulations, scapulae, and elbows (radioulnar synostosis). The syndrome is claimed to be an autosomal recessive trait: several patients were first cousins without other relatives being affected [Fineman, 1981; Hecht et al., 19871. However, no consanguinity was mentioned. Poissonnier et al. (19831 and Kawira et al. [1984] described a form notable for its severity which resembles that of our case. In their cases, as in ours, there was severe dysostosis, associated facial cleft, and several phocomelic limb involvement: affected shoulders and hips

Fig. 2. Roentgenograms of the upper limbs of the infants.

Fig. 3. Roentgenograms of the lower limbs of the infants.

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Le Merrer et al. et al., 19831; but one of Kawira’s cases was born of parents who were first cousins, while our case is compatible with X-linked or more probably autosomal dominant inheritance. Other types of acrofacial dysostosis have also been described

Fig. 4. Mother’s hands: triphalangeal thumb, hypoplastic right thumb.

Fig. 5. Roentgenograms of mother’s face: malar hypoplasia.

with rudimentary scapulae and pelvic hypoplasia. The femora and humeri were either absent or reduced to a triangle. The radii and ulnae were absent or very short [Poissonnier et al., 19831.The thumb was absent (3 cases) or triphalangeal and hypoplastic, and in 2 cases the last fingers were also absent. Lower limbs are characteristic: constant absence of the fibulae or even of the tibiae. This axis of the feet is deviated, and in the 2 cases of Kawira et al. [1984] some of the toes are missing (preaxial). In addition, the 3 children described by Poissonnier et al. [1983] and Kawira et al. [1984] as well as our case had intrauterine growth retardation. These authors reported that their cases also had visceral malformations involving the heart, kidney, and diaphragm. Our patient was not examined anatomically. Of these 4 clinically similar cases, 3 were sporadic [Kawira et al., 1984; Poissonnier

the rare duplication of a distal fragment of the long arm of chromosome 2 resulting in malformation resembling that seen in Nager-Reynier syndrome, but constantly associated with mental retardation Wagner and Cole [ 19791; an ectrodactyly reported by Fontaine et al. [1974] with cleft hands and feet associated with mandibulofacial dysostosis and dominant mode of transmission; hemifacial microsomia with a radial defect and dominant transmission reported by Moeschler and Clarren [ 19821 and discussed by Temtamy and McKusick [ 19781 in relation to the Nager Syndrome; a moderate dysostosis associated with cleft lip and triphalangism of the thumbs reported by Richieri-Costa et al. [1983], which can be included in the Nager syndrome; “Robin sequence and oligodactyly” distinguished by Robinow et al. [1986] from postaxial acrofacial dysostosis by the absence of both mental retardation and especially of the characteristic signs of mandibulofacial dysostosis. However, the photographs in his article show that the mother and child exhibit dysmorphism not incompatible with the latter diagnosis: very large, mouth, and antimongloid palpebral fissures suggestive of malar hypoplasia; lastly, a family reported on by Reynolds et al. [ 19861 with a “new” form of acrofacial dysostosis in which the constant mildness of the mandibular involvement is in contrast to the variable and mainly preaxial involvement of the limbs. All things considered, it appears that the above-mentioned syndromes have been separated according to 2 orders of clinical criteria: on one hand, the type and degree of facial dysmorphism and the involvement of the limbs; on the other, the pattern of their association. Nevertheless, the descriptions that are given tend to confer a systematic character to individual entities that is not always confirmed by careful reading of the reports (Table I). For instance, if the principal malformations of the Nager syndrome [Klein et al., 19701 are mandibulofacial dysostosis and radial defects, other malformations have also been observed upper limbs: clinodactyly or hypoplasia of the 5th finger [Meyerson et al., 19771, syndactyly, double thumb (the equivalent of aplasia or triphalangia) [Giugliani and Pereira, 1984; Temtamy and McKusick, 19781, incurved, sometimes hypoplastic, ulna; lower limbs: limited movement of the knee and clinodactyly of the toes [Meyerson et al., 19771, dislocated hip [Klein et al., 1970; Pfeiffer and Stoess, 19831, abnormal big toes, and clubfeet [Pfeiffer and Stoess, 1983; Lowry, 1977; Schonenberg, 1968; Jones, 1968; Bowen and Harley, 1974; Halal et al., 19831;

Acrofacial Dysostoses TABLE I. Acrofacial Dysostoses

Malar hypoplasia Cleftd Ear anomalies“ Preaxial anomalies Postaxial anomalies Radioulnar‘ synostosis Short humeri Lower limbs Hypoplasia tarsal bones Toe anomalies Hips dislocated Abnormal pelvis Kidney involvement Heart abnormality Early death

Nager svndrome” POADSh 32/32 17/32 25/32 32/32 14/32 20/32 513 2 4/32 13/32 5/32 8/32 4/32 212 3/7 9 10132

Lethal forms‘

Bowen and Harley [1974]; Burton and Nadler [1977]; Fernandez and Ronis [1964]; Gellis and Feingold 119781; Giugliani and Pereira [1984]; Halal e t al. 119831; Hecht et al. [1987]; Jones 119681; Klein et al. [1970]; Krauss et al. 119851; Lowry [1977]; Marden et al. 119641; Meyerson et al. 119771; Neidhart [1968]; Nager and de Reynier [1948]; Pfeiffer [1969]; Pfeiffer and Stoess [1983]; Richieri-Costa e t al. [1983]; Shonenberg et al. [1968]; Temtamy and McKusick 119781; Vatre [1971]; Walker [1974]; Weinbaum e t al. [1981]; personal case. Fineman [1981]; Genle [1969]; Miller e t al. [1979]; Wiedemann et al. 119821. Poissonnier et al. (19831; Kawira et al. [1984]; personal case. And narrow and arch palate (+ 8). And down-slanting ears (+ 4). I Or contracture of elbow.

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vertebral and costal malformations: block vertebrae, cervical spina bifida [Jones, 19681, hypoplastic, or supernumerary ribs [Krauss et al., 19851; visceral malformations: either cardiopulmonary or renal, or sometimes genitourinary [Richieri-Costa et al., 1983; Pfeiffer and Stoess, 1983; Halal et al., 19831. Radial defects are nearly always associated with involvement of the ulna in postaxial forms of acrofacial dysostosis. Lastly, lethal forms could be considered, in this context, as the most severe manifestations of the same spectrum of malformations. The discovery of a minor form of Nager syndrome in the mother of this child affected with a lethal form of acrofacial dysostosis is a weightly argument in favor of the hypothesis that this may be a unique clinical entity with variable expression. As long ago as 1983, Pfeiffer and Stoess stressed the heterogeneity of expression of Nager syndrome; and Halal et al. I19831 pointed out the quite striking correlation between the degree of shortening of the limbs and the severity of mandibular hypoplasia. This correlation is not denied in the lethal cases that Lewin and Opitz [ 19861 do not hesitate to class as GenkeWeidemann syndrome. Other familial cases confirm this variability, sometimes to a lesser extent [Klein et al., 1970; Richieri-Costa et al. 1983; Halal’s et al. case 2, 19831. In addition, the transmission of acrofacial dysostosis, even if of different expression, from mother to daughter, suggests autosomal dominant inheritance, hence, as a good example of an “iceberg phenomenon.” This hypoth-

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esis has already been raised for Nager syndrome by the cases of Weinbaum et al. [1981] and Lowry [1977], but on the basis of more indirect arguments: increased paternal age (not true for the maternal grandfather of our propositus), large number of sporadic cases, variability of clinical expression. In this way, modifier genes, multiples alleles, or post-translational factors could play a major role in infleuncing the phenotypic expression in acrofacia1 dysostosis. Nevertheless, the hypothesis of genetic heterogeneity cannot be ruled out. Without doubt, neither the sporadic cases, nor the occurrence of several cases among sibs of unaffected parents is sufficient reason to exclude dominant transmission. Consanguinity would be a stronger argument in favor of a recessive pattern, but is has only been reported in a few cases. It would, indeed, be extravagant to draw the conclusion, for the considerable intrafamilial variability of acrodysostoses, that they all form a single entity. Certain of them could be lumped together, for the reason mentioned above: it seems justified to consider Nager-Reynier syndrome and postaxial dysostosis (Genke-Wiedmann syndrome) as variable expressions of an anomaly involving the same polytopic developmental fields, as Opitz puts it. On the other hand, we would hesitate to recognize, as Genke did, POADS as a more extensive form of mandibulofacial dysostosis, unless study of a sufficiently large sample provides stronger evidence. Furthermore, we consider that hemifacial microsomia associated with a radial defect, and Pillay syndrome [Pillay and Orth, 19741 (in which dysostosis is primarily mandibular and ocular involvement characteristic) should be excluded from this group. Finally, further studies on these malformation syndromes are needed. However, we would like to emphasize the importance of detailed examination of the parents and relatives of affected children to discover minor signs of the condition as evidence for an autosomal dominant gene.

ACKNOWLEDGMENTS We thank Pr. Jean Frkzal and Dr.Pierre Maroteaux for most helpful advice and critical review of the manuscript, and Gidle Gal for secretarial assistance.

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