American Journal of Medical Genetics 35484-489 (1990)

New Acrofacial Dysostosis Syndrome in 3 Sibs Jose Ignacio Rodriguez, Jose Palacios, and Miguel Urioste Department of Pathology, Hospital La Paz, (J.I.R., JP.) and Estudio Colaborativo Espaiiol ale Malformaciones Congdnitas (ECEMC), School of Medicine, University Complutense (M.U.), Madrid

We performed clinical and autopsy studies on 3 sibs with a n acrofacial dysostosis (AFD) syn- drome. All 3 died neonatally from respiratory complications derived from their severe man- dibular hypoplasia. They presented a malfor- mation syndrome characterized by mandi- bulofacial dysostosis, predominantly preax- ial limb deficiencies, rare postaxial limb anomalies, shoulderlpelvis girdle hypoplasia, and cardiac and CNS malformations. This syndromal form of AFD could represent a dis- tinct entity with autosomal-recessive inheri- tance. Its delineation from other AFD syn- dromes is discussed.

KEY WORDS: new syndrome, Genee-Wie- demann syndrome, post- axial acrofacial dysostosis syndrome, Nager syndrome, familial occurrence, lethal cases, anomaly

INTRODUCTION There are several conditions involving mandibulo-fa-

cia1 dysostosis (MFD) associated with acral anomalies [Halal et al., 1983; Reynolds et al., 1986; Opitz, 19871 that are known as acrofacial dysostosis (AFD) syn- dromes. The differential diagnosis and characterization of these syndromes are important because they are a genetically heterogeneous group of conditions.

The Genee-Wiedemann syndrome [Lewin and Opitz, 19861 or postaxial acrofacial dysostosis syndrome (POADS) [Miller et al., 19791 is an autosomal recessive multiple congenital anomalies syndrome of AFD with lower limb anomalies. The patients have predominantly an absence or incomplete development of the 5th digital rays and, to a lesser degree, some preaxial defects [Ge- nee, 1969; Miller et al., 1979; Meinecke and Wiede- mann, 19871. Traditionally, this syndrome has been dif- ferentiated from Nager syndrome or Nager AFD [Miller

~

Received for publication February 6,1989; revision received May 30, 1989.

Address reprint requests to Dr. Jose Ignacio Rodriguez, Departa- mento de Anatomfa PatolBgica, Hospital La Paz, Paseo de la Cas- tellana 261, Madrid, E-28046, Spain.

et al., 1979; Halal et al., 19831, whichinvolves AFD with preaxial upper limb defects without or with minor lower limbs involvement. Recently, Opitz [19871 postulated that Nager AFD represents an “anomaly” rather than a syndrome because its apparent causal heterogeneity.

We report on 3 successive sibs affected by an appar- ently previously undescribed autosomal recessive AFD syndrome.

CLINICAL REPORTS Patient 1

The patient, a male, was born in 1979 after an uncom- plicated term pregnancy to a 23-year-old primigravid white mother and a 31-year-old white father. Birth- weight was 2,020 g (<loth centile), and Apgar score was 2 at 1 and 5 minutes. He developed respiratory distress and died 10 minutes later.

The face was unusual with severe micrognathia, malar hypoplasia, apparently low-set deformed ears, prominent broad nasal bridge, and down-slanting pal- pebral fissures (Fig. la,b). Scalp hair extended forward laterally onto both cheeks and there was a cleft palate and atretic ear canals. The upper limbs were short with absence of one digit from each hand. Anomalies of the lower limbs were not recorded. Postmortem radiographs (Fig. 2) of upper limbs showed a very short humerus fused to a single, short forearm bone bilaterally and absence of the 3rd metacarpal and first phalanx of the 3rd finger and a hypoplastic 2nd phalanx in the left hand. There was hypoplasia of the scapulae and 11 ribs.

At autopsy atrial and ventricular septa1 defects and arhinencephaly were noted.

Patient 2 This child, a male conceived 5 months after patient 1

died, was born following a 41-week, uncomplicated ges- tation. Delivery occurred spontaneously, birthweight was 2,500 g (<loth centile) and the Apgar score was 1 at 1 and 5 minutes. The child died of respiratory distress in 2 hours.

The infant was noted to have facial anomalies similar to patient 1 (Fig. 3a,b). Cleft palate and atretic ear canals were also noted. Limb defects included severe shortness of upper limbs, absence of the 5th digit on all limbs, and absence of the 4th right toe (Fig. 3 ~ ) . Post- mortem radiographs of upper limbs (Fig. 4a,b) showed hypoplastic scapulae, two rudimentary fused bones forming a synostotic OSS~OUS segment occupying both

0 1990 Wiley-Liss, Inc.

New Acrofacial Dysostosis Syndrome 485

Fig. 1. Patient 1. a: Front view. b: Side view.

arms and forearms. There was no radiographic evidence of the 2nd forearm bone. Hands and feet lacked the 5th digital ray, and there were several anomalies of the 4th digital ray. The fibulae and ischii were absent in the roentgenograms of the lower limbs (Fig. 5).

The autopsy showed an atrial septal defect, ventricu- lar septal defect, subvalvar pulmonary atresia, and overriding aorta. Other findings were arhinencephaly and lack of segmentation of both lungs. Chromosomes (G banded) were normal (46,XY).

Patient 3 The propositus, a male, was born in 1987. The preg-

nancy was uncomplicated, and delivery occurred spon- taneously at 40 weeks of gestation. At birth, the infant weighed 2,850 g (10th centile) and was 50 cm long. The infant died of respiratory distress 6 days after birth.

Facial anomalies included malar and mandibular hy- poplasia, apparently low-set and malformed ears, and broad nasal bridge (Fig. 6a). The external auditory meati and the external ear canals were narrow, and the palate was highly arched. There were a peculiar position of the upper limbs owing to elbow contractures with limitation of extension and syndactyly of the 1st and 2nd fingers of the right hand with hypoplastic thumbs (Fig. 6a, 6c). Also present were a right clubfoot and bilateral syndactyly of the 4th and 5th toes (Fig. 6b).

Postmortem radiographs of upper limbs showed radio- Ulnar Wnostosis, hypoplasia ofthe bones ofthe 1st digi- tal ray, and hypoplasia of 2nd phalanx of both 2nd fin-

Fig. 2. Radiograph of patient 1 demonstrating hypoplastic scapulae and synostotic bones in the upper limbs.

486 Rodriguez et al.

Fig. 3. Patient 2. a: General appearance. b: Unusual face with deformed ear, broad nasal bridge and severe hypoplasia of the maxilla and mandible. c: Feet of the patient.

Fig. 4. Patient 2. Radiographs of the upper limbs. a: Right. b: Left.

New Acrofacial Dysostosis Syndrome 487

Fig. 5. Patient 2. Radiographs of the lower limbs. Note the absence of the ischii and fibulae.

gers (Figs. 6d, 7). Details of the phalanges of the toes could not be seen, but each foot had 5 metatarsals. Only 11 ribs were present.

The autopsy did not show any internal malformations. Chromosomes were normal (46,XY).

Family History Parents were from different geographical areas.

There was no consanguinity or history of birth defects. There was no history of possible teratogenic exposure to medications, drugs, hormones, radiation, or other agents during the 3 gestations. Neither parent had signs of AFD. After the first patient’s birth parental radio- graphs of the face, upper, and lower limbs were taken and were normal. Cardiac evaluation and chromosomes were normal in both parents.

DISCUSSION There are a number of genetically and phenotypically

distinct syndromes or conditions of MFD with acral anomalies [Opitz, 1987; Reynolds et al., 1986; Halal et al., 19831. The anomalies of the present family could represent a new AFD syndrome characterized by MFD, pre- and postaxial limb defects involvement of the shoul- derlpelvis girdle, congenital heart defects, and arhinen- cephaly. This syndrome must be differentiated from other AFD syndromes mainly the Genee-Wiedemann syndrome and Nager syndrome.

The POADS was defined by Miller et al. [19791 as a new malformation syndrome combining a variable de- gree of MFD and symmetrical postaxial limb deficien- cies. Distinctive manifestations included cup-shaped ears, cleft lip and/or palate, coloboma of the eyelids, accessory nipples, and low-arch dermatoglyphics. The upper and lower limb defects all show predominantly postaxial ray deficiencies, although there is some vari-

ability such as absence or incomplete development of the 5th digital rays [Miller et al., 1979; Fryns and Van den Berghe, 19881. In addition, preaxial defects of the upper limbs are commonly observed to a lesser degree. These defects are hypoplasia or absence of the 1st rays [Miller et al., 1979; Meinecke and Wiedemann, 19871. Although clinical variability has been described in the Genee- Wiedemann syndrome, lethal cases in the fetal or neona- tal period are unusual and show more severe anomalies [Poissonnier et al., 1983; Rodriguez and Palacios, 19891. In the Genee-Wiedemann syndrome an autosomal-re- cessive mode of inheritance is accepted. Affected sibs with normal unrelated parents have been reported by Fineman [19811 and Opitz and Stickler [1987].

Our patients showed some characteristics, such as phocomelia, hypoplasia of the shoulderipelvis girdle, ab- sence of the fibulae, vertebral and ribs defects, and con- genital heart defects, that have also been described in the severe cases of the Genee-Wiedemann syndrome. However, all three sibs lack other typical characteristics of the Genee-Wiedemann syndrome such as coloboma of the eyelids and accessory nipples. Moreover, patient 3 clearly showed that preaxial, rather than postaxial, limb involvement predominated. Brunoni et al. 119871 described a patient with MFD and long bone defects similar to infants 1 and 2, but who lacked involvement of the shoulderipelvis girdle, vertebrae, ribs, heart, or ol- factory bulbs.

On the other hand, the anomalies found in our patient 3 could suggest the diagnosis of Nager AFD because he showed a MFD with bilateral thumb hypoplasia and bilateral ulnar synostosis. Although lower limb involve- ment is not common in Nager AFD, minor anomalies such as clubfoot and syndactyly, also present in our third patient, have been reported [Halal et al., 19831. However, the diagnosis of the Nager syndrome is un-

488 Rodriguez et al.

Fig. 6. Patient 3. a: General view. b: Syndactyly in the right clubfoot. c: Right hand with syndactyly of the 1st and 2nd fingers and hypoplastic thumb. d: Radiograph of the right upper limb. Note the severe hypoplasia of the 1st digital ray.

likely due to the different malformations observed in the first 2 sibs. Patient 3 provides further support for the hypothesis that the Nager AFD is an anomaly rather than a syndrome [Opitz, 19871. This hypothesis is based on the apparent causal heterogeneity found in the Nager AFD since it seems likely to be sporadic, autoso- ma1 recessive, autosomal dominant, and was suspected in a case of Down syndrome [Halal et al., 1983; Opitz, 19871.

Several other AFD conditions can be easily separated from our family. The Fontaine syndrome has orofacial and split-feet anomalies but normal upper limbs and an autosomal dominant inheritance. The Reynolds-Webb

syndrome has an autosomal dominant inheritance and only mild acral and mandibulo-facial anomalies. Chro- mosome abnormalities such as distal 2q duplication, trisomy 18, and trisomy 7 mosaicism have been ex- cluded.

Finally, there seems to be a correlation, in all our patients, between the severity of the MFD and the de- gree of the limb deficiencies and the extension of the visceral involvement. Patients with more severe MFD also showed arhinencephaly, indicating a extensive neu- ral crest defect. The absence of ischii and fibulae in one of the patients suggest the existence of a fibular field defect [Lewin and Opitz, 19861.

New Acrofacial Dysostosis Syndrome 489

Fig. 7. Patient 3. Radiograph of the thorax and upper limbs.

ACKNOWLEDGMENTS This work was partially supported by Caja Madrid.

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