American Journal of Medical Genetics 42:343-345 (1992)
Acrofacial Dysostosis Syndrome v p e Rodriguez: A New Lethal MCA Syndrome Paul Petit, Philippe Moerman, and Jean-Pierre F’ryns Center for Human Genetics (PP., JPF.)and Department of Pathology B (P.M.), University of Leuven, Leuven, Belgium
We present a female fetus with the lethal acrofacial dysostosis syndrome recently delineated by Rodriguez et al. “901. The present findings confirm that this syndrome constitutes a true MCA syndrome in which mandibulofacial dysostosis and severe limb reduction defects are associated with complex malformations of different organs and systems especially the CNS, the urogenital tract, heart, and lungs.
KEY WORDS acrofacial dysostosis, autosomal recessive inheritance, CNS and heart malfomations INTRODUCTION A new lethal form of acrofacial dysostosis syndrome characterized by mandibulofacial dysostosis, predominantly preaxial limb deficiencies, rare postaxial limb anomalies, shoulder and pelvic hypoplasia, and cardiac and CNS malformations was delineated recently by Rodriguez et al. 119901. Here we present another example of this true MCA syndrome with apparent autosomal recessive inheritance.
CLINICAL REPORT
telorism, marked exophthalmos with bilateral ectropion, antimongoloid slant of palpebral fissures, malar hypoplasia, high nasal bridge, and poorly formed ears with external canal atresia. The mouth was relatively small with retrognathia and cleft palate. Severe limb anomalies involved the 4 limbs. The arms were short with severe hypoplasia of the left humerus and bilateral absence of radii and ulnae, as confirmed on X-rays (Fig. 3). Both hands showed preaxial reduction with absence of thumbs and first metacarpals, camptodactyly of fingers I1 to IV, and clinodactyly V. Roentgenograms showed, in addition, hypoplasia of the distal phalanges and proximal fusion of the IVth and Vth metacarpals of the right hand. The lower limbs were extremely short with complete absence of all long bones. The pelvic girdle was short and hypoplastic. On the right foot there was partial duplication of the great toe and absence of the Vth ray. Only 11 ribs were bilaterally present, and the 7th cervical and the 6th thoracic vertebrae were hypoplastic. Autopsy showed a gross CNS malformation with triventricular hydrocephaly due to aqueductal stenosis and agenesis of the corpus callosum. A complex cardiac malformation was present with double superior vena cava without bridging innominate vein. The persistent left superior vena cava was connected with the left atrium because of failure of coronary sinus development. In addition there was complete persistent common atrioventricular canal. The lung lobulation was absent. Both kidneys (right 2.3 g; left 2.1 g) showed normal lobulation but microscopic examination revealed a reduced number of renal pyramids with focal absence of glomerular layers. The uterine corpus showed a unicornis unicollis malformation with absence of the left horn. Chromosomes were normal (46,XX).
The female fetus was examined after prostaglandin induction a t 24 weeks gestation because of ultrasonographic diagnosis of hydrocephaly in the second pregnancy of a 31-year-old mother and her nonconsanguineous 25-year-old husband. After the first pregnancy a normal daughter was born. Family history and personal antecedents are negative. Weight, foot length, DISCUSSION and head circumference were 463 g, 35 mm, and 23.5 cm, respectively. The head was elongated and severe mandiThe female fetus of this report has a mandibulofacial bulofacial dysostosiswas evident (Figs. 1,2)with hyper- dysostosis (antimongoloid slant of palpebral fissures, exphthalmos with ectropion, malar hypoplasia, malformed auricles, external atresia, mandibular hypoReceived for publication March 11,1991; revision received June plasia, and cleft palate) associated with severe limb defects (tetraphocomelia, bilateral preaxial deficiencies 3, 1991. Address reprint requests to J.P. Fkyns, Center for Human Ge- at the hands, postaxial deficiency a t the right hand and netics, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, foot), a complex cardiac and CNS (triventricular hydroBelgium. cephaly due to aqueductal stenosis, corpus callosum 0 1992 Wiley-Liss, Inc.
344
Petit et al.
Fig. 1. The malformed fetus.
Fig. 3. Roentgenographic skeletal survey.
Fig. 2. The facial anomalies.
agenesis) malformation, absence of lung lobulation, and urogenital anomalies. This combination of symptoms and malformations constitutes a further example of an apparent lethal acrofacial dysostosis syndrome, as delineated by Rodriguez et al. [19901 in this journal. Table I shows the similarities in clinical and radiological findings in the 3 brothers reported by Rodriguez et al. [19901 and the present female fetus. The female fetus of this report is the first documented female with this true MCA syndrome with autosomal recessive inheritance: in addition to mandibulofacial dysostosis and the skeletal malformations multiple other organs and systems are involved, particularly the central nervous system and the heart. It is of interest to note that absence of lung lobulation was observed in two of the four reported patients, i.e., the second patient of Rodriguez et al. [19901 and the present fetus. The present observation adds renal hypoplasia and uterine anomalies to the spectrum of internal anomalies and also demonstrates that the skeletal malformations may include a variable degree of tetraphocomelia and both pre- and postaxial limb deficiencies. With the limited available data on this new “lethal acrofacial dysostosis Syndrome”, the presence of severe internal malformations seems to constitute the major basis for its differentiation from various other forms of
Lethal Acrofacial Dysostosis Syndrome
345
TABLE I. Clinical, Radiological, and Autopsy Findings in the 4 Reported Patients
Gestation (weeks) Face Severe micrognathia Malar hypoplasia Malformed ears Prominent nasal bridge Cleft palate Atretic ear canal X-ray findings Short (absent) humerus Single (absent) forearm Digital defects preaxial Digital defects postaxial Lower limb defects Toe defects Pelvis girdle hypoplasia Shoulder girdle hypoplasia Rib defects Necropsy Cardiac malformations CNS malformations Absent lung lobulation Renal anomaly Genital anomaly
Case 1 41
Rodriauez et al. D9901 Case 2 41
Case 3 40
24%
+ + + + +
+ + + +
+
+
+ + + + +
-
-
-
-
+ +
+ + + + + + + ? ? ? ?
+ + + + Male
sex
+ + +
+ +
+ + + + +-
-
+-
+-
+ -
-
-
Male
Male
Present case
+
+ + + + + +
+ ? +
+ + + + +
Female
dysostosis syndrome. Report of two further patients. Clin Genet acrofacial dysostosis such as the Miller syndrome [Mil35157-160. ler et al., 19791which includes predominantly postaxial n y n s JP, Klenkowska A, Moerman Ph, Vandenberghe K, Van den limb deficiencies and Nager syndrome [Chnanowska et Berghe H (1987):The Roberts tetraphocomelia syndrome: Identical al., 1989; Hallal et al., 1983; Opitz, 19871 with radial limb defects in two siblings. Ann a n & 30:243-245. limb hypoplasia. It is important to note that the associa- Halal F, Henmann J, Pallister PhD, Opitz JM, Desgranges MF, Gretion of tetraphocomelia with complex craniofacial and nier G (1983):Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discusvisceral anomalies is also observed in Roberts syndrome sion of other related syndromes. Am J Med Genet 14:209-224. [F’ryns et al., 1987;Romke et al., 19871.However, in this Miller M, Fineman R, Smith DW (1979):Postaxial acrofacial dysostosis tetraphocomelia syndrome the orofacial changes comsyndrome. J Pediatr 95:970-975. bining cleft liplcleft palate with protrusion of the preOpitz JM (1987):Nager “syndrome”versus “anomaly” and its nosology maxillary region, microphthalmia, and midfacial capilwith the postaxial acrofacial dysostosis syndrome of GenC and lary hemangiomata are clearly distinct from the typical Wiedemann. Am J Med Genet 27:959-963. mandibulofacial dysostosis observed in the present new Rodriguez JI, Palacios J, Urioste M (1990):New acrofacial dysostosis in 3 sibs. Am J Med Genet 35:484-489. syndrome.
REFERENCES Chranowska KH, Fryns JP, Krajewske-WalasecM, Wisniewski L, Van den Berghe H (1989):Phenotype variability in the Miller acrofacial
Romke C, Froster-Iskenius U, Heyne K, Hohn W, HofM, Gnejsznyk G, Rauskolb R, Rehder H, Schwinger E (1987):Roberts syndrome and SC phocomelia, A single genetic entity. Clin Genet 31:170-177.
Acrofacial Dysostosis Syndrome v p e Rodriguez: A New Lethal MCA Syndrome Paul Petit, Philippe Moerman, and Jean-Pierre F’ryns Center for Human Genetics (PP., JPF.)and Department of Pathology B (P.M.), University of Leuven, Leuven, Belgium
We present a female fetus with the lethal acrofacial dysostosis syndrome recently delineated by Rodriguez et al. “901. The present findings confirm that this syndrome constitutes a true MCA syndrome in which mandibulofacial dysostosis and severe limb reduction defects are associated with complex malformations of different organs and systems especially the CNS, the urogenital tract, heart, and lungs.
KEY WORDS acrofacial dysostosis, autosomal recessive inheritance, CNS and heart malfomations INTRODUCTION A new lethal form of acrofacial dysostosis syndrome characterized by mandibulofacial dysostosis, predominantly preaxial limb deficiencies, rare postaxial limb anomalies, shoulder and pelvic hypoplasia, and cardiac and CNS malformations was delineated recently by Rodriguez et al. 119901. Here we present another example of this true MCA syndrome with apparent autosomal recessive inheritance.
CLINICAL REPORT
telorism, marked exophthalmos with bilateral ectropion, antimongoloid slant of palpebral fissures, malar hypoplasia, high nasal bridge, and poorly formed ears with external canal atresia. The mouth was relatively small with retrognathia and cleft palate. Severe limb anomalies involved the 4 limbs. The arms were short with severe hypoplasia of the left humerus and bilateral absence of radii and ulnae, as confirmed on X-rays (Fig. 3). Both hands showed preaxial reduction with absence of thumbs and first metacarpals, camptodactyly of fingers I1 to IV, and clinodactyly V. Roentgenograms showed, in addition, hypoplasia of the distal phalanges and proximal fusion of the IVth and Vth metacarpals of the right hand. The lower limbs were extremely short with complete absence of all long bones. The pelvic girdle was short and hypoplastic. On the right foot there was partial duplication of the great toe and absence of the Vth ray. Only 11 ribs were bilaterally present, and the 7th cervical and the 6th thoracic vertebrae were hypoplastic. Autopsy showed a gross CNS malformation with triventricular hydrocephaly due to aqueductal stenosis and agenesis of the corpus callosum. A complex cardiac malformation was present with double superior vena cava without bridging innominate vein. The persistent left superior vena cava was connected with the left atrium because of failure of coronary sinus development. In addition there was complete persistent common atrioventricular canal. The lung lobulation was absent. Both kidneys (right 2.3 g; left 2.1 g) showed normal lobulation but microscopic examination revealed a reduced number of renal pyramids with focal absence of glomerular layers. The uterine corpus showed a unicornis unicollis malformation with absence of the left horn. Chromosomes were normal (46,XX).
The female fetus was examined after prostaglandin induction a t 24 weeks gestation because of ultrasonographic diagnosis of hydrocephaly in the second pregnancy of a 31-year-old mother and her nonconsanguineous 25-year-old husband. After the first pregnancy a normal daughter was born. Family history and personal antecedents are negative. Weight, foot length, DISCUSSION and head circumference were 463 g, 35 mm, and 23.5 cm, respectively. The head was elongated and severe mandiThe female fetus of this report has a mandibulofacial bulofacial dysostosiswas evident (Figs. 1,2)with hyper- dysostosis (antimongoloid slant of palpebral fissures, exphthalmos with ectropion, malar hypoplasia, malformed auricles, external atresia, mandibular hypoReceived for publication March 11,1991; revision received June plasia, and cleft palate) associated with severe limb defects (tetraphocomelia, bilateral preaxial deficiencies 3, 1991. Address reprint requests to J.P. Fkyns, Center for Human Ge- at the hands, postaxial deficiency a t the right hand and netics, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, foot), a complex cardiac and CNS (triventricular hydroBelgium. cephaly due to aqueductal stenosis, corpus callosum 0 1992 Wiley-Liss, Inc.
344
Petit et al.
Fig. 1. The malformed fetus.
Fig. 3. Roentgenographic skeletal survey.
Fig. 2. The facial anomalies.
agenesis) malformation, absence of lung lobulation, and urogenital anomalies. This combination of symptoms and malformations constitutes a further example of an apparent lethal acrofacial dysostosis syndrome, as delineated by Rodriguez et al. [19901 in this journal. Table I shows the similarities in clinical and radiological findings in the 3 brothers reported by Rodriguez et al. [19901 and the present female fetus. The female fetus of this report is the first documented female with this true MCA syndrome with autosomal recessive inheritance: in addition to mandibulofacial dysostosis and the skeletal malformations multiple other organs and systems are involved, particularly the central nervous system and the heart. It is of interest to note that absence of lung lobulation was observed in two of the four reported patients, i.e., the second patient of Rodriguez et al. [19901 and the present fetus. The present observation adds renal hypoplasia and uterine anomalies to the spectrum of internal anomalies and also demonstrates that the skeletal malformations may include a variable degree of tetraphocomelia and both pre- and postaxial limb deficiencies. With the limited available data on this new “lethal acrofacial dysostosis Syndrome”, the presence of severe internal malformations seems to constitute the major basis for its differentiation from various other forms of
Lethal Acrofacial Dysostosis Syndrome
345
TABLE I. Clinical, Radiological, and Autopsy Findings in the 4 Reported Patients
Gestation (weeks) Face Severe micrognathia Malar hypoplasia Malformed ears Prominent nasal bridge Cleft palate Atretic ear canal X-ray findings Short (absent) humerus Single (absent) forearm Digital defects preaxial Digital defects postaxial Lower limb defects Toe defects Pelvis girdle hypoplasia Shoulder girdle hypoplasia Rib defects Necropsy Cardiac malformations CNS malformations Absent lung lobulation Renal anomaly Genital anomaly
Case 1 41
Rodriauez et al. D9901 Case 2 41
Case 3 40
24%
+ + + + +
+ + + +
+
+
+ + + + +
-
-
-
-
+ +
+ + + + + + + ? ? ? ?
+ + + + Male
sex
+ + +
+ +
+ + + + +-
-
+-
+-
+ -
-
-
Male
Male
Present case
+
+ + + + + +
+ ? +
+ + + + +
Female
dysostosis syndrome. Report of two further patients. Clin Genet acrofacial dysostosis such as the Miller syndrome [Mil35157-160. ler et al., 19791which includes predominantly postaxial n y n s JP, Klenkowska A, Moerman Ph, Vandenberghe K, Van den limb deficiencies and Nager syndrome [Chnanowska et Berghe H (1987):The Roberts tetraphocomelia syndrome: Identical al., 1989; Hallal et al., 1983; Opitz, 19871 with radial limb defects in two siblings. Ann a n & 30:243-245. limb hypoplasia. It is important to note that the associa- Halal F, Henmann J, Pallister PhD, Opitz JM, Desgranges MF, Gretion of tetraphocomelia with complex craniofacial and nier G (1983):Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discusvisceral anomalies is also observed in Roberts syndrome sion of other related syndromes. Am J Med Genet 14:209-224. [F’ryns et al., 1987;Romke et al., 19871.However, in this Miller M, Fineman R, Smith DW (1979):Postaxial acrofacial dysostosis tetraphocomelia syndrome the orofacial changes comsyndrome. J Pediatr 95:970-975. bining cleft liplcleft palate with protrusion of the preOpitz JM (1987):Nager “syndrome”versus “anomaly” and its nosology maxillary region, microphthalmia, and midfacial capilwith the postaxial acrofacial dysostosis syndrome of GenC and lary hemangiomata are clearly distinct from the typical Wiedemann. Am J Med Genet 27:959-963. mandibulofacial dysostosis observed in the present new Rodriguez JI, Palacios J, Urioste M (1990):New acrofacial dysostosis in 3 sibs. Am J Med Genet 35:484-489. syndrome.
REFERENCES Chranowska KH, Fryns JP, Krajewske-WalasecM, Wisniewski L, Van den Berghe H (1989):Phenotype variability in the Miller acrofacial
Romke C, Froster-Iskenius U, Heyne K, Hohn W, HofM, Gnejsznyk G, Rauskolb R, Rehder H, Schwinger E (1987):Roberts syndrome and SC phocomelia, A single genetic entity. Clin Genet 31:170-177.
