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 acro- facial dysostosis syndrome recently delin- eated by Rodriguez et al. “901. The present findings confirm that this syndrome consti- tutes a true MCA syndrome in which mandi- bulofacial dysostosis and severe limb reduc- tion defects are associated with complex malformations of different organs and sys- tems especially the CNS, the urogenital tract, heart, and lungs.

KEY WORDS acrofacial dysostosis, autoso- mal recessive inheritance, CNS and heart malfomations

INTRODUCTION A new lethal form of acrofacial dysostosis syndrome

characterized by mandibulofacial dysostosis, predomi- nantly 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 inheri- tance.

CLINICAL REPORT The female fetus was examined after prostaglandin

induction at 24 weeks gestation because of ultra- sonographic diagnosis of hydrocephaly in the second pregnancy of a 31-year-old mother and her noncon- sanguineous 25-year-old husband. After the first preg- nancy a normal daughter was born. Family history and personal antecedents are negative. Weight, foot length, and head circumference were 463 g, 35 mm, and 23.5 cm, respectively. The head was elongated and severe mandi- bulofacial dysostosis was evident (Figs. 1,2) with hyper-

Received for publication March 11,1991; revision received June 3, 1991.

Address reprint requests to J.P. Fkyns, Center for Human Ge- netics, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.

0 1992 Wiley-Liss, Inc.

telorism, marked exophthalmos with bilateral ectro- pion, 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 gir- dle 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 tri- ventricular 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 develop- ment. In addition there was complete persistent com- mon atrioventricular canal. The lung lobulation was absent. Both kidneys (right 2.3 g; left 2.1 g) showed normal lobulation but microscopic examination re- vealed 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).

DISCUSSION The female fetus of this report has a mandibulofacial

dysostosis (antimongoloid slant of palpebral fissures, exphthalmos with ectropion, malar hypoplasia, mal- formed auricles, external atresia, mandibular hypo- plasia, and cleft palate) associated with severe limb defects (tetraphocomelia, bilateral preaxial deficiencies at the hands, postaxial deficiency at the right hand and foot), a complex cardiac and CNS (triventricular hydro- cephaly due to aqueductal stenosis, corpus callosum

344 Petit et al.

Fig. 1. The malformed fetus.

Fig. 3. Roentgenographic skeletal survey.

agenesis) malformation, absence of lung lobulation, and urogenital anomalies.

This combination of symptoms and malformations constitutes a further example of an apparent lethal acro- facial dysostosis syndrome, as delineated by Rodriguez et al. [19901 in this journal. Table I shows the sim- ilarities 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 pres- ent 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 Fig. 2. The facial anomalies.

Lethal Acrofacial Dysostosis Syndrome 345

TABLE I. Clinical, Radiological, and Autopsy Findings in the 4 Reported Patients

Rodriauez et al. D9901 Case 1 Case 2 Case 3 Present case

Gestation (weeks) 41 41 40 24% Face

Severe micrognathia + + + + Malar hypoplasia + + + + Malformed ears + + + + Prominent nasal bridge + + + + Cleft palate + + Atretic ear canal + + + + 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 + + + + Cardiac malformations + + CNS malformations + + Absent lung lobulation + Renal anomaly - - - Genital anomaly - - -

+ -

X-ray findings + + + + +

- - - -

- -

- -

Necropsy + + + + +

- -

-

sex Male Male Male Female

acrofacial dysostosis such as the Miller syndrome [Mil- ler et al., 19791 which includes predominantly postaxial limb deficiencies and Nager syndrome [Chnanowska et al., 1989; Hallal et al., 1983; Opitz, 19871 with radial limb hypoplasia. It is important to note that the associa- tion of tetraphocomelia with complex craniofacial and visceral anomalies is also observed in Roberts syndrome [F’ryns et al., 1987; Romke et al., 19871. However, in this tetraphocomelia syndrome the orofacial changes com- bining cleft liplcleft palate with protrusion of the pre- maxillary region, microphthalmia, and midfacial capil- lary hemangiomata are clearly distinct from the typical mandibulofacial dysostosis observed in the present new syndrome.

REFERENCES Chranowska KH, Fryns JP, Krajewske-Walasec M, Wisniewski L, Van

den Berghe H (1989): Phenotype variability in the Miller acrofacial

dysostosis syndrome. Report of two further patients. Clin Genet 35157-160.

n y n s JP, Klenkowska A, Moerman Ph, Vandenberghe K, Van den Berghe H (1987): The Roberts tetraphocomelia syndrome: Identical limb defects in two siblings. Ann a n & 30:243-245.

Halal F, Henmann J, Pallister PhD, Opitz JM, Desgranges MF, Gre- nier G (1983): Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discus- sion of other related syndromes. Am J Med Genet 14:209-224.

Miller M, Fineman R, Smith DW (1979): Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970-975.

Opitz JM (1987): Nager “syndrome” versus “anomaly” and its nosology with the postaxial acrofacial dysostosis syndrome of GenC and Wiedemann. Am J Med Genet 27:959-963.

Rodriguez JI, Palacios J, Urioste M (1990): New acrofacial dysostosis in 3 sibs. Am J Med Genet 35:484-489.

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.