American J o u r n a l of Medical Genetics 37:384-387 (1990)
Acrofacial Dysostosis With Ambiguous Genitalia Eric A. Wulfsberg, Jerri Curtis, Thomas E. Wiswell, Robert A. Puntel, and Sondra W. Levin Medical GeneticslDysmorphology, National Naval Medical Center (E.A.W.); and Neonatology, Uniformed Services University of the Health Sciences (J.C.), Bethesda, Maryland; Neonatology (T.E.W.) and Genetics, Exceptional Family Member Program (S.W.L.), and Department of Pediatrics (R.A.P.), Walter Reed Army Medical Center, Washington,
D.C. We report on a 46,XY infant with mandibulofacial dysostosis, preaxial and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phalliclscrotal transposition. This infant with atypical pre/postaxial acrofacial dysostosis (AFD) is the first to be reported with ambiguous genitalia. The acrofacial dysostoses are a heterogenous group of disorders characterized by varying degrees of mandibulofacia1 dysostosis with acral limb defects and may represent a polytopic field defect. These disorders have generally been separated on the basis of their limb anomalies into preaxial, postaxial, lethal, and atypical types. Most cases are sporadic, but various causes have been postulated including autosomal dominant and recessive inheritance, a chromosome 2q duplication, and a possible case of diabetic embryopathy. We review the nonfacialflimb anomalies in other cases of AFD and compare them to those of our case, thereby expanding the spectrum of anomalies in these disorders.
lies into the Nager type with preaxial limb defects [Nager and de Reynier, 19481, the Genee-Wiedemann type with predominant postaxial limb defects [Opitz, 19871, a lethal form with severe facial and phocomelic limb anomalies [Le Merrer e t al., 19891,and some atypical cases of preipostaxial AFD [Richieri-Costa and Guion-Almeida, 19891. Nonfacialllimb anomalies have only occasionally been described [Le Merrer et al,. 19891. We report on a 46,XY infant with MFD, preaxial and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phalliciscrotal transposition.
INTRODUCTION The acrofacial dysostoses (AFDs) are a heterogenous group of disorders characterized by varying degrees of mandibulofacial dysostosis (MFD) with acral limb defects [Le Merrer et al., 19891. These disorders have generally been separated on the basis of their limb anoma-
CLINICAL REPORT This was a 2,930 g, 40-week-gestation infant born to a 37-year-old G, PoTAB, mother and 38-year-old father. Family history was unremarkable and specifically negative for individuals with facial, limb, renal, or genital anomalies. The pregnancy was complicated by firsttrimester sinusitis treated with pseudoephedrine, thirdtrimester otitis media treated with ampicillin, and third-trimester vaginitis treated with clotrimazole cream. The mother denied use oftobacco, alcohol, and all licit or illicit drugs including exogenous hormones. There was no known exposure t o teratogenic chemicals or radiation. The mother reported active fetal movement. Amniocentesis and fetal ultrasound studies were performed at 16 weeks of gestation for advanced maternal age. Ultrasonography showed left hydronephrosis and a dilated thick-walled bladder that were consistently seen throughout the remainder of the pregnancy. The fetal karyotype was normal 46,XY. Following a spontaneous vertex vaginal delivery the baby had Apgar scores of 8 a t one minute and 9 a t 5 minutes and was noted to have facial, limb, and genital anomalies.
Received for publication November 27, 1989; revision received March 21, 1990. Address reprint requests to Eric A. Wulfsberg, M.D., Department of Pediatrics, National Naval Medical Center, Bethesda, MD 20814. The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U S . Government.
Physical Examination Weight 2,930 g (10th-25th centile), length 50.8 cm (50th centile),and head circumference (OFC) 32 cm (2nd centile). Observed facial anomalies (Fig. 1) included small, apparently low-set ears (left 2.7 cm (3rd centile), right 2.5 cm (3rd centile)) with a deficient upper helix; hypoplastic supraorbital ridges with protruding eyelids; a beaked nose with deficient alar cartilage; bilateral
KEY WORDS: prune belly sequence, Nager syndrome, Genee-Wiedemann syndrome
0 1990 Wiley-Liss, Inc.
Acrofacial Dysostosis
Fig. 1. Patient at age 1 week with protruding eyelids, malar and mandibular hypoplasia, and a small mouth with thin vermillion border.
symmetric malar and mandibular hypoplasia; a small mouth with a thin vermillion border; and projection of the scalp hair onto the lateral cheeks (Fig. 2). Other anomalies included redundant wrinkled abdominal skin with deficient musculature; a single umbilical artery; a 1.5-cm phallus posterior to a small, empty, pigmented scrota1 sac (Fig. 3); a urethral opening left and posterior to the phallus; symphalangism and digitalization of the thumbs with hypoplastic thenar eminences (Fig. 4); mild second-finger and severe fifth-finger clinodactyly; bilateral cutaneous 3-4-5 finger and 2-3 toe syndactyly; broad incurved great toes; and underfolded hypoplastic fifth toes (Fig. 5). There were single transverse palmar creases with prominent connecting creases to the web space between the 2nd and 3rd fingers. Dermatoglyphic examination showed whorls on the thumbs with ulnar loops on all the remaining fingers. There were no thenar or hypothenar patterns with the dermal ridges running straight across the palm and thenar area. The infant had a normal palate, eyes, heart, and neurologic and skeletal status except as noted above. Laboratory Lymphocyte “high-resolution” karyotype was normal 46,XY. Thyroid function studies, testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), serum cortisol, blood urea nitrogen (BUN), and serum creatinine levels were normal. Clinical Course A voiding cystourethrogram showed urethral stenosis, severe left hydronephrosis, and a normal right ure-
385
Fig. 2. Lateral face with deficient ear cartilage and projection of scalp hair onto the cheek.
Fig. 3. Ambiguous genitalia with phalliciscrotal transposition and redundant wrinkled abdominal skin.
ter. Hand films: small middle and distal phalanges of the 2nd and 5th fingers and short thumb metacarpals. Results of brainstem auditory evoked responses (BAERs) and cranial magnetic resonance imaging (MRI) were normal. Genital reconstruction was undertaken a t age one week with the creation of labial folds from the scrotum, movement of the phallus to a normal clitoral location, relief of the urethral obstruction with movement of the urethral opening to the midline, and removal of two normal intra-abdominal testes. At age 6 months the patient is described as a quiet baby who has met all growth and developmental milestones. The parents are adjusting well to the child’s sexual reassign-
386
Wulfsberg et al.
Fig. 5. Foot with broad incurved great toe, 2-3 toe syndactyly, and hypoplastic underfolded fifth toe.
Fig. 4. Hypoplastic thumbs with symphalangism of the distal phalanges and 3-4 finger syndactyly.
ment and anomalies. Thus, this patient has typical mandibulofacial dysostosis with pre- and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phalliciscrotal transposition.
DISCUSSION This infant with preipostaxial AFD is the first to be reported with ambiguous genitalia. While she has predominantly radial limb defects, the significant postaxial anomalies are not typical of the Nager-type AFD and we conclude that this patient has a n atypical preipostaxial AFD. This is a sporadic case. The redundant wrinkled abdominal skin and deficient abdominal muscles represent a mild prune belly sequence. This is most likely a deformationalidisruptional anomaly due to early bladder distention and hydronephrosis and is not a primary malformation. The phalliciscrotal transposition is most unusual. Normally the genital tubercle, which gives rise to phallic structures, is rostra1 to the urogenital folds which develop into the scrotum [Moore, 19881. Nonfacialilimb anomalies are uncommon in the AFDs. Opitz and Stickler [1987] mention a boy examined a t ages 12 days and 3 months with Genee-Wiedemann syndrome (micrognathia, hypoplastic external ears, and absent 5th fingers) with normal genitalia, chest, and cardiovascular system. At age 6 years a follow-up letter from another physician stated that the mother reported the patient had a “micropenis” and very small testes in comparison to his 2 younger brothers. Optiz and Stickler [1987] mentioned other
anomalies that have been described in the Genee-Wiedemann syndrome including supernumerary vertebrae, other vertebral segmentation and rib defects, congenital heart defects (ADS, VSD), extra nipples, a single umbilical artery, absence of a hemidiaphragm, and developmental delay. Jones [19881mentions cleft lip andior cleft palate, “cup-shaped” ears, and conductive deafness. Urogenital anomalies in patients with the Nager syndrome have included right renal agenesis with a duplicated left calyx [Pfeiffer and Stoess, 19831and a dystrophic right kidney and bicornuate uterus [Schonenberg, 19681. Krauss et al. [1985] described a patient with the Nager syndrome who had laryngeal and epiglottic hypoplasia, septation abnormalities of the right middle lobe, hypoplastic first right rib, and a dislocated right hip. Additional anomalies described in the Nager syndrome have included radioulnar synostosis with limited elbow extension, short forearms, club feet, oligodactyly, overlap or syndactyly of toes, and conductive deafness [Halal et al., 19831. Kelly et a1 [1977] described 3 boys from 2 consanguineous matings who had mild MFD (3131, symphalangism of the thumbs (3131, intrauterine growth retardation with later short stature (3131, hypospadias and undescended testes (2131, and mental retardation (313). They thought this condition was distinct from the Nager syndrome and proposed autosomal recessive inheritance based on the parental consanguinity, but could not exclude X-linked recessive inheritance. Richieri-Costa et al. [ 19831reported a “new syndrome” in 2 sisters with AFD, cleft lipicleft palate, and triphalangeal thumbs. Marden et al. [1964] reported a stillborn male infant with a Nager-like syndrome (micrognathia, downslanting palpebral fissures, apparently low-set ears, absent thumbs and radius) with cleft palate, gastroschisis, rudimentary phallus, and unilateral cryptorchidism. The AFDs are a heterogenous group of disorders and probably represent a polytopic field defect [RichieriCosta and Guion-Almeida, 19891. Most cases are spo-
Acrofacial Dysostosis
radic; however, various causes have been reported including autosomal dominant inheritance (Hall, 1989; Halal et al., 19833, autosomal recessive inheritance [Opitz and Stickler, 1987; Kelly et al., 1977; RichieriCosta et al., 19831,partial duplication of 2q [Wagner and Cole, 19791,and an atypical postaxial AFD possibly due to diabetic embryopathy [Richieri-Costa and Guion-Almeida, 19891. Sulik et al. [1987] were able to produce MFD in mice by exposing 9-day embryos (equivalent to the 4th postfertilization week in humans) to 13-cis retinoic acid (RA). Scanning electron microscopic analysis showed mesenchymal cell debris with premature and excessive cell death in areas of the first and 2nd branchial arches. Three of 64 fetuses also had postaxial limb deficiencies resulting in a phenotype they felt was similar to human postaxial AFD. Exposing 12.5-dayembryos to 13-cisRA resulted in 46% of the fetuses having a variety of acral limb defects including small 5th fingers, preaxial and/or postaxial oligodactyly, and preaxial or postaxial polydactyly [Sulik and Dehart, 19881. These defects were also shown to be due to premature and excessive cell death in the apical ectodermal ridges. The action of 13cis RA appears t o involve the labilization of lysosomal membranes [Jarrett et al., 19781. Sulik et al. [19871 hypothesized that the release of lysosomal enzymes from the lysosome-rich ectodermal cells caused the premature and excessive cell death among the ectodermal and mesenchymal tissues. These studies suggest a common pathogenesis for the development of the facial and limb defects in the AFDs. Our case of atypical preipostaxial AFD with major renal and genital anomalies adds to the spectrum of anomalies in these disorders. The classification of these disorders into preaxial, postaxial, lethal, and atypical cases is clinically helpful but probably will change dramatically as we come to better understand the many causes and the pathogenesis of this very heterogeneous group of disorders.
REFERENCES Halal F, Herrmann J, Pallister PD, Opitz JM, Desgranges M, Grenier G (1983): Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209-224.
387
Hall BD (1989):Nager acrofacial dysostosis: Autosomal dominant inheritance in mild to moderately affected mother and lethally affected phocomelic son. Am J Med Genet 33:394-397. Jarrett A, Wrench R, Mahmoud B (1978):The effects of retinyl acetate on epidermal proliferation and differentiation. I. Induced enzyme reactions in the epidermis. Clin Exp Dermatol 3:173-188. Jones KL (1988): Miller syndrome. In Jones KL (ed): “Smith’s Recog nizable Patterns of Human Malformation.” Philadelphia: W.B. Saunders, pp 214-215. Kelly TE, Cooke R J , Kesler RW (1977): Acrofacial dysostosis with growth and mental retardation in three males, one with simultaneous Hermansky-hdlak syndrome. In Bergsma D, Lowry RB, Opitz JM, Paul NW (eds): “New Syndromes.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS XIII(3B):45-52. Krauss CM, Hassell LA, Gang DL (1985):Briefclinical report: Anomalies in an infant with Nager acrofacial dysostosis. Am J Med Genet 21:761-764. Le Merrer M, Cikuli M, Ribier J , Briard ML (1989):Acrofacial dysostosis. Am J Med Genet 33:318-322. MardenPM, Smith DW, McDonaldMJ (1964):Congenital anomalies in the newborn infant, including minor variations. J Pediatr 64:357-371 (Case 653). Moore KL (1988): “Essentials of Human Embryology.” Philadelphia: B.C. Decker, p 124. Nager FR, de Reynier J P (1948):Das Gehororgan bei den angeborenen Kopfmissbildungen. Pract Otorhinolaryngol (Basel) 1O:l-128. Opitz JM (1987):Editorial comment: Nager “syndrome” vs “anomaly” and its nosology with the postaxial dysostosis syndrome of Genee and Wiedemann. Am J Med Genet 27:959-963. Opitz JM, Stickler GB (1987): Letter to the editor: The Genee-Wiedemann syndrome, an acrofacial dysostosis-further observation. Am J Med Genet 27:971-975. Pfeiffer RA, Stoess H (1983):Acrofacial dysostosis (Nager syndrome): Synopsis and report of a new case. Am J Med Genet 15:255-260. Richieri-CostaA, Guion-AlmeidaML (1989):Atypical postaxial acrofacia1 dysostosis (AFD): Diabetic embryopathy or a new AFD syndrome? Am J Med Genet 33:450-452. Richieri-Costa A, Gollop TR, Colletto GM (1983): Brief clinical report: Syndrome of acrofacial dysostosis, cleft lipipalate, and triphalangeal thumb in a Brazilian family. Am J Med Genet 14:225-229. Schonenberg H (1968): Die Differentialdiagnose der radialen Defektbildungen. Padiat Prax 7:455-467. Sulik KK, Johnston MC, Smiley SJ, Speight HS, Jarvis BE (1987): Mandibulofacial dysostosis (Treacher Collins syndrome): A new proposal for its pathogenesis. Am J Med Genet 27:359-372. Sulik KK, Dehart DB (1988): Retinoic-acid-induced limb malformations resulting from apical ectodermal ridge cell death. Teratology 37:527-537. Wagner SF, Cole J (1979):Nager syndrome with partial duplication of the long arm of chromosome 2. Am J Hum Genet 31:116A.
Acrofacial Dysostosis With Ambiguous Genitalia Eric A. Wulfsberg, Jerri Curtis, Thomas E. Wiswell, Robert A. Puntel, and Sondra W. Levin Medical GeneticslDysmorphology, National Naval Medical Center (E.A.W.); and Neonatology, Uniformed Services University of the Health Sciences (J.C.), Bethesda, Maryland; Neonatology (T.E.W.) and Genetics, Exceptional Family Member Program (S.W.L.), and Department of Pediatrics (R.A.P.), Walter Reed Army Medical Center, Washington,
D.C. We report on a 46,XY infant with mandibulofacial dysostosis, preaxial and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phalliclscrotal transposition. This infant with atypical pre/postaxial acrofacial dysostosis (AFD) is the first to be reported with ambiguous genitalia. The acrofacial dysostoses are a heterogenous group of disorders characterized by varying degrees of mandibulofacia1 dysostosis with acral limb defects and may represent a polytopic field defect. These disorders have generally been separated on the basis of their limb anomalies into preaxial, postaxial, lethal, and atypical types. Most cases are sporadic, but various causes have been postulated including autosomal dominant and recessive inheritance, a chromosome 2q duplication, and a possible case of diabetic embryopathy. We review the nonfacialflimb anomalies in other cases of AFD and compare them to those of our case, thereby expanding the spectrum of anomalies in these disorders.
lies into the Nager type with preaxial limb defects [Nager and de Reynier, 19481, the Genee-Wiedemann type with predominant postaxial limb defects [Opitz, 19871, a lethal form with severe facial and phocomelic limb anomalies [Le Merrer e t al., 19891,and some atypical cases of preipostaxial AFD [Richieri-Costa and Guion-Almeida, 19891. Nonfacialllimb anomalies have only occasionally been described [Le Merrer et al,. 19891. We report on a 46,XY infant with MFD, preaxial and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phalliciscrotal transposition.
INTRODUCTION The acrofacial dysostoses (AFDs) are a heterogenous group of disorders characterized by varying degrees of mandibulofacial dysostosis (MFD) with acral limb defects [Le Merrer et al., 19891. These disorders have generally been separated on the basis of their limb anoma-
CLINICAL REPORT This was a 2,930 g, 40-week-gestation infant born to a 37-year-old G, PoTAB, mother and 38-year-old father. Family history was unremarkable and specifically negative for individuals with facial, limb, renal, or genital anomalies. The pregnancy was complicated by firsttrimester sinusitis treated with pseudoephedrine, thirdtrimester otitis media treated with ampicillin, and third-trimester vaginitis treated with clotrimazole cream. The mother denied use oftobacco, alcohol, and all licit or illicit drugs including exogenous hormones. There was no known exposure t o teratogenic chemicals or radiation. The mother reported active fetal movement. Amniocentesis and fetal ultrasound studies were performed at 16 weeks of gestation for advanced maternal age. Ultrasonography showed left hydronephrosis and a dilated thick-walled bladder that were consistently seen throughout the remainder of the pregnancy. The fetal karyotype was normal 46,XY. Following a spontaneous vertex vaginal delivery the baby had Apgar scores of 8 a t one minute and 9 a t 5 minutes and was noted to have facial, limb, and genital anomalies.
Received for publication November 27, 1989; revision received March 21, 1990. Address reprint requests to Eric A. Wulfsberg, M.D., Department of Pediatrics, National Naval Medical Center, Bethesda, MD 20814. The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U S . Government.
Physical Examination Weight 2,930 g (10th-25th centile), length 50.8 cm (50th centile),and head circumference (OFC) 32 cm (2nd centile). Observed facial anomalies (Fig. 1) included small, apparently low-set ears (left 2.7 cm (3rd centile), right 2.5 cm (3rd centile)) with a deficient upper helix; hypoplastic supraorbital ridges with protruding eyelids; a beaked nose with deficient alar cartilage; bilateral
KEY WORDS: prune belly sequence, Nager syndrome, Genee-Wiedemann syndrome
0 1990 Wiley-Liss, Inc.
Acrofacial Dysostosis
Fig. 1. Patient at age 1 week with protruding eyelids, malar and mandibular hypoplasia, and a small mouth with thin vermillion border.
symmetric malar and mandibular hypoplasia; a small mouth with a thin vermillion border; and projection of the scalp hair onto the lateral cheeks (Fig. 2). Other anomalies included redundant wrinkled abdominal skin with deficient musculature; a single umbilical artery; a 1.5-cm phallus posterior to a small, empty, pigmented scrota1 sac (Fig. 3); a urethral opening left and posterior to the phallus; symphalangism and digitalization of the thumbs with hypoplastic thenar eminences (Fig. 4); mild second-finger and severe fifth-finger clinodactyly; bilateral cutaneous 3-4-5 finger and 2-3 toe syndactyly; broad incurved great toes; and underfolded hypoplastic fifth toes (Fig. 5). There were single transverse palmar creases with prominent connecting creases to the web space between the 2nd and 3rd fingers. Dermatoglyphic examination showed whorls on the thumbs with ulnar loops on all the remaining fingers. There were no thenar or hypothenar patterns with the dermal ridges running straight across the palm and thenar area. The infant had a normal palate, eyes, heart, and neurologic and skeletal status except as noted above. Laboratory Lymphocyte “high-resolution” karyotype was normal 46,XY. Thyroid function studies, testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), serum cortisol, blood urea nitrogen (BUN), and serum creatinine levels were normal. Clinical Course A voiding cystourethrogram showed urethral stenosis, severe left hydronephrosis, and a normal right ure-
385
Fig. 2. Lateral face with deficient ear cartilage and projection of scalp hair onto the cheek.
Fig. 3. Ambiguous genitalia with phalliciscrotal transposition and redundant wrinkled abdominal skin.
ter. Hand films: small middle and distal phalanges of the 2nd and 5th fingers and short thumb metacarpals. Results of brainstem auditory evoked responses (BAERs) and cranial magnetic resonance imaging (MRI) were normal. Genital reconstruction was undertaken a t age one week with the creation of labial folds from the scrotum, movement of the phallus to a normal clitoral location, relief of the urethral obstruction with movement of the urethral opening to the midline, and removal of two normal intra-abdominal testes. At age 6 months the patient is described as a quiet baby who has met all growth and developmental milestones. The parents are adjusting well to the child’s sexual reassign-
386
Wulfsberg et al.
Fig. 5. Foot with broad incurved great toe, 2-3 toe syndactyly, and hypoplastic underfolded fifth toe.
Fig. 4. Hypoplastic thumbs with symphalangism of the distal phalanges and 3-4 finger syndactyly.
ment and anomalies. Thus, this patient has typical mandibulofacial dysostosis with pre- and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phalliciscrotal transposition.
DISCUSSION This infant with preipostaxial AFD is the first to be reported with ambiguous genitalia. While she has predominantly radial limb defects, the significant postaxial anomalies are not typical of the Nager-type AFD and we conclude that this patient has a n atypical preipostaxial AFD. This is a sporadic case. The redundant wrinkled abdominal skin and deficient abdominal muscles represent a mild prune belly sequence. This is most likely a deformationalidisruptional anomaly due to early bladder distention and hydronephrosis and is not a primary malformation. The phalliciscrotal transposition is most unusual. Normally the genital tubercle, which gives rise to phallic structures, is rostra1 to the urogenital folds which develop into the scrotum [Moore, 19881. Nonfacialilimb anomalies are uncommon in the AFDs. Opitz and Stickler [1987] mention a boy examined a t ages 12 days and 3 months with Genee-Wiedemann syndrome (micrognathia, hypoplastic external ears, and absent 5th fingers) with normal genitalia, chest, and cardiovascular system. At age 6 years a follow-up letter from another physician stated that the mother reported the patient had a “micropenis” and very small testes in comparison to his 2 younger brothers. Optiz and Stickler [1987] mentioned other
anomalies that have been described in the Genee-Wiedemann syndrome including supernumerary vertebrae, other vertebral segmentation and rib defects, congenital heart defects (ADS, VSD), extra nipples, a single umbilical artery, absence of a hemidiaphragm, and developmental delay. Jones [19881mentions cleft lip andior cleft palate, “cup-shaped” ears, and conductive deafness. Urogenital anomalies in patients with the Nager syndrome have included right renal agenesis with a duplicated left calyx [Pfeiffer and Stoess, 19831and a dystrophic right kidney and bicornuate uterus [Schonenberg, 19681. Krauss et al. [1985] described a patient with the Nager syndrome who had laryngeal and epiglottic hypoplasia, septation abnormalities of the right middle lobe, hypoplastic first right rib, and a dislocated right hip. Additional anomalies described in the Nager syndrome have included radioulnar synostosis with limited elbow extension, short forearms, club feet, oligodactyly, overlap or syndactyly of toes, and conductive deafness [Halal et al., 19831. Kelly et a1 [1977] described 3 boys from 2 consanguineous matings who had mild MFD (3131, symphalangism of the thumbs (3131, intrauterine growth retardation with later short stature (3131, hypospadias and undescended testes (2131, and mental retardation (313). They thought this condition was distinct from the Nager syndrome and proposed autosomal recessive inheritance based on the parental consanguinity, but could not exclude X-linked recessive inheritance. Richieri-Costa et al. [ 19831reported a “new syndrome” in 2 sisters with AFD, cleft lipicleft palate, and triphalangeal thumbs. Marden et al. [1964] reported a stillborn male infant with a Nager-like syndrome (micrognathia, downslanting palpebral fissures, apparently low-set ears, absent thumbs and radius) with cleft palate, gastroschisis, rudimentary phallus, and unilateral cryptorchidism. The AFDs are a heterogenous group of disorders and probably represent a polytopic field defect [RichieriCosta and Guion-Almeida, 19891. Most cases are spo-
Acrofacial Dysostosis
radic; however, various causes have been reported including autosomal dominant inheritance (Hall, 1989; Halal et al., 19833, autosomal recessive inheritance [Opitz and Stickler, 1987; Kelly et al., 1977; RichieriCosta et al., 19831,partial duplication of 2q [Wagner and Cole, 19791,and an atypical postaxial AFD possibly due to diabetic embryopathy [Richieri-Costa and Guion-Almeida, 19891. Sulik et al. [1987] were able to produce MFD in mice by exposing 9-day embryos (equivalent to the 4th postfertilization week in humans) to 13-cis retinoic acid (RA). Scanning electron microscopic analysis showed mesenchymal cell debris with premature and excessive cell death in areas of the first and 2nd branchial arches. Three of 64 fetuses also had postaxial limb deficiencies resulting in a phenotype they felt was similar to human postaxial AFD. Exposing 12.5-dayembryos to 13-cisRA resulted in 46% of the fetuses having a variety of acral limb defects including small 5th fingers, preaxial and/or postaxial oligodactyly, and preaxial or postaxial polydactyly [Sulik and Dehart, 19881. These defects were also shown to be due to premature and excessive cell death in the apical ectodermal ridges. The action of 13cis RA appears t o involve the labilization of lysosomal membranes [Jarrett et al., 19781. Sulik et al. [19871 hypothesized that the release of lysosomal enzymes from the lysosome-rich ectodermal cells caused the premature and excessive cell death among the ectodermal and mesenchymal tissues. These studies suggest a common pathogenesis for the development of the facial and limb defects in the AFDs. Our case of atypical preipostaxial AFD with major renal and genital anomalies adds to the spectrum of anomalies in these disorders. The classification of these disorders into preaxial, postaxial, lethal, and atypical cases is clinically helpful but probably will change dramatically as we come to better understand the many causes and the pathogenesis of this very heterogeneous group of disorders.
REFERENCES Halal F, Herrmann J, Pallister PD, Opitz JM, Desgranges M, Grenier G (1983): Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209-224.
387
Hall BD (1989):Nager acrofacial dysostosis: Autosomal dominant inheritance in mild to moderately affected mother and lethally affected phocomelic son. Am J Med Genet 33:394-397. Jarrett A, Wrench R, Mahmoud B (1978):The effects of retinyl acetate on epidermal proliferation and differentiation. I. Induced enzyme reactions in the epidermis. Clin Exp Dermatol 3:173-188. Jones KL (1988): Miller syndrome. In Jones KL (ed): “Smith’s Recog nizable Patterns of Human Malformation.” Philadelphia: W.B. Saunders, pp 214-215. Kelly TE, Cooke R J , Kesler RW (1977): Acrofacial dysostosis with growth and mental retardation in three males, one with simultaneous Hermansky-hdlak syndrome. In Bergsma D, Lowry RB, Opitz JM, Paul NW (eds): “New Syndromes.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS XIII(3B):45-52. Krauss CM, Hassell LA, Gang DL (1985):Briefclinical report: Anomalies in an infant with Nager acrofacial dysostosis. Am J Med Genet 21:761-764. Le Merrer M, Cikuli M, Ribier J , Briard ML (1989):Acrofacial dysostosis. Am J Med Genet 33:318-322. MardenPM, Smith DW, McDonaldMJ (1964):Congenital anomalies in the newborn infant, including minor variations. J Pediatr 64:357-371 (Case 653). Moore KL (1988): “Essentials of Human Embryology.” Philadelphia: B.C. Decker, p 124. Nager FR, de Reynier J P (1948):Das Gehororgan bei den angeborenen Kopfmissbildungen. Pract Otorhinolaryngol (Basel) 1O:l-128. Opitz JM (1987):Editorial comment: Nager “syndrome” vs “anomaly” and its nosology with the postaxial dysostosis syndrome of Genee and Wiedemann. Am J Med Genet 27:959-963. Opitz JM, Stickler GB (1987): Letter to the editor: The Genee-Wiedemann syndrome, an acrofacial dysostosis-further observation. Am J Med Genet 27:971-975. Pfeiffer RA, Stoess H (1983):Acrofacial dysostosis (Nager syndrome): Synopsis and report of a new case. Am J Med Genet 15:255-260. Richieri-CostaA, Guion-AlmeidaML (1989):Atypical postaxial acrofacia1 dysostosis (AFD): Diabetic embryopathy or a new AFD syndrome? Am J Med Genet 33:450-452. Richieri-Costa A, Gollop TR, Colletto GM (1983): Brief clinical report: Syndrome of acrofacial dysostosis, cleft lipipalate, and triphalangeal thumb in a Brazilian family. Am J Med Genet 14:225-229. Schonenberg H (1968): Die Differentialdiagnose der radialen Defektbildungen. Padiat Prax 7:455-467. Sulik KK, Johnston MC, Smiley SJ, Speight HS, Jarvis BE (1987): Mandibulofacial dysostosis (Treacher Collins syndrome): A new proposal for its pathogenesis. Am J Med Genet 27:359-372. Sulik KK, Dehart DB (1988): Retinoic-acid-induced limb malformations resulting from apical ectodermal ridge cell death. Teratology 37:527-537. Wagner SF, Cole J (1979):Nager syndrome with partial duplication of the long arm of chromosome 2. Am J Hum Genet 31:116A.
