American Journal of Medical Genetics 4 2 180- 183 (1992)
Acromelic F’rontonasal “Dysplasia”:Further Delineation of a Subtype With Brain Malformation and Polydactyly (Toriello Syndrome) Alain Verloes, Yves Gillerot, Elisabeth Walczak, Lionel Van Maldergem, and Lucien Koulischer Centre for Human Genetics, L 2 e University, (A.V.,L.K.). Institute for Morphologic Pathology, Loverval (Y.G.; L.V.M.), and Clinique Saint Vincent de Paul, Rocourt (E.W.),Belgium
We report on a stillborn boy with frontonasal malformation (Sedano-Jirasek type D-DeMyer type I), associated with encephalocoele, occipital meningocele and preaxial polydactyly of the feet. This form of frontonasal dysplasia was documented previously in a few other cases with various combinations of postaxial polydactyly, tibia1 hypoplasia, epibulbar dermoid, occipital encephalocoele, corpus callosum agenesis and Dandy-Walker malformation. Most cases are sporadic. KEY WORDS acrocallosal syndrome, encephalocoele, frontonasal dysplasia, MCA syndrome, preaxial polydactyly. INTRODUCTION Frontonasal abnormalities have been reported for over a century. About 70 cases were collected by Sedano et al. in 1970. Recently, a comprehensive review was given in “Syndromes of the Head and Neck” [Gorlin et al., 19901. We report on a severely affected child where this “classical” malformation is associated with limb anomalies, and we review the previously reported cases. CLINICAL REPORT Our propositus is a 31-week-old male fetus born to non-consanguineous Caucasian parents. The father was 33 years old. His G2POAl wife was 28 years old. For suspected hypothyroidism, she underwent 9 9 T ~ scintigraphy (3 Years >7
Ia D
N N L + R N N N Y Y Y
N R N N N N Y N Y Y
Y
Edwards Warkanv e t al. et al.
N L + R N N N Y Y Y IR Y
2,900
M F Months >5 Months >9 Months
Neidich Toriello et al. [19871 119881 Our case
N IR
Ia D N N N Y N L + R N N N N N N IR
2,500
3,740
F
F
M
4
2
2
N
Ia D Y Y Y
Ia D
N L + R N R L + R Y N N Y Y
Y R N N
Ia D N N N
117 216 1/5 214 218
Y L+R6/8 N 018 N 218 N 118 N 317 N 418 N 217
N N Y
IR
3,650
1,770
M 3:4 Stillbirths
Months Months Months Fatherlmother age L
=
Left; R = Right; Y
=
40130 Present; N = Absent; IR
?I25 =
?I14
?I19
?I34
?I?
33128
irrelevant.
Derocque [1908]. Toriello et al. [1986] were the first to treat this clinical phenotype as a distinct entity. Their opinion was followed by Gorlin et al. [1990] and Cohen [19901. We suggest the term acromelicFND. Brain anomalies are common but inconstant findings in this condition. Mental retardation seems the rule among the surviving children. This high prevalence of cerebral malformation or dysfunction contrasts sharply with the usually good mental prognosis of individuals with non-syndromal FND [DeMyer, 19671. Epibulbar dermoids are frequent in acromelic FND but have been observed in FND patients without polydactyly [Gupta et al., 1968; Fontaine et al., 1983, patient 11. Some clinical geneticists would consider acromelic FND the end of the “clinical spectrum’’ of FND. However, presence of acral anomalies implies that a t least 2 developmental field defects are involved. From a pathogenetic point of view, this could mean that the dysmorphogenetic process involved in acromelic FND is different, or more complex, than in non-syndromal FND, and justifies its delineation as a separate entity. Differential diagnosis of acromelic FND is listed in Table 111. The differentiation from acrocallosal syndrome is difficult when agenesis of the corpus callosum (ACC) is present, as both syndromes, in their most severe forms, are phenotypically very close: Schinzel [19871stated that the children reported by Toriello could be a severe example of acrocallosal syndrome; this suggestion was accepted by Toriello herself [19871 but not by Gorlin et al. [19901. Although severe central nervous system midline involvement and polydactyly are observed in acromelicFND and acrocallosal syndrome, the latter never shows severe median craniofacial involvement, and coexistence of both phenotypes within a sibship was not observed. It must be stressed that ACC was
observed in rare cases of non-syndromal FND [DeMyer, 1967, patients 2 and 13; Fontaine et al., 1983, patients 1,3,4]. In Fontaine’s report ACC was associated twice with Dandy-Walker malformation. In Warkany’s report, one of the half-sisters with FND had normal limbs and ACC, the other had FND, polydactyly,and normal brain (except for an area of porencephaly). Most cases of acromelicFND are sporadicbut parental consanguinity and occurrence in identical twins have been documented [unpublished cases quoted by Gorlin
TABLE 111. Differential Diagnosis of Cerebrofrontonasomelic Dysplasia. Syndromes With Frontonasal Malformation and Abnormal Limbs Acrocallosal syndrome Acrofrontofacionasal dysostosis type 1 Acrofrontofacionasal dysostosis type 2 Brachycephalofrontonasal dysplasia Carpenter-Hunter syndrome Craniofrontonasal dysplasia Hypertelorism-colobomaACC-hypoplastic thumbs syndrome Greig acrocephalopolysyndactyly Hartsfield syndrome Hypothalamic hamartomafrontonasal dysplasia syndrome Pallister-Hall syndrome Thurston median cleft lip/ nose-postaxial polydactyly W svndrome
(M.I.M. 200990) (M.I.M. 201180) Richieri-Costa et al. [19891 Teebi [19871 Carpenter and Hunter [19821 (M.I.M. 304110) FranGois et al. [19731 (M.I.M. 175700) Hartsfield e t al. [19841 Hennekam et al. [19861 (M.I.M. 146510) Thurston [19091 Pallister et al. [19741
Acromelic Frontonasal Dysplasia
et al., 19901.There is no simple genetic explanation for the half-sisters reported by Warkany et al. [19731.Autosoma1 dominant inheritance, with lack of penetrance or germinal mosaicism in the mother, or a teratogenic environmental factor was discussed by the authors, but a single father was not totally ruled out, as paternity testing could not be done.
183
Hennekam RCM, Beemer FA, Ekanka VM, Van Ketel BA, Kramer PPG (1986):Congenital hypothalamic hamartoblastoma associated with severe midline defect: a developmental field defect. Am J Genet Suppl. 2:45-52. McKusick VA, Francomano CA, Antonotakis SE (1990): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes.” 9th Ed. Baltimore: The Johns Hopkins University Press. Neidich JA, Whitaker LA, Zakai EH (1988). Frontonasal malformation. Two new syndromes? Am J Med Genet 1988 Suppl. 4:202-203. REFERENCES Oldfield M (1937):An encephaloceleassociated with hypertelorism and cleft palate. Br J Surg 25:757-764. Bougon, Derocque (1908): Fissure mkdiane de la face. Rev Orthop Pallister PD, Herrmann J, Spranger JW, Gorlin RJ, Langer LO, Opitz 9:219-224. JM (1974): Studies on malformation in man XXVIII. The W synCalli LJ (1971): Ocular hypertelorism and nasal agenesis (midface drome. In D. Bergsma (ed.), “Malformation Syndromes.” Internasyndrome) with limb anomalies. In D. Bergsma (ed.) “The Third tional Medical Book Corp., New York. BD:OAS X (7):51-60. Conference on the clinical Delineation of Birth Defects. Part X I Orofacial Structures”. Williams and Wilkins, Baltimore. BD:OAS Prescott KE, Sheridan-Pereira M, Manchester DK, Eilers B, Hall BD (1989):The median facial clefthkeletal syndrome (frontonasal dysVII (7):268. plasia): a distinct subgroup with nasal agenesis, tibia1 aplasia, Carpenter BF, Hunter AGW (1982):Micromelia, polysyndactyly, mulhallucal polydactyly and mental retardation. Am J Hum Genet 45 tiple malformations, and fragile bones in a stillborn child. J Med (suppl.):A59 (Abstract). Genet 19:311. Richieri-Costa A, Montagnoli L, Kamiya TY (1989):Autosomal recesCohen MM Jr (1990):Selected clinical research involving the central sive acro-fronto-facio-nasal dysostosis associated with genitourinnervous system. J Craniof Genet Dev Biol 10:215-238. ary anomalies. Am J Med Genet 33:121-124. DeMyer W (1967):The median cleft face syndrome. Differential diagSchinzel A (1987): New and old syndromes. Am J Med Genet 32:318. nosis of cranium bifidum occultum, hypertelorism, and median cleft Sedano HO, Cohen MM Jr, Jiritsek J , Gorlin R J (1970): Frontonasal nose, lip, and palate. Neurology 17:961-971. dysplasia. J Pediatr 76906-913. Edwards WC, Askew W, Weisskopf B (1971): Median cleft face synTeebi AS (1987):New autosomal dominant syndrome resembling cranidrome. Am J Ophthalmol 72:202-205. ofrontonasal dysplasia. Am J Med Genet 28:581-592. Fontaine G, Walbaum R, Poupard B, Bonte C, Dhellemans P, Maquet E, Ythier H, Stevenard C (1983):La dysplasie fronto-nasale (it propos Thurston E (1909): A case of median harelip associated with other malformations. Lancet 2:996. de quatre observations). J G6net Hum 31:351-365. Francois J , Eggermont E, Evens L, Logghe N, De Bock F (1973): Toriello HV (1987):Response to new and old syndromes, by A. Schinzel. Am J Med Genet 32:319. Agenesis of the corpus callosum in the median facial cleft syndrome and associated ocular malformations. Am J Ophthalmol 76:241- Toriello HV, Radecki LL, Sharda J , Looyenga D, Mann R (1986):Fron245. tonasal “dysplasia,” cerebral anomalies, and polydactyly: report of Gorlin RI,Cohen MM Jr, Levin S (1990):“Syndromes of the Head and a new syndrome and discussion from a developmental field perspecNeck.” 3rd Ed. Oxford: Oxford University Press. tive. Am J Med Genet Suppl 2539-96. Gupta JS, Gupta SD, Prashar S (1968):Oculo-auricular-cranial dyspla- Warkany J, Bofinger MK, Benton C (1973): Median facial cleft syndrome in half-sisters. Dilemmas in genetic counseling. Teratology sia. Br J Ophthalmol 52:346-347. 8:273-286. Hartsfield J K Jr. Bixler D. DeMver WE (1984): Svndrome identification case report 119:hyperte1o“rism associated i i t h holoprosenceph- Zunin C (1955):L’ipertelorismo di Greig e suoi rapporti con le syndromi di disostosi craniche et facialo. Minerva Pediatr 7:71-79. aly and ectrodactyly. J Clin Dysmorphol 2:27-31.
Acromelic F’rontonasal “Dysplasia”:Further Delineation of a Subtype With Brain Malformation and Polydactyly (Toriello Syndrome) Alain Verloes, Yves Gillerot, Elisabeth Walczak, Lionel Van Maldergem, and Lucien Koulischer Centre for Human Genetics, L 2 e University, (A.V.,L.K.). Institute for Morphologic Pathology, Loverval (Y.G.; L.V.M.), and Clinique Saint Vincent de Paul, Rocourt (E.W.),Belgium
We report on a stillborn boy with frontonasal malformation (Sedano-Jirasek type D-DeMyer type I), associated with encephalocoele, occipital meningocele and preaxial polydactyly of the feet. This form of frontonasal dysplasia was documented previously in a few other cases with various combinations of postaxial polydactyly, tibia1 hypoplasia, epibulbar dermoid, occipital encephalocoele, corpus callosum agenesis and Dandy-Walker malformation. Most cases are sporadic. KEY WORDS acrocallosal syndrome, encephalocoele, frontonasal dysplasia, MCA syndrome, preaxial polydactyly. INTRODUCTION Frontonasal abnormalities have been reported for over a century. About 70 cases were collected by Sedano et al. in 1970. Recently, a comprehensive review was given in “Syndromes of the Head and Neck” [Gorlin et al., 19901. We report on a severely affected child where this “classical” malformation is associated with limb anomalies, and we review the previously reported cases. CLINICAL REPORT Our propositus is a 31-week-old male fetus born to non-consanguineous Caucasian parents. The father was 33 years old. His G2POAl wife was 28 years old. For suspected hypothyroidism, she underwent 9 9 T ~ scintigraphy (3 Years >7
Ia D
N N L + R N N N Y Y Y
N R N N N N Y N Y Y
Y
Edwards Warkanv e t al. et al.
N L + R N N N Y Y Y IR Y
2,900
M F Months >5 Months >9 Months
Neidich Toriello et al. [19871 119881 Our case
N IR
Ia D N N N Y N L + R N N N N N N IR
2,500
3,740
F
F
M
4
2
2
N
Ia D Y Y Y
Ia D
N L + R N R L + R Y N N Y Y
Y R N N
Ia D N N N
117 216 1/5 214 218
Y L+R6/8 N 018 N 218 N 118 N 317 N 418 N 217
N N Y
IR
3,650
1,770
M 3:4 Stillbirths
Months Months Months Fatherlmother age L
=
Left; R = Right; Y
=
40130 Present; N = Absent; IR
?I25 =
?I14
?I19
?I34
?I?
33128
irrelevant.
Derocque [1908]. Toriello et al. [1986] were the first to treat this clinical phenotype as a distinct entity. Their opinion was followed by Gorlin et al. [1990] and Cohen [19901. We suggest the term acromelicFND. Brain anomalies are common but inconstant findings in this condition. Mental retardation seems the rule among the surviving children. This high prevalence of cerebral malformation or dysfunction contrasts sharply with the usually good mental prognosis of individuals with non-syndromal FND [DeMyer, 19671. Epibulbar dermoids are frequent in acromelic FND but have been observed in FND patients without polydactyly [Gupta et al., 1968; Fontaine et al., 1983, patient 11. Some clinical geneticists would consider acromelic FND the end of the “clinical spectrum’’ of FND. However, presence of acral anomalies implies that a t least 2 developmental field defects are involved. From a pathogenetic point of view, this could mean that the dysmorphogenetic process involved in acromelic FND is different, or more complex, than in non-syndromal FND, and justifies its delineation as a separate entity. Differential diagnosis of acromelic FND is listed in Table 111. The differentiation from acrocallosal syndrome is difficult when agenesis of the corpus callosum (ACC) is present, as both syndromes, in their most severe forms, are phenotypically very close: Schinzel [19871stated that the children reported by Toriello could be a severe example of acrocallosal syndrome; this suggestion was accepted by Toriello herself [19871 but not by Gorlin et al. [19901. Although severe central nervous system midline involvement and polydactyly are observed in acromelicFND and acrocallosal syndrome, the latter never shows severe median craniofacial involvement, and coexistence of both phenotypes within a sibship was not observed. It must be stressed that ACC was
observed in rare cases of non-syndromal FND [DeMyer, 1967, patients 2 and 13; Fontaine et al., 1983, patients 1,3,4]. In Fontaine’s report ACC was associated twice with Dandy-Walker malformation. In Warkany’s report, one of the half-sisters with FND had normal limbs and ACC, the other had FND, polydactyly,and normal brain (except for an area of porencephaly). Most cases of acromelicFND are sporadicbut parental consanguinity and occurrence in identical twins have been documented [unpublished cases quoted by Gorlin
TABLE 111. Differential Diagnosis of Cerebrofrontonasomelic Dysplasia. Syndromes With Frontonasal Malformation and Abnormal Limbs Acrocallosal syndrome Acrofrontofacionasal dysostosis type 1 Acrofrontofacionasal dysostosis type 2 Brachycephalofrontonasal dysplasia Carpenter-Hunter syndrome Craniofrontonasal dysplasia Hypertelorism-colobomaACC-hypoplastic thumbs syndrome Greig acrocephalopolysyndactyly Hartsfield syndrome Hypothalamic hamartomafrontonasal dysplasia syndrome Pallister-Hall syndrome Thurston median cleft lip/ nose-postaxial polydactyly W svndrome
(M.I.M. 200990) (M.I.M. 201180) Richieri-Costa et al. [19891 Teebi [19871 Carpenter and Hunter [19821 (M.I.M. 304110) FranGois et al. [19731 (M.I.M. 175700) Hartsfield e t al. [19841 Hennekam et al. [19861 (M.I.M. 146510) Thurston [19091 Pallister et al. [19741
Acromelic Frontonasal Dysplasia
et al., 19901.There is no simple genetic explanation for the half-sisters reported by Warkany et al. [19731.Autosoma1 dominant inheritance, with lack of penetrance or germinal mosaicism in the mother, or a teratogenic environmental factor was discussed by the authors, but a single father was not totally ruled out, as paternity testing could not be done.
183
Hennekam RCM, Beemer FA, Ekanka VM, Van Ketel BA, Kramer PPG (1986):Congenital hypothalamic hamartoblastoma associated with severe midline defect: a developmental field defect. Am J Genet Suppl. 2:45-52. McKusick VA, Francomano CA, Antonotakis SE (1990): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes.” 9th Ed. Baltimore: The Johns Hopkins University Press. Neidich JA, Whitaker LA, Zakai EH (1988). Frontonasal malformation. Two new syndromes? Am J Med Genet 1988 Suppl. 4:202-203. REFERENCES Oldfield M (1937):An encephaloceleassociated with hypertelorism and cleft palate. Br J Surg 25:757-764. Bougon, Derocque (1908): Fissure mkdiane de la face. Rev Orthop Pallister PD, Herrmann J, Spranger JW, Gorlin RJ, Langer LO, Opitz 9:219-224. JM (1974): Studies on malformation in man XXVIII. The W synCalli LJ (1971): Ocular hypertelorism and nasal agenesis (midface drome. In D. Bergsma (ed.), “Malformation Syndromes.” Internasyndrome) with limb anomalies. In D. Bergsma (ed.) “The Third tional Medical Book Corp., New York. BD:OAS X (7):51-60. Conference on the clinical Delineation of Birth Defects. Part X I Orofacial Structures”. Williams and Wilkins, Baltimore. BD:OAS Prescott KE, Sheridan-Pereira M, Manchester DK, Eilers B, Hall BD (1989):The median facial clefthkeletal syndrome (frontonasal dysVII (7):268. plasia): a distinct subgroup with nasal agenesis, tibia1 aplasia, Carpenter BF, Hunter AGW (1982):Micromelia, polysyndactyly, mulhallucal polydactyly and mental retardation. Am J Hum Genet 45 tiple malformations, and fragile bones in a stillborn child. J Med (suppl.):A59 (Abstract). Genet 19:311. Richieri-Costa A, Montagnoli L, Kamiya TY (1989):Autosomal recesCohen MM Jr (1990):Selected clinical research involving the central sive acro-fronto-facio-nasal dysostosis associated with genitourinnervous system. J Craniof Genet Dev Biol 10:215-238. ary anomalies. Am J Med Genet 33:121-124. DeMyer W (1967):The median cleft face syndrome. Differential diagSchinzel A (1987): New and old syndromes. Am J Med Genet 32:318. nosis of cranium bifidum occultum, hypertelorism, and median cleft Sedano HO, Cohen MM Jr, Jiritsek J , Gorlin R J (1970): Frontonasal nose, lip, and palate. Neurology 17:961-971. dysplasia. J Pediatr 76906-913. Edwards WC, Askew W, Weisskopf B (1971): Median cleft face synTeebi AS (1987):New autosomal dominant syndrome resembling cranidrome. Am J Ophthalmol 72:202-205. ofrontonasal dysplasia. Am J Med Genet 28:581-592. Fontaine G, Walbaum R, Poupard B, Bonte C, Dhellemans P, Maquet E, Ythier H, Stevenard C (1983):La dysplasie fronto-nasale (it propos Thurston E (1909): A case of median harelip associated with other malformations. Lancet 2:996. de quatre observations). J G6net Hum 31:351-365. Francois J , Eggermont E, Evens L, Logghe N, De Bock F (1973): Toriello HV (1987):Response to new and old syndromes, by A. Schinzel. Am J Med Genet 32:319. Agenesis of the corpus callosum in the median facial cleft syndrome and associated ocular malformations. Am J Ophthalmol 76:241- Toriello HV, Radecki LL, Sharda J , Looyenga D, Mann R (1986):Fron245. tonasal “dysplasia,” cerebral anomalies, and polydactyly: report of Gorlin RI,Cohen MM Jr, Levin S (1990):“Syndromes of the Head and a new syndrome and discussion from a developmental field perspecNeck.” 3rd Ed. Oxford: Oxford University Press. tive. Am J Med Genet Suppl 2539-96. Gupta JS, Gupta SD, Prashar S (1968):Oculo-auricular-cranial dyspla- Warkany J, Bofinger MK, Benton C (1973): Median facial cleft syndrome in half-sisters. Dilemmas in genetic counseling. Teratology sia. Br J Ophthalmol 52:346-347. 8:273-286. Hartsfield J K Jr. Bixler D. DeMver WE (1984): Svndrome identification case report 119:hyperte1o“rism associated i i t h holoprosenceph- Zunin C (1955):L’ipertelorismo di Greig e suoi rapporti con le syndromi di disostosi craniche et facialo. Minerva Pediatr 7:71-79. aly and ectrodactyly. J Clin Dysmorphol 2:27-31.
