Clinical Genetics 1979: 15: 203-206
Letters to the Editors Familial holoprosencep haly K e y words: Familial; holoprosencephaly.
Sirs, Martin et al. (1977) recently reported an autosomal dominant midline facial clefting syndrome. The authors made the point that, despite the resemblance to familial holoprosencephaly, the disorder seems to be a previously undescribed distinct entity. We disagree with this statement. Three other families in which a very similar condition appears to be segregating have appeared in the literature. DeMyer et al. (1963) described two sisters with holoprosencephaly associated with median cleft lip and palate. A paternal aunt may also have been affected. Dallaire et al. (1971) described several affected persons in different sibships of a French-Canadian family. Cohen & Gorlin (1969) described a sibship in which one sib had cyclopia and four others had cleft lip and/or cleft palate. At the Birth Defects Conference in Memphis, Tennessee in June 1977, an additional family was described (Cant6 et al. 1977). The family, of Mexican origin, was ascertained when the proposita (aged 4 months) presented with severe microcephaly, median cleft lip and palate, ocular hypotelorism, severe frontonasal hypoplasia and bilateral choroidal coloboma. Family studies revealed an 8-yearold brother who has microcephaly, hypotelorism, median cleft lip and palate and frontonasal hypoplasia. Five other deceased children had, by history, a similar disorder varying from small head, hypotelorism and mongoloid slant of the palpebral fissures to a form of the disorder as severe as in the
proposita. The mother, who has two normal children, showed microcephaly (OFC 49.5 cm), hypotelorism and very small upper central incisors. Both the mother and the 8year-old brother showed mild mental deficiency. No other relatives were found to be affected. The diagnosis of holoprosencephaly of varying degrees in each affected individual was made. Although additional cases will be needed to define this entity, common clinical findings in these families include mental retardation, microcephaly, craniofacial anomalies including cleft lip and palate, hypotelorism and mongoloid slant of the palpebral fissures, and anomalies of the foot and spine. Incomplete penetrance and variable expressivity are features of this condition. However, this is expected in view of the autosomal inheritance pattern which this disorder seems to follow. X-linked inheritance is ruled out by father-son transmission (Martin et al. 1977). It is interesting, however, that some females seem to be more severely affected than the males in these families. The possibility then exists that these five families represent variable expression of the same disorder. Perhaps the sporadic occurrences of holoprosencephaly actually represent new mutations at the locus responsible for this familial phenotype. If true, a clinical investigation of 1st degree relatives of families in which holoprosencephaly has occurred should be carried out before genetic counseling is given. From the families
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reported by Martin et al. and Cantu et al., it appears that normal-appearing obligate heterozygotes can occur in the same family in which severely affected individuals exist. Fortunately this type of holoprosencephaly seems to be very rare, but genetic counselors must be aware of this possibility, Victor Escobar, DDS, MS Jose Maria Cantu, M.D. Addresses: Oral DiagnosislOral Medicine Dept. Health Sciences Center University of Louisville Dental School P.O. Box 35260 Louisville, K Y 40232 U.S.A. and Dirision de Genetica y Hematologia Unidad de Investigacion Biomedica d e Occidente instituto Mexican0 del Seguro Social Guadalajara, Jalisco, Mexico
Reply to Escobar and Cantti Sirs, Drs. Escobar and Cantu have questioned our belief that the kindred we reported (Martin et al. 1977) “. . . represents a previously unrecognized autosomal dominant syndrome . . .’’ Whereas controversies regarding the boundaires of syndromes are inevitable, we d o not believe the letter of Escobar & Cantti contributes additional information. We have already acknowledged the similarities between our kindred and those with familial holoprosencephaly (Dallaire et al. 1971) in our discussion. Moreover, the kindred reported by DeMeyer et al. (1963) is discussed in the paper by Dallaire; it was, therefore, not referenced separately in our report. The sibship described by Cohen & Gorlin (1969) was not included because of insufficient evidence of dominant segregation. The family of Cantu et al. (1977) requires formal publication for adequate evaluation.
Thus, we are still aware of n o families other than that reported by us in which similar cranial, facial and skeletal anomalies (notably clubfeet) coexist in a kindred characterized by: 1) dominant segregation, 2 ) affected males who reach adulthood and are severely retarded, 3) affected females who exhibit classic holoprosencephaly and die early in infancy, and 4) chronic constipation in all affected members. Additional features in the families specified by Escobar & Cantu include “convulsions” and coloboma. Such findings were not present in the kindred we described. Because midline craniofacial defects are etiologically heterogenous, it seems premature to group (“lump”) all cases of familial holoprosencephaly into a single syndrome, particularly if concurrence of associated anomalies is uncertain. If one does not appreciate heterogeneity, differences in the action of alleles at different loci, may fail to be elucidated. That is, mutations at one locus can certainly have pleiotropic effects; however, similar phenotypes can also be affected by mutations at different loci, particularly with regard to complex processes such as palate closure and diverticulation of the prosencephalon. Finally, irrespective of the question of syndrome classification, genetic counsellors must be cognizant of familial instances of midline craniofacial defects and the relatively high recurrence risk in such families. Alice 0. Martin, Ph.D. Address: Assistant Professor Department of Obstetrics and Gynecology Northwestern University Medical School Co-Director, Laboratory o f Human Genetics Northwestern Memorial Hospital Chicago, Illinois 60611, U.S.A.
References
cant^, J. M., R. Fragoso, D. Garcia-Cruz & J. Sinchez-Corona (1977). Dominant inheri-
Letters to the Editors Familial holoprosencep haly K e y words: Familial; holoprosencephaly.
Sirs, Martin et al. (1977) recently reported an autosomal dominant midline facial clefting syndrome. The authors made the point that, despite the resemblance to familial holoprosencephaly, the disorder seems to be a previously undescribed distinct entity. We disagree with this statement. Three other families in which a very similar condition appears to be segregating have appeared in the literature. DeMyer et al. (1963) described two sisters with holoprosencephaly associated with median cleft lip and palate. A paternal aunt may also have been affected. Dallaire et al. (1971) described several affected persons in different sibships of a French-Canadian family. Cohen & Gorlin (1969) described a sibship in which one sib had cyclopia and four others had cleft lip and/or cleft palate. At the Birth Defects Conference in Memphis, Tennessee in June 1977, an additional family was described (Cant6 et al. 1977). The family, of Mexican origin, was ascertained when the proposita (aged 4 months) presented with severe microcephaly, median cleft lip and palate, ocular hypotelorism, severe frontonasal hypoplasia and bilateral choroidal coloboma. Family studies revealed an 8-yearold brother who has microcephaly, hypotelorism, median cleft lip and palate and frontonasal hypoplasia. Five other deceased children had, by history, a similar disorder varying from small head, hypotelorism and mongoloid slant of the palpebral fissures to a form of the disorder as severe as in the
proposita. The mother, who has two normal children, showed microcephaly (OFC 49.5 cm), hypotelorism and very small upper central incisors. Both the mother and the 8year-old brother showed mild mental deficiency. No other relatives were found to be affected. The diagnosis of holoprosencephaly of varying degrees in each affected individual was made. Although additional cases will be needed to define this entity, common clinical findings in these families include mental retardation, microcephaly, craniofacial anomalies including cleft lip and palate, hypotelorism and mongoloid slant of the palpebral fissures, and anomalies of the foot and spine. Incomplete penetrance and variable expressivity are features of this condition. However, this is expected in view of the autosomal inheritance pattern which this disorder seems to follow. X-linked inheritance is ruled out by father-son transmission (Martin et al. 1977). It is interesting, however, that some females seem to be more severely affected than the males in these families. The possibility then exists that these five families represent variable expression of the same disorder. Perhaps the sporadic occurrences of holoprosencephaly actually represent new mutations at the locus responsible for this familial phenotype. If true, a clinical investigation of 1st degree relatives of families in which holoprosencephaly has occurred should be carried out before genetic counseling is given. From the families
204
LETTERS TO THE EDITORS
reported by Martin et al. and Cantu et al., it appears that normal-appearing obligate heterozygotes can occur in the same family in which severely affected individuals exist. Fortunately this type of holoprosencephaly seems to be very rare, but genetic counselors must be aware of this possibility, Victor Escobar, DDS, MS Jose Maria Cantu, M.D. Addresses: Oral DiagnosislOral Medicine Dept. Health Sciences Center University of Louisville Dental School P.O. Box 35260 Louisville, K Y 40232 U.S.A. and Dirision de Genetica y Hematologia Unidad de Investigacion Biomedica d e Occidente instituto Mexican0 del Seguro Social Guadalajara, Jalisco, Mexico
Reply to Escobar and Cantti Sirs, Drs. Escobar and Cantu have questioned our belief that the kindred we reported (Martin et al. 1977) “. . . represents a previously unrecognized autosomal dominant syndrome . . .’’ Whereas controversies regarding the boundaires of syndromes are inevitable, we d o not believe the letter of Escobar & Cantti contributes additional information. We have already acknowledged the similarities between our kindred and those with familial holoprosencephaly (Dallaire et al. 1971) in our discussion. Moreover, the kindred reported by DeMeyer et al. (1963) is discussed in the paper by Dallaire; it was, therefore, not referenced separately in our report. The sibship described by Cohen & Gorlin (1969) was not included because of insufficient evidence of dominant segregation. The family of Cantu et al. (1977) requires formal publication for adequate evaluation.
Thus, we are still aware of n o families other than that reported by us in which similar cranial, facial and skeletal anomalies (notably clubfeet) coexist in a kindred characterized by: 1) dominant segregation, 2 ) affected males who reach adulthood and are severely retarded, 3) affected females who exhibit classic holoprosencephaly and die early in infancy, and 4) chronic constipation in all affected members. Additional features in the families specified by Escobar & Cantu include “convulsions” and coloboma. Such findings were not present in the kindred we described. Because midline craniofacial defects are etiologically heterogenous, it seems premature to group (“lump”) all cases of familial holoprosencephaly into a single syndrome, particularly if concurrence of associated anomalies is uncertain. If one does not appreciate heterogeneity, differences in the action of alleles at different loci, may fail to be elucidated. That is, mutations at one locus can certainly have pleiotropic effects; however, similar phenotypes can also be affected by mutations at different loci, particularly with regard to complex processes such as palate closure and diverticulation of the prosencephalon. Finally, irrespective of the question of syndrome classification, genetic counsellors must be cognizant of familial instances of midline craniofacial defects and the relatively high recurrence risk in such families. Alice 0. Martin, Ph.D. Address: Assistant Professor Department of Obstetrics and Gynecology Northwestern University Medical School Co-Director, Laboratory o f Human Genetics Northwestern Memorial Hospital Chicago, Illinois 60611, U.S.A.
References
cant^, J. M., R. Fragoso, D. Garcia-Cruz & J. Sinchez-Corona (1977). Dominant inheri-
