American Journal of Medical Genetics 42122-126 (1992)
Thanatophoric Dysplasia in Monozygotic Twins Discordant for Cloverleaf Skull: Prenatal Diagnosis, Clinical and Pathological Findings ~
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Giovanni Corsello, Emiliano Maresi, Cinzia Rossi, Liborio Giuffre, and Ettore Cittadini Istituto Materno-Infantile (G.C.. C.R.. L.G.. E.C.) and Instituto di Anatomia Patologica (E.M.), University of Palermo, Palerrno, Italy We present male monozygotic twins with thanatophoric dysplasia (TD) type I concordant for long bone abnormalities and discordant for cloverleaf skull. The twins were the product of the second pregnancy of unrelated parents, with advanced paternal age. Prenatal diagnosis and postmortem examination showed severe rhizomelic shortness of limbs, bowing of the long bones with “telephone-receiver” femora in both twins, and cloverleaf skull and hydrocephalus in one of them. It is now acceptedthat most of cases of TD, such as in the present report, represent an autosomal dominant mutation with a high new mutations rate. KEY
WORDS: thanatophoric dysplasia, monozygotic twins, cloverleaf skull, bone dysplasia, autosomal dominantinheritance
INTRODUCTION Thanatophoric dysplasia (TD) is a sporadic bone dysplasia whose birth prevalence has been estimated from 0.28 to 0.60/10,000 [Stoll et al., 19891. A distinction between TD type I and TD type I1 has been made on the basis of milder deformities of long bones in TD type I1 [Spranger, 19891. Although familial occurrence suggests autosomal recessive inheritance [Bouvet et al., 1974; Connor et al., 19851, most cases are sporadic. TD is now considered an autosomal dominant condition with a high new mutations rate (MIM number 18760). TD has been reported in monozygotic twins [Sabry, 1974; Horton et al., 1983; Serville et al., 1984; Young et al., 19891, which is comReceived for publication November 28, 1990; revision received March 22, 1991. Address reprint requests to Giovanni Corsello, Cattedra di Patologia Neonatale, Instituto Materno Infantile Universita di Palerrno, Via Cardinaie Rampolla, l, 90142 Palerrno, Italy.
0 1992 Wiley-Liss, Inc.
patible with a new autosomal dominant mutation. Prenatal diagnosis of TD is possible within the first trimester of gestation by fetal ultrasound; severe shortness of long bones, a “telephone-receiver” shape of femora, and dysproportionate thorax with short ribs are the main findings. A cloverleaf skull, i.e., a severe form of craniosynostosis due to the premature closure of coronal, sagittal, and lambdoid sutures has been seen in TD I1 [Isaacson et al., 19831. We present monozygotic twins with prenatally diagnosed TD type I discordant for cloverleaf skull and hydrocephalus.
CLINICAL REPORT A 42-year-old healthy woman was admitted at 15 weeks of gestation for amniocentesis. Her 50-year-old husband and a 5-year-oldfirst child, a boy, were healthy. This pregnancy was reported uneventful. Routine ultrasound study showed the presence of 2 fetuses with rhizomelic shortness of limbs, whose length was below the 5th centile for age. Both fetuses had bowed femora. In one of them a cloverleaf skull was suspected because of an increase of biparietal diameter (Fig. 1); both fetuses showed hyperextension of the spine with hypoplastic short ribs. Polyhydramnios, a thin septum between the two amniotic sacs and a partial detachment of the membranes from the chorial plate were also noted. A second ultrasound scan performed at 16 weeks of gestation confirmed the previous findings and showed in one of the fetuses a dilatation of lateral cerebral ventricles. The pregnancy was terminated at 17 weeks without performing amniocentesis. Two male fetuses with a single placenta were delivered. Both fetuses had a flat face with prominent forehead, hypertelorism and depressed nasal bridge, severe rhyzomelic shortness of limbs, and narrow and hypoplastic thorax with cloverleaf skull in one of them (Fig. 2). The length of the twins was 16 cm (twin 1) and 15 cm (twin 2); the weight was 120 and 115 g, respectively. Roentgenograms showed severe shortness of long bones, bowing of the humeri and femora, which had a “telephone-receiver” appearance, and lateral expansion of temporal bones in one of them (Fig. 3a,b). Postmortem examination confirmed the severe shortness of the limbs with inversion of feet. n b u l a r
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Fig. 1. Ultrasound scan at 15 weeks of gestation. Note the lateral expansion of the cranium in one twin with the increase of biparietal diameter (left side). On the right side note the severe rhizomelic shortness of a lower limb in the other twin.
Fig. 3. Roentgenographic of the twins, (a) Note in both of them the shortness and bowing of the humeri and femora, the short ribs and platyspondyly. (b)Note lateral expansion of temporal bones due to mild cloverleaf skull in twin 1.
Fig. 2. Twin fetuses with thanatophoric dysplasia a t 17 weeks of gestation. Note severe rhizomelic shortness of limbs in both with bulging temporal bones in twin 1 on the left side.
bones were short and bowed; the femora showed a marked bowing with “telephone-receiver” appearance (Fig. 4a,b,c). The lower femoral epiphyses were abnormal with large ossificationcenter; the histological study performed on paraffin sections stained with H and E and Masson Trichrome methods [Sillence et al., 19791 showed a severely disturbed enchondral ossification with typical fibrous dysplasia. The growth plate was
partially disrupted by proliferating connective tissue from the perichondral ring and showed an irregular distribution of chondrocytes which appeared hypertrophic and arranged in a disordered way (Fig. 5a,b,c). The ribs were short and horizontal with typical pearshape thorax. One of the fetuses had lateral expansion of temporal bones and craniosynostosis of coronal and sagittal sutures, interpreted as a mild cloverleaf skull and hydrocephalus with temporal lobe abnormalities (Fig. 6a,b).
DISCUSSION TD in monozygotic twins is an undoubtedly rare event. Our report is the first observation of TD in monozygotic twins in the Italian population, where the birth prevalence of TD seems to be higher than in other countries [Camera and Mastroiacovo, 19821. These twins are strikindv similar to the twins described bv Horton et al. [1983],iisowith respect to the discordancefor cloverleaf
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Fig. 4. (a) Ultrasonographic, (b)roentgenographic, and ( c )postmortem aspect of “telephone-receiver’’ bowing of femora.
skull. Although the cloverleaf skull is usually described in cases of TD type 11,in which the abnormalities of long bones are milder and the femora do not have typical telephone-receiver appearance [Andersen, 19891,in the present case both fetuses were concordant for long bones abnormalities, which were typical of TD type I, but not concordant for cloverleaf skull, present in only one of them. In our cases the discordance for cloverleaf skull was evidenced by ultrasonographic prenatal diagnosis and confirmed by radiological and autopsy findings. Lack of concordance and mild aspect probably represented low gestational age (16weeks). In cloverleaf skull craniosynostosis the lateral expansion of the brain and skull can be explained by the increased size of temporal lobes due to obstruction of cerebral ventricles [Partington et al., 19711. Several abnormalities of the temporal lobes of the brain, such as microgyria, were described in newborn infants with TD [GoutiBreset al., 19711. The low gestational age of our twins did not allow the neuropathological evaluation of brain cellular migration defects; the hemispheric walls of man show rather smooth convexities at up to 4 or 5 months of gestational age [Warkany et al., 19811. Although the histological appearance of the growth plate is identical in TD cases with or without cloverleaf skull [Horton et al., 19831, the occurrence of cloverleaf skull has been related to a greater severity of the en-
chondral ossification abnormalities [Isaacson et al., 19831. The present case shows that changes in severity of enchondral ossifications can also occur in monozygotic twins concordant for TD. We think that the presence of the cloverleaf skull cannot be considered a differential manifestation between the two types of TD. Since its original description by Maroteaux et al. [ 19671, TD has been considered genetically heterogeneous. It is now accepted that most cases represent a fresh autosomal dominant mutation. The rate of new dominant mutations is considered to be in the order of 11.8 f 4.1 x per gene per generation [Connor et al., 19851,with a frequency in monozygotic twins which is relatively higher than in nontwin sibs [Partington et al., 1971; Bouvet et al., 19741. The high paternal age of our twin cases supports autosomal dominant mutation. Although TD is usually lethal a t birth, recent reports emphasize the occurrence of long survival with severe development delay, dramatic growth failure, and hydrocephalus [Stensvold and Hovland, 1986; Tonoki, 1987; MacDonald et al., 19891. Phenotypic and genetic analysis of these cases suggest that long survival does not seem to be related to genetic heterogeneity but rather on variability. Although we have no data on the vital parameters of the present twins, the severe abnormalities of the thorax do not seem to be compatible with a long survival.
Thanatophoric Dysplasia in Monozygotic Twins
Fig. 5. Appearance of the growth plate of the femur. Note severely disturbed enchondral ossification with fibrous dysplasia due to hypertrophy of the perichondral fibrotic ring which partially interrupts the growth plate (a, b). The chondrocytes are in a disorderly arrangement and hypertrophic;the resting cartilage appears normal (c). (a, c ) H and E stain; (b)Masson trichrome stain.
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Fig. 6 Brains of the twins, with hydrocephalus and temporal lobe abnormalities in twin 1, on the right.
REFERENCES Andersen PE (1989): Prevalence of lethal osteochondrodysplasias in Denmark. Am J Med Genet 32:484-489. Bouvet J-P, Maroteaux P, Feingold J (1974): Etude genetique du nanisme thanatophore. Ann &n& 17:181-188. Camera G, Mastroiacovo P (1982):Birth prevalence of skeletal dysplasias in the Italian Multicentric Monitoring System for Birth Defects. In Papadatos C.J., Bartsocas C.S. (eds):“Skeletal Dysplasias.” New York, Alan R Liss, pp 441-449. Connor JM, Connor RAC, Sweet EM, Gibson AAM, Patrick WJA, McNay MB, Redford DHA (1985): Lethal neonatal chondrodysplasias in the West ofscotland, 1970-1983, with a description of
a thanatophoric, dysplasia-like, autosomal recessive disorder, Glasgow variant. Am J Med Genet 22:243-253. Goutieres F, Aicardi J , Farkas-Bargeton E. (1971):Une malformation c6r6bral particuliere associee au nanisme thanatophore. Rev Neurol 125:435-440. Horton WA, Harris DJ, Collins DL (1983): Discordance for Kleeblattschadel anomaly in monozygotic twins with thanatophoric dysplasia. Am J Med Genet 15:97-101. Isaacson G, Blakemore KJ, Chervenak FA (1983):Thanatophoric dysplasia with cloverleaf skull. Am J Dis Child 137:896-898. MacDonald IM. Hunter AGW. MacLeod PM. MacMurrav SB (19891: Growth and development in thanatophoric dysplasia”. Am J Med Genet 33:508-512. Maroteaux P, Lamy M, Robert J-M (1967):Le nanisme thanatophore. Presse M6d 49:2519-2524. Partington MW, Gonzales-Crussi F, Khakee SG, Wollin DG (1971): Cloverleaf skull and thanatophoric dwarfism. Report of four cases, two in the same sibship. Arch Dis Child 46:656-664. Sabry A (1974): Thanatophoric dwarfism in triplets. Lancet ii:533. Serville F, Carles D, Maroteaux P (1984):Thanatophoric dysplasia of identical twins. Am J Med Genet 17:703-706. Sillence DO, Horton WA, Rimoin DL (1979):Morphological studies in the skeletal dysplasias. Am J Pathol 96:860-870. Spranger J 11989):Radiologic nosology of bone dysplasias. Am J Med Genet 34:96-104. Stensvold K, Ek J, Hovland AR (1986):An infant with thanatophoric dwarfism surviving 169 days. Clin Genet 29:157-159. Stoll C, Dott B, Roth M-P, Alembik Y (1989):Birth prevalence rates of skeletal dysplasias. Clin Genet 3588-92. Tonoki H (1987): A boy with thanatophoric dysplasia surviving 212 days. Clin Genet 30:415-416. Warkany J , Lemire RJ, Cohen MM (1981): “Mental Retardation and Congenital Malformations of the Central Nervous system.” Chicago: Year Book Medical Publishers, pp 200-210. Young ID, Pate1 I, Lamont AC (1989): Thanatophoric dysplasia in identical twins. J Med Genet 26:276-279.
Thanatophoric Dysplasia in Monozygotic Twins Discordant for Cloverleaf Skull: Prenatal Diagnosis, Clinical and Pathological Findings ~
~
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Giovanni Corsello, Emiliano Maresi, Cinzia Rossi, Liborio Giuffre, and Ettore Cittadini Istituto Materno-Infantile (G.C.. C.R.. L.G.. E.C.) and Instituto di Anatomia Patologica (E.M.), University of Palermo, Palerrno, Italy We present male monozygotic twins with thanatophoric dysplasia (TD) type I concordant for long bone abnormalities and discordant for cloverleaf skull. The twins were the product of the second pregnancy of unrelated parents, with advanced paternal age. Prenatal diagnosis and postmortem examination showed severe rhizomelic shortness of limbs, bowing of the long bones with “telephone-receiver” femora in both twins, and cloverleaf skull and hydrocephalus in one of them. It is now acceptedthat most of cases of TD, such as in the present report, represent an autosomal dominant mutation with a high new mutations rate. KEY
WORDS: thanatophoric dysplasia, monozygotic twins, cloverleaf skull, bone dysplasia, autosomal dominantinheritance
INTRODUCTION Thanatophoric dysplasia (TD) is a sporadic bone dysplasia whose birth prevalence has been estimated from 0.28 to 0.60/10,000 [Stoll et al., 19891. A distinction between TD type I and TD type I1 has been made on the basis of milder deformities of long bones in TD type I1 [Spranger, 19891. Although familial occurrence suggests autosomal recessive inheritance [Bouvet et al., 1974; Connor et al., 19851, most cases are sporadic. TD is now considered an autosomal dominant condition with a high new mutations rate (MIM number 18760). TD has been reported in monozygotic twins [Sabry, 1974; Horton et al., 1983; Serville et al., 1984; Young et al., 19891, which is comReceived for publication November 28, 1990; revision received March 22, 1991. Address reprint requests to Giovanni Corsello, Cattedra di Patologia Neonatale, Instituto Materno Infantile Universita di Palerrno, Via Cardinaie Rampolla, l, 90142 Palerrno, Italy.
0 1992 Wiley-Liss, Inc.
patible with a new autosomal dominant mutation. Prenatal diagnosis of TD is possible within the first trimester of gestation by fetal ultrasound; severe shortness of long bones, a “telephone-receiver” shape of femora, and dysproportionate thorax with short ribs are the main findings. A cloverleaf skull, i.e., a severe form of craniosynostosis due to the premature closure of coronal, sagittal, and lambdoid sutures has been seen in TD I1 [Isaacson et al., 19831. We present monozygotic twins with prenatally diagnosed TD type I discordant for cloverleaf skull and hydrocephalus.
CLINICAL REPORT A 42-year-old healthy woman was admitted at 15 weeks of gestation for amniocentesis. Her 50-year-old husband and a 5-year-oldfirst child, a boy, were healthy. This pregnancy was reported uneventful. Routine ultrasound study showed the presence of 2 fetuses with rhizomelic shortness of limbs, whose length was below the 5th centile for age. Both fetuses had bowed femora. In one of them a cloverleaf skull was suspected because of an increase of biparietal diameter (Fig. 1); both fetuses showed hyperextension of the spine with hypoplastic short ribs. Polyhydramnios, a thin septum between the two amniotic sacs and a partial detachment of the membranes from the chorial plate were also noted. A second ultrasound scan performed at 16 weeks of gestation confirmed the previous findings and showed in one of the fetuses a dilatation of lateral cerebral ventricles. The pregnancy was terminated at 17 weeks without performing amniocentesis. Two male fetuses with a single placenta were delivered. Both fetuses had a flat face with prominent forehead, hypertelorism and depressed nasal bridge, severe rhyzomelic shortness of limbs, and narrow and hypoplastic thorax with cloverleaf skull in one of them (Fig. 2). The length of the twins was 16 cm (twin 1) and 15 cm (twin 2); the weight was 120 and 115 g, respectively. Roentgenograms showed severe shortness of long bones, bowing of the humeri and femora, which had a “telephone-receiver” appearance, and lateral expansion of temporal bones in one of them (Fig. 3a,b). Postmortem examination confirmed the severe shortness of the limbs with inversion of feet. n b u l a r
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Fig. 1. Ultrasound scan at 15 weeks of gestation. Note the lateral expansion of the cranium in one twin with the increase of biparietal diameter (left side). On the right side note the severe rhizomelic shortness of a lower limb in the other twin.
Fig. 3. Roentgenographic of the twins, (a) Note in both of them the shortness and bowing of the humeri and femora, the short ribs and platyspondyly. (b)Note lateral expansion of temporal bones due to mild cloverleaf skull in twin 1.
Fig. 2. Twin fetuses with thanatophoric dysplasia a t 17 weeks of gestation. Note severe rhizomelic shortness of limbs in both with bulging temporal bones in twin 1 on the left side.
bones were short and bowed; the femora showed a marked bowing with “telephone-receiver” appearance (Fig. 4a,b,c). The lower femoral epiphyses were abnormal with large ossificationcenter; the histological study performed on paraffin sections stained with H and E and Masson Trichrome methods [Sillence et al., 19791 showed a severely disturbed enchondral ossification with typical fibrous dysplasia. The growth plate was
partially disrupted by proliferating connective tissue from the perichondral ring and showed an irregular distribution of chondrocytes which appeared hypertrophic and arranged in a disordered way (Fig. 5a,b,c). The ribs were short and horizontal with typical pearshape thorax. One of the fetuses had lateral expansion of temporal bones and craniosynostosis of coronal and sagittal sutures, interpreted as a mild cloverleaf skull and hydrocephalus with temporal lobe abnormalities (Fig. 6a,b).
DISCUSSION TD in monozygotic twins is an undoubtedly rare event. Our report is the first observation of TD in monozygotic twins in the Italian population, where the birth prevalence of TD seems to be higher than in other countries [Camera and Mastroiacovo, 19821. These twins are strikindv similar to the twins described bv Horton et al. [1983],iisowith respect to the discordancefor cloverleaf
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Fig. 4. (a) Ultrasonographic, (b)roentgenographic, and ( c )postmortem aspect of “telephone-receiver’’ bowing of femora.
skull. Although the cloverleaf skull is usually described in cases of TD type 11,in which the abnormalities of long bones are milder and the femora do not have typical telephone-receiver appearance [Andersen, 19891,in the present case both fetuses were concordant for long bones abnormalities, which were typical of TD type I, but not concordant for cloverleaf skull, present in only one of them. In our cases the discordance for cloverleaf skull was evidenced by ultrasonographic prenatal diagnosis and confirmed by radiological and autopsy findings. Lack of concordance and mild aspect probably represented low gestational age (16weeks). In cloverleaf skull craniosynostosis the lateral expansion of the brain and skull can be explained by the increased size of temporal lobes due to obstruction of cerebral ventricles [Partington et al., 19711. Several abnormalities of the temporal lobes of the brain, such as microgyria, were described in newborn infants with TD [GoutiBreset al., 19711. The low gestational age of our twins did not allow the neuropathological evaluation of brain cellular migration defects; the hemispheric walls of man show rather smooth convexities at up to 4 or 5 months of gestational age [Warkany et al., 19811. Although the histological appearance of the growth plate is identical in TD cases with or without cloverleaf skull [Horton et al., 19831, the occurrence of cloverleaf skull has been related to a greater severity of the en-
chondral ossification abnormalities [Isaacson et al., 19831. The present case shows that changes in severity of enchondral ossifications can also occur in monozygotic twins concordant for TD. We think that the presence of the cloverleaf skull cannot be considered a differential manifestation between the two types of TD. Since its original description by Maroteaux et al. [ 19671, TD has been considered genetically heterogeneous. It is now accepted that most cases represent a fresh autosomal dominant mutation. The rate of new dominant mutations is considered to be in the order of 11.8 f 4.1 x per gene per generation [Connor et al., 19851,with a frequency in monozygotic twins which is relatively higher than in nontwin sibs [Partington et al., 1971; Bouvet et al., 19741. The high paternal age of our twin cases supports autosomal dominant mutation. Although TD is usually lethal a t birth, recent reports emphasize the occurrence of long survival with severe development delay, dramatic growth failure, and hydrocephalus [Stensvold and Hovland, 1986; Tonoki, 1987; MacDonald et al., 19891. Phenotypic and genetic analysis of these cases suggest that long survival does not seem to be related to genetic heterogeneity but rather on variability. Although we have no data on the vital parameters of the present twins, the severe abnormalities of the thorax do not seem to be compatible with a long survival.
Thanatophoric Dysplasia in Monozygotic Twins
Fig. 5. Appearance of the growth plate of the femur. Note severely disturbed enchondral ossification with fibrous dysplasia due to hypertrophy of the perichondral fibrotic ring which partially interrupts the growth plate (a, b). The chondrocytes are in a disorderly arrangement and hypertrophic;the resting cartilage appears normal (c). (a, c ) H and E stain; (b)Masson trichrome stain.
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Fig. 6 Brains of the twins, with hydrocephalus and temporal lobe abnormalities in twin 1, on the right.
REFERENCES Andersen PE (1989): Prevalence of lethal osteochondrodysplasias in Denmark. Am J Med Genet 32:484-489. Bouvet J-P, Maroteaux P, Feingold J (1974): Etude genetique du nanisme thanatophore. Ann &n& 17:181-188. Camera G, Mastroiacovo P (1982):Birth prevalence of skeletal dysplasias in the Italian Multicentric Monitoring System for Birth Defects. In Papadatos C.J., Bartsocas C.S. (eds):“Skeletal Dysplasias.” New York, Alan R Liss, pp 441-449. Connor JM, Connor RAC, Sweet EM, Gibson AAM, Patrick WJA, McNay MB, Redford DHA (1985): Lethal neonatal chondrodysplasias in the West ofscotland, 1970-1983, with a description of
a thanatophoric, dysplasia-like, autosomal recessive disorder, Glasgow variant. Am J Med Genet 22:243-253. Goutieres F, Aicardi J , Farkas-Bargeton E. (1971):Une malformation c6r6bral particuliere associee au nanisme thanatophore. Rev Neurol 125:435-440. Horton WA, Harris DJ, Collins DL (1983): Discordance for Kleeblattschadel anomaly in monozygotic twins with thanatophoric dysplasia. Am J Med Genet 15:97-101. Isaacson G, Blakemore KJ, Chervenak FA (1983):Thanatophoric dysplasia with cloverleaf skull. Am J Dis Child 137:896-898. MacDonald IM. Hunter AGW. MacLeod PM. MacMurrav SB (19891: Growth and development in thanatophoric dysplasia”. Am J Med Genet 33:508-512. Maroteaux P, Lamy M, Robert J-M (1967):Le nanisme thanatophore. Presse M6d 49:2519-2524. Partington MW, Gonzales-Crussi F, Khakee SG, Wollin DG (1971): Cloverleaf skull and thanatophoric dwarfism. Report of four cases, two in the same sibship. Arch Dis Child 46:656-664. Sabry A (1974): Thanatophoric dwarfism in triplets. Lancet ii:533. Serville F, Carles D, Maroteaux P (1984):Thanatophoric dysplasia of identical twins. Am J Med Genet 17:703-706. Sillence DO, Horton WA, Rimoin DL (1979):Morphological studies in the skeletal dysplasias. Am J Pathol 96:860-870. Spranger J 11989):Radiologic nosology of bone dysplasias. Am J Med Genet 34:96-104. Stensvold K, Ek J, Hovland AR (1986):An infant with thanatophoric dwarfism surviving 169 days. Clin Genet 29:157-159. Stoll C, Dott B, Roth M-P, Alembik Y (1989):Birth prevalence rates of skeletal dysplasias. Clin Genet 3588-92. Tonoki H (1987): A boy with thanatophoric dysplasia surviving 212 days. Clin Genet 30:415-416. Warkany J , Lemire RJ, Cohen MM (1981): “Mental Retardation and Congenital Malformations of the Central Nervous system.” Chicago: Year Book Medical Publishers, pp 200-210. Young ID, Pate1 I, Lamont AC (1989): Thanatophoric dysplasia in identical twins. J Med Genet 26:276-279.
