American Journal of Medical Genetics 39:ll-12 (1991)
Brief Clinical Report
Holoprosencephaly in a Newborn Girl With 46,XX,i( 18s) Nancy B. Spinner, Deborah L. Eunpu, Jocelyn R. Austria, and Peter Mamunes Department of Pediatrics, Albert Einstein Medical Center, Philadelphia, Pennsylvania (N.B.S., D.L.E., J.R.A., P.M.) and Department of Pediatrics, Nazareth Hospital, Philadelphia, Pennsylvania (J.R.A.)
We report on a newborn girl with holoprosencephaly, microcephaly, absent right radius, and other anomalies with an 46,XX,i(lSq) chromosome constitution. This is the first report of an i(18q) in syndromal alobar holoprosencephaly. KEY WORDS: holoprosencephaly, isochromosome, i(18q) INTRODUCTION Holoprosencephaly is a causally heterogeneous disorder. It has been associated with teratogenic agents and genetic factors, which have been reported as autosomal dominant, autosomal recessive, and chromosomal. Among chromosome abnormalities associated with holoprosencephaly, aberrations of chromosome 13 and 18 are most common [Muenke, 19891. We report on a patient with holoprosencephaly and a 46,XX,i(18q) chromosome constitution. CLINICAL REPORT Abnormalities in the fetus were first detected on ultrasonography at 41 weeks of gestation. The ultrasound study was performed because of uterine size too small for dates. The studies showed microcephaly, closely set eyes, a proboscis in place of a nose, and a large cystic mass in the skull. The proband was delivered a t 42 weeks of gestation and at birth the head was noted to be small, with a 4 cm long tubular proboscis present between 2 closely set, microphthalmic eyes. Birth weight was 1.97 kg (less than the 5th centile), length was 43.25 cm (less than the 5th centile), and head circumference was 30.5 cm (less than the 2nd centile). There was a large confluent single fontanel and a protruding left ear. The neck was short and webbed. The upper limbs were abnormal with clinically apparent severe radial hypoplasia on the
Received for publication February 9,1990; revision received May 21, 1990. Address reprint requests to Nancy B. Spinner, Ph.D., Department of Pediatrics, Korman 317, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia, PA 19141.
0 1991 Wiley-Liss, Inc.
right, and hypoplastic thumbs, 8 fingertip arches, and a right simian crease. Radiographs showed a n absent radius on the right. There was a heart beat, but only gasping respirations and the patient died 1 hr after birth. In addition to the external malformations described, postmortem examination showed a bicornuate uterus. All other internal organs were normally formed, except for the brain. The brain weighed only 90 g; the front half of the cerebral hemispheres was present with no fissure between the hemispheres. Also, there was a single ventricle, confirming the diagnosis of alobar holoprosencephaly. Posterior to the cerebral hemispheres was a large fluid filled cyst measuring a t least 7 cm in diameter. The family history was unremarkable for consanguinity and for congenital malformations. At the time of birth of this child, the mother was 25 and the father was 27 years old.
CYTOGENETIC STUDIES Chromosome analysis was performed on PHA-stimulated lymphocytes obtained a t birth and on fibroblasts obtained from the pleural lining at autopsy using standard trypsin-Giemsa banding techniques. All cells studied demonstrated a 46,XX,i(18q) chromosome constitution (Fig. 1). Parental chromosomes were normal. DISCUSSION Holoprosencephaly has previously been associated with a variety of chromosome abnormalities, with structural and numerical aberrations of chromosomes 13 and 18 being the most frequent [Muenke et al, 19891. Such abnormalities of chromosome 18 have included trisomy [Gulotta et al., 19811, ring chromosome [Dumars et al., 1970; Yanoff et al., 1970; Cohen et al., 19721, and deletion of 18p [Lurie and Lazjuk, 1972; Muenke et al., 19881. Patients with a n i(18q) are rendered trisomic for 18q and monosomic for 18p; therefore a n association between i(18q) and holoprosencephaly might be expected. However, of 9 patients reported in the literature with pure i(18q) [Bass et al., 1979; Kleczkowska et al., 1986; Ieshima et al., 1985; Kruger et al., 1987; RosterIskenius et al., 1984; Surana et al., 1973; Rodiere et al., 1977; Wiswell et al., 19861, none has had alobar holoprosencephaly. Roster-Iskenius et al. [1984] described a fetus a t 20 weeks gestation with hypoplasia of both
12
Spinner et al.
119841suggests a CT or MRI scan should be performed in patients with i(18q) to look for cleavage defects of the brain. Conversely, i(18q) is added to the list of cytogenetic abnormalities associated with holoprosencephaly.
REFERENCES
18
iI18ql
Fig. 1. Partial karyotype of the proposita demonstrating the normal 18 and the i(18q).
olfactory tracts and a defect of the crista galli ethmoidalis, a milder form of the abnormal cleavage disorder of the brain leading to holoprosencephaly. Their patient was also the only one of the 9 patients with a n i(18q) to demonstrate radial anomalies, observed in our patient. The finding of 2/10 patients with i(18q) and some form of the holoprosencephaly sequence is consistent with the finding of 10%ofpatients with deletion 18p having holoprosencephaly [Cohen, 19891. Review of the phenotypic findings of 10 published cases of i(18q) (including the present case) does not show a definitive pattern of malformations associated with this cytogenetic abnormality. Eight of the 10 patients were liveborn (2 were identified prenatally and the pregnancies were terminated) and of these, 7 died neonatally and one patient was studied a t age 7 years [Surana et al., 19731. Manifestations shared by more than 2 of the patients included 6/10 with a short webbed neck, 3/10 with a prominent occiput, 8/10 with apparently low-set and/ or malformed ears, 5110 with micrognathia, 3/10 with widely spaced nipples, 4/10 with overlapping digits, 4110 with cardiac abnormalities, and 4/10 with genital abnormalities. Genital abnormalities included 2 with cryptorchidism, 1 with hypoplastic external genitalia, and our case with bicornuate uterus. The association of holoprosencephaly in our patient and the finding of hypoplastic olfactory tracts (arhinencephaly) in the patient studied by Roster-Iskenius et al.
Bass HN, Sparkes RS, Miller AA (1979): Features of trisomy 18 and 18p- syndromes in an infant with 46,XX,i(18q). Clin Genet 16:163-68. Cohen MM, Storm DF, Capraro VJ (1972):A ring chromosome (no. 18) in a cyclops. Clin Genet 3:249-252. Cohen MM (1989):Perspectives on holoprosencephaly: Part 111. Spectra, distinctions, continuities, and discontinuities. Am J Med Genet 35:271-288. Dumars KW, Carnahan LG, Barrett RV (1970): Median facial cleft associated with ring E chromosome. J Med Genet 7:86-90. Froster-Iskenius U, Coerdt W, Rehder H, Schwinger E (1984): Isochromosome 18q with karyotype 46,XX,i(18q).Cytogenetics and pathology. Clin Genet 26:549-554. Gulotta F, Rehder H, Gropp A (1981): Descriptive neuropathology of chromosomal disorders in man. Hum Genet 57:337-344. Ieshima A, Takashima S, Takada K, Akamatsu Y, Ohtani K, Ando G (1985): Clinicopathological study in a female infant with 46,XXi(18q)showing mixed features of both trisomy 18 and monosomy 18p. Jpn J Hum Genet 30:219-226. Kleczkowska A, Fryns JP, Buttiens M, de Bisschop F, Emmery L, Van den Berghe H 11986): Trisomy (18q)and tetrasomy ( 1 8 ~resulting ) from isochromosome formation. Clin Genet 30:503-508. Kruger, G, Gotz J , Dunker, H, Pelz L (1987):Isochromosome (18q) in siblings. Clin Genet 32:249-253. Lurie IW, Lazjuk GI (1972): Partial monosomies 18. Review of cytogenetical and phenotypic variants. Humangenetick 15:203-333. Muenke M, Page DC, Brown LG, Armson A, Zackai EH, Mennuti M, Emanuel BS (1988):Molecular detection of a Ypil8 translocation in a 45,X holoprosencephalic male. Hum Genet 80:219-223. Muenke M (1989): Invited Editorial Comment: Clinical, cytogenetic and molecular approaches to the genetic heterogeneity of holoprosencephaly. Am J Med Genet 34~237-345. Rodiere M, Donadio D, Emberger JM (1977): Isochromosome 18: i(18q). Ann Pediatr 24:611-616. Surana RB, McKendry JB, Bailey JD, Conen PE (1973): Isochromosome long arm 18. Am J Hum Genet 25:77A. Wiswell TE, Edwards RG (1986): Preparation of the isochromosome trisomy 18 syndrome in a n infant with the Robin Anomalad. Hawaii Med J 45:126-128. Yanoff M, Rorke LB, Niederer BS (1970): Ocular and cerebral abnormalities in chromosome 18 deletion defect. Am J Ophthalmol 70:391-402.
Brief Clinical Report
Holoprosencephaly in a Newborn Girl With 46,XX,i( 18s) Nancy B. Spinner, Deborah L. Eunpu, Jocelyn R. Austria, and Peter Mamunes Department of Pediatrics, Albert Einstein Medical Center, Philadelphia, Pennsylvania (N.B.S., D.L.E., J.R.A., P.M.) and Department of Pediatrics, Nazareth Hospital, Philadelphia, Pennsylvania (J.R.A.)
We report on a newborn girl with holoprosencephaly, microcephaly, absent right radius, and other anomalies with an 46,XX,i(lSq) chromosome constitution. This is the first report of an i(18q) in syndromal alobar holoprosencephaly. KEY WORDS: holoprosencephaly, isochromosome, i(18q) INTRODUCTION Holoprosencephaly is a causally heterogeneous disorder. It has been associated with teratogenic agents and genetic factors, which have been reported as autosomal dominant, autosomal recessive, and chromosomal. Among chromosome abnormalities associated with holoprosencephaly, aberrations of chromosome 13 and 18 are most common [Muenke, 19891. We report on a patient with holoprosencephaly and a 46,XX,i(18q) chromosome constitution. CLINICAL REPORT Abnormalities in the fetus were first detected on ultrasonography at 41 weeks of gestation. The ultrasound study was performed because of uterine size too small for dates. The studies showed microcephaly, closely set eyes, a proboscis in place of a nose, and a large cystic mass in the skull. The proband was delivered a t 42 weeks of gestation and at birth the head was noted to be small, with a 4 cm long tubular proboscis present between 2 closely set, microphthalmic eyes. Birth weight was 1.97 kg (less than the 5th centile), length was 43.25 cm (less than the 5th centile), and head circumference was 30.5 cm (less than the 2nd centile). There was a large confluent single fontanel and a protruding left ear. The neck was short and webbed. The upper limbs were abnormal with clinically apparent severe radial hypoplasia on the
Received for publication February 9,1990; revision received May 21, 1990. Address reprint requests to Nancy B. Spinner, Ph.D., Department of Pediatrics, Korman 317, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia, PA 19141.
0 1991 Wiley-Liss, Inc.
right, and hypoplastic thumbs, 8 fingertip arches, and a right simian crease. Radiographs showed a n absent radius on the right. There was a heart beat, but only gasping respirations and the patient died 1 hr after birth. In addition to the external malformations described, postmortem examination showed a bicornuate uterus. All other internal organs were normally formed, except for the brain. The brain weighed only 90 g; the front half of the cerebral hemispheres was present with no fissure between the hemispheres. Also, there was a single ventricle, confirming the diagnosis of alobar holoprosencephaly. Posterior to the cerebral hemispheres was a large fluid filled cyst measuring a t least 7 cm in diameter. The family history was unremarkable for consanguinity and for congenital malformations. At the time of birth of this child, the mother was 25 and the father was 27 years old.
CYTOGENETIC STUDIES Chromosome analysis was performed on PHA-stimulated lymphocytes obtained a t birth and on fibroblasts obtained from the pleural lining at autopsy using standard trypsin-Giemsa banding techniques. All cells studied demonstrated a 46,XX,i(18q) chromosome constitution (Fig. 1). Parental chromosomes were normal. DISCUSSION Holoprosencephaly has previously been associated with a variety of chromosome abnormalities, with structural and numerical aberrations of chromosomes 13 and 18 being the most frequent [Muenke et al, 19891. Such abnormalities of chromosome 18 have included trisomy [Gulotta et al., 19811, ring chromosome [Dumars et al., 1970; Yanoff et al., 1970; Cohen et al., 19721, and deletion of 18p [Lurie and Lazjuk, 1972; Muenke et al., 19881. Patients with a n i(18q) are rendered trisomic for 18q and monosomic for 18p; therefore a n association between i(18q) and holoprosencephaly might be expected. However, of 9 patients reported in the literature with pure i(18q) [Bass et al., 1979; Kleczkowska et al., 1986; Ieshima et al., 1985; Kruger et al., 1987; RosterIskenius et al., 1984; Surana et al., 1973; Rodiere et al., 1977; Wiswell et al., 19861, none has had alobar holoprosencephaly. Roster-Iskenius et al. [1984] described a fetus a t 20 weeks gestation with hypoplasia of both
12
Spinner et al.
119841suggests a CT or MRI scan should be performed in patients with i(18q) to look for cleavage defects of the brain. Conversely, i(18q) is added to the list of cytogenetic abnormalities associated with holoprosencephaly.
REFERENCES
18
iI18ql
Fig. 1. Partial karyotype of the proposita demonstrating the normal 18 and the i(18q).
olfactory tracts and a defect of the crista galli ethmoidalis, a milder form of the abnormal cleavage disorder of the brain leading to holoprosencephaly. Their patient was also the only one of the 9 patients with a n i(18q) to demonstrate radial anomalies, observed in our patient. The finding of 2/10 patients with i(18q) and some form of the holoprosencephaly sequence is consistent with the finding of 10%ofpatients with deletion 18p having holoprosencephaly [Cohen, 19891. Review of the phenotypic findings of 10 published cases of i(18q) (including the present case) does not show a definitive pattern of malformations associated with this cytogenetic abnormality. Eight of the 10 patients were liveborn (2 were identified prenatally and the pregnancies were terminated) and of these, 7 died neonatally and one patient was studied a t age 7 years [Surana et al., 19731. Manifestations shared by more than 2 of the patients included 6/10 with a short webbed neck, 3/10 with a prominent occiput, 8/10 with apparently low-set and/ or malformed ears, 5110 with micrognathia, 3/10 with widely spaced nipples, 4/10 with overlapping digits, 4110 with cardiac abnormalities, and 4/10 with genital abnormalities. Genital abnormalities included 2 with cryptorchidism, 1 with hypoplastic external genitalia, and our case with bicornuate uterus. The association of holoprosencephaly in our patient and the finding of hypoplastic olfactory tracts (arhinencephaly) in the patient studied by Roster-Iskenius et al.
Bass HN, Sparkes RS, Miller AA (1979): Features of trisomy 18 and 18p- syndromes in an infant with 46,XX,i(18q). Clin Genet 16:163-68. Cohen MM, Storm DF, Capraro VJ (1972):A ring chromosome (no. 18) in a cyclops. Clin Genet 3:249-252. Cohen MM (1989):Perspectives on holoprosencephaly: Part 111. Spectra, distinctions, continuities, and discontinuities. Am J Med Genet 35:271-288. Dumars KW, Carnahan LG, Barrett RV (1970): Median facial cleft associated with ring E chromosome. J Med Genet 7:86-90. Froster-Iskenius U, Coerdt W, Rehder H, Schwinger E (1984): Isochromosome 18q with karyotype 46,XX,i(18q).Cytogenetics and pathology. Clin Genet 26:549-554. Gulotta F, Rehder H, Gropp A (1981): Descriptive neuropathology of chromosomal disorders in man. Hum Genet 57:337-344. Ieshima A, Takashima S, Takada K, Akamatsu Y, Ohtani K, Ando G (1985): Clinicopathological study in a female infant with 46,XXi(18q)showing mixed features of both trisomy 18 and monosomy 18p. Jpn J Hum Genet 30:219-226. Kleczkowska A, Fryns JP, Buttiens M, de Bisschop F, Emmery L, Van den Berghe H 11986): Trisomy (18q)and tetrasomy ( 1 8 ~resulting ) from isochromosome formation. Clin Genet 30:503-508. Kruger, G, Gotz J , Dunker, H, Pelz L (1987):Isochromosome (18q) in siblings. Clin Genet 32:249-253. Lurie IW, Lazjuk GI (1972): Partial monosomies 18. Review of cytogenetical and phenotypic variants. Humangenetick 15:203-333. Muenke M, Page DC, Brown LG, Armson A, Zackai EH, Mennuti M, Emanuel BS (1988):Molecular detection of a Ypil8 translocation in a 45,X holoprosencephalic male. Hum Genet 80:219-223. Muenke M (1989): Invited Editorial Comment: Clinical, cytogenetic and molecular approaches to the genetic heterogeneity of holoprosencephaly. Am J Med Genet 34~237-345. Rodiere M, Donadio D, Emberger JM (1977): Isochromosome 18: i(18q). Ann Pediatr 24:611-616. Surana RB, McKendry JB, Bailey JD, Conen PE (1973): Isochromosome long arm 18. Am J Hum Genet 25:77A. Wiswell TE, Edwards RG (1986): Preparation of the isochromosome trisomy 18 syndrome in a n infant with the Robin Anomalad. Hawaii Med J 45:126-128. Yanoff M, Rorke LB, Niederer BS (1970): Ocular and cerebral abnormalities in chromosome 18 deletion defect. Am J Ophthalmol 70:391-402.
