American Journal of Medical Genetics 43:688-692 (1992)
Craniosynostosis Associated With Partial Duplication of 15q and Deletion of 2q _
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M.I. Van Allen, J. Siegel-Bartelt,A. Feigenbaum, and I.E. Teshima Department of Medical Genetics, University Hospital-Shaughnessy Site and the University of British Columbia, Vancouver, and Department of Genetics (A.F.,I.E.T.), The Hospital for Sick Children, Toronto, Ontario, Canada We report on an infant with multiple congenital anomaliesincluding complex craniosynostosis associated with an unbalanced karyotype, 46,XY, - 2, + der(2),t(2;15)(q37;q26)pat. The previous report of a child with cloverleaf skull and partial duplication of 15q2bqter and the Man-on-Mouse Homology map sug gests that a critical segment for synostosis of sutures may be in this region. o 1992 Wiley-Lies, Inc.
KEY WORDS: craniosynostosis, sagittal, metopic and lambdoidal synostosis, partial deletion 2q, partial duplication 15q, chromosomal deletion syndrome, M,XY, - 2, + der(2), t(2;15)(q37;q36)pat. INTRODUCTION Multiple causes of craniosynostosis have been reviewed comprehensively [Cohen, 1979, 1986; Gorlin et al., 19901. Chromosome abnormalities are a less frequent cause of craniosynostosis than monogenic disorders, but should be considered in the presence of associated malformations, growth, and developmental delay. The propositus of our study had duplication 15q and deletion 2q in a derivative chromosome 2 from a paternal balanced reciprocal translocation, 46,XY, t(2;15)(q37;q26).Although this represents a unique familial chromosome rearrangement [Borgaonkar, 1987, 1989;Schinzel, 19831,the previous report of a child with cloverlead skull and partial duplication of 15q is consistent with Pedersen’s [1976] hypothesis that this region may be important for suture formation. CLINICAL REPORT History The propositus was a term infant born by repeat cesarean section to a 23-year-oldG2P1 mother. There were Received for publication March 8, 1991; September 18, 1991. Address reprint requests to M. I. Van Allen, Department of Medical Genetics, University Hospital-Shaughnessy Site, 4500 Oak Street, Vancouver, British Columbia, Canada V6H 3N1.
0 1992 Wiley-Liss, Inc.
no reported pregnancy complications or medications. The birthweight was 3,350 g. There was reported amniotic fluid aspiration at birth and subsequent respiratory distress treated in a neonatal intensive care unit. Seizures developed at 10 hours postpartum and responded to treatment. Craniosynostosis was evident at the time of discharge in the neonatal period. The family immigrated to Canada from Nicaragua when the propositus was 3 112 months old. He was admitted to The Hospital for Sick Children at age 4 112 months for evaluation of craniosynostosis and other problems including poor weight gain with swallowing dysfunction and developmental delay. By 6 months he was smiling, fixed, and followed well, was able to bring his hands to midline and put his fist to his mouth. He could not roll over, sit unsupported, or reach for objects. He had limited vocalization.
PHYSICAL EXAMINATION At 6 months he had marked scaphocephaly, minor facial anomalies, hypotonia, and developmental delay (Fig. 1).The weight was 6.4 kg (lo%), length 68 cm (50%), and OFC 43 cm (25%).There was craniosynostosis with ridging of the sagittal and metopic sutures and fusion of the lambdoid sutures. The head shape was unusual with frontal bossing, bitemporal indentations with supraauricular bulging, and scaphocephaly. There was mild hypotelorism (inner canthal distance 2.0 cm, - 1.5 SD), upslanting palpebral fissures, and normal palpebral fissure length (2.4 cm). There was a normal pupillary response and no coloboma was present. The nose (2.6 cm) had a long nasal tip and the columella nasi extended below the alae nasi. He had a prominent upper lip and the philtrum measured 1.0 (25%). He had mild retrognathia and a high arched palate without palpable defects. The ears were posteriorly rotated with a prominent crus. The chest had mild flattening of the A-P diameter and was symmetrical. The lungs were clear to auscultation and percussion. There was a soft systolic ejection murmur and normal heart sounds. The abdomen was soft, without hepatosplenomegaly. There was a left inguinal hernia. There was arachnodactyly and the right thumb had limited flexion of the distal interphalangeal joint. CNS examination was abnormal with marked generalized hypotonia, with minimal neck control. The deep tendon reflexes were brisk and equal
Craniosynostosis
689
Fig. 1. (a)AP and (b) lateral of face. The propositus at 6 months.
bilaterally. Sensation was intact. The Babinki reflex was not elicited. There were minimal residual Moro and suck reflexes. He was visually alert, fixed and followed objects, and had minimal response to noise.
in stool samples. He was treated with broad spectrum antibiotics, but shortly after had a cardiac arrest and was resuscitated. In the intensive care unit he required mechanical ventilation. He developed disseminated intravascular coagulation, renal failure, and died. The parents did not wish to have an autopsy.
DIAGNOSTIC STUDIES The skull films and CT scan of the head (Fig. 2a,b) CHROMOSOME RESULTS confirmed the presence of craniosynostosis. There was fusion of the sagittal, metopic and lambdoid sutures, Chromosome analyses on PHA-stimulated lymphoand early synostosis of the coronal suture in the tempo- cytes with GTG banding [Seabright, 19711 showed a ral region. The orbits had a “harlequin” shape. There 46,XY,2q + karyotype in the propositus. Analysis of were no structural brain malformations or evidence of parental chromosomes indicated that this 2q + chromoincreased intracranial pressure. Abdominal ultrasound some was a derivative chromosome from a balanced and renal scan studies identified a horseshoe kidney and reciprocal translocation between the long arms of 2 and a right ureterocele. Visual evoked potentials were nor- 15 in the father. The karyotype in the father was mal. Auditory evoked potentials were abnormal, with a 46,XY,t(2;15)(q37;q26);the karyotype of the propositus moderate to severe neurosensory hearing loss. Upper GI was 46,XY, - 2, + der(2),t(2;15)(q37;q26)pat (Fig. 3). studies confirmed gastroesophageal reflux. Cardiology DISCUSSION evaluation demonstrated a structurally normal heart A limited number of chromosome deletion and dupliwith a functional murmur. cation syndromes have been associated with synostosis CLINICAL COURSE of multiple sutures [Cohen, 1979,1986; Schinzel, 1983; The propositus continued to have problems with swal- Gorlin et al, 1990; POSSUM database, 19901. This palowing dysfunction, requiring intermittent nasal gas- tient demonstrates the importance of chromosome antric feedings. Gastroesophageal reflux improved with alyses in the evaluation of any child with syndromal thickened feeds and postprandial upright positioning. craniosynostosis not recognized as a known monogenic He also continued to have developmental delay and hy- disorder. potonia. He was on prophylactic BactrimB to prevent Cloverleaf skull, with synostosis of multiple sutures, urinary tract infections related to the ureterocele. has been reported with partial duplication of 15q from At 7 months, he was admitted to hospital with an an unbalanced 12 /15 translocation [Pedersen, 19761. urinary tract infection. The patient initially responded The region of duplication was 1 5 q 2 S q t e r in Pedersen’s well to antibiotic treatment, but developed viral diar- patient compared to 1 5 q 2 h q t e r in our patient. We are rhea. Two weeks after admission, he developed sep- not aware of primary craniosynostosis being reported in ticemia and was found to have salmonella and roto-virus other individuals with partial duplication of 15q [Tur-
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Van Allen et al.
2 der(2) 15 der(l5) father
2
15
15
2 der(2)
son
Fig. 3. Chromosome 2,der(Z), 15, and der(l5) from the balanced reciprocal translocation in the father on the left; the ideograms of 2 and 15 in the center; and chromosomes 2, der(2), 15, and 15 from the unbalanced segregant of the translocation in the son on the right.
15
Craniosynostosis
leau et al., 1972; Coldwell et al., 1981; Tzancheva et al., 1981; Anneren and Gustavson, 1982; Yip et al., 1982; Schinzel, 1983; Lacro et al., 1987; F’ryns et al., 19883 or with partial deletion of 2q [Jansen et al., 1982;Schinzel, 1983; Young et al., 1983; Sanchez and Pantono, 1984; Glover et al., 1989; Palmer et al., 1990; Ramer et al., 19901. A distinct phenotype may be present with partial deletion of 2q, especially in those individuals with deletions in the 2q31 to 2q33 region [Palmer et al., 1990; Ramer et al., 19901. The common traits include intrauterine and postnatal growth retardation, developmental delay, microcephaly with variable brain malformations, prominent forehead, apparently low-set large or abnormal ears, antimongoloid slant of palpebral fissures, eye abnormalities including ptosis, microphthalmia, corneal abnormalities, large or beaked nose in older individuals, micrognathia, skeletal abnormalities, and variable life span. Internal abnormalities included cardiac and renal malformations. Although some of the manifestations in our patients overlap with this phenotype, the presence of sagittal synostosis results in a different facial appearance. One of the break points in the reciprocal translocation, 2q37, occurred in the region of a common fragile site [Yunis and Soren, 19841. However, there is yet no strong evidence supporting the view that fragile sites and break points of reciprocal translocations are associated [David and Hagaman, 19871. Deletion syndromes with craniosynostosis have now been recognized in the areas of 7p21 (CRS1, MIM #123100) and 7p14-p11.2 (CRS2) [Frezal et al., 19901. Greig cephalopolysyndactyly syndrome has been mapped to 7p13 in 2 patients with microdeletions [Wagner et al., 19901.Partial deletion of 7p has been reported to be associated with craniosynostosis [Moteqi et al., 1985; Garcia-Esquivel et al., 1986;Aughton et al., 1988; F’rezal et al., 19901. The suture involved in the reported individuals was variable, affecting the sagittal, coronal, and metopic sutures. The region 7p in humans is homologous to mouse chromosome 2 for a cluster of genes involved in craniofacial and limb morphogenesis in the mouse [Peters et al., 1989; Nadeau, 19901. The Man-on-Mouse Homology Map shows genes from human 15q and 7p to be contiguous on mouse chromosome 2 [Nadeau, 19901. The mouse homologous area for CRS2 is identified by the gene for biliverdin reductase (BLVR-human; blvrmouse), which has been assigned to the 7p14+cen region [Meera Khan et al., 1983; Peters et al., 19891.Contiguous to the mouse blvr (human BLVR, 7p) locus is a large region homologous t o human 15q [Nadeau, 19901. Synteny and gene order have been conserved in this region since the divergence of lineages leading to mouse and man [Nadeau, 19901. The homology map of mouse chromosome 2 includes the loci for (32-microglobulin (B2m;B2M) located in human 15q13-ql5;human skeletal and cardiac actin (Actc-1; ACTC) located in 15qllqter; and sorbital dehydrogenase (sdh-1; SORD) located in 15q12-q21[references summarized in Nadeau, 19901. We hypothesize, along with Pedersen 119761, that a t least one of a cluster of genes important for suture for-
691
mation is located in 15q. It would be derived from a cluster of genes for suture formation from an ancestral chromosome. The synteny for the suture formation genes would be preserved in the mouse chromosome 2; however, in the human it is found on chromosomes 7p and 15q. Further patient observations and delineation of the genome will confirm or refute the hypothesis that distal 15q is associated with craniosynostosis and is phylogenetically related to the genes on 7p.
ACKNOWLEDGMENTS Our thanks to Effie Economidos, Vicki Viero, and Margot Cairns for their library and secretarial assistance. We gratefully acknowledge the assistance of Marija Djokic for assistance with electronic databases including MIM-online, POSSUM, and MEDLINE. REFERENCES Anneren G, Gustavson K-H (1982):A boy with proximal trisomy 15and a male fetus with distal trisomy 15 due to a familial 13p;15qtranslocation. Clinical Genetics 22:16-21. Aughton DJ, Cassidy SB, Whiteman SAH, Delach JA (1988):Chromosome 7p- syndrome: Craniosynostosis with preservation of region 7p2. Am J Hum Genet 43:A36,1988. Borgaonkar DS (199): “Chromosomal Variation in Man: A Catalogue of Chromosomal Variants and Anomalies,” 5th ed. New York: Alan R. Liss. Borgaonkar DS, Shaffer R, Reisor N (1987): “Repository of Human Chromosomal Variants and Anomalies: An International Registry of Abnormal Karyotypes,” 12th listing. Newark, DE: Medical Center of Delaware. Cohen MM, Jr (1979): Craniosynotosis and syndromes with craniosynostosis: Incidence, genetics, penetrance, variability and new syndrome updating. Birth Defects 15 (5B):13-63. Cohen MM (1986): “Craniosynostosis,Diagnosis, Evaluation and Management.” New York: Raven Press, pp 431-433, 573. Coldwell S, Fitzgerald B, Semmens JM, Ede R, Bateman C (1981): A case of trisomy of chromosome 15. J Med Genetics 18:146-148. Davis JR, Hagaman RM (1987):Fragile sites are unrelated to reciprocal translocation breakpoints. Clin Genet 31:308-310. Frezal J, Schinzel A, Baule MS (1990): Report of the committee on clinical disorders and chromosomal deletion syndromes. Cytogenet. Cell Genet 55321-357. Fryns JP, Kleczkowska A, Moerman PH, Vandenberghe K, Van Den Berghe H (1988): The fetal phenotype of 15q2 duplication. Ann Genet 31:123-125. Garcia-Esquivel L, Garcia-Cruz D, Rivera H, Plascencia ML, Cantu JM, (1986): De novo del(7)(pter-p21::pl5.2-qter) and craniosynostosis. Implications for the critical segment assignment in the 7p2 monosomy syndrome. Ann Genet (Paris) 29:36-38. Glover TW, Cox BA, Uhlmann W, Kiyne M, LoeMer K, Gorski J L (1989): Deletions of distal 2q in two children. Karyogram 15:14. Gorlin JR, Cohen MM, Jr, Levin LS (1990):“Syndromesofthe Head and Neck,” 3rd ed. New York Oxford University Press. Gregoire MJ, Boue J, Junien C, Pernot C, Gilgenkrantz S, Zergollern L (1981): Duplication 15q22-15qter and its phenotypic expression. Hum Genet 59:429-433. Jansen M, Beemer FA, van der Heiden C, Van Hemel JO, Van den Brande J L (1982):Ring chromosome 2: Clinical, chromosomal, and biochemical aspects. Hum Genet 60:91-95. Lacro RV, Jones KL, Mascarello JT, Jones OW, Wilson N, Jones MC (1987): Duplication of distal 15q: Report of five new cases from two different translocation kindreds. Am J Med Genet 26:719-728. McPherson E, Hall JG, Hickman R, Gong BT, Norwood TH, Hoehn H (1976): Chromosome 7 short arm deletion and craniosynostosis. A 7p- syndrome. Hum Genet 35117-123. Meera Khan P, Wijnene LMM, Grzeschik HKH (1983):Electrophoretic characterization and genetics of human biliverdin reductase (BLVR;EC 1.3.1.24):assignment of BLVR to the pl4-cen region of
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human chromosome 7 in mouse-human somatic cell hybrids. Biochem Genet 21:123-133. Motegi T, Ohuchi M, Ohtaki C, fijiwara K, Enomotn S, Hasegawa, T, Kishi K, Hayakwa H (1985): A craniosynostosis in a boy with a de1(7)(~15.3~21.3): Assignment by deletion mapping of the critical segment for craniosynostosis to the mid-portion of 7p21. Hum Genet 71:160-162. Nadeau, J H (1990):“Linkage and Synteny HomologiesBetween Mouse and Man.” Bar Harbor, ME: Jackson Laboratory. Palmer CG, Heerema N, Bull M (1990):Deletions in chromosome 2 and fragile sites. Am J Med Genet 36:214-218. Pedersen C, (1976): Partial trisomy 15 as a result of an unbalanced 12/15 translocation in a patient with a cloverleaf skull anomaly. Clin Genet 9:378-380. Peters J , Ball ST. Von DeimlingA (1989):Localization ofBLVR, biliverdin reductase, on mouse chromosome 2. Genomics 5270-274. Ramer JC, Mowre PN, Robins DB, Ligato S, Towfighi J , Ladda RL (1990):Five children with del(2Xq31q33) and one individual with dup (2Xq31q33)from a single family: Review of brain, cardiac, and limb malformations. Am J Med Genet 37:392-400. Sanchez JM, Pantano AM (1984):A case of deletion 2 q 3 h q t e r and a peculiar phenotype. J Med Genet 21:147-149.
Schnizel A (1983):“Catalogue of Unbalanced Chromosome Abernethy in Man.” Berlin: Walter de Gruyter. Seabright M (1971): A rapid banding technique for human chromosomes. Lancet 2:971-972. Turleau C, De Grouchy J , Chavin-Colin F, Roubin M (1977):Trisomie 15q distale. Ann a n & 20:214-216. Tzancheva M, Krachounova M, Damjanova Zv (1981): Two Familial cases with trisomy 15q dist. due to arcp(5;15)(p14;q21).Hum Genet 56:275-277. Wagner K, Kroisel PM, Rosenkranz W, (1990): Molecular and cytogenetic analysis in two patients with microdeletionsof 7p and Greig syndrome: Hemizygosity for PGAM2 and TCRG genes. Genomics 8:487-491. Young RS, Shapiro SD, Hansen KL, Hine I, Rainoeek DE, Guerra FA (1983): Deletion 2q: Two new cases with karyotypes 46,XY, del(2Xq31q33) and 43,XXde1(2)(q36).J Med Genet 20:199-202. Yip M-Y, Parsons A, Hulten M (1982): A de novo tandem duplication 15(q21-qter) mosaic. Clinical Genetics 22:l-6. Yunis JJ and Soreng AL (1984):Constitutive fragile sites and cancer. Science 226119-1204.
Craniosynostosis Associated With Partial Duplication of 15q and Deletion of 2q _
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M.I. Van Allen, J. Siegel-Bartelt,A. Feigenbaum, and I.E. Teshima Department of Medical Genetics, University Hospital-Shaughnessy Site and the University of British Columbia, Vancouver, and Department of Genetics (A.F.,I.E.T.), The Hospital for Sick Children, Toronto, Ontario, Canada We report on an infant with multiple congenital anomaliesincluding complex craniosynostosis associated with an unbalanced karyotype, 46,XY, - 2, + der(2),t(2;15)(q37;q26)pat. The previous report of a child with cloverleaf skull and partial duplication of 15q2bqter and the Man-on-Mouse Homology map sug gests that a critical segment for synostosis of sutures may be in this region. o 1992 Wiley-Lies, Inc.
KEY WORDS: craniosynostosis, sagittal, metopic and lambdoidal synostosis, partial deletion 2q, partial duplication 15q, chromosomal deletion syndrome, M,XY, - 2, + der(2), t(2;15)(q37;q36)pat. INTRODUCTION Multiple causes of craniosynostosis have been reviewed comprehensively [Cohen, 1979, 1986; Gorlin et al., 19901. Chromosome abnormalities are a less frequent cause of craniosynostosis than monogenic disorders, but should be considered in the presence of associated malformations, growth, and developmental delay. The propositus of our study had duplication 15q and deletion 2q in a derivative chromosome 2 from a paternal balanced reciprocal translocation, 46,XY, t(2;15)(q37;q26).Although this represents a unique familial chromosome rearrangement [Borgaonkar, 1987, 1989;Schinzel, 19831,the previous report of a child with cloverlead skull and partial duplication of 15q is consistent with Pedersen’s [1976] hypothesis that this region may be important for suture formation. CLINICAL REPORT History The propositus was a term infant born by repeat cesarean section to a 23-year-oldG2P1 mother. There were Received for publication March 8, 1991; September 18, 1991. Address reprint requests to M. I. Van Allen, Department of Medical Genetics, University Hospital-Shaughnessy Site, 4500 Oak Street, Vancouver, British Columbia, Canada V6H 3N1.
0 1992 Wiley-Liss, Inc.
no reported pregnancy complications or medications. The birthweight was 3,350 g. There was reported amniotic fluid aspiration at birth and subsequent respiratory distress treated in a neonatal intensive care unit. Seizures developed at 10 hours postpartum and responded to treatment. Craniosynostosis was evident at the time of discharge in the neonatal period. The family immigrated to Canada from Nicaragua when the propositus was 3 112 months old. He was admitted to The Hospital for Sick Children at age 4 112 months for evaluation of craniosynostosis and other problems including poor weight gain with swallowing dysfunction and developmental delay. By 6 months he was smiling, fixed, and followed well, was able to bring his hands to midline and put his fist to his mouth. He could not roll over, sit unsupported, or reach for objects. He had limited vocalization.
PHYSICAL EXAMINATION At 6 months he had marked scaphocephaly, minor facial anomalies, hypotonia, and developmental delay (Fig. 1).The weight was 6.4 kg (lo%), length 68 cm (50%), and OFC 43 cm (25%).There was craniosynostosis with ridging of the sagittal and metopic sutures and fusion of the lambdoid sutures. The head shape was unusual with frontal bossing, bitemporal indentations with supraauricular bulging, and scaphocephaly. There was mild hypotelorism (inner canthal distance 2.0 cm, - 1.5 SD), upslanting palpebral fissures, and normal palpebral fissure length (2.4 cm). There was a normal pupillary response and no coloboma was present. The nose (2.6 cm) had a long nasal tip and the columella nasi extended below the alae nasi. He had a prominent upper lip and the philtrum measured 1.0 (25%). He had mild retrognathia and a high arched palate without palpable defects. The ears were posteriorly rotated with a prominent crus. The chest had mild flattening of the A-P diameter and was symmetrical. The lungs were clear to auscultation and percussion. There was a soft systolic ejection murmur and normal heart sounds. The abdomen was soft, without hepatosplenomegaly. There was a left inguinal hernia. There was arachnodactyly and the right thumb had limited flexion of the distal interphalangeal joint. CNS examination was abnormal with marked generalized hypotonia, with minimal neck control. The deep tendon reflexes were brisk and equal
Craniosynostosis
689
Fig. 1. (a)AP and (b) lateral of face. The propositus at 6 months.
bilaterally. Sensation was intact. The Babinki reflex was not elicited. There were minimal residual Moro and suck reflexes. He was visually alert, fixed and followed objects, and had minimal response to noise.
in stool samples. He was treated with broad spectrum antibiotics, but shortly after had a cardiac arrest and was resuscitated. In the intensive care unit he required mechanical ventilation. He developed disseminated intravascular coagulation, renal failure, and died. The parents did not wish to have an autopsy.
DIAGNOSTIC STUDIES The skull films and CT scan of the head (Fig. 2a,b) CHROMOSOME RESULTS confirmed the presence of craniosynostosis. There was fusion of the sagittal, metopic and lambdoid sutures, Chromosome analyses on PHA-stimulated lymphoand early synostosis of the coronal suture in the tempo- cytes with GTG banding [Seabright, 19711 showed a ral region. The orbits had a “harlequin” shape. There 46,XY,2q + karyotype in the propositus. Analysis of were no structural brain malformations or evidence of parental chromosomes indicated that this 2q + chromoincreased intracranial pressure. Abdominal ultrasound some was a derivative chromosome from a balanced and renal scan studies identified a horseshoe kidney and reciprocal translocation between the long arms of 2 and a right ureterocele. Visual evoked potentials were nor- 15 in the father. The karyotype in the father was mal. Auditory evoked potentials were abnormal, with a 46,XY,t(2;15)(q37;q26);the karyotype of the propositus moderate to severe neurosensory hearing loss. Upper GI was 46,XY, - 2, + der(2),t(2;15)(q37;q26)pat (Fig. 3). studies confirmed gastroesophageal reflux. Cardiology DISCUSSION evaluation demonstrated a structurally normal heart A limited number of chromosome deletion and dupliwith a functional murmur. cation syndromes have been associated with synostosis CLINICAL COURSE of multiple sutures [Cohen, 1979,1986; Schinzel, 1983; The propositus continued to have problems with swal- Gorlin et al, 1990; POSSUM database, 19901. This palowing dysfunction, requiring intermittent nasal gas- tient demonstrates the importance of chromosome antric feedings. Gastroesophageal reflux improved with alyses in the evaluation of any child with syndromal thickened feeds and postprandial upright positioning. craniosynostosis not recognized as a known monogenic He also continued to have developmental delay and hy- disorder. potonia. He was on prophylactic BactrimB to prevent Cloverleaf skull, with synostosis of multiple sutures, urinary tract infections related to the ureterocele. has been reported with partial duplication of 15q from At 7 months, he was admitted to hospital with an an unbalanced 12 /15 translocation [Pedersen, 19761. urinary tract infection. The patient initially responded The region of duplication was 1 5 q 2 S q t e r in Pedersen’s well to antibiotic treatment, but developed viral diar- patient compared to 1 5 q 2 h q t e r in our patient. We are rhea. Two weeks after admission, he developed sep- not aware of primary craniosynostosis being reported in ticemia and was found to have salmonella and roto-virus other individuals with partial duplication of 15q [Tur-
690
Van Allen et al.
2 der(2) 15 der(l5) father
2
15
15
2 der(2)
son
Fig. 3. Chromosome 2,der(Z), 15, and der(l5) from the balanced reciprocal translocation in the father on the left; the ideograms of 2 and 15 in the center; and chromosomes 2, der(2), 15, and 15 from the unbalanced segregant of the translocation in the son on the right.
15
Craniosynostosis
leau et al., 1972; Coldwell et al., 1981; Tzancheva et al., 1981; Anneren and Gustavson, 1982; Yip et al., 1982; Schinzel, 1983; Lacro et al., 1987; F’ryns et al., 19883 or with partial deletion of 2q [Jansen et al., 1982;Schinzel, 1983; Young et al., 1983; Sanchez and Pantono, 1984; Glover et al., 1989; Palmer et al., 1990; Ramer et al., 19901. A distinct phenotype may be present with partial deletion of 2q, especially in those individuals with deletions in the 2q31 to 2q33 region [Palmer et al., 1990; Ramer et al., 19901. The common traits include intrauterine and postnatal growth retardation, developmental delay, microcephaly with variable brain malformations, prominent forehead, apparently low-set large or abnormal ears, antimongoloid slant of palpebral fissures, eye abnormalities including ptosis, microphthalmia, corneal abnormalities, large or beaked nose in older individuals, micrognathia, skeletal abnormalities, and variable life span. Internal abnormalities included cardiac and renal malformations. Although some of the manifestations in our patients overlap with this phenotype, the presence of sagittal synostosis results in a different facial appearance. One of the break points in the reciprocal translocation, 2q37, occurred in the region of a common fragile site [Yunis and Soren, 19841. However, there is yet no strong evidence supporting the view that fragile sites and break points of reciprocal translocations are associated [David and Hagaman, 19871. Deletion syndromes with craniosynostosis have now been recognized in the areas of 7p21 (CRS1, MIM #123100) and 7p14-p11.2 (CRS2) [Frezal et al., 19901. Greig cephalopolysyndactyly syndrome has been mapped to 7p13 in 2 patients with microdeletions [Wagner et al., 19901.Partial deletion of 7p has been reported to be associated with craniosynostosis [Moteqi et al., 1985; Garcia-Esquivel et al., 1986;Aughton et al., 1988; F’rezal et al., 19901. The suture involved in the reported individuals was variable, affecting the sagittal, coronal, and metopic sutures. The region 7p in humans is homologous to mouse chromosome 2 for a cluster of genes involved in craniofacial and limb morphogenesis in the mouse [Peters et al., 1989; Nadeau, 19901. The Man-on-Mouse Homology Map shows genes from human 15q and 7p to be contiguous on mouse chromosome 2 [Nadeau, 19901. The mouse homologous area for CRS2 is identified by the gene for biliverdin reductase (BLVR-human; blvrmouse), which has been assigned to the 7p14+cen region [Meera Khan et al., 1983; Peters et al., 19891.Contiguous to the mouse blvr (human BLVR, 7p) locus is a large region homologous t o human 15q [Nadeau, 19901. Synteny and gene order have been conserved in this region since the divergence of lineages leading to mouse and man [Nadeau, 19901. The homology map of mouse chromosome 2 includes the loci for (32-microglobulin (B2m;B2M) located in human 15q13-ql5;human skeletal and cardiac actin (Actc-1; ACTC) located in 15qllqter; and sorbital dehydrogenase (sdh-1; SORD) located in 15q12-q21[references summarized in Nadeau, 19901. We hypothesize, along with Pedersen 119761, that a t least one of a cluster of genes important for suture for-
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mation is located in 15q. It would be derived from a cluster of genes for suture formation from an ancestral chromosome. The synteny for the suture formation genes would be preserved in the mouse chromosome 2; however, in the human it is found on chromosomes 7p and 15q. Further patient observations and delineation of the genome will confirm or refute the hypothesis that distal 15q is associated with craniosynostosis and is phylogenetically related to the genes on 7p.
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