American Journal of Medical Genetics 36:506-510 (1990)
Partial Trisomy 18 With Minimal Anomalies: Lack of Correspondence Between Phenotypic Manifestations and Triplicated Loci Along Chromosome 18 Golder N. Wilson, Karen B. Heller, Roy D. Elterman, and Nancy R. Schneider Departments of Pediatrics (G.N.W.)and Pathology (N.R.S.), University of Texas Southwestern Medical Center, Children’s Medical Center of Dallas (K.B.H.),and Dallas Pediatric Neurology Associates (R.D.E.),Dallas, Texas
A 2-year-oldboy with microcephaly, developmental delay, and minimal anomalies was found to have an extra submetacentric chromosome equivalent to 18ptewql2. Review of the phenotypes produced by various triplicated 18 regions supports the hypothesis that no one chromosome 18 region is sufficient to produce the phenotype of trisomy 18. The mild phenotype of trisomy Up, the variable phenotype of trisomy l8ptewql2, and the discontinuous phenotype of triplication for band 18q12 alone emphasizes that the contribution of triplicated loci to the phenotype is neither additive nor invariant.
fect of this triplicated region and, together with other partial 18 trisomies, emphasizes the interaction of chromosome 18 loci in producing the manifestations of trisomy 18.
Clinical Report The propositus (Fig. 1) was referred at 2 years for neurological evaluation because of developmental delay. He had a normal brother: there was no evidence of parental consanguinity. Following a term uncomplicated gestation and normal delivery to a 34-year-old gravida 2 para 1woman, the birth weight was 3,060 g, length 51 cm, and the OFC 33 cm (all a t about the 10th centile). No neonatal complications occurred, and the subsequent course was normal except for delay in speech and motor development. Physical examination at age 2 7/12 years KEY WORDS: dup 18p syndrome, MR/MCA demonstrated an OFC of 48 cm, a height of 93.5 cm, and syndrome, trisomy 18, phenoa weight of 13.7 kg. Height and weight were at the 50th typekaryotype correlation centile, but the head circumference was at the 5th centile for age. The face (Fig. 1)appeared normal and the only major anomalies were mild hypospadias with INTRODUCTION cryptorchidism on the left. Dermatoglyphic analysis reTrisomy of chromosome 18 is associated with a dis- vealed R, U, U, U, U on the right and R, R, U, U, U on the tinctive pattern of dysmorphogenesis which inflicts con- left hand with no arch patterns. Minor anomalies consissiderable intrauterine and postnatal morbidity and ted of a preauricular pit on the left and a broad space mortality. Although the manifestations are sufficiently between the first and second toes bilaterally. Of interest characteristic to allow design of a diagnostic scoring was the fact that the mother also had these minor anomsystem [Marion et al., 19881, their relation to triplica- alies but was of normal intelligence. Development was tion of specific chromosome 18 segments remains con- estimated t o be at about age 14 months compared to the troversial. Turleau et al. [1980] suggested that triplica- chronologic age of 2 years. tion of 18p has little influence on the trisomy 18 phenotype, while interaction of the triplicated segments RESULTS AND DISCUSSION 18qll+q13 and 18q22-+qter was critical. Matsuoka et Chromosome studies with trypsin-Giemsa banding al. [1981] emphasized the role of segment 18q21 while were performed on peripheral blood lymphocytes from Miicke et al. [19821 concluded that if triplication of a the propositus and his parents using standard methods. single band were responsible for the trisomy 18 phe- An extra small chromosome (Fig. 2) was observed in all notype, it must be above 18q122. We report a case of 21 metaphase spreads examined from the propositus. triplication (18ptewq12) which confirms the mild ef- This extra chromosome had a small central C-bandpositive region and a G-band pattern characteristic of the short arm and proximal long arm of chromosome 18. Received for publication August 4,1989; revision received JanuThe karyotype designation was 47,XY, + de1(18)(q12). ary 12, 1990. The parents’ chromosomes were normal, including 50 Address reprint requests to Golder N. Wilson M.D., Ph.D., Division of Pediatric Genetics, University of Texas Southwestern Medi- cells on the mother examined to rule out mosaicism. Manifestations of the propositus are compared with cal School, 5323 Harry Hines Blvd., Dallas, TX 75235. 0 1990 Wiley-Liss, Inc.
Dup ( 1 8 ~Syndrome )
507
Fig. 1. Frontal view (A) and foot (B) of the propositus.
those of other partial 18 trisomies in Table I. Omitted from the analysis are the 29 patients reported with tetrasomy 18p which have the distinctive phenotype of microcephaly, facial asymmetry, small pinched nose with a small mouth, clenched hands, and renal defects [Kleczkowskaet al., 19861. Lack of these manifestations in the propositus supports the karyotypic interpretation described above. The propositus is most similar to the 6 patients with partial trisomy 18p ( p t e w p l l ) with an extremely mild phenotype [Jacobsen and Mikkelsen, 1968; Gardner et al., 1978; Johansson et al., 19881. These patients are summarized in category a of Table I and share manifestations such as intrauterine growth retardation (2/6), minimal facial anomalies, abnormal ears (2/6),subtle hand (1/4)or foot (1/4)anomalies, mild mental retardation (4/6-1Q 75, 75-90 in 2 patients), and seizures (2/4). Patients with trisomy for all of 18p and part of 18q have a progressively more severe phenotype as the trisomic portion extends down the chromosome. Three patients with trisomy 1 8 p t e w q l l (category b in Table I) have been reported [Hernandez et al., 1979;San Martin et al., 1981; Meinicke and Kocke-Westphal, 19811 and have more severe mental retardation
Partial Trisomy 18 With Minimal Anomalies: Lack of Correspondence Between Phenotypic Manifestations and Triplicated Loci Along Chromosome 18 Golder N. Wilson, Karen B. Heller, Roy D. Elterman, and Nancy R. Schneider Departments of Pediatrics (G.N.W.)and Pathology (N.R.S.), University of Texas Southwestern Medical Center, Children’s Medical Center of Dallas (K.B.H.),and Dallas Pediatric Neurology Associates (R.D.E.),Dallas, Texas
A 2-year-oldboy with microcephaly, developmental delay, and minimal anomalies was found to have an extra submetacentric chromosome equivalent to 18ptewql2. Review of the phenotypes produced by various triplicated 18 regions supports the hypothesis that no one chromosome 18 region is sufficient to produce the phenotype of trisomy 18. The mild phenotype of trisomy Up, the variable phenotype of trisomy l8ptewql2, and the discontinuous phenotype of triplication for band 18q12 alone emphasizes that the contribution of triplicated loci to the phenotype is neither additive nor invariant.
fect of this triplicated region and, together with other partial 18 trisomies, emphasizes the interaction of chromosome 18 loci in producing the manifestations of trisomy 18.
Clinical Report The propositus (Fig. 1) was referred at 2 years for neurological evaluation because of developmental delay. He had a normal brother: there was no evidence of parental consanguinity. Following a term uncomplicated gestation and normal delivery to a 34-year-old gravida 2 para 1woman, the birth weight was 3,060 g, length 51 cm, and the OFC 33 cm (all a t about the 10th centile). No neonatal complications occurred, and the subsequent course was normal except for delay in speech and motor development. Physical examination at age 2 7/12 years KEY WORDS: dup 18p syndrome, MR/MCA demonstrated an OFC of 48 cm, a height of 93.5 cm, and syndrome, trisomy 18, phenoa weight of 13.7 kg. Height and weight were at the 50th typekaryotype correlation centile, but the head circumference was at the 5th centile for age. The face (Fig. 1)appeared normal and the only major anomalies were mild hypospadias with INTRODUCTION cryptorchidism on the left. Dermatoglyphic analysis reTrisomy of chromosome 18 is associated with a dis- vealed R, U, U, U, U on the right and R, R, U, U, U on the tinctive pattern of dysmorphogenesis which inflicts con- left hand with no arch patterns. Minor anomalies consissiderable intrauterine and postnatal morbidity and ted of a preauricular pit on the left and a broad space mortality. Although the manifestations are sufficiently between the first and second toes bilaterally. Of interest characteristic to allow design of a diagnostic scoring was the fact that the mother also had these minor anomsystem [Marion et al., 19881, their relation to triplica- alies but was of normal intelligence. Development was tion of specific chromosome 18 segments remains con- estimated t o be at about age 14 months compared to the troversial. Turleau et al. [1980] suggested that triplica- chronologic age of 2 years. tion of 18p has little influence on the trisomy 18 phenotype, while interaction of the triplicated segments RESULTS AND DISCUSSION 18qll+q13 and 18q22-+qter was critical. Matsuoka et Chromosome studies with trypsin-Giemsa banding al. [1981] emphasized the role of segment 18q21 while were performed on peripheral blood lymphocytes from Miicke et al. [19821 concluded that if triplication of a the propositus and his parents using standard methods. single band were responsible for the trisomy 18 phe- An extra small chromosome (Fig. 2) was observed in all notype, it must be above 18q122. We report a case of 21 metaphase spreads examined from the propositus. triplication (18ptewq12) which confirms the mild ef- This extra chromosome had a small central C-bandpositive region and a G-band pattern characteristic of the short arm and proximal long arm of chromosome 18. Received for publication August 4,1989; revision received JanuThe karyotype designation was 47,XY, + de1(18)(q12). ary 12, 1990. The parents’ chromosomes were normal, including 50 Address reprint requests to Golder N. Wilson M.D., Ph.D., Division of Pediatric Genetics, University of Texas Southwestern Medi- cells on the mother examined to rule out mosaicism. Manifestations of the propositus are compared with cal School, 5323 Harry Hines Blvd., Dallas, TX 75235. 0 1990 Wiley-Liss, Inc.
Dup ( 1 8 ~Syndrome )
507
Fig. 1. Frontal view (A) and foot (B) of the propositus.
those of other partial 18 trisomies in Table I. Omitted from the analysis are the 29 patients reported with tetrasomy 18p which have the distinctive phenotype of microcephaly, facial asymmetry, small pinched nose with a small mouth, clenched hands, and renal defects [Kleczkowskaet al., 19861. Lack of these manifestations in the propositus supports the karyotypic interpretation described above. The propositus is most similar to the 6 patients with partial trisomy 18p ( p t e w p l l ) with an extremely mild phenotype [Jacobsen and Mikkelsen, 1968; Gardner et al., 1978; Johansson et al., 19881. These patients are summarized in category a of Table I and share manifestations such as intrauterine growth retardation (2/6), minimal facial anomalies, abnormal ears (2/6),subtle hand (1/4)or foot (1/4)anomalies, mild mental retardation (4/6-1Q 75, 75-90 in 2 patients), and seizures (2/4). Patients with trisomy for all of 18p and part of 18q have a progressively more severe phenotype as the trisomic portion extends down the chromosome. Three patients with trisomy 1 8 p t e w q l l (category b in Table I) have been reported [Hernandez et al., 1979;San Martin et al., 1981; Meinicke and Kocke-Westphal, 19811 and have more severe mental retardation
