In 1962, Wang et al. reported the first observation of the ring chromosome 18.
GENETICS/BASIC DEFECTS
1. Caused by the presence of a ring chromosome 18 or mosaic ring chromosome 18 with a loss of 18p segment and a loss of 18q segment
2. Phenotypic variability depends on the extent of the deleted chromosome 8 segments
3. Rare occurrence of a ring chromosome 18 together with a duplication of a segment of chromosome 18 or with a marker chromosome
CLINICAL FEATURES
1. Clinical features of r(18) syndrome a. Growth and development
i. Mental retardation ii. Hypotonia iii. Short stature b. Head/brain
i. Microcephaly ii. Dolichocephaly iii. Holoprosencephaly
iv. Cebocephaly v. Arhinencephaly c. Midface: flat d. Ears
i. Asymmetric ii. Low-set
iii. Atretic external ear canals iv. Prominent anti-helix e. Eyes
i. Deep-set ii. Hypertelorism
iii. Down slanting palpebral fissures iv. Epicanthal folds
v. Nystagmus vi. Strabismus vii. Ptosis viii. Coloboma f. Nose
i. Broad base
ii. Depressed nasal bridge iii. Broad tip
g. Mouth
i. Micrognathia
ii. Carp-like down-turned corners iii. Thin upper and lower lips
iv. High/narrow palate v. Dental caries
h. Neck: short i. Chest
i. Pectus excavatum ii. Wide-spaced nipples j. Congenital heart defect
i. PDA ii. PS iii. VSD
iv. AS k. Abdomen
i. Umbilical hernia ii. Inguinal hernia l. Genitourinary
i. Male genitalia a) Cryptorchidism b) Hypoplastic scrotum c) Micropenis
ii. Female genitalia: hypoplastic labia minora m. Musculoskeletal
i. Spine: scoliosis ii. Hands
a) Clinodactyly b) Camptodactyly c) Short fingers
d) Long tapering fingers e) Proximally placed thumbs f) Single transverse palmar crease iii. Legs/feet
a) Club feet (varus) b) Over-riding toes c) Long/broad toes d) Genu valgum n. Other features
i. Hypothyroidism ii. Hypoparathyroidism iii. Growth hormone deficiency o. Atypical features
i. Van der Woude syndrome
ii. Insulin-dependent diabetes mellitus iii. Agammaglobulinemia
2. Most patients share the features of del(18q) syndrome, which are highly variable depending on the extent of the terminal or interstitial 18q deletion:
a. Mental retardation b. Hypotonia c. Microcephaly d. Short stature e. Flat midface
f. Carp-shaped mouth
g. Prominent antihelix and antitragus h. Atretic/stenotic ear canals
831
R(18) Syndrome
832 R(18) SYNDROME
i. Proximally placed thumbs j. Long tapering digits k. Foot deformity
l. Abnormal male genitalia
3. Some patients share the features of del(18p) syndrome, which are highly variable depending on the extent of the terminal or interstitial 18p deletion:
a. Mental retardation b. Speech delay c. Hypotonia d. Short stature
e. Midface defects including holoprosencephaly f. Ptosis of eyelids
g. Small mandible h. Dental caries
i. Short neck j. IgA deficiency
4. Some patients share the combined features of del(18p) syndrome and del(18q) syndrome
DIAGNOSTIC INVESTIGATIONS
1. Conventional cytogenetic studies a. Nonmosaic r(18)
b. Mosaic r(18)
2. Molecular cytogenetic studies using fluorescence in situ hybridization (FISH) technique
a. Ring chromosome positive for chromosome 18 centro- meric probe
b. Absence of 18q subtelomeric probe
3. Microdissection followed by FISH to determine the ori- gin of the marker chromosome
4. Using a number of microsatellite markers to determine the parental origin and possible mode of formation of the r(18) 5. Low IgA
GENETIC COUNSELING
1. Recurrence risk
a. Patient sibling: not increased in cases of de novo instances (majority of cases)
b. Patient’s offspring
i. Vertical transmission of ring chromosome 18 from a mother to her offspring reported
ii. Mosaic monosomy 18 with familial ring chro- mosome 18 reported
2. Prenatal diagnosis by chromosome analysis from amnio- centesis, CVS, and fetal blood
3. Management
a. Mainly supportive
b. Multidisciplinary team approach with physical, occu- pational, and speech therapies
c. Supportive treatment for chronic sinopulmonary infections associated with IgA deficiency
d. Treat endocrine dysfunction, if present
REFERENCES
Baumer A, Uzielli MLG, Guarducci S, et al.: Meiotic origin of two ring chro- mosomes 18 in a girl with developmental delay. Am J Med Genet 113:101–104, 2002.
Christensen KR, et al. Ring chromosome 18 in mother and daughter. J Ment Defic Res 14:49–67, 1970.
Cody JD, Ghidoni PD, DuPont BR, et al.: Congenital anomalies and anthro- pometry of 42 individuals with deletions of chromosome 18q. Am J Med Genet 85:455–462, 1999.
De Grouchy J: The 18p-, 18q- and 18r-syndromes. Birth Defects Orig Artic Ser V(5):74–87, 1969.
Donlan MA, Dolan CR: Ring chromosome 18 in a mother and son. J Med Genet 24:171–174, 1986.
Eiben B, Unger M, Stoltenberg G, et al.: Prenatal diagnosis of monosomy 18 and ring chromosome 18 mosaicism. Prenat Diagn 12:945–950, 1992.
Grouchy J de: The 18p-, 18q-, and 18r-syndromes. Birth Defects Original Article Series V(5):74–87, 1969.
Jenderny J, Caliebe A, Beyer C, et al.: Transmission of a ring chromosome 18 from a mother with 46,XX/47,XX,+r(18) mosaicism to her daugh- ter, resulting in a 46,XX,r(18) karyotype. J Med Genet 30:964–965, 1993.
Karda SI, Wirth J, Mazurczak T, et al.: Clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226–239, 2001.
Litzman J, Brysova V, Gaillyova R, et al.: Agammaglobulinaemia in a girl with a mosaic of ring 18 chromosome. J Paediatr Child Health 34:92–94, 1998.
Los FJ, van den berg C, Braat PG, Ring chromosome 18 in a fetus with only facial anomalies. Am J Med Genet 66:216–220, 1996.
Miller K, Pabst B, Ritter H, et al.: Chromosome 18 replaced by two ring chro- mosomes of chromosome 18 origin. Hum Genet 112:343–347, 2003.
Schaub RL, Leach RJ, Cody JD: Reevaluation of frequencies of selected features in patients with the 18p syndrome. Am J Hum Genet 63 (Suppl A342):
1931, 1999.
Stankiewicz P, Brozek I, Hélias-Rodzewicz Z, et al.: Clinical and molecular- cytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226–239, 2001.
Stewart J, Go S, Ellis E, et al.: Absent IgA and deletions of chromosome 18.
J Med Genet 7:11–19, 1970.
Strathdee G, Zackai EH, Shapiro R, et al.: Analysis of clinical variation seen in patients with 18q terminal deletions. Am J Med Genet 59:476–483, 1995.
Thies U, Bartels I, von Beust G, et al.: Prenatal diagnosis and fetopathological findings in a fetus with ring chromosome 18. Fetal Diagn Ther 13:315–320, 1998.
Wertelecki W, Gerald PS: Clinical and chromosomal studies of the 18q- syndrome.
J Pediatr 78:44–52, 1971.
Wilson MG, Towner JW, Forsman I, et al.: Syndromes associated with dele- tion of the long arm of chromosome 18[del(18q)]. Am J Med Genet 3:155–174, 1979.
Yardin C, Esclaire F, Terro F, et al.: First familial case of ring chromosome 18 and monosomy 18 mosaicism. Am J Med Genet 104:257–259, 2001.
Zumel RM, Darnaude MT, Delicado A, et al.: The 18p-syndrome. Report of five cases. Ann Génét 32:160–163, 1989.
R(18) SYNDROME 833
Fig. 1. A 4-year-old boy with de novo r(18) syndrome showing growth deficiency (prenatal and postnatal), speech delay, hypertelorism, downward slanting of the palpebral fissures, strabismus, slightly low- set ears, mild pectus carinatum, clinodactyly of the 5th fingers, and syndactyly of toes. He also has IgA deficiency.
Fig. 2. Chromosome analysis of the patient showed 46,XY,r(18), illus- trated by a G-banded karyotype, a partial karyotype with idiograms, and FISH with whole chromosome 18 painting probe.
834 R(18) SYNDROME
Fig. 3. A girl with del(18p) showing hypotonia, ptosis of the eyelids, and small mandible. The G-banded karyotype shows deletion of the short arm of a chromosome 18.
Fig. 4. A boy with del(18q) showing hypotonia, ptosis of the eyelids, and carp-like mouth.
