Pallister-Killian Syndrome
Pallister-Killian syndrome is a rare sporadic cytogenetic abnormality, first described in three adults by Pallister et al. in 1977 and followed by report of a child by Teschler-Nicola and Killian in 1981. The syndrome is also known as Teschler- Nicola/Killian syndrome, Pallister mosaic aneuploidy syn- drome, or isochromosome 12p mosaicism. It is the most frequent autosomal tetrasomy in humans.
GENETICS/BASIC DEFECTS
1. Genetics
a. Always reported as sporadic
b. Appears to be associated with increased maternal age 2. Basic cytogenetic defect
a. Caused by tetrasomy 12p b. Generally a mosaic
c. Frequently undetectable by standard cytogenetic analysis of peripheral blood
CLINICAL FEATURES
1. Normal or large birth weight 2. Craniofacial dysmorphism
a. Brachycephaly
b. High and broad forehead with frontal bossing c. Temporal alopecia
d. Sparse eyebrows and eyelashes e. Hypertelorism
f. Short nose with anteverted nares g. A thick philtrum
h. A large mouth with down slanting corners i. Full cheeks
j. Cleft lip/palate k. High-arched palate
l. Micrognathia m. Macroglossia n. Oral frenulae
o. Delayed dental eruption p. Dental anomalies
q. Low-set and posteriorly rotated ears r. Hypertrophy of anthelix crux s. Thick earlobes
3. Short neck
4. Diaphragmatic hernia with or without lung hypoplasia 5. Imperforate anus
6. CNS/neurologic abnormalities a. Severe hypotonia
b. Mental retardation c. Dilated ventricles d. Bifrontal cortical atrophy e. Absent speech
f. Poor vision g. Epilepsy
7. Congenital heart defects
a. Ventricular septal defect: the most frequent single malformation
b. Coarctation of the aorta c. Patent ductus arteriosus d. Atrial septal defect e. Aortic stenosis 8. Limb defects
a. Talipes
b. Broad and short hands and fingers c. Hypoplastic nails
d. Abnormal palmar creases e. Lymphedema
9. Skin anomalies a. Loose/excess skin b. Pigmentary dysplasia c. Mild hyperkeratosis d. Dry skin
e. Sweating abnormalities
10. Occasional internal organ malformations a. Umbilical hernia
b. Malrotation of the gut c. Omphalocele
d. Abnormalities of urogenital tract including cystic or dysplastic kidneys
e. Genital anomalies in males i. Cryptorchidism ii. Small scrotum
f. Occasional genital anomalies in females i. Ambiguous external genitalia ii. Hypoplasia of the labia majora
iii. Absence of the upper vagina and uterus
11. Majority of patients die prenatally, perinatally or early postnatally, and may die even after 10 or 15 years.
12. Phenotype in older children and young adults: marked phenotypic changes occurring during childhood and ado- lescence
a. Coarse and flat facies b. Macroglossia c. Prognathia d. Everted lower lip e. Muscular hypertonia
f. Contractures
g. Severe psychomotor retardation
DIAGNOSTIC INVESTIGATIONS
1. Cytogenetic studies
a. Demonstration of a supernumerary isochromosome of 12p
b. Confirmation of 12p tetrasomy by FISH techniques
i. Using centromere probe on chromosome 12
ii. Using whole chromosome 12 painting probe
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c. Cytogenetic studies of several tissues because of mosaicism
i. Circulating lymphocytes: mosaicism as low as 1–3%
ii. Amniocytes, chorionic cells and skin fibroblasts:
mosaicism ranging from 6–100%
2. Radiography
a. Asymmetry of diaphyseal length b. Short humerus or femur
c. Radial notch
d. Diaphyseal irregularities e. Costo-vertebral defect
3. Echocardiography for congenital heart defect 4. EEG for seizure activities
5. Postmortem pathologic examinations a. Malpositioned feet
b. Diaphragmatic defect c. Hypoplastic nails d. Genital malformation
e. Imperforate or anteriorly placed anus f. Supernumerary spleen
g. Heart valvular dysplasia h. Hypoplasia of the fibula
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: low recurrence risk (all cases are sporadic with only one preliminary case report of recurrence) b. Patient’s offspring: not surviving to reproductive
age or severely handicapped by profound mental retardation
2. Prenatal diagnosis a. Ultrasound anomalies
i. Hydramnios (84%)
ii. Diaphragmatic hernia (16%)
iii. Short limbs, predominantly rhizomelic type of micromelia (10%)
iv. Hydrops fetalis (6%) v. Cystic hygroma (3%)
vi. Increased nuchal translucency (3%) vii. Fetal overgrowth (3%)
viii. Ventriculomegaly (3%)
ix. Dilatation of cavum pellucidum (3%) x. Absence of visualization of the stomach (3%) xi. Presence of a sacral appendix (3%)
xii. Cardiac malformation xiii. Hypertelorism
xiv. Short neck
xv. Other congenital anomalies
b. Cytogenetic studies on amniocytes, cells from CVS, or fetal blood cells from cordocentesis
i. Conventional karyotyping
ii. FISH using chromosome 12 centromeric and whole chromosome painting probes
a) Interphase cells b) Metaphase cells 3. Management
a. Supportive treatment
b. Surgical repair of diaphragmatic hernia or other con- genital anomalies in non-lethal cases
REFERENCES
Bernert J, Bartels I, Gatz G, et al.: Prenatal diagnosis of the Pallister-Killian mosaic aneuploidy syndrome by CVS. Am J Med Genet 42:747–750, 1992.
Bresson JL, Arbez-Gindre F, Peltie J, et al.: Pallister Killian-mosaic tetrasomy 12 p syndrome. Another prenatally diagnosed case. Prenat Diagn 11:271–275, 1991.
Bulter MG, Dev VG: Pallister-Killian syndrome detected by fluorescence in situ hybridization. Am J Med Genet 57:498–500, 1995.
Buyse ML, Korf BR: “Killian Syndrome”, Pallister mosaic syndrome, or mosaic tetrasomy 12P?—an analysis. J Clin Dysmorphol 1:2–5, 1983.
Chiesa J, Hoffet M, Rousseau O, et al.: Pallister-Killian syndrome [i(12p)]: first pre-natal diagnosis using cordocentesis in the second trimester confirmed by in situ hybridization. Clin Genet 54:294–302, 1998.
Doray B, Girard-Lemaire F, Gasser B, et al.: Pallister-Killian syndrome: diffi- culties of prenatal diagnosis. Prenat Diagn 22:470–477, 2002.
Genevieve D, Cormier-Daire V, Sanlaville D, et al.: Mild phenotype in a 15- year-old boy with Pallister-Killian syndrome. Am J Med Genet 116A:90–93, 2003.
Hall BD: Mosaic tetrasomy 21 is mosaic tetrasomy 12p some of the time. Clin Genet 27:284–286, 1985.
Horneff G, Majewski F, Hildebrand B, et al.: Pallister-Killian syndrome in older children and adolescents. Pediatr Neurol 9:312–315, 1993.
Hunter AG, Clifford B, Cox DM: The characteristic physiognomy and tissue specific karyotype distribution in the Pallister-Killian syndrome. Clin Genet 28:47–53, 1985.
Mathieu M, Piussan C, Thepot F, et al.: Collaborative study of mosaic tetra- somy 12p or Pallister-Killian syndrome (nineteen fetuses or children).
Ann Genet 40:45–54, 1997.
Pallister PD, Meisner LF, Elejalde BR, et al.: The Pallister mosaic syndrome.
Birth Defects Original Article Series XIII(3B):103–110, 1977.
Peltomaki P, Knuutila S, Ritvanen A, et al.: Pallister-Killian syndrome: cytoge- netic and molecular studies. Clin Genet 31:399–405, 1987.
Quarrell OW, Hamill MA, Hughes HE: Pallister-Killian mosaic syndrome with emphasis on the adult phenotype. Am J Med Genet 31:841–844, 1988.
Reynolds JF, Daniel A, Kelly TE, et al.: Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister-Killian syndrome): report of 11 cases. Am J Med Genet 27:257–274, 1987.
Schinzel A: Tetrasomy 12p (Pallister-Killian syndrome). J Med Genet 28:122–125, 1991.
Shivashankar L, Whitney E, Colmorgen C, et al.: Prenatal diagnosis of tetra- somy 47,XY,+i(12p) confirmed by in situ hybridization. Prenat Diagn 8:85–91, 1988.
Soukup S, Neidich K: Prenatal diagnosis of Pallister-Killian syndrome. Am J Med Genet 35:526–528, 1990.
Speleman F, Leroy JG, Van Roy N, et al.: Pallister-Killian syndrome: charac- terization of the isochromosome 12p by fluorescent in situ hybridization.
Am J Med Genet 41:381–387, 1991.
Teschler-Nicola M, Killian W: Case report 72: Mental retardation, unusual facial appearance, abnormal hair. Synd Ident 7:6–7, 1981.
Warburton D, Anyana-Yeboa K, Francke U: Mosaic tetrasomy 12p: Four new cases, and confirmation of the chromosomal origin of supernumerary chromosome in one of the original Pallister-mosaic syndrome cases.
Am J Med Genet 27:275–283, 1988.
Wenger SL, Steele MW, Yu W-D: Risk effect of maternal age in Pallister i(12p) syndrome. Cg 34:181–184, 1988.
Young ID, Duckett DP, O’Reilly KM: Lethal presentation of mosaic tetrasomy 12p (Pallister-Killian) syndrome. Ann Genet 32:62–64, 1989.
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Fig. 1. Postmortem picture of a neonate with prenatally diagnosed mosaic i(12p). Amniocentesis was performed because of ultrasono- graphic finding of diaphragmatic hernia.
Fig. 2. A G-banded karyotype showing a supernumerary i(12p) (arrow).
Fig. 3. FISH of an interphase cell with centromere specific probe for chromosome 12 showing 3 signals.
Fig. 4. FISH of a metaphase chromosome spread with a whole chro- mosome probe specific for chromosome 12 showing two chromosome 12s and the i(12p) (arrow).
Fig. 5. FISH of a metaphase chromosome spread with a centromere probe specific for chromosome 12 showing two chromosome 12s and the i(12p) (arrow).
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Fig. 6. Another child with Pallister-Killian syndrome confirmed by cytogenetic studies showing prominent forehead, flat nasal bridge, sparse eyebrows, bitemporal alopecia, and everted lower lip.
