Pallister-Killian Syndrome

A number sign (#) is used with this entry because Pallister-Killian syndrome (PKS) is a dysmorphic condition caused by mosaicism for tetrasomy of chromosome 12p.

Description

Pallister-Killian syndrome is a dysmorphic condition involving most organ systems, but also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).

Clinical Features

Schinzel (1991) reviewed the clinical and cytogenetic features of the Pallister-Killian syndrome. Clinical features include profound mental retardation, seizures, streaks of hypo- or hyper-pigmentation, and facial anomalies, including prominent forehead with sparse anterior scalp hair, flat occiput, hypertelorism, short nose with anteverted nostrils, flat nasal bridge, and short neck. At birth, affected the infants have temporofrontal balding or sparseness, which, together with the abundant hair over the top of the head, gives a pattern like that of Iroquois Indians. This pattern disappears later if the child continues to have abnormal hair.

Zakowski et al. (1992) described absence of the pericardium and focal aplasia cutis in the axillary area in PKS.

Mauceri et al. (2000) reported a 15-year-old girl with Pallister-Killian syndrome and pineal tumor. They pointed out that isochromosome 12p is a frequent cytogenetic marker of germ cell tumors (testicular and ovarian) and has been observed in pineal germ cell tumors (de Bruin et al., 1994).

Genevieve et al. (2003) described an unusual case of i(12p) in a 15-year-old boy who had mild mental retardation, minor facial features, normal weight, length, and cranial measurements, as well as hyperpigmented streaks. The boy attended normal school until the age of 14 years. Because of the hyperpigmented streaks, chromosome analysis was performed on skin fibroblasts, which showed 37% of cells had an additional isochromosome for the short arm of chromosome 12.

Yeung et al. (2009) reported a girl with PKS who was referred at age 7 months for developmental delay and dysmorphic features. She had temporal alopecia, periorbital fullness, ptosis, nystagmus, wide mouth, long philtrum, and cleft palate. Other features included single palmar creases, bilateral accessory nipples, small hands and feet with dorsal edema, and hypoplasia of the labia with a common anal and vaginal opening. She had delayed growth parameters, moderate hypotonia, and global developmental delay. Although considerable developmental progress was achieved over the ensuing year, including gross motor skills and ability to stand and vocalize, this progression did not continue after 2 years. FISH analysis detected a supernumerary ring chromosome in 38% of buccal mucosa cells and 41% of skin fibroblasts, but did not detect the abnormality in blood cells. In this patient, tetrasomy 12p resulted from a ring chromosome containing 2 copies of chromosome 12p13-cen, not the usual i(12p). Yeung et al. (2009) postulated that the more advanced developmental progress in this patient compared to patients with typical PKS may have resulted from a smaller tetrasomic segment or different tissue distribution of the ring chromosome. Tissue distribution would be expected to differ if the ring chromosome arose during a postzygotic mitotic division, rather than at meiosis, as is typical for isochromosome PKS.

Blyth et al. (2015) reported the clinical features of 22 living patients with Pallister-Killian syndrome in a population-based study in Great Britain. The patients ranged in age from 4 months to 31 years, although half were under 5 years of age. There was a statistically significant increase in the risk of the disorder with increasing parental age. There was not an excess of high birth weights, and all patients were within 2.67 SD of the mean. All patients except the 4-month-old baby showed some degree of global developmental delay, and most were unable to communicate verbally. However, 27.3% had only mild or moderate intellectual disability. Common features included neonatal hypotonia with feeding difficulties, scoliosis, early-onset seizures, hearing impairment, and visual anomalies, such as myopia or strabismus. As babies, all had absent frontotemporal hair which gradually improved with age. Most continued to have areas of alopecia or other hair abnormalities, such as sparse or thick eyebrows. Dysmorphic facial features were common but variable, and included slanted palpebral fissures, short nose with anteverted nares, long philtrum, tented lip, low-set ears, micrognathia, prognathia, delayed tooth eruption, and overall coarse facial features. Additional features included accessory nipples (43%), short broad hands (57%), pigmentary skin lesions (67%), limb shortening (24%), anhidrosis or hypohidrosis (40%), hyperventilation (23%), and autistic features (27%). There was no suggestion of a genotype/phenotype correlation on any tissue examined. Two individuals (9.1%) had hexasomy of chromosome 12p.

Pallister-Killian Syndrome Due to Hexasomy of Chromosome 12p

Vogel et al. (2009) reported a 5-year-old girl with PKS resulting from mosaicism for 2 supernumerary isochromosomes, or hexasomy 12p. Polyhydramnios, preaxial polydactyly, and congenital heart disease were detected at 36 weeks' gestation. After birth, she was noted to have a large nuchal fold, sparse woolly hair, frontal bossing, micrognathia, hypertelorism, large low-set ears, broad nose, anteverted nostrils, long philtrum, high palate, nail hypoplasia, and atypical palmar creases. She also had hearing deficit and hypermetropia. She was hypotonic, and motor skills were delayed, and she was not able to stand at age 24 months due to hip dystrophy. At 4 months of age, she had poor growth parameters, hypertrophic cardiomyopathy with an ejection fraction of 30%, bilateral inguinal hernias, and hypopigmented streaks with dry skin. By 5 years of age she had only a mild developmental delay, with an IQ of 81. Analysis of cultured skin fibroblasts with FISH and comparative genomic hybridization showed hexasomy 12p in 18% of cells. Vogel et al. (2009) noted that this was the second second live case of mosaicism for hexasomy 12p to be reported; the first being that of Choo et al. (2002) in a 2-year-old girl with coarse facies, mental and motor retardation, cleft palate, rhizomelic shortening of limbs, and a diaphragmatic hernia, due to 35% tetrasomy and 15% hexasomy 12p. Vogel et al. (2009) suggested that phenotypic variation in PKS is most likely a result of which tissue types carry the mosaic cell line more than the percentage of mosaic cells or gene-dosage effects.

Cytogenetics

Peltomaki et al. (1987) used a probe of the KRAS2 gene (190070) to confirm that the extra chromosome in Pallister-Killian syndrome is composed of 2 short arms of chromosome 12. Hunter et al. (1985) used LDHB (150100) for the same purpose. Peltomaki et al. (1987) showed that the 2 short arms are identical, thus indicating that it represents an isochromosome 12p. Peltomaki et al. (1987) reported findings that may explain the mechanism of origin of the tissue-limited mosaicism: the proportion of abnormal mitoses fell dramatically during long-term culture of fibroblasts. See also Zhang et al. (1989). Wenger et al. (1990) concluded that the tissue-specific mosaicism in the 12p isochromosome syndrome is best explained by in vivo and perhaps also in vitro loss of the isochromosome from 47,XY (or XX), plus i(12p) cells.

Cormier-Daire et al. (1997) used microsatellite DNA markers on 12p alleles of maternal origin in cultured skin fibroblasts of a case of PKS. The findings suggested that the tetrasomy 12p was the result of a prezygotic event, with a nondisjunction event during maternal meiosis.

Schubert et al. (1997) reported 2 cases of Pallister-Killian syndrome in which the distribution of the additional isochromosome of 12p was analyzed in various tissues. One case, diagnosed prenatally, showed mosaicism for i(12p) in chorionic villi and in amniocytes but the isochromosome was absent in cultured lymphocytes of fetal blood taken at 21 weeks. Long-term culture of umbilical cord showed the isochromosome in 100% of metaphases. In the second case of a term infant, the i(12p) was diagnosed in cultured lymphocytes (4%) and fibroblasts (93%). Secondary loss of the isochromosome was demonstrated in the second case by analyzing metaphases and interphases of fibroblasts in the first, fourth, and fifth subculture using fluorescence in situ hybridization. The proportion of cells with the isochromosome decreased from 93% to 40% and then to 28%, respectively. DNA analysis in case 1 showed a maternal meiotic origin of the i(12p). In case 1, the mother was 44 and the father was 54 years old. Ultrasonography showed flat profile, diaphragmatic hernia, and enlargement of the fourth cerebral ventricle. The infant was stillborn at 27 weeks.

Diagnosis

Speleman et al. (1991) used fluorescence in situ hybridization with chromosome 12-specific DNA probes for the rapid and reliable detection of the i(12p) chromosome. Detection was possible also in interphase cells.

Ohashi et al. (1993) used interphase fluorescence in situ hybridization with a chromosome 12-specific alpha satellite probe for diagnosis of PKS in buccal mucosal cells. Isochromosome 12p-positive cells showed 3 signals over the nucleus, while diploid cells had 2 signals.

Prenatal Diagnosis

Soukup and Neidich (1990) made the diagnosis of Pallister-Killian syndrome on routine amniocentesis. In the aborted fetus, various degrees of mosaicism were found in 4 tissues.

Thakur et al. (2019) reviewed the prenatal findings associated with Pallister-Killian syndrome. Prenatal diagnosis was usually incidentally made by karyotyping and performed because of advanced maternal age, increased nuchal translucency thickness, or fetal anomaly. The most frequent and distinctive prenatal findings were rhizomelic limb shortening, diaphragmatic hernia, thickened nuchal fold, increased prenasal thickness, postaxial polydactyly, and polyhydramnios. Other findings included a flat facial profile, congenital diaphragmatic hernia, cardiac malformations, and intrauterine growth retardation. Gestational age at diagnosis varied from 13 to 32 weeks. Cytogenetic studies most commonly showed a supernumerary marker isochromosome 12p in a mosaic state, with maternal meiosis II nondisjunction as a mechanism. The recommended sample for testing prenatally is amniotic fluid, since cytogenetic diagnosis on chorionic villi can be misleading. The authors recommended a microarray on uncultured amniocytes, with a karyotype on amniotic fluid. All reported cases have been sporadic.

Population Genetics

In a population-based study in Great Britain, Blyth et al. (2015) estimated the birth incidence of Pallister-Killian syndrome to be 5.1 per million live births.

History

This syndrome was independently reported by Pallister et al. (1977) and Teschler-Nicola and Killian (1981) because of the characteristic combination of clinical manifestations, especially the combination of coarse face, pigmentary skin anomalies, localized alopecia, profound mental retardation and seizures, and the relatively frequent occurrence of diaphragmatic defects and supernumerary nipples. The presence of tetrasomy 12p was not recognized because chromosomal studies of fibroblasts were not done. In fact, according to Pallister (2003), chromosome studies of fibroblasts were performed by his colleague Lorraine Meisner, but the anonymous chromosome was misinterpreted.