Name
PALLISTER-KILLIAN SYNDROME

Synonyms
TETRASOMY 12P SYNDROME (codes)

Definition
Pallister-Killian syndrome is a rare disorder comprising multiple congenital anomalies, streaks of hypo(hyper)pigmentation, seizures, profound mental retardation, and the presence of an extra metacentric chromosome i(12)(p10), usually limited to skin fibroblasts. The mechanism and parental origin of the extra chromosome i(12)(p10) are unknown. (Cormier et al. Prezygotic origin of the isochromosome 12p in Pallister-Killian syndrome. Am-J-Med-Genet. 1997 Mar 17; 69(2): 166-8)

Signs & symptoms
Pallister-Killian syndrome (PKS) is characterized by multiple congenital anomalies including pigmentary skin changes, mental retardation, and the mosaic presence of a tissue-limited isochromosome 12p [i(12p)]. (Struthers et al. Parental origin of the isochromosome 12p in Pallister-Killian syndrome: molecular analysis of one patient and review of the reported cases. Am-J-Med-Genet. 1999 May 21; 84(2): 111-5) Pallister-Killian syndrome is a rare disorder comprising multiple congenital anomalies, streaks of hypo(hyper)pigmentation, seizures, profound mental retardation, and the presence of an extra metacentric chromosome i(12)(p10), usually limited to skin fibroblasts. (Cormier et al. Prezygotic origin of the isochromosome 12p in Pallister-Killian syndrome. Am-J-Med-Genet. 1997 Mar 17; 69(2): 166-8) The Pallister-Killian syndrome is a sporadic multiple congenital anomaly syndrome characterized by "coarse" face, profound mental retardation, and epilepsy. (Rodriguez et al. Lethal Pallister-Killian syndrome: phenotypic similarity with Fryns syndrome. Am-J-Med-Genet. 1994 Nov 1; 53(2): 176-81) The phenotype of younger children has already been well documented. During childhood and adolescence, however, the phenotype changes markedly. The disorder in older children and young adults is characterized by a coarse and flat facies, macroglossia prognathia, everted lower lip, and severe psychomotor retardation with muscular hypertonia and contractures. (Horneff et al. Pallister-Killian syndrome in older children and adolescents. Pediatr-Neurol. 1993 Jul-Aug; 9(4): 312-5)

Etiology
Patients with this condition are tetrasomic for the short arm of chromosome 12. Affected individuals have mosaicism form an isochromosome consisting of the short arms of chromosome 12. Cormier-Daire et al., (1997) presented data in one case suggesting that the origin of the isochromosome was prezygotic. Struthers et al., (1999) presented a case where the extra marker chromosome was shown to be of maternal origin. On reviewing the literature they suggested that a premeoitic mitotic error may be the most likely mechanism. (R.M. Winter, M. Baraitser, London Dysmorphology Database, Oxford Medical Databases, 2000)

Diagnosis
As the condition can only be diagnosed by looking at skin chromosomes, and this is not routinely done when the blood karyotype is normal, it is necessary to recognize this condition clinically, and the facial features are distinct. They tend to be coarse, with a broad forehead, normal OFC, apparent hypertelorism, sagging cheeks and a droopy mouth. Hair seems sparse especially over the temporal areas. Birth-weight is often normal. Hypopigmented macules, and even a swirly hyperpigmentation, reminiscent of incontinentia pigmenti, can be found. Zakowski et al., (1992) reported a case with aplasia cutis of the axilla and lateral neck. Mental retardation can be severe. Supernumerary nipples are commonly found. The facial coarsening becomes progressively more severe with age (Horneff et al., 1993). Cases with trisomy for 12p show somewhat similar features (Allen et al., 1996; Rauch et al., 1996). Two cases have been reported that were initially diagnosed as Fryns syndrome (McPherson et al., 1993; Stratton et al., 1994) - this is an important differential diagnosis. Rodriguez et al., (1994) reported three further cases that emphasise this point. Mild cases can be difficult to diagnose (see Bielanska et al., 1996, for example). Schaefer et al., (1997) also emphasise the variability of the phenotype, including cases with mild developmental delay and hypomelanosis of Ito, but without characteristic facial abnormalities. (R.M. Winter, M. Baraitser, London Dysmorphology Database, Oxford Medical Databases, 2000) Diagnosis based on clinical appearance alone is often difficult due to the broad spectrum of clinical anomalies not specific to this syndrome. Due to mosaicism, it is altogether necessary to examine several tissues for the presence of tetrasomy 12p, including circulating lymphocytes in which mosaicism can be as low as 1-3%, amniocytes, chorionic cells and skin fibro-blasts in which mosaicism ranges from 6-100%. When highly suspected on ultrasound examination, the diagnosis recommends prenatal cytogenetic studies because survivors are severely mentally retarded. All the cases are sporadic with only a single preliminary report of recurrence. The cytogenetic diagnosis is therefore helpful in order to reassure family members in regard to genetic counseling. (Mathieu et al. Collaborative study of mosaic tetrasomy 12p or Pallister-Killian syndrome (nineteen fetuses or children). Ann-Genet. 1997; 40(1): 45-54) Tissue-specific mosaic distribution of an additional isochromosome 12p is the characteristic chromosomal aberration in Pallister-Killian syndrome. Often it is confined to fibroblasts, whereas lymphocytes show a normal karyotype. (Schubert et al. Report of two new cases of Pallister-Killian syndrome confirmed by FISH: tissue-specific mosaicism and loss of i(12p) by in vitro selection. Am-J-Med-Genet. 1997 Oct 3; 72(1): 106-10) The chromosomal abnormality is often missed if only peripheral lymphocytes are examined, and bone marrow or cultured skin fibroblasts may be required for confirmation. (Lo et al. Pallister-Killian syndrome: the first reported case in Hong Kong. Chung-Hua-Min-Kuo-Hsiao-Erh-Ko-I-Hsueh-Hui-Tsa-Chih. 1998 Sep-Oct; 39(5): 333-5) In situ hybridization of peripheral lymphocyte interphase cells with chromosome 12 specific probes may be a useful supplemental procedure for the diagnosis of PKS, at least in the newborn infant. (Reeser et al. Failure of PHA-stimulated i(12p) lymphocytes to divide in Pallister-Killian syndrome. Am-J-Med-Genet. 1992 Apr 1; 42(6): 815-9)

Pren. diag. preven.
Pallister-Killian syndrome (tetrasomy 12p) is an uncommon aneuploidy, which may present in the prenatal period with an ultrasonographically detected fetal abnormality or following karyotyping for maternal age. (Langford et al. Pallister-Killian syndrome presenting through nuchal translucency screening for trisomy 21. Prenat-Diagn. 2000 Aug; 20(8): 670-2) The most consistent pre-natal ultrasound findings include hypertelorism, broad neck, shorts limbs, abnormal hands or feet, diaphragmatic hernia and hydramnios. Recognition of this congenital malformation pattern pre-natally may allow utilization of FISH (fluorescence in situ hybridization). (Chiesa et al. Pallister-Killian syndrome [i(12p)]: first pre-natal diagnosis using cordocentesis in the second trimester confirmed by in situ hybridization. Clin-Genet. 1998 Oct; 54(4): 294-302) It is suggested that a perinatal-lethal form of Pallister-Killian syndrome is underdiagnosed and recommend that all cases of prenatally detected diaphragmatic hernia be tested for Pallister-Killian syndrome using interphase FISH on uncultured amniocytes. (Mowery et al. The use of interphase FISH for prenatal diagnosis of Pallister-Killian syndrome. Prenat-Diagn. 1997 Mar; 17(3): 255-65) The most consistent reported prenatal ultrasound findings for tetrasomy 12p include polyhydramnios with short femurs and a diaphragmatic hernia. (Wilson et al. Tetrasomy 12p (Pallister-Killian syndrome): ultrasound indicators and confirmation by interphase fish. Prenat-Diagn. 1994 Sep; 14(9): 787-92)

References
Anderlid-BM; Sahlen-S; Schoumans-J; Holmberg-E; Ahsgren-I; Mortier-G; Speleman-F; Blennow-E
Detailed characterization of 12 supernumerary ring chromosomes using micro-FISH and search for uniparental disomy
AMERICAN-JOURNAL-OF-MEDICAL-GENETICS. MAR 15 2001; 99 (3) : 223-233

Paladini-D; Borghese-A; Arienzo-M; Teodoro-A; Martinelli-P; Nappi-C
Prospective ultrasound diagnosis of Pallister-Killian syndrome in the second trimester of pregnancy: the importance of the fetal facial profile
PRENATAL-DIAGNOSIS. DEC 2000; 20 (12) : 996-998

Mauceri-L; Sorge-G; Incorpora-G; Pavone-L
Pallister-Killian syndrome: Case report with pineal tumor
AMERICAN-JOURNAL-OF-MEDICAL-GENETICS. NOV 6 2000; 95 (1) : 75-78

Langford-K; Hodgson-S; Seller-M; Maxwell-D
Pallister-Killian syndrome presenting through nuchal translucency screening for trisomy 21
PRENATAL-DIAGNOSIS. AUG 2000; 20 (8) : 670-672

Manasse-BF; Lekgate-N; Pfaffenzeller-WM; de-Ravel-TJL
The Pallister-Killian syndrome is reliably diagnosed by FISH on buccal mucosa
CLINICAL-DYSMORPHOLOGY. JUL 2000; 9 (3) : 163-165

Tanabe-H; Nakagawa-Y; Minegishi-D; Hashimoto-K; Tanaka-N; Oshimura-M; Sofuni-T; Mizusawa-H
Human monochromosome hybrid cell panel characterized by FISH in the JCRB/HSRRB
CHROMOSOME-RESEARCH. 2000; 8 (4) : 319-334

References from
Luglio 2000

References to
22/5/2001

Database
Medline Current Contents

Codes
icd9: - icd9cm: 758.5 - icd10: - mim: #601803 - esenzione: RN1590

By
Francesco Zambon