Pallister-Killian Syndrome Research Articles

Prenatal diagnosis of a mosaic supernumerary marker iso (8p) (tetrasomy 8p): discordance between chorionic villi culture and amniotic fluid karyotypes

We describe the first case of mosaic supernumerary marker iso (8p) displaying a karyotype discordance between chorionic villi (CV) and amniotic fluid (AF) cultures during prenatal cytogenetic diagnosis. In the first trimester, cytogenetic analysis after chorionic villi sampling (CVS) was normal in all metaphases in the short-term cytotrophoblast cell culture, but an undefined supernumerary marker was detected in 60% of mesenchymal cells in the long-term CV culture. Informed of the mosaicism, the couple selected amniotic fluid sampling as a second-trimester confirmatory diagnostic procedure. The supernumerary marker was absent in all of the 25 available AF cells metaphases. The prospective parents received genetic counselling and were informed that the discordance could be interpreted as a placental confined mosaicism or as a true foetal mosaicism with low percentage of affected cells. The couple opted to continue the pregnancy. In the second month of life, the child had abnormal development with severe psychomotor delay and frequent episodes of epilepsy. Postnatal cytogenetic extensive re-evaluation discovered that the previously detected supernumerary marker was indeed an isochromosome (8p) rearrangement present at low frequency in 5% of the blood lymphocytes.

Pallister—Killian syndrome: an unusual cause of epileptic spasms

Pallister‐Killian syndrome (PKS) is a rare, sporadic, genetic disorder characterized by dysmorphic features, learning disability *, and epilepsy. It is caused by a mosaic supernumerary isochromosome 12p (i[12p]). The i(12p) is rarely found in peripheral blood but it is present in skin fibroblasts. Recognition is essential for cytogenetic diagnosis. We describe a male aged 2 years 6 months and a female aged 11 years with PKS and epileptic spasms (ES). This type of seizure is not unusual in patients with brain malformations and with severe developmental delay, but it is sometimes difficult to recognize without video‐electroencephalogram studies and could be mistaken for other types of seizure or behavioural manifestations. In these two patients with PKS, spasms had late onset, persisted beyond infancy, and were drug resistant. Clinicians should be aware of this possibility in PKS, which appears to be a rare cause of ES.

Pallister–Killian syndrome: an unusual cause of epileptic spasms

Pallister-Killian syndrome (PKS) is a rare, sporadic, genetic disorder characterized by dysmorphic features, learning disability, and epilepsy. It is caused by a mosaic supernumerary isochromosome 12p (i[12p]). The i(12p) is rarely found in peripheral blood but it is present in skin fibroblasts. Recognition is essential for cytogenetic diagnosis. We describe a male aged 2 years 6 months and a female aged 11 years with PKS and epileptic spasms (ES). This type of seizure is not unusual in patients with brain malformations and with severe developmental delay, but it is sometimes difficult to recognize without video-electroencephalogram studies and could be mistaken for other types of seizure or behavioural manifestations. In these two patients with PKS, spasms had late onset, persisted beyond infancy, and were drug resistant. Clinicians should be aware of this possibility in PKS, which appears to be a rare cause of ES.

Congenital diaphragmatic hernia in a patient with tetrasomy 9p

Tetrasomy of the short arm of chromosome 9 constitutes a rare condition resulting in a well clinically recognized syndrome. In our case, in addition to the characteristic phenotype at birth, the existence of a hernia-type Bochdalek diaphragmatic defect was found. Cytogenetic analysis revealed a nonmosaic case of an isochromosome of the entire short arm of chromosome 9 with no involvement of the heterochromatic region of the long arm: 47, XX, +i (9p). Because chromosome 9 contains several gene locus for enzymes and receptors of the retinoid pathway, this case potentially contributes to retinoid hypothesis in the etiology of congenital diaphragmatic hernia.

P02.15: Prenatal diagnosis of tetrasomy 9p associated to Dandy‐Walker malformation

Objective: To describe the possibility of rotation of the vermis as the cause of enlarged posterior fossa in the fetus. Methods: Eight women were referred to our ultrasound unit for evaluation of enlarged posterior fossa with suspected agenesis of the vermis on axial plane. All women underwent thorough ultrasound evaluation, including demonstration of the posterior fossa on midsagittal plane with measurements of the vermis. All patients received a genetic as well as pediatric neurologist consultation. Results: The mean age of the women was 27 (with range of 20–33) years and the mean gestational week at diagnosis was 19.5 (with range of 15–25). On standard axial plane, there was a ‘‘direct communication’’ between the cysterna magna and the 4th ventricle. On mid-sagittal plane, however, the vermis could be very well delineated with slight anterior rotation. Its measurements were within normal limits for gestational age. The normality of the vermis was confirmed in prenatal MRI in 2 cases, on postnatal MRI and/or US in 5 cases and in PM in one case. The 7 alive children are well developed with no neurological sequels after a mean follow-up of 4 years (with range of 1–7.5). Conclusion: The demonstration of the normal vermis on mid-sagittal plane in cases with ‘‘enlarged posterior fossa’’ on standard plane raises the possibility of rotation of the vermis. We suggest that in every case of enlarged posterior fossa or suspected vermian agenesis, the mid-sagittal plane should be utilized and rotation of the normal vermis should be excluded.

Forty-two supernumerary marker chromosomes (SMCs) in 43 273 prenatal samples: chromosomal distribution, clinical findings, and UPD studies

Fluorescence in situ hybridization (FISH) analyses were performed on supernumerary marker chromosomes (SMCs) detected in 43,273 prenatal diagnoses over a period of 11 years, 1993-2003. A total of 42 pregnancies with SMC were identified, indicating a prevalence of one in 1032. A total of 15 SMCs were endowed with detectable euchromatin (prevalence, 1/2884), including six SMCs containing the cat eye critical region (CECR) on chromosome 22q11.21 (1/7212). De novo SMCs were found in 29 pregnancies (1/1492), including 14 euchromatic SMCs (48.2%). Follow-up studies were available for 24 cases. Nine pregnancies (37.5%) were terminated; two children (8.3%) were born with Pallister-Killian syndrome and cat eye syndrome (CES), respectively; 13 children (54.1%) showed apparently normal development. Familial SMCs were identified in 13 pregnancies (1/3328) from 11 unrelated women. They were all acrocentric. In all, 10 were heterochromatic and one was an extra der(22)t(11;22) chromosome. A total of 12 cases were available for follow-up. One pregnancy was terminated due to anhydramnios, spina bifida, and cystic-dysplastic kidneys; one child suffered from a der(22) syndrome; 10 children (83.3%) appeared unaffected. Studies for uniparental disomy were performed on seven pregnancies and revealed a case of maternal heterodisomy for chromosome 22. So far this is the largest FISH study of prenatally ascertained SMCs and the first study with detailed data on the prevalence. Findings illustrate the spectrum and clinical outcomes of prenatally diagnosed SMCs, and indicate a higher frequency of SMCs than generally assumed.

Tetrasomy 9q in an infant with cleft palate and multiple anomalies

We report a patient with partial tetrasomy 9q resulting from a de novo triplication of 9q13q22.1. The clinical features, including microcephaly, beaked nose, short palpebral fissures, camptodactyly, joint contractures, and moderate developmental delay were similar to trisomy 9q, although our patient also had unique features including cleft palate and several unexplained fractures. The latter could be secondary to abnormal tone and contractures. Although tetrasomy 9p is a well-known entity, our patient, to our knowledge, is the first and only individual reported to have tetrasomy 9q.

Tetrasomy 12pter-12p13.31 in a girl with partial Pallister–Killian syndrome phenotype

A dysmorphic patient was shown to carry a small supernumerary marker chromosome. Multicolor, centromere-multicolor and regular FISH experiments proved the marker to be an analphoid 12pter derived isochromosome. Microdissection of the marker followed by reverse painting and array CGH analysis showed that the isochromosome contains approximately 6 Mb of 12pter-12p13.31 derived sequence. This is only the second report of a marker with a neocentromere 12pter and the molecular fine mapping of the duplicated region further refines the 12p region defining the Pallister–Killian syndrome phenotype. In addition, we show the feasibility of using microdissected chromosomes or chromosomal fragments to molecularly map the chromosomal breakpoints on array CGH. This technology may aid in the identification of chromosomal translocation breakpoints.

Brain MRI findings of older patients with Pallister–Killian syndrome

Pallister–Killian syndrome (PKS) is a disorder caused by a mosaic tetrasomy of chromosome 12p, which manifests with dysmorphism, intellectual disabilities, auditory disturbance, and epilepsy. Here, we describe the findings of brain magnetic resonance (MR) imaging in two patients with PKS. One patient, a 43-year-old man, showed multiple lesions with high signal intensity on T2-weighted image (WI) in the basal ganglia, and widespread T2 elongation in the periventricular white matter. The same signal change was also present in the pontine base. The other patient, a 37-year-old woman, showed T2-high lesions in the bilateral putamina and the parietal periventricular white matter. There was prominent atrophy of the cerebellum and brainstem in this latter case. Both cases showed cortical atrophy with frontal predominance, with accompanying dilatation of the lateral ventricles. Hypoplastic corpus callosum was also present in both cases. Cerebral atrophy with ventricular dilatation has been often described in PKS cases, but many of the MR findings in the present patients have never been reported. Such findings may appear with advancing age in PKS. Since 12p mosaicism is rarely detected in peripheral blood lymphocytes, examination of buccal mucosal cells with fluorescent in situ hybridization method is preferable for the diagnosis of PKS. Recognition of the characteristic features on cranial MR imaging, in addition to the characteristic facial appearance in adulthood, should prompt the correct diagnosis of adult PKS patients.

Pallister-Killian Syndrome: Rapid Decrease of Isochromosome 12p Frequency during Amniocyte Subculturing. Conclusion for Strategy of Prenatal Cytogenetic Diagnostics

Pallister-Killian syndrome (PKS) is characterized cytogenetically by mosaic tetrasomy of chromosome 12p. Routine prenatal diagnosis of PKS is still complicated because of the difficulties of discriminating between the supernumerary isochromosome 12p and the duplication 21q and because of the variable level of mosaicism. The frequency of cells with an extra metacentric chromosome i(12)(p10) is usually determined by tissue-limited or tissue-specific mosaicism. We demonstrated a decrease of the abnormal clone with extra i(12p) in the amniotic fluid cells of the PKS fetus during amniocyte subculturing. The rapid loss of the i(12p) in the course of amniocyte subculturing should be the focus of attention during prenatal karyotyping. This is especially necessary for cultures with slow growth, which require further interpretation of the result during cytogenetic diagnosis of PKS.

Prenatal Diagnosis of Congenital Diaphragmatic Hernia in a Fetus with 46,XY/46,X,-Y,+der(Y)t(Y;1)(q12;q12) Mosaicism : A Case Report

Congenital diaphragmatic hernia (CDH) is often associated with major anomalies and chromosomal abnormalities. Chromosomal abnormalities are usually detected in 9.5% to 34% of fetuses with CDH prenatally diagnosed and the defect has also been reported in association with multiple syndromes such as Pallister-Killian syndrome, Fryns syndrome, Di George syndrome and Apert syndrome. Among the chromosomal abnormalities associated with CDH, trisomy 21, 18, and 13 are most common. Association with complex chromosomal aberrations such as mosaicism has also been reported. However, CDH presented in a fetus with Y-autosome translocation is extremely rare. Herein, we reported a case of fetus with 46,XY/46,X,-Y,+der(Y)t(Y;1)(q12;q12) mosaicism who presented with CDH diagnosed by ultrasonography at 19 weeks' gestation.

Post‐zygotic origin of isochromosome 12p

Advance knowledge about the mechanism of isochromosome formation. Echographic examination of the foetus. G- and/or T-banded chromosome and FISH analysis using chromosome 12p subtelomeric probes on short- and long-term CVS cultures, amniocytes and foetal fibroblasts. Polymorphic CA repeat analysis on DNA from the foetus and both parents. Short-term CVS cultures showed a 46,XX karyotype, whilst long-term CVS cultures showed a 47,XX,+12 karyotype. FISH on amniocytes indicated 2, 3 and 4 signals. Foetal fibroblasts showed both 47,XX,+12 and 47,XX,+i(12)(p10) karyotypes. DNA analysis revealed the isochromosome to be paternal in origin, whilst the other two foetal chromosomes 12 were maternal, part iso- and part heterodisomy. The cytogenetic and DNA constitution of the foetus indicated the isochromosome 12p to be of paternal origin, and implied post-zygotic formation of the isochromosome 12p in the Pallister-Killian syndrome.

Anestesia em criança com síndrome de Pallister-Killian: relato de caso

JUSTIFICATIVA E OBJETIVOS: A síndrome de Pallister-Killian (SPK) é uma doença genética rara causada por uma anomalia, em mosaico, no cromossomo 12. Há pouca informação sobre esta síndrome na literatura anestésica. O objetivo deste relato foi divulgar e discutir as características que podem ser de interesse para a anestesia. RELATO DO CASO: Paciente do sexo masculino, 5 anos de idade, foi submetido a anestesia geral para a realização de ressonância magnética do crânio. Apresentava as características típicas da SPK: dismorfismo facial, alopecia temporal, micrognatismo, macroglossia, retardo mental, convulsões e alterações pigmentares cutâneas. A anestesia foi induzida e mantida com sevoflurano sob máscara facial e cânula orofaríngea, com ventilação assistida manual durante a indução. Não houve intercorrências e o exame foi feito em regime ambulatorial. CONCLUSÕES: A importância da avaliação pré-anestésica é enfatizada, devido às malformações, inclusive cardíacas, associadas a esta síndrome. É recomendada a preparação para possível dificuldade de intubação traqueal ou de manutenção das vias aéreas.

Prenatal diagnosis of tetrasomy 9p in a 19‐week‐old fetus with Dandy–Walker malformation: a case report

The presentation of sonographic and perinatal findings of tetrasomy 9p. Chorionic villus sampling and amniocentesis were performed at 19 weeks of gestation because of the sonographic findings of Dandy-Walker malformation with bilateral ventriculomegaly. Cytogenetic analysis showed 47,XX,+i psu dic(9)(pter->q12::q12>-pter). The pregnancy was terminated at 20 weeks of gestation at the request of the parents. At post-mortem examination, the presumed hypoplasia of the vermis could not be confirmed for technical reasons. No other pathological findings were seen. From our experience and from the literature, we conclude that Dandy-Walker malformation is an important finding in tetrasomy 9p. Chromosomal studies should be carried out in fetuses with sonographically detected Dandy-Walker malformation, even in the absence of other abnormalities.

Congenital diaphragmatic hernia and chromosomal anomalies: autopsy study.

In a 10-year review of autopsy records from Lutheran General Hospital (1992-2002), 13 cases of congenital diaphragmatic hernia (CDH) were found. The fetuses ranged between 21 and 35 wk of gestation. Four were born alive and five were diagnosed prenatally. The defect was left-sided in 11 cases. Cytogenetic study revealed five cases with normal karyotype and three cases with complex karyotypes. In five cases, no karyotype was performed. The three complex karyotypes were: 46,XX,del(8)(p23.1), 47,XX, +i(12)(p10)[6]/46XX[14] (Pallister-Killian syndrome), and 47,XY,+der(22)t(11:22) (q23.3:q11.2). The unbalanced translocation of chromosomes 11 and 22 in congenital diaphragmatic hernia has not been previously described. Three fetuses had heart abnormalities, including one which was associated with the 8p deletion. The other two had no karyotype study. Neither in this study, nor in the literature, is there a consistent or prevailing association between a specific chromosomal anomaly and CDH. The embryologic closure of the diaphragmatic leaflets may be mediated by a nonstructural chromosomal defect, more than one gene, and/or may be related to abnormalities not currently detectable.

Prenatal diagnosis of tetrasomy 9p

Prenatal diagnosis of tetrasomy 9p

Clinical, cytogenetic, and molecular observations in a patient with Pallister‐Killian‐syndrome with an unusual karyotype

Pallister-Killian syndrome is a clinically recognizable syndrome, usually due to a tissue-limited mosaicism for a supernumary 12p isochromosome (i12p). Here we report an unusual case with tetrasomy/trisomy/disomy 12p mosaic in fibroblasts and trisomy/disomy 12p mosaic in lymphocytes. The tetrasomy 12p was due to an i12p, the trisomy 12p to a single 12p marker. Both marker chromosomes were investigated with conventional cytogenetic techniques and fluorescent in situ hybridization (FISH). Stability under culturing conditions was studied. DNA-analysis revealed prezygotic maternal origin of the extra 12p material. Clinically, the patient seems to have less retardation than most patients with Pallister-Killian syndrome.

Prenatal management of mosaic tetrasomy 5p. K. S. Reddy and B. Huang. Prenatal Diagnosis 2003; 1: 82–85

AbstractThe original article to which this Erratum refers was published in Prenatal Diagnosis (2003; 1: 82–85). Copyright © 2003 John Wiley & Sons, Ltd.

Prenatal diagnosis of mosaic tetrasomy 8p.

Tetrasomy 8p is a rare chromosomal disorder that has only been detected in a mosaic form. At the present time, 11 cases have been reported; their phenotype included agenesis of the corpus callosum, enlarged ventricles, minor facial dysmorphism, rib and vertebral anomalies, and mild to moderate developmental delay. To the best of our knowledge, tetrasomy 8p has never been prenatally diagnosed. This 43-year-old woman was referred for amniocentesis at 20 weeks' gestation because of advanced maternal age. Amniotic fluid cells were cultured according to standard techniques by the in situ method. A supernumerary chromosomal marker was detected in a single clone of cultured amniotic cells and interpreted by RHG banding as an isochromosome of the short arm of chromosome 8 (i(8p)). The ultrasound investigation at 27 weeks gestation revealed enlarged ventricles and agenesis of the corpus callosum, which were confirmed at fetal autopsy after medical termination of the pregnancy. Chromosomal analyses, including RHG banding and FISH, of several tissues showed different levels of i(8p) mosaicism. Whereas no i(8p) was detected on cytotrophoblast nor additional amniotic fluid cells, 97% and 30% of cells from long-term cultures of placenta and lymphocytes, respectively, had the i(8p). Using DNA markers, the isochromosome 8p was interpreted as the result of a prezygotic event during maternal meiosis. Our findings suggest that the i(8p) is the subject of tissue selection. Tetrasomy 8p might be underdiagnosed during pregnancy; therefore, karyotyping on a fetal blood sample following detection of agenesis of the corpus callosum when no chromosomal abnormality has been found on the amniotic fluid cell cultures should be discussed with the parents.

Tetrasomy 12p—unusual presentation in CVS

CVS direct preparations usually achieve limited resolution and are better at detecting numerical rather than structural abnormalities. A CVS direct preparation analyzed using G-banding revealed a 47,XY,+G karyotype in 5 of 11 cells and was reported as mosaic for trisomy 21. Subsequent analysis of the CVS culture found only normal male cells. Amniocentesis revealed both normal male cells and cells with an extra F-group chromosome. Fluorescence in situ hybridization (FISH) identified this chromosome to be an isochromosome from the short arm of chromosome 12 [i(12)(p10)]. The amniocyte karyotype was reported as 47,XY,+i(12)(p10)[12]/46,XY[8].ish i(12)(p10)(wcp12+), which is associated with Pallister-Killian syndrome. Reexamination of the CVS direct preparation by FISH with a chromosome 12 centromere probe confirmed the karyotype of this tissue to be 47,XY,+mar[5]/46,XY[6].nuc ish 12cen(D12Z3 x 3)/12cen(D12Z3 x 2). Thus, multiple studies, including amniocentesis and fluorescence in situ hybridization, may be required to fully and accurately evaluate abnormalities detected by CVS. This case also indicates that mosaicism for supernumerary isochromosomes may have a complex origin.