2003-05-20-14 Pallister Killian syndrome © Cuillier www.thefetus.net/
Pallister Killian syndrome
Fabrice Cuillier, M. Deshayes, J.F. Cartault
Hôpital Félix Guyon, Topazes street, 97400 Saint-Denis, Reunion Island, France. Ph : 0262 90 55 22. Fax : 0262 90 77 30.
Definition: Pallister-Killian syndrome (Pallister-Killian syndrome ) or 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. The Pallister-Killian syndrome is characterized by a tissue-specific mosaic distribution of an additional isochromosome 12p 1-2. Pallister-Killian syndrome is a syndrome that results in a characteristic facial dysmorphia, severe mental retardation and epilepsy 2. Pallister-Killian syndrome is associated too with a wide range of abnormalities including congenital diaphragmatic defects, rhizomelic limb shortening, congenital heart defect, pulmonary abnormalities, urogenital abnormalities and eye defects 3. Nether the less facial anomalies and rarely acral hypoplasia can be found.
Synonyms: Pallister Killian syndrome, tetrasomy 12 p, Teschler-Nicola/Killian syndrome.
Case report: A 37-year-old G5P2 (two miscarriage), Caucasian woman, was referred to our unit for evaluation of a frontal edema in her fetus. She and her husband, who were not consanguineous, were of Reunion island origin. They were healthy and the many members of the large family showed no particular abnormalities. The pregnancy has been uncomplicated and there was no significant medical of family history. The husband was fifty-five years old. The initial screening scan was performed at 13 weeks gestation and an increased nuchal translucency (3,1 mm) was obtained. But the patient refused investigation. At 22 weeks gestation, the ultrasound examination demonstrated:
- A thick nuchal fold (7 mm) and the skin of the occipital region was thickened too (Figure N°1).
- An pre-frontal edema (Figure N°2). The profile was flat with a small nose and thin lips but neither micrognathia nor clefting were noted.
- A short femur (34 mm for a feet at 37 mm). The hands were described to be "square " (Figure N°3).
Sagittal scan of the fetal face at 21 weeks of gestation. The flat profile, with the small nose and prefrontal edema are evident.
Scan of the right hand, described to be "square".
The couple was counseled concerning the options of invasive tests for karyotyping. Indeed on the basis of the unusual association between the aforementioned anomalies, karyotyping was offered to the patient who had previously refused an amniocentesis for pathologic translucency. So the parents accepted to perform an amniocentesis at 23 weeks gestation. The cytogenetic analysis was reported showing that 1/3 % of cells in two out of three cultures had a supernumerary, metacentric marker chromosome characteristic of an isochromosome 12p. The remaining cells had a normal male karyotype. In situ hybridization studies confirmed that the extra chromosome was derived from chromosome 12. Protein electrophorese was normal. The parents were referred for genetic counseling and were advised that although a confined placental mosaicism was possible, the clinical findings in the fetus, were highly suggestive that the fetus was affected by Pallister Killian syndrome. On the basis of this, given the poor prognosis for Pallister Killian syndrome and after counseling, the couple elected to terminate the pregnancy at 29 weeks gestation. Labor was induced with prostaglandins at 29 weeks. The fetus was dead. The presence of the i(12p) was confirmed in cultures of fetal skin and the isochromosome was observed in cells derived from fibroblasts culture. These findings were all consistent with Pallister Killian syndrome. The parental karyotypes were subsequently checked and were both normal.
Fetal autopsy revealed a 1310 g female fetus. On external examination of the face, a long philtrum, up-slanting palpebral fissures and a broad nasal bridge were noted. The weight and the measurement of the fetus were consistent with a gestational age of 29 weeks. There were also cutaneous edema on the neck and the trunk. The internal examination revealed normal interrelationship of the organs and no gross abnormalities. The shape and weights of the hearts, lungs, liver, spleen, pancreas, kidneys and adrenal glands were within the expected range of a 29-week fetus. The size, shape, gyral pattern and cross-sectional morphology of the brain were also consistent with that gestational age.
The postmortem examination confirms the presence of an abnormally flat facial. dysmorphic low-set ears are also evident.
History : Tetrasomy for the short arm of chromosome 12 was first described in 1977 by Pallister et al5 in two adults with profound psychomotor retardation, severe hypotonia, “coarse” facial appearance, hypertelorism and other congenital anomalies (wide-spread pigmentary dysplasia of the skin and severe hypotonia). It was noted to be associated with the curious finding of normal chromosomes in blood lymphocyte cultures but extra chromosome in fibroblast cultures, i.e., tissue specific. The extra-chromosome was identified as a probable i(12p) by Pallister et al 5. Subsequently, the i(12p) was confirmed by LDH-B dosage increase6. Despite the fact that this chromosome abnormality has probably been missed in a number of cases where fibroblasts were not suited, or possibly confused with i(21p), at least 40 cases has been reported with documented or probable i(12p). The majority patients have survived the perinatal period.
Killian and Teschler-Nicola in 1981, independently described a child with an unusual facial appearance, mental retardation, absence of hair in the frontal region of the scalp and hypopigmentation of the skin on the face 7-8-9. Subsequently, several other patients with a similar phenotype were reported 8.
In 1983, a whole issue of the "Journal of clinical dysmorphology" was devoted to Teschler-Nicola/Killian syndrome. The cases of Hersh et al and of Rimoin reported in that same journal 10 and since then those of Lubinsky (1983, 1984) 11 and of Hall, were found to be tetrasomy 12p 12. In that same issue of "Journal Clinical Dysmorphology", Buyse and Korf (1983), pointed out the similarity between Teschler-Nicola/Kjillian syndrome7 and Pallister syndrome 5. In the later syndrome, the extra chromosome, which was found in the fibroblasts but not in the lymphocytes, was finally, after several interpretations, considered to be an isochromosome containing the short arms of 12 by Francke 10. Therefore, most of the cases described as Pallister syndrome, Teschler-Nicola/Killian syndrome and tetrasomy 21 constitute a single clinical entity.
Prenatal diagnosis of the Pallister-Killian syndrome has been reported in several instances, with the first description by Gilgenkrantz et al in 1985 13 and then fortunately, the i(12p) persists in amniocentesis cultures making prenatal diagnosis possible. It has been reported in four cases of routine prenatal diagnosis plus one case done for abnormal ultrasound. Soukup and Neidich (1990) report another cases of i(12p) ascertained in routine prenatal diagnosis at 21 weeks gestation, there was some suspicion of fetal edema, nuchal folds and short femur length, but no evidence of major malformation, like our case6. They made a prenatal diagnosis of tetrasomy 12p from amniocytes, using the R-banding technique and the study of gene dosage effects for SOD1 and LDH-B, after an ultrasound study was carried out first. Chiesa in 1998, report the first prenatal diagnosis on fetal blood cells after cordocentesis during the second trimester 2. The extra-chromosome was first diagnosed by in-situ hybridization. Fluorescence in situ hybridization (FISH) was used to count the interphase and/or metaphase cells containing isochromosome. A review of the literature identified 27 other reports of Pallister-Killian syndrome diagnosed prenatally. Recognition of this congenital malformation pattern pre-natally may allow utilization of FISH.
Prevalence: Human autosomal tetrasomies are rare. Among them, tetrasomy 12p is undoubtedly the least unsual 13. It is more common in woman of advanced age. But we don¹t know the really frequency.
Etiology: All the cases are sporadic with only a single preliminary report of recurrence.
Pathogenesis: Tetrasomy 12p is not always diagnosed, because the tissues are differently affected. Although it is present in a high percentage of fibroblasts, it is practically absent from the blood 13. Individuals with Pallister-Killian syndrome are often mosaic of isochromosom 12p, but in some case, the degree of mosaicism in the chorion villus sample is much more lower than that in the fetal tissues subsequently examined. Confined placental mosaicism is a well-recognized phenomenon in a number of chromosomal abnormalities and is said to contribute to their intra-uterine survival 3.
Conventional GTG banding techniques initially suggested a 21 tetrasomy mosaicism in some patients through the appearance of an additional isochromosome derived from fusion of two chromosome 21 15. An increase in LDHB (lacticodeshydrogenase activity), a locus on the short arm of chromosome 12, suggested an isochromosome 12. This was subsequently confirmed by cytogenetic studies using RHG and RBA banding 4.
The mechanism of the increased nuchal translucency and drops in the syndrome in unclear but in the case of Langford, the fetus had two congenital anomalies which have been reported to be associated with increased nuchal translucency 3. Lalatta report a case of Pallister-Killian syndrome, which demonstrate that prenatal identification is possible by fetal blood sampling, which revealed a normal karyotype 14. All other routine biochemical investigations were normal, with the exception of an LDH abnormal high level. Pallister-Killian syndrome is generally associated with tetrasomy 12p, the chromosomal abnormality being observed in either a mosaic or a non-mosaic state on selected tissues, such as bone marrow and skin fibroblast. The percentage of the abnormal cell line is variable and the feasibility of the clinical diagnosis without the cytogenetic hallmark is still debated. Despite the normal karyotype, the clinical features in this case, together with exceedingly LDH fetal serum levels, are compatible with a diagnosis of Pallister-Killian syndrome.
Associated anomalies: Phenotypic expression has varied from multiple anomalies resulting in perinatal death to the more characteristic situation of profound mental retardation, coarse facial, appearance, pigmentary anomalies, localized alopecia in the temporofrontal area, hypertelorism and long philtrum 4. The difficulties in the diagnosis of Pallister-Killian syndrome are illustrated in the Mathieu et all"s study 4. 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 low as 1-3 %, amniocytes, chorionic cells and skin fibroblasts in which mosaicism ranges from 6-100 %. When highly suspected on ultrasound examination, the diagnosis should suggest prenatal cytogenetic studies because survivors are severely mentally retarded.
The prenatal diagnosis of Pallister-Killian syndrome has previously been reported as an unexpected findings after karyotyping for maternal age and following ultrasound detection of fetal abnormalities 6.
There was no evidence at autopsy of a major anomaly in our case, although several minor anomalies described in the Pallister-Killian syndrome , e.g. coarse facial anomalies, high forehead, apparent hypertelorism, anteverted nostrils, small and apparently low-set ears, simian crease and clinodactyly were present. As gestation progressed, an increasing number of the features of Pallister-Killian syndrome became apparent on ultrasound examination of the fetus. The fetal abnormalities have been detected in a routine anomaly scan at 20 weeks gestation.
Diaphragmatic hernia, congenital heart disease and rhizomelic limb shortening represent the sonographic detectable anomalies, which lead to prenatal diagnosis of Pallister-Killian syndrome 4.
Hypoplastic left heart is not a common feature of Pallister-Killian syndrome but fetuses with cardiac abnormalities may present with increased nuchal translucency16. The fetus also had a diaphragmatic hernia, which is associated with increased nuchal translucency17. However, Pallister-Killian syndrome is associated also with significant facial anomalies, but little attention has been paid to the possibility of diagnosing these by ultrasound, despite the fact that their recognition may represent a significant-contribution to the differential diagnosis of the syndrome. The association between a small nose, a thin upper lip with a protruding lower one represents an important marker of Pallister-Killian syndrome which has several advantages:
- It can be detect at midtrimester ultrasound, as demonstrated by the present case report.
- It can be considered a fairly constant indicator of the syndrome.
- It is usually not associated with Fryns syndrome which represents the main differential diagnosis of Pallister-Killian syndrome (diaphragmatic hernia, acral hypoplasia and, to a lesser extent, facial anomalies are present in both syndromes1.
The echography indications found in Chiesa’ study, were polyhydramnios, short long bones, dilated cerebral lateral ventricles, renal pelvis and no visualization of the stomach, which suggested a diaphragmatic hernia 2. The abnormalities of the CNS may be responsible for deglutition or regurgitation that in turn may explain the esophageal atresia 2.
Differential diagnosis: The diagnosis of Pallister-Killian syndrome depends mainly on the demonstration of cytogenetic abnormalities because the clinical pictures can be confused with that of Fryns syndrome.
Fryns syndrome since diaphragmatic hernia and acral hypoplasia can be also found. The differential diagnosis between the two conditions depends on the demonstration of the 12p isochromosom by FISH. In fact, in Fryns syndrome, the most common dysmorphic facial features include micrognathia in 92 % of case and cleft lip and/or palate in 70 % of cases 18-19. Neither of these anomalies are associated with Pallister-Killian syndrome, in which only micrognathia can occasionally be found. On the contrary, hypertelorism is frequent in Pallister-Killian syndrome and rare in Fryns syndrome 20. Therefore Palladini thought that the diagnosis of Pallister-Killian syndrome should be considered whenever diaphragmatic hernia and short limbs are detected. In such cases the detection of the typical profile may significantly contribute to establishing a diagnosis 1.
Facial dysmorphism, short limbs and vertebral dysostosis also suggest chondrodysplasia of Robinow type and macrosomia, macroglossia could also hint at a metabolic disorder. Preaxial polydactyly along with corpus callosum agenesis could suggest acrocallosal syndrome, while anal imperforation and cardiac malformations could bias the diagnosis toward the Vater anomaly 4.
Sonographic findings: Prenatal diagnosis of Pallister-Killian syndrome has been reported in cases submitted to karyotyping due to advanced age or congenital anomalies detected on second trimester like our case. Among the ultrasound detected malformations, little attention has been paid to facial anomalies. We described our case in which Pallister-Killian syndrome was prospectively suspected on the basis of the various anomalies detected at ultrasound, namely abnormal facial profile, and also the nuchal translucency measurement was 3 mm. Pallister-Killian syndrome has previously been diagnosed following diagnosis of fetal hydrops in the first trimester (Sharland et al, 1991) 3 and nuchal edema has been reported in later pregnancy (Wilson et al, 1994) 3. Langford et al described the first report of a case diagnosed after detection of increased nuchal translucency 3. The echography indicators and the possible signs of Pallister-Killian syndrome found during fetal autopsies for the 27 cases collected by Chiesa, published to date that there are six main elements indicative of Pallister-Killian syndrome 2:
- broad neck,
- short limbs,
- abnormal hands and feet with short metacarpals,
- diaphragmatic hernia and
They seems to indicate a clinical condition combining advanced maternal age and the six echographic signs listed above.
Implications for targeted examinations: Positive diagnosis is still difficult for two reasons. First, the chromosomal marker may be wrongly interpreted as a 21q tetrasomy or as a trisomy 20 and it is only in the 1980s that FISH has unambiguously revealed the nature of the i(12p). The use of a chromosome 12 painting probe provided a non-subjective, rapid diagnosis of Pallister-Killian syndrome. Chiesa think that it is absolutely necessary to use FISH each time the exact nature of the chromosome marker cannot be confirmed 2. FISH is also the only accurate way to determine the real distribution of the isochromosome in various tissues. Tetrasomy 12p generally occurs as a mosaic and the pattern intensity varies from one tissue to another 2. The reference tissues for i12p) is still the skin fibroblast where the abnormality is most common and clear. Prenatal diagnosis can be performed using placental tissue (chorionic villus sampling), but there have been two negative reports 2
Prognosis: Less severely affected individuals may present in postnatal life with profound mental retardation seizures, abnormal skin pigmentation, facial anomalies and short necks 4. The psychomotor retardation is an extremely severe and is accompanied by vertebral and joint deformities, with muscular atrophy in older subjects. The blood karyotype is normal. In fibroblast cultures, the extra-chromosome resembles chromosome 20. The appearance of R bands suggests the fusion of two 12p chromosomes.
Recurrence risk: All the cases of Pallister-Killian syndrome described up to 1997 were sporadic 2. Prenatal diagnosis can be done on amniotics cells, chorionic villus material and cord blood2.
The occurrence of 12p tetrasomy cells decrease with age of the fetus, the mitotic index and the time the tissues has been in culture.
Management: The diagnosis of Pallister-Killian syndrome depends on the demonstration of chromosome abnormalities that are not detected in the blood by standard methods, but are present to varying degrees in medullary cells and fibroblasts2. The diagnosis is now based upon the demonstration by FISH of the 12p isochromosome and is commonly made after amniocentesis performed for advanced age or for the disclosure of fetal anomalies1.
Nevertheless a suspicion by echography of Pallister-Killian syndrome prior to karyotyping is advantageous in order to plan sampling of more than a single fetal tissue. In fact, it has been reported that the supernumerary isochromosome 12p may not be found in fetal blood cells, though in the Palladini¹s case and in another report2, the marker chromosome was indeed found in fetal peripheral lymphocytes 1.
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2- Chiesa J, Hoffet M., Rouseau O., Bourgeois J.M., Sarda P. et al-Pallister-Killian syndrome [i(12p)] : First pre-natal diagnosis using cordocentesis in the second trimester confirmed by in situ hybrydization. Clin Genet 1998; 54 : 294-302.
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