Mosaic Tetrasomy Research Articles

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children

BackgroundPallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population.ResultsThirty-one individuals were enrolled (17 females/14 males; age range 0.1–17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14.ConclusionsBrain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Mosaic tetrasomy 9p at amniocentesis in a pregnancy associated with a favorable fetal outcome, perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy in various tissues

ObjectiveWe present mosaic tetrasomy 9p at amniocentesis in a pregnancy associated with a favorable fetal outcome, perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy in various tissue. Case reportA 33-year-old primigravid woman underwent elective amniocentesis at 18 weeks of gestation because of anxiety, and the karyotype of cultured amniocytes was 47,XX,+i (9) (p10)[20]/46,XX [55]. Cordocentesis was performed at 20 weeks of gestation, and the karyotype of cord blood was 47,XX,+i (9) (p10)[7]/46,XX [15]. She was referred for genetic counseling at 23 weeks of gestation, and repeat amniocentesis revealed a karyotype of 47,XX,+i (9) (p10)[1]/46,XX [16] with seven cells in one colony having tetrasomy 9p in cultured amniocytes, and in uncultured amniocytes, quantitative fluorescence polymerase chain reaction (QF-PCR) analysis excluded uniparental disomy (UPD) 9 and determined paternal origin of the extra i (9p), array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr 9p24.3p13.1 × 3.0 consistent with 50% mosaicism for tetrasomy 9p, and interphase fluorescence in situ hybridization (FISH) on uncultured amniocytes showed 22.6% (12/53 cells) mosaicism for tetrasomy 9p. A third amniocentesis at 27 weeks of gestation revealed a karyotype of 46, XX (10/10 colonies) in cultured amniocytes, and interphase FISH analysis on uncultured amniocytes revealed 20% (20/100 cells) mosaicism for tetrasomy 9p. The parental karyotypes and prenatal ultrasound were normal. At 39 weeks of gestation, a phenotypically normal 3388-g female baby was delivered. The karyotypes of cord blood, umbilical cord and placenta were 47,XX,+idic (9) (q12)[19]/46,XX [21] or 47,XX,+idic (9) (pter→q12:q12→pter)[19]/46,XX [21], 47,XX,+idic (9) (q12)[1]/46,XX [39] and 47,XX,+idic (9) (q12)[4]/46,XX [36], respectively. When follow-up at age two months, the neonate was phenotypically normal, the peripheral blood had a karyotype of 47,XX,+idic (9) (q12)[18]/46,XX [22], and interphase FISH analysis on 100 buccal mucosal cells revealed 1% (1/100 cells) mosaicism for tetrasomy 9p. When follow-up at age seven months, the neonate was phenotypically normal, and the peripheral blood had a karyotype of 47,XX,+idic(9)(q12)[14]/46,XX[26]. ConclusionMosaic tetrasomy 9p at amniocentesis can be a transient and benign condition, and can be associated with a favorable fetal outcome and perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy in various tissue.

Third-Generation Cytogenetic Analysis: Diagnostic Application of Long-Read Sequencing

Copy number variants (CNVs) play important roles in the pathogenesis of several genetic syndromes. Traditional and molecular karyotyping are considered the first-tier diagnostic tests to detect macroscopic and cryptic deletions/duplications. However, their time-consuming and laborious experimental protocols protract diagnostic times from 3 to 15 days. Nanopore sequencing has the ability to reduce time to results for the detection of CNVs with the same resolution of current state-of-the-art diagnostic tests. Nanopore sequencing was compared to molecular karyotyping for the detection of pathogenic CNVs of seven patients with previously diagnosed causative CNVs of different sizes and cellular fractions. Larger chromosomal anomalies included trisomy 21 and mosaic tetrasomy 12p. Among smaller CNVs, two genomic imbalances of 1.3 Mb, a small deletion of 170 kb, and two mosaic deletions (1.2 Mb and 408 kb) were tested. DNA was sequenced and data generated during runs were analyzed in online mode. All pathogenic CNVs were identified with detection time inversely proportional to size and cellular fraction. Aneuploidies were called after only 30 minutes of sequencing, whereas 30 hours were needed to call small CNVs. These results demonstrate the clinical utility of our approach that allows the molecular diagnosis of genomic disorders within a 30-minute to 30-hour time frame and its easy implementation as a routinary diagnostic tool.

EP101: The diagnostic odyssey towards detection of mosaic distal 5p tetrasomy through buccal swab DNA analysis

Somatic mosaicism for pathogenic genetic variants can explain the clinical findings of individuals with highly suspected genetic disorders who have uninformative results on genetic analysis of peripheral blood mononuclear cells (PBMCs). Indeed, mosaic small supernumerary chromosomes may be undetected in tissues with high cellular turnover, such as PBMCs, due to their intrinsic instability during mitosis. Features suggestive of somatic mosaicism include segmental pigmentary skin or hair changes, body asymmetry, and mild presentations of well-characterized syndromes such as Trisomy 21.

Sleep in Children With Pallister Killian Syndrome: A Prospective Clinical and Videopolysomnographic Study.

Objectives: Pallister-Killian syndrome (PKS) is a rare genetic disorder with multi-organ involvement caused by mosaic tetrasomy of chromosome 12p. Although many caregivers report the presence of impaired sleep in their children, there are no clear data in the literature on this issue and no systematic study has ever been performed. With this study, we aimed to characterize the features of sleep in Pallister-Killian syndrome and identify the possible influence of clinical and demographic features. Moreover, our aim was to verify the effectiveness of conventional screening questionnaires in this particular group of patients.Methods: We prospectively enrolled 14 patients aged 1–17 years in collaboration with PKS Kids Italia ONLUS. The Sleep Disturbance Scale for Children (SDSC) questionnaire was administered to caregivers. Then, video polysomnography (VPSG) of at least 24 h was performed and results were compared with a same-aged control group.Results: A total of 92% of patients had abnormal SDSC scores, extremely high in the “disorder of initiating and maintaining sleep” (DIMS) and “sleep breathing disorders” (SBD) subscales. VPSG showed a significantly impaired macrostructure in PKS patients, with a higher Arousal Index (p < 0.00001) and percentage of time spent in N3 (p < 0.00001), and reduced Sleep Efficiency (p = 0.0006). After dividing both PKS and controls into two groups based on median age, some peculiarities emerged: the younger group had higher Awakenings Index (p = 0.0207) and percentage of time spent in N1 (p = 0.015) while the older group showed higher time in bed (TIB) (p = 0.0485), compared with controls. Due to poor compliance, the Apnea-Hypopnea Index (AHI) was evaluated only for 10 PKS children, being significantly increased (p = 0.0427) compared with controls. SBD subscale scores in SDSC were significantly related to AHI values in VPSG (p = 0.0099).Conclusions: This study constitutes the first attempt to describe the sleep pattern in PKS. Despite small numbers due to the rarity of the syndrome, our VPSG results confirm the high prevalence of sleep disorders (SDs) in these patients. It is therefore essential to investigate and treat them. The SDSC scale is a good screening tool for early detection also in these patients, with particular sensitivity in detecting breathing disorders.

Primary Amenorrhea in Pallister Killian Syndrome: Clinical Manifestation or Complication?

Introduction: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by a mosaic tetrasomy of the short arm of chromosome 12 (12p). PKS has a wide spectrum of clinical manifestations which vary in different age groups. However, in the up to date literature there are no reported cases of puberty disorder associated with this syndrome. We describe a caucasian 17- year-old girl with PKS with primary amenorrhea as failure of appropriate pubertal progression. Patient: at first general examination, the patient shows a phenotype compatible with the PKS of adulthood was noted. Auxological data revealed undernutrition (BMI ?3 z-score), with pubertal Tanner stage 3. A retarded bone age was detected. At pelvic ultrasound prepubertal uterus and microfollicular ovaries were noted. The laboratory data was compatible with hypogonadotropic hypogonadism. Conclusion: this is the first case of primary amenorrhea in PKS. It would be interesting to reassess this novel finding in other patients affected by the same condition in order to establish whether hypogonadotropic hypogonadism is a typical clinical manifestation of the syndrome or it’s secondary to nutritional and stressful status.

Low-level mosaic tetrasomy 18p at amniocentesis can be associated with a favorable pediatric outcome: The follow-ups of three consecutive cases

Low-level mosaic tetrasomy 18p at amniocentesis can be associated with a favorable pediatric outcome: The follow-ups of three consecutive cases

Seizures and Cardiomyopathy in a Patient with Pallister-Killian Syndrome due to Hexasomy 12p Mosaicism

Pallister-Killian syndrome (PKS) is a rare disorder presenting with developmental delay, numerous dysmorphic features, and skin pigmentation anomalies. It is caused by mosaic tetrasomy of the short arm of chromosome 12. In most instances, tetrasomy is due to a supernumerary isochromosome i(12)(p10). Although mitotic instability is a generally accepted behavior for supernumerary chromosomes, hexasomy 12p due to a gain of an isochromosome 12p, has been hardly ever reported. We report a 10 year follow-up on a girl with 2 copies of isochromosome consisting of the short arm of chromosome 12, who has craniofacial features seen in PKS, such as sparse hair with an unusual pattern, sparse eyebrows, lacrimal duct stenosis, submucous cleft palate, Pallister lip (a relatively long philtrum continuing into the vermillion border of the upper lip), narrow palate, and wide alveolar ridges. She also has other abnormalities, including unilateral renal dysgenesis, rectovaginal fistula, pre-axial polydactyly of the right hand, severe global developmental delay, and hypotonia as well as some features suggestive of mosaicism such as bilateral asymmetry, patchy areas of rough skin, and retinal mottling. Initial cytogenetic studies from peripheral blood showed a normal female karyotype. Further cytogenetic studies on a skin biopsy showed mosaicism with 2 copies of the supernumerary isochromosome 12p.

Analyzing false-negative results detected in low-risk non-invasive prenatal screening cases.

BackgroundThe non‐invasive prenatal screening (NIPS) has been introduced into clinical practice with a high sensitivity and specificity. Although the false‐negative results are inevitable and important, limited false‐negative NIPS results have been reported and studied previously. In this study, we aim to report and analyze false‐negative results detected in the NIPS cases with a low‐risk result.MethodsNIPS was performed using whole‐genome massively parallel shotgun sequencing for screening common trisomies, rare autosomal aneuploidies, and subchromosome copy number variants. All the NIPS cases with a low‐risk result performed in our center in 2017 were followed‐up using medical records and telephone interview at 3 months after delivery. Fetal ultrasound results and available genetic diagnostic testing results were collected for pregnancies with adverse outcomes. The genetic diagnostic testing referred to chromosomal microarray analysis or fluorescent in situ hybridization on amniotic fluid cells, fetal skin tissue, neonatal peripheral blood, or available placental biopsies.ResultsBy following‐up 10,975 low‐risk results, we found 166 NIPS cases with adverse pregnancy outcomes, in which eight cases had diagnostic testing. Among them, four false‐negative cases were confirmed, including one trisomy 18 caused by placental mosaicism, one mosaic tetrasomy 12p, and 2 microdeletion/microduplication cases.ConclusionOur results revealed that mosaicism contributes to a major cause of false negative in NIPS, and highlighted the importance of ultrasound in identifying these false‐negative results.

A Systematic Clinical Review of Prenatally Diagnosed Tetrasomy 9p.

Tetrasomy 9p was first described in 1973 and approximately 68 cases with a variable phenotype have been reported to date with 22 of them being detected prenatally. The objective of this study was to review prenatally-reported cases of tetrasomy 9p thus far and to identify ultrasound phenotypes that may be suggestive of this specific syndrome. A PubMed database search was done in February 2018 without any restriction of publication date orjournals, with the use of the following keywords: tetrasomy 9p, tetrasomy 9p prenatal, mosaic tetrasomy 9p, mosaic tetrasomy 9p prenatal, isochromosome 9p, duplication 9p prenatal, trisomy 9p prenatal. Reported cases were included if the clinical presentation and diagnostic approach of each case was clearly described. The most common characteristics of prenatally-detected tetrasomy 9p are intrauterine growth retardation (IUGR, 57.0%), central nervous system (CNS) abnormalities (59.0%), skeletal anomalies (29.0%), genitourinary and renal anomalies (29.0%) and cardiac defects (29.0%). The phenotypic spectrum of tetrasomy 9p is rather unspecific as these findings are commonly associated with other chromosome anomalies, as well as microdeletion/microduplication or monogenic syndromes. The combination of early fetal morphology and diagnostic genetic testing enables a definite tetrasomy 9p diagnosis and effective further pregnancy management.

The type and prevalence of chromosomal abnormalities in couples with recurrent first trimester abortions: A Turkish retrospective study

ObjectiveChromosomal abnormalities are more common in the first trimester abortions. We aimed to investigate the types and prevalence of chromosomal abnormalities in couples with recurrent first trimester miscarriages in Sivas, Turkey. Materials and medhodsThree hundred couples (600 individuals) who had a story of recurrent abortion were included in the study. Chromosome analysis was performed after the preparation of lymphocyte culture with the standard method. Karyotype analyses were supported by FISH and aCGH studies. ResultsTotal 26 chromosome abnormalities (8.7%) were found in the couples (19 females and 7 males). Fifteen cases (57.7%) were structural anomalies and eleven cases (42.3%) were numerical chromosomal aberrations. We detected 5 balanced translocations (33.3%), 4 Robertsonian translocations (26.7%), 3 inversions (20%), 2 duplications (13.3%) and one deletion (6.7%) among the structural anomalies. Mosaic monosomy X in five cases (45.4%), the combination of mosaic monosomy-trisomy X in three cases (27.3%), the combination of mosaic monosomy-trisomy and tetrasomy X in two cases (18.2%) and mosaic pentasomy X in only one individual (9.1%) were encountered as numerical chromosome aberrations. 19 cases had heterochromatic changes or other chromosomal variations (satellite increments and inv9). ConclusionChromosome analysis in couples with recurrent miscarriage is necessary for possible preimplantation genetic diagnosis. As well as numerical and structural chromosome abnormalities, some chromosomal variations (heterochromatin and satellite increments etc.) may also contribute to recurrent miscarriages. Numerical chromosomal abnormalities are often associated with sex chromosomes and usually seen in females.

Case presentation: persistent adenovirus B3 infections associated with bronchiolitis obliterans treated with cidofovir in a child with mosaic tetrasomy 9p

BackgroundAdenoviruses (AdV) are non-enveloped, double-stranded DNA viruses with multiple serotypes, which cause a variety of end-organ disease in both immunocompetent and immunocompromised individuals. Some adenoviruses can become latent in the mucosa-associated lymphoid tissue (e.g. adenoids and tonsils), with the potential to reactivate sporadically, leading to upper or lower respiratory tract infection and disease. Bronchiolitis Obliterans (BO) is a rare chronic lung disorder which usually follows a severe insult to the respiratory tract. In children, it is a complication of severe infections (as post-infectious BO), typically manifesting after a severe respiratory infection, in previously healthy pre-school children. Symptoms and signs of air trapping (hyperinflated chest, expiratory wheeze) with persistent oxygen requirement are characteristic. The presence of the unusual mosaic tetrasomy 9p genotype in this case, despite standard cidofovir therapy for persistent or chronic adenovirus infection, may have impacted on the child’s long-term clinical outcomes.Case presentationWe present a case of persistent AdV B3 infection in a 14-month old boy with mosaic tetrasomy 9p, which persisted for 10 weeks, resulting in radiologically-confirmed BO, requiring cidofovir to control the persistent AdV B3 infection and standard therapy with pulsed steroids. We argue that in the presence of the mosaic tetrasomy 9p, earlier antiviral therapy may have decreased the severity of BO, as this mutation is known to be associated with some degree of immune dysregulation.ConclusionsAdenovirus infections are common in children and may persist as latent infections, with subsequent reactivations during loss of immune control, related to systemic illness arising from other causes. In chronic, reactivated AdV infection with pneumonia, BO is a recognised complication. However, in this case, with the presence of the mosaic tetrasomy 9p mutation, earlier antiviral therapy may have reduced such longer term complications, due to the immune dysregulatory nature of this mutation.

Mosaic Tetrasomy of 9p24.3q21.11 postnatally identified in an infant born with multiple congenital malformations: a case report

BackgroundSupernumerary Marker Chromosomes consist in structurally abnormal chromosomes, considered as an extra chromosome in which around 70% occur as a de novo event and about 30% of the cases are mosaic. Tetrasomy 9p is a rare chromosomal abnormality described as the presence of a supernumerary isochromosome 9p. Clinical features of tetrasomy 9p include a variety of physical and developmental abnormalities.Case presentationHerein, we reported a postnatal case of a newborn who died in early infancy with multiple congenital malformations due to a mosaic de novo tetrasomy 9p detected by Chromosomal Microarray Analysis. Conventional cytogenetics analysis of the proband was 47,XY,+mar[45]/46,XY[5]. The parental karyotypes presented no visible numerical or structural alterations. Microarray Analysis of the proband revealed that the marker chromosome corresponded to a mosaic de novo gain at 9p24.3q21.11.ConclusionsChromosomal Microarray Analysis was helpful to identify the origin of the supernumerary marker chromosome and it was a powerful tool to carry out genetic diagnostic, guiding the medical diagnosis. Furthermore, the CMA allowed observing at the first time in Central Brazil the tetrasomy 9p and partial tetrasomy 9q in mosaic, encompassing a large duplicated region with several morbid genes, in an infant with multiple congenital malformations.

Report of new case of Pallister – Killian syndrome in fetus

Pallister — Killian syndrome (PKS) is a sporadic chromosomal anomaly caused by a tissue-specific mosaic distribution of an additional isochromosome 12p. A case of second trimester fetus with PKS is presented. Antenatal ultrasound examination showed left diaphragmatic hernia. Standard cytogenetic analysis of cultured amniocytes supposed mosaic tetrasomy 12p: 46,XY/ 47,XY,+?i(12p). Fluorescent in situ hybridization (FISH) was used to confirm the nature of the additional chromosome. Pathological examination confirmed prenatal diagnosis.

Fetoplacental cytogenetic discrepancy in a pregnancy with fetal mosaic tetrasomy 12p and Pallister–Killian syndrome detected by amniocentesis

ObjectiveWe present fetoplacental cytogenetic discrepancy in a pregnancy with prenatally detected mosaic tetrasomy 12p by amniocentesis. Case reportA 34-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 47,XX,+i(12)(p10)[7]/46,XX[16]. Array comparative genomic hybridization (aCGH) analysis of the DNA extracted from cultured amniocytes revealed arr (12p)×3, (X)×2. Prenatal ultrasound findings were unremarkable. The pregnancy was subsequently terminated, and a fetus was delivered with facial dysmorphism consistent with the clinical features of Pallister–Killian syndrome (PKS). Postnatal cytogenetic analysis of the cultured cells from umbilical cord, skin, cord blood and placenta revealed 47,XX,+i(12)(p10)[6]/46,XX[34] in umbilical cord, 47,XX,+i(12)(p10)[11]/46,XX[29] in skin, 47,XX,+i(12)(p10)[3]/46,XX[47] in cord blood and 46,XX[40] in placenta. The mosaic tetrasomy 12p levels of the umbilical cord, skin, cord blood and placenta were 15%, 27.5%, 6% and 0%, respectively. aCGH analysis of the DNA extracted from uncultured cord blood and placenta revealed arr 12p13.33p11.1 (230,421-34,756,209)×3.0 in cord blood but no genomic imbalance in placenta. Polymorphic DNA marker analysis showed a maternal origin of the supernumerary isochromosome 12p in cord blood but biparental inheritance with equal fluorescent activity in placenta. ConclusionPregnancy with fetal PKS and mosaic tetrasomy 12p may present fetoplacental cytogenetic discrepancy. Therefore, genetic analysis on placenta alone may fail to detect fetal mosaic tetrasomy 12p associated with PKS.

Prenatal diagnosis and molecular cytogenetic characterization of low-level mosaicism for tetrasomy 18p at amniocentesis in a pregnancy with a favorable outcome

ObjectiveWe present prenatal diagnosis of low-level mosaicism for tetrasomy 18p at amniocentesis in a pregnancy with a favorable outcome. Case ReportA 40-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a de novo supernumerary isochromosome 18p in eight of 39 colonies of cultured amniocytes. The karyotype was 47,XX,+i(18)(p10)[8]/46,XX[31]. Array comparative genomic hybridization (aCGH) analysis using uncultured amniocytes revealed arr 18p11.32p11.21 [hg 19] (148,963–14,081,887) × 2–3. Repeat amniocentesis was performed at 20 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis showed four 18p11.22-specific probe (RP11-918F20) signals in 11.7% (12/103 cells) of uncultured amniocytes. aCGH analysis on uncultured amniocytes did not detect genomic imbalance in chromosome 18. The parental karyotypes were normal. Polymorphic DNA marker analysis excluded uniparental disomy 18. Cytogenetic analysis of cultured amniocytes at repeat amniocentesis revealed a karyotype of 47,XX,+i(18)(p10)[2]/46,XX[12]. Prenatal ultrasound was unremarkable. The pregnancy was carried to 38 weeks of gestation, and a 2742-g phenotypically normal female baby was delivered with a cord blood karyotype of 46,XX. When examined at 8 months of age, the infant was normal in growth and psychomotor development. Interphase FISH analysis on 21 uncultured urinary cells revealed normal signals in all cells and no mosaic tetrasomy 18p. ConclusionLow-level mosaic tetrasomy 18p at amniocentesis without ultrasound abnormalities can be associated with a favorable outcome.

Unclassifiable pattern of hypopigmentation in a patient with mosaic partial 12p tetrasomy without Pallister-Killian syndrome.

Pallister-Killian syndrome (PKS-#OMIM601803) is a multisystem developmental disorder typically due to the presence of an aneuploidy cell line, consisting of a supernumerary tetrasomic chromosomal marker (SCM) arisen from the short arm of chromosome 12 (12p isochromosome). The clinical phenotype, which is strictly related to the percentage and tissue distribution of aneuploid cells, is characterized by craniofacial dysmorphisms, pigmentary skin anomalies, limb shortening, congenital heart defects, diaphragmatic hernia, hypotonia, intellectual disability, and epilepsy. We report on a 4 year-old girl harboring a 12p partial isochromosome, involving the PKS critical region, affecting about 70% of circulating lymphocytes, urine, and saliva cells and fibroblast from a hyperpigmented skin spot, and 100% of fibroblasts from a hypopigmented skin spot. Interestingly, despite the high proportion of affected cells this patient did not present with PKS, and a pattern of linear and patchy pigmentary mosaicism was the sole clinical manifestation. The present observation suggests that partial 12p SCM can also result in mild phenotypes, and its prevalence in the human population could have been underestimated. Accurate dermatologic evaluation could be a major handle for genetic testing.

12番短腕テトラソミーモザイク（Pallister-Killian症候群）の1例～染色体異常モザイク疾患における診断名“hypomelanosis of Ito”の位置づけ～

12番短腕テトラソミーモザイク（Pallister-Killian症候群）の1例～染色体異常モザイク疾患における診断名“hypomelanosis of Ito”の位置づけ～

Pallister–Killian syndrome: Cytogenetics and molecular investigations of mosaic tetrasomy 12p in prenatal chorionic villus and in amniocytes. Strategy of prenatal diagnosis

ObjectivePallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). Clinically, PKS is characterized by several systemic abnormalities, such as intellectual impairment, hearing loss, epilepsy, hypotonia, craniofacial dysmorphism, pigmentary skin anomalies, epilepsy, and a variety of congenital malformations. Prenatally, PKS can be suspected in the presence of ultrasound anomalies: diaphragmatic hernia, rhizomelic micromelia, hydrops fetalis, fetal overweight, ventriculomegaly in the central nervous system, congenital heart defects, or absent visualization of the stomach. In all these cases, a detailed genetic study is required. PKS is diagnosed by prenatal genetic analysis through chorionic villus sampling, genetic amniocentesis, and cordocentesis. Case ReportWe report two cases of PKS with prenatal diagnosis of isochromosome 12p made by cytogenetic studies. The first case is of a 36-year-old pregnant woman who underwent genetic chorionic villus sampling at 13th weeks of gestation after 1st trimester prenatal ultrasound revealed clinical features of PKS: flat nasal bridge and fetal hydrops. The second case is of a 32-year-old pregnant woman with genetic amniocentesis at 17th weeks of gestation that showed mos46,XX[21]/47,XX,+i(12p) associated to PKS. ConclusionNew molecular cytogenetic techniques array comparative genomic hybridization and fluorescence in-situ hybridization in association with conventional karyotype are pivotal innovative tools to search for chromosomic anomalies and for a complete prenatal diagnosis, especially in cases such as PKS where array comparative genomic hybridization analysis alone could not show mosaicism of i(12p).

Oro-dental features of Pallister-Killian syndrome: Evaluation of 21 European probands.

Pallister-Killian syndrome (PKS) is a rare sporadic multi-systemic developmental disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. A wide range of clinical characteristics including intellectual disability, seizures, and congenital malformations has previously been described. Individuals with PKS show a characteristic facial phenotype with frontal bossing, alopecia, sparse eyebrows, depressed nasal bridge, long philtrum, telecanthus, and posteriorly rotated ears. Oro-dental features, such as "Pallister lip," macroglossia, delayed eruption of primary teeth, high arched-palate, prognathism, and cleft palate have been occasionally reported in the medical literature. The aim of the study was to assess the oro-dental phenotype of PKS and to describe the oral health status in a cohort participating in the First European Workshop on PKS. A clinical dental examination was performed in 21 Caucasian probands and data regarding medical and dental history collected. Twelve probands (57%) showed an atypical dental pattern, with multiple missing teeth (primarily the first permanent molars) and 2 (10%) a double teeth. The severity of gingivitis and dental caries increased with age and gingival overgrowth was a common finding. A characteristic occlusive phenotype was found: a high-arched palate with mandibular prognathism associated with an anterior openbite and crossbite and with posterior crossbite (unilateral or bilateral). The prevalence of oral habits (non-nutritive sucking, mouth breathing, bruxism) was high, even in older probands. This study suggests that individuals affected by PKS should be observed closely for oro-dental diseases and a multidisciplinary approach is needed to implement the right preventive measures. © 2016 Wiley Periodicals, Inc.