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Pallister-Killian Syndrome

PKS

Pallister-Killian syndrome, also known as Teschler-Nicola-Killian syndrome is a genetic condition characterized by mosaicism: 47, XX or XY, i(12)(p10)/ 46, XX or XY. The 47th chromosome is a 12p isochromosome. 12p tetrasomy and hexasomy cases have been described. The disease affects tissues in a differential manner, as most fibroblasts have a defective karyotype, whereas few lymphocytes are affected. This reflects on the clinical traits of the condition.


Presentation

Routine prenatal ultrasound evaluation may reveal traits such as abnormal presentation close to due date, rhizomelia, diaphragmatic abnormalities such as hernias, anal defects, and heart malformations, especially ventricular septal defect, all of which are highly suggestive of this syndrome.

After birth, the first sign that draws the clinician's attention is hypotonia, that may be severe enough to interfere with respiration and deglutition. Newborns and children also have a specific phenotype, characterized by facial dimorphism: "coarse" facies, high forehead, sparse lashes and eyebrows, shallow supraorbital ridges, hypertelorism, flat nasal bridge, long philtrum [1], short neck, low-implanted ears, large tongue, hypoplastic nails and small hands, sparse hair and areas of unusual skin pigmentation [2]. The hypotonia persists as the child grows older, leading to difficulties in sitting, standing, and mobility. The clinical picture is completed by intellectual disability, manifested as severe or profound mental deficiency, deafness, seizures, hypoplastic lungs and speaking difficulties. Other abnormalities such as cleft palate, supernumerary nipples, genital malformations, auditory canal stenosis, extra fingers or toes or bald scalp areas may also occur. The neurologic prognosis of these patients is grim, with severely disabled motor capabilities and incontinence [3] [4].

Diaphragmatic hernias are considered to be highly specific and are frequent [5].

These traits may not be present in all affected individuals or may be less prominent. The severity of genotype abnormalities does not correlate with the clinical features of the newborn [6]. In other cases, different sides of the body may be affected unevenly.

Coarse Facial Features
  • The clinical symptoms associated with this condition were first recognized in 1977, when Pallister described two adults, aged 19 and 37, who had profound retardation, severe hypotonia, coarse facial features, and pigmentary abnormalities.[mhmedical.com]
  • facial features as child gets older, broad nasal bridge, streaks or patches of lighter or darker skin, sparse hair or bald patches, high arched or cleft palate, shorter arms and legs, disproportionate to the body and extra nipples.[dailymail.co.uk]
  • Systemic features in childhood are numerous and variable, and include most frequently "coarse" facial features, midface malformations, psychomotor delay, hypotonia, scalp hair sparsity, and variegated lightly and darkly pigmented skin. 1 - 9 We describe[jamanetwork.com]
  • facial features Large forehead Pronounced appearance of ears and cheeks Visual defects, such as strabismus, increased distance between the two eyes, skin folds at the upper eyelids, separation between the two eyelids Flat, short nose Oral defects, such[dovemed.com]
Short Finger
  • The dysmorphic features included a board forehead with high anterior hairline, hypertelorism, flat nasal bridge, short upturned nose, down turned corners of the mouth, short fingers, single transverse crease in the right hand, and hypotonia.[ashg.org]
Failure to Thrive
  • Her growth curve is below the third centile, indicating failure to thrive. She has global delay in development and is presently attending the Early Intervention Program for Infants and Children at a special school.[nature.com]
High Arched Palate
  • 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.[ncbi.nlm.nih.gov]
  • PKS has the following characteristics: low muscle tone facial features that are common to the syndrome-high forehead, broad nasal bridge, wide space between the eyes sparse scalp hair at birth high, arched palate hypopigmentation extra nipples cognitive[pkskids.net]
  • Some affected children are born with an opening in the roof of the mouth ( cleft palate ) or a high arched palate. Most children with Pallister-Killian mosaic syndrome have sparse hair on their heads, particularly around the temples.[ghr.nlm.nih.gov]
  • Autopsy verified the following multiple congenital anomalies of fetus: craniofacial dysmorphies were oxycephaly, wide, flat nasal bridge, low-set malformed ears, high-arched palate, short webbed neck, brachydactyly, clinodactyly of five fingers, single[dx.doi.org]
Macroglossia
  • 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.[ncbi.nlm.nih.gov]
  • 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.[ncbi.nlm.nih.gov]
  • Macroglossia and pointed chin occur with age. Hypotonia is present at birth with contractures developing with age. A wide range of congenital malformations may be present, the most specific being diaphragmatic and anal defects.[orpha.net]
  • As patients pass into adolescence , the syndrome is characterized by a coarse and flat face, macroglossia , prognathism, inverted lower lip and psychomotor retardation with muscular hypertonia and contractures .[popflock.com]
  • As patients pass into adolescence, the syndrome is characterized by a coarse and flat face, macroglossia, prognathism, inverted lower lip and psychomotor retardation with muscular hypertonia and contractures.[en.wikipedia.org]
Macrostomia
  • The syndrome presents with a recognizable pattern of findings including: pigmentary skin changes, characteristic facial features (sparse anterior scalp hair, flattened midface, macrostomia, and coarsening of the facial features), and developmental delay[ncbi.nlm.nih.gov]
Bruxism
  • The prevalence of oral habits (non-nutritive sucking, mouth breathing, bruxism) was high, even in older probands.[ncbi.nlm.nih.gov]
Gingival Overgrowth
  • The severity of gingivitis and dental caries increased with age and gingival overgrowth was a common finding.[ncbi.nlm.nih.gov]
Small Hand
  • Most common signs include facial dysmorphism, rhizomelic limb shortness, small hands and feet with nail hypoplasia.[orpha.net]
  • hands, sparse hair and areas of unusual skin pigmentation.[symptoma.com]
Macrocephaly
  • We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum.[ncbi.nlm.nih.gov]
Hearing Impairment
  • Vision and hearing impairments may occur. Patients may also exhibit congenital heart defects , gastroesophageal reflux , cataracts and supernumerary nipples . Diaphragm problems are also possible.[popflock.com]
  • Vision and hearing impairments may occur. Patients may also exhibit congenital heart defects, gastroesophageal reflux, cataracts and supernumerary nipples. Diaphragm problems are also possible.[en.wikipedia.org]
  • impairment Underdeveloped or improperly developed genitals Gastrointestinal defects, abnormal kidney function Reduced growth of head size and body length Severe mental retardation Severe heart defects Hip dislocation at birth, abnormally curved spine[dovemed.com]
Epicanthal Folds
  • folds large ears with lobes that are thick and protrude outward.[en.wikibooks.org]
  • Patients also exhibit a distinctive facial structure, characterized by high foreheads, sparse hair on the temple, a wide space between the eyes, epicanthal folds and a flat nose. Vision and hearing impairments may occur.[popflock.com]
  • Other ocular abnormalities overlap with those of PKS ( Table 1 ), and include strabismus, hypertelorism, epicanthal folds, scleralization of the cornea, iris heterochromia, and microphthalmia. The karyotype in hypomelanosis of Ito is normal.[jamanetwork.com]
Hypertelorism
  • We showed that the most consistent pre-natal ultrasound findings include hypertelorism, broad neck, shorts limbs, abnormal hands or feet, diaphragmatic hernia and hydramnios.[ncbi.nlm.nih.gov]
  • Clinically PKS is characterized by craniofacial dysmorphism with neonatal frontotemporal alopecia, hypertelorism, and low-set ears as well as kyphoscoliosis, severe intellectual disability, epilepsy, and abnormal muscle tone.[ncbi.nlm.nih.gov]
  • The syndrome presents with a recognizable pattern of findings including pigmentary skin changes, coarse face, high forehead, sparse anterior scalp hair, hypertelorism, seizures and progressive psychomotor developmental delay.[ncbi.nlm.nih.gov]
  • Craniofacial manifestations include a coarse'' face with flat profile, high forehead with temporo-frontal balding, sparseness of eyebrows and lashes, shallow supraorbital ridges, upslanting palpebral fissures, hypertelorism, flat and broad nasal bridge[orpha.net]
  • Newborns and children also have a specific phenotype, characterized by facial dimorphism: "coarse" facies, high forehead, sparse lashes and eyebrows, shallow supraorbital ridges, hypertelorism, flat nasal bridge, long philtrum, short neck, low-implanted[symptoma.com]
Broad Nasal Bridge
  • Craniofacial manifestations include a coarse'' face with flat profile, high forehead with temporo-frontal balding, sparseness of eyebrows and lashes, shallow supraorbital ridges, upslanting palpebral fissures, hypertelorism, flat and broad nasal bridge[orpha.net]
  • PKS has the following characteristics: low muscle tone facial features that are common to the syndrome-high forehead, broad nasal bridge, wide space between the eyes sparse scalp hair at birth high, arched palate hypopigmentation extra nipples cognitive[pkskids.net]
  • Subsequent interphasic FISH with a centromeric probe detected tetrasomy 12p in mosaic.The postnatal phenotype of PKS is quite severe and include coarse facies with a high forehead, sparce scalp hair, hypertelorism, broad nasal bridge, hypotonia, streaks[fupress.net]
  • nasal bridge highly arched palate epicanthal folds large ears with lobes that are thick and protrude outward.[en.wikibooks.org]
Short Neck
  • Here, we report on an unusual case of i(12p) in a 15-year-old boy presenting with mild mental retardation, minor facial features (long face, prognathism, short neck), normal weight, length, and OFC parameters as well as hyperpigmented streaks.[ncbi.nlm.nih.gov]
  • Newborns and children also have a specific phenotype, characterized by facial dimorphism: "coarse" facies, high forehead, sparse lashes and eyebrows, shallow supraorbital ridges, hypertelorism, flat nasal bridge, long philtrum, short neck, low-implanted[symptoma.com]
  • neck [ 8 , 9 ].[synapse.koreamed.org]
  • neck (OMIM #601803; ).[dx.doi.org]
Incontinence
  • The neurologic prognosis of these patients is grim, with severely disabled motor capabilities and incontinence. Diaphragmatic hernias are considered to be highly specific and are frequent.[symptoma.com]
Neurologic Manifestation
  • Neurological manifestations include mental retardation, hypotonia, and seizures. Epilepsy incidence ranged from 39 to 59% in a previously reported series.[ncbi.nlm.nih.gov]

Workup

The diagnosis relies on the detection of the mosaic tetrasomy of isochromosome 12p. This can be done by various techniques, performed on different cell types. The most reliable choice is to perform an amniocentesis, as i(12p) is found in all amniocytes in fetuses suffering from this condition [7]. Similarly, all newborn bone marrow cells have this trait [8], whereas a variable percentage of fibroblasts, lung, liver, testes and spleen cells exhibit the abnormality, hence the "tissue-specific mosaicism" term. Lymphocytes are infrequently affected, therefore blood karyotype may not be a reliable method to diagnose this illness, especially due to the high turnover of blood cells. Fibroblasts may be obtained from buccal smears or skin areas with different pigmentation. The percentage of i(12p) cells does not correlate with disease severity [9]. Furthermore, the number of detectable diseased cells decreases as the patient ages [10].

Fluorescence in situ hybridization (FISH) [11] [12] and interphase FISH are reliable diagnostic methods [13]. Other methods include karyotype analysis, array comparative genomic hybridization (CGH) and chromosomal microarray. A normal karyotype of blood cells does not exclude the diagnose. In case clinical doubt persists, newer diagnostic methods, such as spectral karyotyping and multiplex-FISH may shed light over the case [14].

3 Hz Spikes
  • Renzo Guerrini, Michelle Bureau, Marie‐Geneviève Mattei, Agatino Battaglia, Marie‐Claude Galland and Joseph Roger, Trisomy 12p Syndrome: A Chromosomal Disorder Associated with Generalized 3Hz Spike and Wave Discharges, Epilepsia, 31, 5, (557-566), (2007[doi.org]

Treatment

  • The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.[orpha.net]
  • Combination treatment with high-dose pyridoxal phosphate and sodium valproate eliminated seizures and improved the electroencephalographic abnormalities.[ncbi.nlm.nih.gov]
  • A better electroclinical characterization of epileptic seizures in Pallister-Killian syndrome using appropriate polygraphic tests (video-electroencephalography, electromyography) may lead to an early diagnosis and specific treatment for this form of epileptic[ncbi.nlm.nih.gov]
  • Treatment and management of Pallister-Killian Mosaic Syndrome is based on the severity of the condition and signs and symptoms presented.[dovemed.com]

Prognosis

  • Prognosis Prognosis is usually poor. Death may occur perinatally, mainly due to diaphragmatic hernias, or during the first years of life in about a half of patients.[orpha.net]
  • Despite a variable prognosis in terms of response to therapy, a significant proportion of patients achieved good seizure control. Copyright 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.[ncbi.nlm.nih.gov]
  • It is generally observed that the child’s mobility is affected, in most cases The prognosis depends on the severity of the signs and symptoms.[dovemed.com]
  • […] be an error in the skin cells that is not present in other tissues that came from other germ layers Surveillance, management, and treatment options [ edit ] There is no specific therapy for individuals with Pallister-Killian Syndrome Because of poor prognosis[en.wikibooks.org]

Etiology

  • Extra ring chromosomes might be a more common etiology for PKS than previously thought, given the difficulty in their characterization before the advent of aCGH.[ncbi.nlm.nih.gov]
  • Etiology Patients with PKS have mosaïcism for a supernumerary isochromosome 12p, resulting in four copies of the short arm of chromosome 12 instead of the normal two. The isochromosome is mostly of maternal origin.[orpha.net]
  • The genetic etiology is a result of isochromosomes that have either two q arms (long) or two p arms (short). Therefore isochromosome 12p is a chromosome 12 with two p arms. Most cells have two copies of each chromosome with one from each parent.[slideshare.net]
  • Etiology : Mosaic tissue-limited tetrasomy for chromosome 12p. (Presence of an extra isochromosome 12p. So in effect there are 4 copies of 12p.) Usually picked up only on a buccal smear or skin biopsy sample. Inheritance : Sporadic condition.[genetics4medics.com]
  • Jump to navigation Jump to search Pallister-Killian Syndrome Genetic Etiology [ edit ] Tetrasomy 12p (mosaicism) Incidence and carrier frequency [ edit ] Very rare disorder Affects males and females in equal numbers 30 cases reported in the literature[en.wikibooks.org]

Epidemiology

  • Summary Epidemiology Incidence is uncertain and is estimated around 1/25,000. Clinical description A number of cases are prenatally diagnosed because of abnormal ultrasonic findings, and abnormal presentation at birth is usual.[orpha.net]
Sex distribution
Age distribution

Prevention

  • 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.[ncbi.nlm.nih.gov]
  • Abdul-Rahman 1 1) Dept Preventive Medicine; 2) Dept Pediatrics, Univ of Mississippi Med Ctr, Jackson, MS. Pallister-Killian Syndrome (PKS) was first reported in 1977 with mosaicism in fibroblasts for an extra chromosome composed of 12p.[ashg.org]
  • Medical researchers are still trying to understand the unique Pallister-Killian Syndrome and find ways to prevent its occurrence Even though PKS is not an inherited syndrome, those with a family history of tetrasomy (disorder with extra pairs of chromosomes[dovemed.com]
  • April 18, 2019 Measles Surge and Importance of Prevention, Protection Given the recent measles outbreak in Minnesota, Gillette is sharing helpful information for parents courtesy of the Minnesota Department of Health.[gillettechildrens.org]

References

Article

  1. Izumi K, Krantz I. Pallister–Killian syndrome. Am J Med Gen C Semin Med Genet. 2014;166C:406-413.
  2. Vermeesch J, Melotte C, Salden I, et al.Tetrasomy 12pter-12p13.31 in a girl with partial Pallister–Killian syndrome phenotype. Eur J Med Genet.2005;48:319-327.
  3. Schinzel A. Tetrasomy 12p (Pallister-Killian syndrome). J Med Genet. 1991;28:122–5.
  4. Day-Salvatore D, Smulian J, Guzman E, et al. Genetics casebook. Pallister-Killian syndrome. J Perinatol. 1996;16:406–12.
  5. Bergoffen J, Punnett H, Campbell T, et al. Diaphragmatic hernia in tetrasomy 12p mosaicism. J Pediatr. 1993;122:603–6.
  6. Shen J, Liang D, Zhou Z, Y. Xia, et al. Pallister–Killian syndrome: meiosis II non-disjunction may be the first step in the formation of isochromosome 12p. Chin Med J (Engl). 2010;123: 3482–3485.
  7. Ward B, Hayden M, Robinson A. Isochromosome 12p mosaicism (Pallister-Killian syndrome): newborn diagnosis by direct bone marrow analysis. Am J Med Genet. 1988;31:835–9.
  8. Wenger S, Boone L, Steele M. Mosaicism in Pallister i(12p) Syndrome. Am J Med Genet. 1990;35:523–5.
  9. Horn D, Majewski F, Hildebrandt B, Körner H. Pallister-Killian syndrome: normal karyotype in prenatal chorionic villi, in postnatal lymphocytes, and in slowly growing epidermal cells, but mosaic tetrasomy 12p in skin fibroblasts. J Med Genet. 1995;32:68–71.
  10. Peltomaki P, Knuutila S, Ritvanen A, et al. Pallister-Killian syndrome: cytogenetic and molecular studies. Clin Genet. 1987;31:399–405.
  11. Speleman F, Leroy J, Van Roy N, et al. Pallister-Killian syndrome: characterization of the isochromosome 12p by fluorescent in situ hybridization. Am. J. Med. Genet. 1991;41:381-387.
  12. Ohashi H, Ishikiriyama S, Fukushima Y. New diagnostic method for Pallister-Killian syndrome: detection of i(12p) in interphase nuclei of buccal mucosa by fluorescence in situ hybridization. Am. J. Med. Genet. 1993;45: 123-128.
  13. Manasse B, Lekgate N, Pfaffenzeller W, et al. The Pallister-Killian syndrome is reliably diagnosed by FISH on buccal mucosa. Clin Dysmorphol. 2000; 9:163–165.
  14. Bint S, Davies A, Ogilvie C. Multicolor banding remains an important adjunct to array CGH and conventional karyotyping. Mol Cytogenet.2013; 6:55.

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Last updated: 2019-07-11 20:28