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European Journal of Medical Genetics 51 (2008) 303e314 http://www.elsevier.com/locate/ejmg

Original article

Patau syndrome with long survival in a case of unusual mosaic trisomy 13

Giuseppina Fogu a,*, Emanuela Maserati b, Francesca Cambosu a, Maria Antonietta Moro a, Fausto Poddie a, Giovanna Soro a, Pasquale Bandiera c, Gigliola Serra d, Gianni Tusacciu d, Giuseppina Sanna d, Vittorio Mazzarello c, Andrea Montella c
Clinical Genetics, Department of Biomedical Sciences, University of Sassari, viale San Pietro, 43/C, 07100 Sassari, Italy b Department of Experimental and Clinical Biomedical Sciences, University of Insubria, Varese, Italy c Anatomy and Histology Division, Department of Biomedical Sciences, University of Sassari, Italy d Institute of Child Neuropsychiatry, University of Sassari, Italy Received 21 January 2008; accepted 27 March 2008 Available online 9 April 2008
a

Abstract We report a 12-year-old patient with Patau syndrome, in whom two cell lines were present from birth, one with total trisomy 13 due to isochromosome (13q), and one with partial trisomy 13. A cytogenetic re-evaluation at 9 years of age brought to light in skin broblasts a third cell line, partially monosomic for chromosome 13. The derivatives (13) present in the three cell lines were characterized through uorescence in situ hybridization (FISH) experiments with suitable probes; the results suggested a sequence of rearrangements which beginning from an isochromosome (13q) could have led to the other two derivatives. We report the clinical data at birth and at the age of 12; at this age pigmentary lesions with phylloid pattern were noted. Cytogenetic ndings of the chromosomal analyses on different tissues, including skin broblasts from differently pigmented areas, are also reported. 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Patau syndrome; Trisomy 13; Mosaicism; FISH; Phylloid hypomelanosis

* Corresponding author. Tel.: 39 079 228534; fax: 39 079 228520. E-mail address: gfogu@uniss.it (G. Fogu). 1769-7212/$ - see front matter 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2008.03.004

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1. Introduction Trisomy 13, or Patau syndrome [14], represents the third autosomic trisomy in order of frequency, after trisomy 21 (Down syndrome) and trisomy 18 (Edwards syndrome), with a prevalence at birth estimated as between 1:12,000 and 1:29,000 [5,9]. Among the autosomic trisomies compatible with postnatal life, trisomy 13 is certainly the most severe as to congenital defects, psychomotor delay, mental retardation and life expectancy [1,2]. Magenis et al. [12], in their study on 172 patients with full trisomy 13, found a death rate of 28% within the rst week, 44% within the rst month, and 86% in the rst year. Survivals beyond the rst year of life are unusual, and beyond the rst decade are exceptional, only seven patients over 10 being reported to date [11,16,17,20e22], three of which over 18 [17,20,21]. The oldest patient so far reported is an adult of 32 years of age [21]. In this work we describe a patient with Patau syndrome born in 1995 and still living, in whom an unusual mosaic is present, including three cell lines with different rearrangements involving one chromosome 13. 2. Case report The patient, a 12-year-old girl, was the second child born to non-consanguineous, healthy parents when the mother was 23 and the father 26 years old. The rst daughter was normal and the family history was unremarkable. The pregnancy was remarkable for a reduction in foetal motility and a failure to progress from the 29th week. The infant was delivered at 32 weeks of gestation by caesarean section. Birth weight was1420 g (3SD), length 37 cm (3SD), and head circumference 27 cm (3SD). APGAR score was 8 at 1 min. She was admitted to the intensive neonatology unit due to respiratory distress, generalized increase in muscle tone and abnormal crying. The newborn examination revealed multiple dysmorphic features with major somatic abnormalities, including microcephaly, dolichocephalous cranium, high sloping forehead, at haemangioma of the scalp, prominent coronal and occipital sutures, low set ears, hypertelorism, long eyelashes, downslanting palpebral ssures, at nasal bridge, long smooth philtrum, micrognathia, wide mouth, thin upper lip, short lingual fraenulum, and high arched palate. Deformities of hands, feet and body were associated to the facial deformities as well as short neck (Fig. 1A), pectus excavatum, kyphoscoliosis, cubitus valgus, overlapping and exed ngers, camptodactyly of the third and fourth ngers, hypoplasia of distal phalange of the fth nger of the right hand, clubfoot, adduct metatarsus (Fig. 1C), allux valgus, and overlapping toes. Associated ophthalmic, cardiovascular, and urogenital defects have been identied: pale optical disc and retinal dysplasia, ostium secundum, interventricular defect, patent Botallos duct, calico-pyelic ectasia, and anterior anus. Global developmental delay was noticed from early infancy. She began babbling at 2 years of age, smiling and speaking at 3 years, sitting at 2 years, standing up with help at 5 years and crawling at 12 years. She has never trained toilet. Severe feeding and chewing difculties and failure to thrive persisted despite normal dentition. The patient takes Niaprazina because of signicant disorder of sleep/wake cycle and inability to fall asleep or maintain sleep. At 1 year she was treated with Valproate because of generalized seizures. EEG revealed abnormalities of background activity without paroxysmal discharges. Neurological examination showed poor motility and muscular hypertonia both in the lower and upper limbs.

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Fig. 1. Phenotypic aspects of the patient. The infant at birth (A) and at 12 years (B); pigmentary mosaicism on the back (C); feet (D). Linear white streaks are evident on both feet.

At some time she began to suffer from frequent urinary infections always treated with antibiotic therapies. Neurological examination at 2 years revealed spastic quadriplegia; at this age she started a program of physical and cognitive therapy. At 11 years the patient had a single menstrual cycle without physical signs of puberty. At 12 years she was admitted at Institute of Child Neuropsychiatry of Sassari University. At examination, her weight was 24.6 kg (3SD), length was 135 cm (3SD) and head circumference was 48 cm (3SD). Severe kyphosis and scoliosis, joints ankylosis most pronounced in the lower limbs, associated to the dysmorphic features and malformations above delineated were also noticed. Respiratory insufciency due to thoracic deformity was a severe problem. Neurological examination demonstrated signicative hypotrophy of muscles and severe spastic quadriplegia predominantly right-sided. The patient spoke sometimes few words to communicate, didnt stand nor walk alone. She was already taking Valproate and was seizures free. Her intellectual capacities were severely compromised. She was not able to perform standard intellectual tests. According to the Vineland scales for adaptive behaviour, she results as a child of 18 months of age, motor and daily skills being more compromised than communication and socialisation skills.

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Magnetic resonance imaging showed periventricular leukomalacia probably due to hypoxice ischemic insult, mild hypoplasia of corpus callosum, enlarged cisterna magna, and small heterotopias in the subcortical white matter of the right cerebral hemisphere. Abnormal position of the rst and second cervical vertebra was also observed. This MRI was similar to that performed when the patient was 2 years old. Nerve conduction showed motor and sensor neuropathy. The results of other instrumental examinations as EEG, EKG, echocardiography, and ultrasound of kidneys and bladder were normal. 2.1. Cutaneous symptomatology From the age of 1 the patient started to show white cutaneous streaks following the lines of Blaschko, according to the classical hypomelanosis of Ito, meeting with hyperchromic spots of several centimetres in size. These lesions evolved with the progressive appearance on the back of various oval or roundish hypopigmented patches, irregular areas of a white coffee colour and hypopigmented streaks in a V formation (Fig. 1C). Hypopigmented linear streaks and hypopigmented oval spots are also present on the internal side of the lower limbs (Fig. 1D). The current appearance seems to agree with the form of pigmentary dysplasia denominated phylloid hypomelanosis, classied as type 3 by Happle [6]. 3. Materials and methods 3.1. Cytogenetics Routine cytogenetic analyses in QFQ banding were carried out at birth on peripheral lymphocytes, cutaneous broblasts and lymphoblastoid cells; at the age of 9 a cytogenetic re-evaluation was performed on peripheral lymphocytes and on cutaneous broblasts from two different skin biopsies, coming from differently pigmented areas, one hyperpigmented and the other seemingly normal. Routine cytogenetic analyses of the parents were carried out on peripheral lymphocytes. 3.2. Molecular cytogenetics FISH experiments were performed with the following commercial DNA probes: whole chromosome painting probe (13) (Vysis) and LSI 13 (RB-1) (Vysis) according to the protocols suggested by the manufacturers. The BAC probes used in this study, selected for their chromosomal localization (UCSC, March 2006; http://genome.ucsc.edu/cgi-bin/hgGateway) and kindly supplied by Professor Mariano Rocchi (Institute of Genetics, Bari, Italy), were prepared according to the protocols of the Sanger Centre Institute for bacterial cultures, DNA extraction and probe labelling with biotin-16-dUTP or digoxigenin-11-dUTP. Hybridization, post-hybridization washings and detection were carried out according to standard procedures. The FISH slides, stained with 40 ,6-diamidino-2-phenylindole (DAPI), were observed with Olympus BX61 epiuorescence microscope equipped with specic lters. 3.3. Molecular analysis The genomic DNA of the patient and parents was extracted from blood following the standard salting-out procedures. Thirteen microsatellite markers on chromosome 13 (D13S175,

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D13S217, D13S218, D13S263, D13S153, D13S156, D13S170, D13S265, D13S159, D13S158, D13S173, D13S1265, and D13S285) were genotyped and analysed. These markers were part of the whole genome linkage commercial panels from Applied Biosystems (ABI PRISM Linkage Mapping Sets V2.5). Microsatellites were rst amplied by PCR using uorescently labelled primers in a reaction volume of 7.5 ml (containing 5.25 pmol of each primer, 1.5 nmol of each of the four deoxynucleotide triphosphates and 0.2 units of AmpliTaq Gold polymerase (Applied Biosystems) in a 2.5 mM MgCl2 buffer). PCRs were performed in ABI thermal cyclers using a standard le for all markers: 12 min at 96  C (30 s at 94  C/30 s at 55  C/30 s at 72  C) 10 times, (30 s at 89  C/30 s at 55  C/30 s at 72  C) 20 times, 10 min at 72  C, 15  C ad innitum. PCR was performed separately for each microsatellite marker, and then pooled in panels. PCR products were then separated on a polyacrylamide polymer using a 3100 ABI DNA capillary sequencer (Applied Biosystems). After electrophoresis separation, the PCR fragments were sized and genotyped using appropriate softwares. Alleles at each microsatellite were then given a numerical value (1, 2, 3, and 4) starting with the allele with the lowest number of base pairs. 4. Results 4.1. Standard cytogenetics As reported in Table 1, at birth two cell lines were present, where a normal chromosome 13 was replaced in one by a derivative (13), interpreted at the time as rob(13;13)(q10;q10), later found to be isochromosome (13q) and in the other by a submetacentric derivative (13), with a shorter arm apparently extended from 13q14 to 13qter, which could thus be described as follows: der(13)(13qter/cen::13q14/qter) (Fig. 2A and B). For simplicity, this chromosome hereafter will be referred to as large der(13). The reciprocal proportion of the two cell lines, with i(13q) and large der(13), respectively, was almost the same in the lymphoblasts, whereas in peripheral lymphocytes the cells with i(13q) were prevalent, with a ratio of the two cell types of 30:10. On the contrary, in the cutaneous broblasts the cell line with large der(13) was largely predominant, with a ratio of the two cell types of 131:18. No normal cells were found in any of the tissues examined. The parents both had normal chromosomes. At the age of 9 a routine analysis on peripheral lymphocytes conrmed the result already seen at birth, while in the cutaneous broblasts coming from the two distinct skin biopsies
Table 1 Percentage distribution of the three cell lines in different tissues examined at different ages Tissue Lymphoblasts Lymphocytes Age Birth Birth 9 years 12 years Birth 9 years (Norm.a) 9 years (Hyperpig.b) Total cells 80 40 116 120 149 70 61 Iso(13q) 41 (51%) 30 (75%) 86 (74.14%) 90 (75%) 18 (12%) n.d. n.d. Large der(13) 39 (49%) 10 (25%) 30 (25.86%) 30 (25%) 131 (88%) 50 (71%) 47 (77%) Small der(13) n.d. n.d. n.d. n.d. n.d. 20 (29%) 14 (23%)

Skin broblasts

n.d., not detected. a Normal skin. b Hyperpigmented skin.

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Fig. 2. Cut-out of normal (left) and derivative (right) chromosomes (13) in QFQ banding. (A) Isochromosome (13q); (B) large der(13); and (C) small der(13).

the cell line with i(13q) seemed to have disappeared, while the cell line with the large der(13) was still present, together with a new cell line, where a normal chromosome 13 was replaced by a tiny submetacentric chromosome, interpreted as der(13)(13q11/cen/13q13), hereafter indicated as small der(13) (Fig. 2C). The reciprocal proportion of the two cell types was almost the same in the two cutaneous samples, in both being prevalent the cell line with large der(13), with a ratio of 50:20 in the normal skin and 47:14 in the hyperpigmented skin. 4.2. Molecular cytogenetics All the three derivatives (13) showed complete painting with the whole chromosome painting probe of chromosome 13; the LSI 13 (RB-1) probe, mapping to 13q14.2, gave a single FISH signal on the normal chromosome 13, two FISH signals (on both arms) both on the i(13q) and on the large der(13) and no signals on the small der(13). Further FISH analyses were carried out with the BAC probes shown in Fig. 3; the isochromosome was positive on both arms for all the probes tested (not shown in gure), while the large and the small derivatives (13) showed a pattern of FISH signals specular to one another. According to FISH results one of the breakpoints from which the large der(13) and the small der(13) both could originate from the i(13q) was found inside the BAC clone RP11-186J16 in 13q13.3; a second breakpoint was proximal to the probe RP11-71I1, mapping in 13q12.11. We can therefore characterize as follows the three cell lines present in our patient: the cell line with i(13q) is totally trisomic for chromosome 13; the cell line with the large der(13) is trisomic for 13q13.3/qter (w75 terminal Mb) and the cell line with the small der(13) is monosomic for the same region. The patients karyotype can be indicated as: 46,XX,i(13q)/ 46,XX,der(13)(13qter/cen::13q13.3/qter)/46,XX,der(13)(13q11/cen/13q13.3). 4.3. Molecular analysis The analysis of the microsatellite polymorphisms reported in Table 2 showed the presence in our patient of only two alleles, one of maternal, and one of paternal origin at all the loci tested, which spans the whole long arm of chromosome 13. This result leads us to hold that the presumed der(13) rob(13;13)(q10;q10) is in all probability an isochromosome (13q).

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Fig. 3. List of BAC probes used and FISH results on large and small derivatives (13). In bold the BAC clone identied as one of the breakpoints on i(13q).

Table 2 Microsatellite results Locus D13S175 D13S217 D13S218 D13S263 D13S153 D13S156 D13S170 D13S265 D13S159 D13S158 D13S173 D13S265 D13S285
a

Localization 13q12.11 13q12.3 13q13.3 13q14.1 13q14.2 13q22.1 13q31.1 13q31.3 13q32.2 13q33.1 13q33.3 13q33.3 13q34

Father 1 1 1 1 2 2 2 1 3 1 1 1 1 1 2 2 4 3 3 3 3 4 3 2 3 2

Patienta 1 2 1 4 2 2 2 3 4 1 2 3 2 1 2 3 3 1 1 4 3 1 3 1 1 1

Mother 1 2 2 2 1 1 1 2 2 2 1 1 1 1 3 3 3 4 2 4 3 1 3 3 2 3

Proband: two alleles at all loci tested; paternal allele (left) and maternal allele (right).

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5. Discussion Chromosomal mosaics made up of cell lines with different structural rearrangements involving the same chromosome are unusual, and their origin often remains obscure. A case similar to ours was reported by Reardon et al. [16] in an 11-year-old patient, in whom two cell lines were present, one with an apparent rob(13;13)(q10;q10) and the other with a submetacentric der(13), seemingly the same as the large der(13) of our case. The authors suggested three different possible mechanisms which could explain the origin of the two cell lines, but none of the formulated hypotheses had cytogenetic evidence. On the contrary, in our case a third cell line is present, which would explain the origin of the unusual mosaic, starting from a cell with isochromosome (13q). This cell is most likely the zygote, since no normal cells were found in any of the cytogenetic analyses performed at different ages of the patient and on different tissues. Our hypothesis is that in one of the post-fertilization divisions two breakages may have occurred in the isochromosome at the stage of two chromatids, in one arm at q11 band and in the other at q13.3; erroneous rejoinings would lead to both large and small derivatives, with loss of acentric fragments (Fig. 4). Thus two offspring cells would be formed, originating two distinct cell lines. The FISH results seem to conrm our hypothesis, as the probes which give positive signals on the large der(13) come up negative on the small der(13), and vice versa, which is just the expected result. The persistence of the cell line with i(13q), still present in blood lymphocytes, implies that this rearrangement occurred in a late post-zygotic cell division. Therefore in our patient, besides the two cell lines totally or partially trisomic, a third cell line is present, almost entirely monosomic for chromosome 13, which could possibly play some role in mitigating the clinical severity of the classical Patau syndrome.

Fig. 4. Hypothetic origin of both large and small derivatives (13) from an isochromosome (13q). (A) Two breaks at q11 and q13.3 of the opposite arms of an i(13q), with loss of acentric fragments; (B) correct and erroneous rejoining of residual fragments; and (C) large der(13) and small der(13).

Table 3 Comparison of clinical features in seven long-surviving patients with Patau syndrome and in our patient (from Zoll et al. [22], modied) Trisomy 13 common symptoms Birth time Birth weight Neonatal asphyxia Pregnancy Brain Microcephaly Holoprosencephaly Eyes Microphthalmia Coloboma/cataracts Ears Hearing loss Low-set ears Dysmorphic ears Head and face Scalp defect Sloping forehead Broad, at nose Cleft lip and or palate Highly arched palate Protruding lower lip Heart defects Renal malformations Genital anomalies Limb anomalies Hexadactily Flexion deformity of ngers Club feet, rocker-bottom feet Joint contractures Others limb anomalies Preterm Mean 2600 g () (Complicated) () () () () Boy, 11 ya Girl, 19 ya Boy, 10 yb Adult, male, 22 yc Girl, 11 yd Adult, Girl, 12 yf e female, 32 y Preterm n.m. n.m. 2540 g Present case, girl, 12 y Preterm 1420 g

Preterm 2370 g

At term 2760 g

At term 2610 g

At term Preterm 3400 g 1560 g

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Uncomplicated Uncomplicated Uncomplicated n.m. n.m. n.m. n.m. Dextrocardia n.m. n.m. n. m. Dextrocardia n.m. n.m. n.m. n.m. n.m. n.m. n.m. n.m. n.m. n.m.

Complicated n.m.

Uncomplicated Complicated n.m. n.m. n.m. n.m. n.m. n.m n.m. (continued on next page)

Sunken eyes n.m. n.m. n.m. n.m. Prominent n.m. n.m. Dextrocardia n.m.

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Table 3 (continued ) Trisomy 13 common symptoms Kyphosis, scoliosis Mental retardation Seizures Failure to thrive Recurrent infections Cytogenetics () () L Boy, 11 ya Girl, 19 ya Boy, 10 yb Adult, male, 22 yc n.m. n.m. L Girl, 11 yd Adult, Girl, 12 yf e female, 32 y n.m. L n.m n.m. L Present case, girl, 12 y L: full/partial trisomy 13 SK: full/partial trisomy/ partial monosomy 13

312

SK

SK

n.m. n.m. n.m. L: full/partial trisomy 13 SK: full/partial trisomy 13

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SK: mos?

SK

SK

, symptom present; , symptom not present; (), not obligatory; n.m., not mentioned. L, SK e trisomy 13 present in lymphocytes and skin broblasts; mos, mosaic trisomy 13. a Redheendran et al. [17]. b Reardon et al. [16]. c Singh [20]. d Zoll et al. [22]. e Tunka et al. [21]. f Iliopoulos et al. [11].

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A possible complementation at tissutal level of the two opposite imbalances (trisomy and monosomy), suggested by some authors [3,8], may be an attractive hypothesis, but nowadays there is no experimental evidence for this. On the other hand the composition of the mosaic in the broblasts, with a prevalence of the partially trisomic line, may be on its own sufcient to justify the mild phenotype in our patient. The chromosomal mosaicism, together with translocation trisomy, could also account for her long survival. Longer survivals, compared with cases of classical, free, full trisomy 13, have in fact been noted by several authors in patients with translocations and mosaics [3,12,17]; nevertheless, out of seven patients over the age of 10 to date reported, four had free and homogeneous trisomy, found both in blood lymphocytes and cutaneous broblasts, so with a reasonable exclusion of mosaics [17 (patient 1), 20e22], two had free and homogeneous trisomy ascertained in peripheral lymphocytes only [11,17 (patient 2)] and only one, the already cited patient reported by Reardon et al. [16], had translocation trisomy in mosaic in peripheral lymphocytes. A comparison of the phenotype of these long-surviving patients, including the present case (Table 3), highlights the lack in all of severe cardiac and cerebral malformations, in particular the absence of holoprosencephaly, which seems to affect unfavourably the prognosis quoad vitam [4]. An interesting feature of our patient is represented by pigmentary anomalies, resembling in their current aspect the so-called phylloid hypomelanosis. This is a form of pigmentary dysplasia, classied by Happle [6] as type 3, which is characterized by variable combinations of hypochromic and hyperchromic lesions arranged in such a way as to resemble the leaves of a begonia. This peculiar form of pigmentary mosaicism seems to be closely related to mosaic trisomy 13; indeed among six patients with phylloid hypomelanosis collected in a review by Happle [7], ve resulted as having anomalies involving one chromosome 13 in peripheral lymphocytes [10,13,15,18,19], and in four of these a condition of mosaicism was highlighted in the cutaneous broblasts [13,18,19]. Cytogenetic data from skin biopsies coming from differently pigmented areas, available in two cases [10,13], showed in both patients the same proportion of the cell lines making up the mosaic in all the samples examined, therefore suggesting that none of the cell lines could be mostly assigned to specic pigmentary areas. The cytogenetic results in our patient seem to agree with this, so from this point of view the present report is a useful contribution. To conclude, we feel that our work, with the report of an unusual cytogenetic variant of the classical Patau syndrome, could contribute to explain other cases of chromosomal mosaicisms of uncertain origin. Also, the clinical description of our patient may help to illustrate some clinical aspects of Patau syndrome that can only be observed in long-surviving patients, such as the cutaneous symptomatology. What is more, our experience suggests that it is suitable to examine more than one tissue not only in cases of ascertained mosaics, but also when some discrepancy is observed between cytogenetics and phenotype, such as an unexpected long survival in subjects with chromosomal anomalies that are known to be cause of early death.

Acknowledgements We wish to thank the family of our patient for having authorized this research and Professor Mariano Rocchi, General Biology, University of Bari, Italy, for the supply of BAC/PAC probes used in this work.

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