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European Journal of Medical Genetics 51 (2008) 303e314

Original article

Patau syndrome with long survival in a case of unusual mosaic trisomy 13Giuseppina 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 cClinical 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 2008a

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: (G. Fogu). 1769-7212/$ - see front matter 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2008.03.004


G. Fogu et al. / European Journal of Medical Genetics 51 (2008) 303e314

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.

G. Fogu et al. / European Journal of Medical Genetics 51 (2008) 303e314


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.


G. Fogu et al. / European Journal of Medical Genetics 51 (2008) 303e314

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; 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 cul