Original article 123

Mosaic and complete tetraploidy in live-born infants: two new patients and review of the literature
Irina Stefanovaa, Jutta Jendernyb, Elke Kaminskyc, Anca Mannhardtd, Peter Meineckee, Liliana Grozdanovaf and Gabriele Gillessen-Kaesbacha
Tetraploidy is a very rare finding in live-born infants. Nine infants with tetraploidy have been reported earlier. The phenotype is of variable severity and consists of prenatal and/or postnatal growth retardation, developmental delay, mental retardation, dysmorphic features, and skeletal and internal abnormalities. Here we present a girl aged 2 years and 7 months with a mosaic tetraploidy detected in lymphocytes, and a newborn boy with a complete tetraploidy, who died 30 h after birth. They both show growth retardation, microcephaly, developmental delay, and craniofacial dysmorphisms. The clinical features of 22 patients reported earlier are reviewed. Clin Dysmorphol
c 2010 Wolters Kluwer Health | Lippincott 19:123127 Williams & Wilkins. Clinical Dysmorphology 2010, 19:123127 Keywords: mosaicism, polyploidy, tetraploidy
a t zu Lu r Humangenetik, Universita beck, Lu beck, bLabor Institut fu r Humangenetik, dWerner-Otto-Institut, eMedizinische Lademannbogen, cPraxis fu Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany and fDepartment of Medical Genetics, University Hospital, Medical University, Plovdiv, Bulgaria

r Humangenetik, Correspondence to Dr Irina Stefanova, MD, Institut fu tsklinik SH, Ratzeburger Allee 160, Lu beck 23538, Germany Universita Tel: + 49 4515002624; fax: + 49 4515004187; e-mail: Irina.Stefanova@uk-sh.de Received 13 March 2009 Accepted 10 November 2009

Introduction
Complete tetraploidy has often been described in et al., 1975; Genest et al., spontaneous abortions (Boue 1995; Nagaishi et al., 2004). It is however a rare finding in live-born infants; only nine patients have been described so far (Golbus et al., 1976; Pitt et al., 1981; Scarbrough et al., 1984; Lafer and Neu, 1988; Shiono et al., 1988; Pajares et al., 1990; Guc-Scekic et al., 2002). The clinical phenotype is severe with multiple congenital anomalies and limited life expectancy. Tetraploiddiploid mosaicism has been reported in 15 patients (Kohn et al., 1967; Kelly and Rary, 1974; Reddy et al., 1977; Veenema et al., 1982; Quiroz et al., 1985; Rojanasakul et al., 1985; Wittwer and Wittwer, 1985; Aughton et al., 1988; Wilson et al., 1988; Wullich et al., 1991; Edwards et al., 1994; Sousa et al. 1996; Alonso et al., 2002). The phenotype of these patients is variable; the most consistent features are growth retardation and developmental delay. We report a girl, aged 2 years and 7 months with mosaic tetraploidy in lymphocytes and a newborn boy with complete tetraploidy who died 30 h after birth. at birth was 26 cm ( 2.8 SD). A mild pulmonary hypoplasia was diagnosed after birth. At 14 months, she showed psychomotor developmental delay, not being able to sit or walk independently. She did not have any expressive speech. She had reduced body measurements: height 66 cm ( 3.4 SD), weight 5330 g ( 4.2 SD), and head circumference 39.5 cm ( 5.3 SD). The patient presented with microbrachycephaly, very mild dysmorphic features (prominent forehead, broad nasal root), complete 2/3 toe syndactyly on both feet, and two small haemangiomas (on the upper lip and on the abdomen). At the age of 2 years and 7 months (Figs 2 and 3) the patient was able to walk with aid. She could speak in sentences with unclear speech and had a rather good comprehension of speech. She showed severe feeding difficulties. Her body measurements were: height 85 cm ( 1.8 SD), weight 7.5 kg ( 4.7 SD), and occipitofrontal circumference 43 cm ( 4.5 SD). The peripheral lymphocyte karyotype was mos 92,XXXX [45]/46,XX[55]. FISH analysis on buccal smear with probes DXZ1 for the X-chromosome and D3Z1 for chromosome 3 showed the karyotype nuc ish(DXZ1,D3Z1)x2 [74] as in a diploid karyotype. The karyotype in fibroblasts was 46,XX[30]. Cytogenetic analyses were not performed on the parents.
Patient 2

Clinical reports
Patient 1

The patient was referred to us at the age of 14 months (Fig. 1). Intrauterine growth retardation was diagnosed at 24 weeks of gestation. The delivery was at 32 weeks of gestation by Cesarean section. The parents were a 19-year-old mother and a 20-year-old father. The family history was unremarkable. Birth weight was 995 g ( 2.3 SD), birth length 35 cm ( 1.2 SD), and head circumference
c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827

Patient 2 is a newborn boy, first child of a healthy 26-yearold mother and a healthy 33-year-old father. He was born at term after uncomplicated pregnancy and vaginal delivery complicated by amniotic infection. He was small
DOI: 10.1097/MCD.0b013e3283353877

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124 Clinical Dysmorphology 2010, Vol 19 No 3

Fig. 1

Fig. 3

Patient 1 at age 2 years and 7 months.

Patient 1 at age 14 months.

Fig. 2

and low set ears, oligodactyly (four toes on both feet), and syndactyly of toes. Further findings included hydrocephalus, hypotonia, hyporeflexia and ambiguous genitalia. Pathological examination revealed an atrial septal defect as well as cephalhaematoma. The karyotype in lymphocytes was 92,XXYY. No cytogenetic analyses were performed on the parents.

Review of the literature and discussion Diploidtetraploid mosaicism

We report on a 14-month-old girl with a mosaic tetraploidy in blood. She showed delayed development, growth retardation, microcephaly, and syndactyly of toes. These findings have already been described in patients with diploidtetraploid mosaicism. Two cases described earlier (Rojanasakul et al., 1985) as well as two mothers of index patients (Scarbrough et al., 1984; Rojanasakul et al., 1985) showed low percentages of tetraploid cells in association with a normal or slightly abnormal phenotype. The index patients described by Rojanasakul et al. (1985) presented with polycystic ovary syndrome.
Patient 1 at age 2 years and 7 months.

for gestational age. The placenta was small and calcified. The family history was unremarkable. Birth weight was 1910 g ( 3.8 SD), length 45 cm ( 3.3 SD), and head circumference 33 cm ( 2.0 SD). His spontaneous breathing ceased after birth and he was required assisted ventilation until he died 30 h later. The patient presented with a wide-open sagittal suture, exophthalmus, epicanthus, broad saddled nose with narrow nares, dysmorphic

The phenotype of 13 live-born patients with earlier described diploidtetraploid mosaicism is reviewed in Table 1 and compared with the findings in our patient. All patients show different degrees of growth and mental retardation. Five patients present with intrauterine growth retardation. Six of six patients show postnatal short stature. Hypotonia and motor developmental delay seem to be a common feature (present in seven previously described patients and in our patient). Seizures have been described only in two patients reported by Edwards et al. (1994). There is no information regarding the age at which seizures did develop. But

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Mosaic and complete tetraploidy in live-born infants Stefanova et al. 125

Table 1

Diploidtetraploid mosaicism
Kelly Kohn and et al., Rary, 1967 1974 Reddy Veenema et al., et al., 1977 1982 Wittwer Quiroz and Aughton et al., Wittwer, et al., 1985 1985 1988 Wilson et al., 1988 Edwards Edwards Wullich et al., et al., Sousa Alonso et al., 1994, 1994, et al., et al., 1991 Patient 1 Patient 2 1996 2002 Our patient 1

Male Last report at age of Died at 36 weeks 42

Female 2 years

Male

Male

Male

Male

Female

Female

Male Died at 9 weeks 41

Female

Female

Male

7 males/ Female Female 7 females

Died after 2 years birth 40 32 1580 34 2690 + + + + + + + + + + +

Died at 2 15 months months 32 1060 + + 38 3900

11 years 21 years

Week of 40 gestation Birth weight (g) 2000 IUGR + + Abnormal + + fontanelles Hypotonia + Growth + deficiency Failure to thrive + + Motor + + retardation Mental + retardation Seizures Craniofacial dysmorphisms + Prominent forehead Microcephaly + + Blue sclerae Broad nasal + + root Small mouth + + Dysmorphic + ears Low set rotated ears Micrognathia/ + + retrognathia Extremities Abnormalities of hands Abnormalities + of feet Syndactyly + + of feet Internal abnormalities Cardiac + defects Hypoplastic lungs CNS malformations Renal/ urinary tract Skin changes

Died 5 years 14 at 8 and 3 months months months 40 40 32 2050 + + + + 995 +

+ + + + + + + + + + + + + +

+ +

5/9 6/7 8/12 7/7 8/9 8/8 5/6

+ + + +

+ +

+ + + + + + +

2/7 4/8 6/8 1/2 6/7 5/7 6/10 4/8

+ +

+ + +

+ +

+ + +

7/10

+ + +

+ + +

3/7 4/8 4/6

HOON, AVS

TVD, VSD, HRV Right lung Mild CA

PVS

5/12

+ + +

1/6 5/6

+ Marmoration PD PD Haemangiomas 55 0 4/6

Tetraploid cells (%) Lymphocytes 69 Fibroblasts Bone 1 marrow

6 9 2

22

16

68/12

11

0 0 95

7.2 29

0 33

0 > 60

63

AVS, absence of ventricular system; CA, cortical atrophy; CNS, central nervous system; HOON, hypoplasia of optical and olfactory nerves; HRV, hypoplastic right ventricle; IUGR, intrauterine growth retardation; PD, pigmentary dysplasia; PVS, pulmonary valve stenosis; TVD, tricuspid valve displacement; VSD, ventricular septum defect.

these patients were reported to have developed seizures at ages 11 and 21 years, so it seems possible that lack of seizures in the other described patients were due to their young age. Mental retardation was reported in all patients

with the exception of the patient described by Alonso et al. (2002). The latter had a mild phenotype with only a slight developmental delay compatible with attendance of regular school.

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126 Clinical Dysmorphology 2010, Vol 19 No 3

All patients with diploidtetraploid mosaicism seem to have recognizable dysmorphic features. Microcephaly, prominent forehead, broad nasal bridge, small mouth, malformed ears, and micrognathia are common. In our patient 1, these signs are very mild. Abnormalities of the extremities are found in about half of the patients. Cutaneous syndactyly of the toes is also a common

feature. Five out of 14 patients have a cardiac defect. CNS abnormalities have been described in five patients. Tetraploid cells are found in different tissues in the reported patients. Most of them have a diploidtetraploid mosaicism detected in blood lymphocytes. The patients reported by Aughton et al. (1988) with a severe phenotype showed 95% tetraploid cells in bone marrow but a normal

Table 2

Complete tetraploidy
Golbus Pitt et al., et al., 1976 1981 Scarbrough Scarbrough Scarbrough et al., 1984, et al., 1984, et al., 1984, Patient 1 Patient 2 Patient 3 Shiono et al., 1988 Lafer and Neu, 1988 Pajares et al., 1990 Guc-Scekic Our et al., 2002 patient 2 6 males/ 4 females

Sex

Male

Male 3638 2650 +

Male 4142 2360 + +

Female 36 2120 + + +

Male 37 2360 + + + +

Female 38 2360 + +

Female 41 + + +

Male 37 1900 + + + +

Female Term 1800 + + + +

Male Term 1910 + +

Weeks of gestation Term Birth weight (g) 2150 IUGR + Hypotonia + Failure to thrive + Delayed psychomotor + development Craniofacial dysmorphisms Microcephaly + Prominent forehead + Anophthalmia/ + Microphthalmia Short palpebral fissures + Coloboma Hypertelorism Dysmorphic ears + Low set rotated ears + High arched of cleft palate Micrognathia/ retrognathia Abnormalities of the extremities Abnormalities of the hands Abnormalities of the feet Positional limb defects + Arachnodactyly Internal abnormalities Cardiac defect Hypoplastic lungs Meningomyelocele CNS malformations Polymicrogyria Renal/urinary tract malformations Genital ambiguity Others Survival Karyotype Tissues showing tetraploidy karyotypes Parents

7/10 9/10 5/6 8/8

+ + +

+ + + + + + + + +

+ + + + + + +

+ + + + + + +

+ + + + + + + + + +

+ + + + +

+ + + +

5/8 8/8 5/9 8/9 2/3 6/8 6/7 9/10 6/7 6/8

+ + +

+ +

+ +

+ + + + TGV + + + + + + TF + TF ASD

2/2 3/3 8/9 7/9 6/9 1/1 3/10 5/5 3/5 6/9 5/8

+ +

+ +

+ + VSD, ASD, MP

PDA, PFO + + H, ACM + +

UE

HOON + + +

+ HOON, ACM, CH + + + 2 days 92,XXXX ly Father normal, mother: months 92, XXXX[6]/ 46,XX[97] in ly

CA +

+ 2 months 92,XXYY ly, sf NE

+ +

At least 26 months 92,XXXX ly, sf Normal

+ 30 h 92, XXYY ly NE

TH 12 months 92,XXYY

15 days 92,XXYY ly, sf, lf, pf, spf, tf

11 h 92,XXYY ly Normal

At least 15 At least 22 At least 3 months months months 92,XXXX 92,XXXX 92,XXYY ly, sf Normal ly, sf Normal ly, sf NE

ACM, ArnoldChiari malformation; ASD, atrial septal defect; CA, cerebral atrophy; CH, cerebellar hypoplasia; CNS, central nervous system; H, hydrocephalus; HOON, hypoplasia of optical and olfactory nerves; IUGR, intrauterine growth retardation; lf, lung fibroblasts; ly, lymphocytes; MP, mitral valve prolapse; NE, not examined; PDA, persistent ductus arteriosus; pf, pericard fibroblasts; PFO, patent foramen ovale; sf, skin fibroblasts; spf, spleen fibroblasts; tf, testes fibroblasts; TF, tetralogy of Fallot; TGV, transposition of the great vessels; TH, hypoplasia of thymus; UE, unexplained encephalopathy; VSD, ventricular septal defect.

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Mosaic and complete tetraploidy in live-born infants Stefanova et al. 127

karyotype in blood lymphocytes and skin fibroblasts. Our patient has a mild phenotype and showed tetraploid cells in blood lymphocytes, whereas a normal karyotype was found in skin fibroblasts. It is possible that the variable phenotype is determined by the degree of tetraploid cells in different tissues.

clinical geneticist to make a prognosis in terms of development and survival for those patients.

References
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Complete tetraploidy
Nine live-born patients with a complete tetraploidy have been reported (Table 2). The phenotype is severe with multiple congenital anomalies and limited life expectancy. Most patients show severe intrauterine growth retardation, hypotonia, and failure to thrive. In all cases a developmental delay is present. These features are similar to the patients with diploidtetraploid mosaicism but are much more severely expressed in patients with complete tetraploidy. There seems to be a consistent craniofacial phenotype comprising a prominent forehead, short palpebral fissures, hypertelorism, malformed lowset rotated ears, and high arched or cleft palate. Approximately 50% of the individuals with tetraploidy show microcephaly and microphthalmia. Limb defects and arachnodactyly are a common finding. Cardiac, CNS, renal, and/or genital malformations are present in all reported patients.

Conclusion

We report a patient with tetraploidy, pointing out the unusually long survival until 30 h after birth at term, as well as a patient with diploidtetraploid mosaicism, which is also a very rare finding in live-born infants. The phenotype of patients with tetraploidy seems to be consistent, showing a recognizable pattern in all described patients. However, the prognosis in terms of survival seems to be different which is an important issue for genetic counseling. The review of all descriptions of patients with tetraploidy and diploidtetraploid mosaicism showed that there is no clear correlation between a severe congenital anomaly and a poor prognosis. One explanation is that some patients probably have a diploidtetraploid mosaicism in tissues that have not been examined cytogenetically. It is important for genetic counseling to note that in rare cases complete tetraploidy is compatible with life. The phenotype of patients with diploidtetraploid mosaicism is extremely variable, thus it is very difficult for the

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