PRENATAL DIAGNOSIS

Prenat Diagn 2010; 30: 168–172. Published online 17 December 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2427

RESEARCH LETTER

Mosaic trisomy 22: five new cases with variable outcomes. Implications for genetic counselling and clinical management Sandrine Leclercq,* Xavier Baron, Marie-Line Jacquemont, Fabrice Cuillier and Fran¸cois Cartault Centre Hospitalier Felix Guyon, Service de G´en´etique, Pˆole Femme M`ere Nouveau-n´e G´en´etique, Bellepierre, 97405 St Denis Cedex KEY WORDS:

trisomy 22; mosaicism; prenatal diagnosis

Non-mosaic trisomy 22 is the second most common aneuploidy identified in spontaneous miscarriage with an incidence of almost 2.2% (Warburton et al., 1991). Live births are rare with survival expected only during the neonatal period. On the contrary, mosaic trisomy 22 is rare but compatible with prolonged survival. To our knowledge, 19 prenatal cases and 21 postnatal cases have been reported. Regarding postnatal cases, mosaic trisomy 22 has variable clinical presentations that often include growth retardation (GR), dysmorphic features (DF), mental retardation (MR), hemiatrophy, cardiac, ophthalmic, ear and limb malformations (Wang et al., 2007). On the contrary, two patients were recently reported to have normal intelligence (Thomas et al., 2004; Florez and Lacassie, 2005). Prenatal detection of mosaic trisomy 22 in chorionic villus or amniotic fluid samples may generate difficulties in terms of genetic counselling and clinical management. As has been reported, heterogeneous pregnancy outcomes can range from normal to severely impaired (Hsu et al.,1997). Further investigations are usually required to discriminate confined placental mosaicism (CPM) and true foetal mosaicism. We present here five new cases of mosaic trisomy 22: four of them were prenatally diagnosed and one at the age of four. These clinical observations combined with previously published data help us to delineate how to manage follow-up and genetic counselling in such pregnancies with variable outcomes. Clinical findings of these five new cases are presented in Table 1. Cytogenetic analysis was performed on cultured amniocytes, blood lymphocytes or skin fibroblast using standard techniques. For case 1 and 2, FISH investigation was conducted on uncultured tissue sample using the Di George syndrome probe (MD Di George N25, KBI 40 102, Kreatech Poseidon ). In case 5, intrauterine growth retardation (IUGR) with oligoamnios was discovered at 28 weeks as a result of poor follow-up of pregnancy. All patients had a noncontributory family history except for case 5 who had a *Correspondence to: Sandrine Leclercq, Centre Hospitalier Felix Guyon, Service de G´en´etique, Pˆole Femme M`ere Nouveau-n´e G´en´etique, Bellepierre, 97405 St Denis Cedex. E-mail: [email protected]

Copyright  2009 John Wiley & Sons, Ltd.

mentally retarded older brother but not cytogenetically explored. All parental karyotypes were found to be normal. Regarding cytogenetic analysis, four cases (case 1, 3, 4 and 5) were consistent with true foetal mosaicism conforming affected foetus. Confirmation studies were performed on foetal blood sampling or by skin biopsy after birth. For case 2, it was not possible to discriminate true foetal mosaicism and CPM as intrauterine foetal death (IUFD) occurred 1 week after amniocentesis. Our five cases demonstrated the variable outcomes associated with mosaic trisomy 22. A completely normal outcome (case 1) occurs in one case. Karyotyping on skin showed the trisomy in 6% of the mitoses. On the contrary, three other cases have poor outcome, considering IUFD, GR and multiple congenital anomalies (MCA) for cases 2, 4 and 5. Interestingly, true foetal mosaicism was cytogenetically established for three of them (case 1, 4 and 5) on skin fibroblast or foetal blood samples. To our knowledge, case 1 is the first reported case of true foetal mosaic trisomy 22 without congenital malformation, DF or delayed developmental milestones. Chromosomes on skin fibroblasts confirmed the diagnosis of mosaicism: 47,XX,+22[6]/46,XX[94]. The two previous cases of true mosaic trisomy 22 with normal intelligence presented either minor anomalies (isolated ocular manifestations, Thomas et al, 2004) or IUGR (Florez and Lacassie, 2005). Our case remains unclear as full trisomy 22 on placenta tissue is not associated with IUGR and emphasizes how genetic counselling and prognosis are challenging in such pregnancies. Focusing on the 19 previously published prenatally cases, 8 cases are true foetal mosaicism (Wang et al., 2007, 3 cases—XVII-1 XVII-2 XVII-6—from Phillips et al., 1996; De Pater et al., 1997; Hsu et al., 1997; Berghella et al., 1998; Schinzel, 1981). Three other cases refers to CPM (Balmer et al., 1999; Stioui et al., 1989; Bryan et al., 2002). We omitted eight cases which do not contain sufficient detail on cytogenetic confirmation studies (one case from Hall et al., 2009; seven cases from Hsu et al., 1997). Reviewing clinical reports of these eight cases of true mosaicism with information available on pregnancy outcome, diagnosis of trisomy 22 often follows an investigation for IUGR with six out of eight cases. IUGR is often associated with various sonographic findings such as nuchal thickening, cardiac Received: 19 June 2009 Revised: 6 November 2009 Accepted: 13 November 2009 Published online: 17 December 2009

Copyright  2009 John Wiley & Sons, Ltd.

Wang (2007)

Case 5

Case 4

Case 3

Case 2

Case 1

Published cases

G3T1A1

34

G6P5

37

G1P0

AU

—

AU

Nuchal thickening

G3P2

37.5

AMA + AU

AU

AMA

Indication for karyotyping

44

G2 P1

26

G1 P0

39

Age parity

AF: 47,XX+22[7]/46,XX[43] [14%] by FISH

AF: 47,XX+22[84]/46,XX[16] [16%] by FISH

Prenatal cytogenetic exploration

Hydrothorax (35 weeks) tricuspid regurgitation

CHD/IUGR

IUGR, oligoamnios (28 weeks)

IUGR 24 weeks

AF: 47,XX,+22 [6]/46,XX[11] [35%]

Foetal blood: 47,XX,+22[5]/46,XX[109] [4%] AF (single culture flask, pseudomosaicism?): 47,XY,+22[43] [100%] Foetal blood: 47,XY,+22[3]/46,XY[18] [14%] ?

Postnatal cytogenetic exploration

IUFD (34 weeks)

Skin: 47,XX,+22[16]/46,XX[5] [76%]

Birth (35 weeks) Blood: 46,XX

Skin biopsy (4 years): 47,XX,+22[33]/46,XX[67] [33%]

Birth (29 weeks) Blood: 46,XX

IUFD (33 weeks)

Placenta: 47,XX,+22[100] [100%]

Birth (41 weeks) Skin: 47,XX,+22[6]/46,XX[94] Blood: 46,XX[100] [100%]

Pregnancy outcome

- hypoplasic ears - preauricular pits IUGR, increased NT, AF: 47,XX,+22[17]/46,XX[49] MTP (28 weeks) hydrothorax 24 weeks [26%]

IUGR, 33 weeks

Normal

Ultrasound follow-up

Table 1—Five cases of mosaicism trisomy 22 and review of literature with regard to pregnancy cause and outcomes

- Patent ductus arteriosus - Hemiatrophy

- Atrial septal defect

Four years: GR, RM GR–DF

At birth: GR, MCA, DF Nine months: cortical atrophy

GR–MCA

Post-mortem examination: MCA

Post-mortem examination: isolated GR

Post-mortem examination: DF

At birth: normal clinical examination At 4-years-old: normal cognitive, behavioural and physical development

Clinical evaluation

PRENATAL MANAGEMENT OF MOSAIC TRISOMY 22

169

Prenat Diagn 2010; 30: 168–172. DOI: 10.1002/pd

Copyright  2009 John Wiley & Sons, Ltd.

43

Phillips (1996)

?

Hsu XVII—6 (1997)

37 weeks

IUGR CHD

Choroid plexus cyst (18 weeks)

—

AU

AU

AU

AF: 47,XX,+22[50]/46,XX [50%]

47,XY,+22[17]/46,XY[23] [42%] CVS 11 weeks AF: 46,XY[50] [0%]

CVS: 47,XX,+22[12] [100%] AF: 47,XX,+22[2]/46,XX[8] [20%]

Foetal skin biopsy (20 weeks) 47,XY,+22[7]/46,XY[8] [47%]

AF: 47,XY,+22[4]/46,XY[15][21%] Blood: 46,XY[101] [0%]

Facial asymmetry

47,XX,+22/46,XX

Blood: 47,XX,+22[1]/46,XX[26][4%] AF: IUGR cardiopathy/abnormal 47,XX,+22[2]/46,XX[18][11%] ears IUGR hydrocephaly AF 47,XX,+22/46,XX

IUGR (32 weeks)

10.6 weeks

AMA + AU IUGR CVS

AU

AU mosaicism different tissues blood, lung

Not UPD

MTP

Neonatal death

—

Neonatal death

MTP

- Bilateral pulmonary polylobation - Up slanted palpebral fissures proptosis At birth: GR–DF—Hypotonia

- Large low-set ears

Post-mortem examination - Hypertelorism

Skin: 47/46 47,XX,+22[9]/46,XX[1] [90%] Skin 47,XX,+22[18]/46,XX[2] [90%]

- hydrocephaly - DF–GR

- GR

- Cardiopathy—DF

- Ventricular septal defect - Short nose broad nasal bridge long philtrum, micrognathia, hypoplasic nails, clinodactylie fifth fingers. Foetal lung: 47,XY,+22[47] — [100%] Umbilical cord: 46,XY[29] Renal cells: 47,XY,+22[2]/46,XY[48] [4%] - DF Blood: 47,XX,+22[18]/46,XX[2] [90%] - Cardiopathy—MCA

Birth (39.6 weeks) Blood: 46,XX Skin: 47,XX,+22[7]/46,XX[25] [22%]

MTP

AMA, advanced maternel age; AF, amniotic fluid; AV, abnormal ultrasond; MTP; medical termination of pregnancy; DF, dysmorphic features; GR, growth retardation; MCA, multiple congenital anomalies; ?, data not available.

?

?

Hsu XVII—1 (1997)

Hsu XVII—2 (1997)

?

Schinzel (1981)

G1P0

34 G3P1

G2P1

35

De Pater (1997)

Berghella(1998)

170 S. LECLERCQ ET AL.

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PRENATAL MANAGEMENT OF MOSAIC TRISOMY 22

defects or hydrocephaly (four out of eight cases). Six out of eight cases were female foetus. Our experience is in agreement with this result as IUGR is noticed at 2nd or 3rd trimester for four out of five cases (case 2, 3, 4 and 5), with four out of five females and is associated in three cases of true foetal mosaicism (case 3,4 and 5) with heterogeneous congenital malformations. However, owing to the limited number of reported cases, it remains difficult to attribute specific sonographic features to foetal mosaicism. However, commonly described postnatal clinical features could help clinicians to refine further ultrasound explorations. Among them, heart defects including ventricular septal defect, atrial septal defect, pulmonary or aortic stenosis, hemiatrophy, craniofacial and limbs anomalies could provide further elements consistent with foetal involvement. In case 2, post-mortem examination shows: proeminent forehead, small low-set and posteriorly angulated ears, bilateral epicanthal fold, short neck with redundant skin and case 4, anal atresia, distal caecal atresia, macro and micro kidney cysts. On the contrary, some foetal mosaicism cases presenting subtle phenotypic characteristics (Thomas et al., 2004; Florez and Lacassie et al., 2005; our case 1) may not be identifiable through sonographic exploration. Therefore, foetal sonography is recommended but not exclusively for the evaluation of foetal mosaicism. Confirmation studies by foetal blood sampling could be proposed but have also limited predictive value as trisomic cells may be absent from haematological lines despite foetal involvement. There is no correlation between the number of trisomic cells in the amniotic fluid and the pregnancy outcome. In our observations, the percentage is included between 14 and 100%. We observed IUFD in cases 2 and 4. Cytogenetic confirmation of foetal mosaicism was proven by karyotyping fibroblasts or blood. Some authors (Berghella et al., 1998) suggest that foetal skin biopsy may have higher diagnostic value in these cases. In French general practice, skin biopsy is proposed postnatally, but is not included in routine prenatal evaluation of foetal mosaicism as several clinical questions such as skin sites or number of biopsies remain unsolved. Concerning post-natal follow-up of prenatally diagnosed cases, little is known as only 6 out of 11 cases were liveborns. Most often, true foetal mosaicism seems to result in a poor outcome (GR with DF and/or MCA: De Pater et al., 1997; Wang et al, 2007; case XVII-1 from Hsu et al., 1997) while CPM to an isolated GR with sometimes minor anomalies (Stioui et al., 1989; Balmer et al., 1999; Bryan et al., 2002). On the contrary, we reported here two liveborn cases (cases 1 and 5) displaying true mosaicism and presenting contrasted clinical findings with an unexpected normal phenotype for case 1 and a severely impaired one for case 5. In case 1, the clinical examination was normal without DF and/or malformations. At 4 years, the mental development was normal. In case 5 the diagnosis was postnatal. The clinical examination at 4 years showed malformations with posterior cleft palate, facial and body asymmetry and left coxa valga, distal phalange agenesis of the left hand and foot, C2 C3 synostosis, bilateral glaucoma, ventricular septum defect and DF with sparse hair, high frontal hairline, hypertelorism, prominent forehead, Copyright  2009 John Wiley & Sons, Ltd.

anteverted nares, long philtrum, low-set large ears, slant down palpebral fissures. In conclusion, we emphasize the fact that the prenatal diagnosis of mosaic trisomy 22 generates difficulties in counselling and pregnancy management. Moreover, the rare cases published of prenatal and postnatal diagnosis show the great variability of the clinical expression of such an anomaly. In the case of abnormal ultrasound findings leading to amniocentesis and diagnosis of mosaic trisomy 22 (with or without proved foetal mosaicism), prenatal management will be facilitated by a prognosis of IUGR and associated malformation. The karyotyping from chorionic villus sampling or amniotic fluid is not sufficient to confirm a definitive diagnosis, giving rise to difficult counselling for both clinicians and parents. To confirm the diagnosis, knowing that the number of trisomic cells is very low in lymphocytes, the karyotyping is more effective using fibroblasts. There is no correlation between the percentage of trisomic cells and intelligence. Moreover, in cases of fortuitous diagnosis of mosaic trisomy 22 with normal ultrasound follow-up, genetic counselling will not be aided. Even if normal outcomes have been described (as case 1) and are probably underestimated in literature, the trisomic cells distribution in foetal tissues is not predictable. Parental decision to continue pregnancy should rely on their willingness to accept a certain degree of risk, as normal ultrasound studies do not necessarily signify the absence of impaired psychomotor development.

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Prenat Diagn 2010; 30: 168–172. DOI: 10.1002/pd