Clinical findings and cytogenetic analysis of small supernumerary ring chromosomes 7: report of two new cases

Clinical findings and cytogenetic analysis of small supernumerary ring chromosomes 7: report of two new cases

Annales de Génétique 47 (2004) 241–249 www.elsevier.com/locate/anngen Original article Clinical findings and cytogenetic analysis of small supernume...

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Annales de Génétique 47 (2004) 241–249 www.elsevier.com/locate/anngen

Original article

Clinical findings and cytogenetic analysis of small supernumerary ring chromosomes 7: report of two new cases Sandra Chantot-Bastaraud a, Christine Muti b, Eva Pipiras c, Marie Claude Routon d, Anne Roubergue e, Lydie Burglen f, Jean Pierre Siffroi a,*, Brigitte Simon-Bouy b a

: Service d’Histologie, Biologie de la Reproduction et Cytogénétique (UPMC-EA 1533), Hôpital Tenon (AP-HP), 75020 Paris, France. b : Laboratoire SESEP. Université de Versailles, 78000, Versailles, France. c : Service d’Histologie, Embryologie, Cytogénétique et Biologie de la Reproduction. Hôpital Jean Verdier (AP-HP), 93140 Bondy, France. d : Service de Pédiatrie. Centre Hospitalier, 91400, Orsay, France. e : Service de Neuropédiatrie. Hôpital Armand Trousseau (AP-HP), Paris, France. f : Unité de Génétique, Service de Neuropédiatrie. Hôpital Armand Trousseau (AP-HP), Paris, France. Received 11 March 2003; accepted 29 January 2004 Available online 1 March 2004

Abstract Two new patients, mosaic for a small supernumerary ring chromosome 7 are described. There are only seven published reported concerning supernumerary ring chromosome 7 and we reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important for genetic counselling and clinical genetics. Our first case was a 20 months old girl who was referred for a mild motor developmental delay, an asymmetric facial appearance, a plagiocephaly and a short nose with anteverted nostrils. Our second case was a 9 years old boy who was referred for a IQ at the lower end of the normal range (≅ 80), obesity, hyperactivity and some dysmorphic features including hypertelorism and down slanting palpebral fissures. In both cases, chromosome analysis after G and R banding and FISH showed a small ring chromosome 7 in respectively 76% and 50% of consecutively scored metaphases. Both ring chromosomes were labelled by FISH using the Williams Syndrome locus probe (Elastin Gene D7S486). Comparison between these two cases and previously published cases allowed to delineate frequent clinical * Corresponding author : Dr Jean Pierre Siffroi Hôpital Tenon (AP-HP), 4 rue de la Chine, 75020 PARIS Tel : 01 56 01 78 01 Fax : 01 56 01 78 03. E-mail address: [email protected] (J.P. Siffroi). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.anngen.2004.02.003

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findings. A mild mental retardation was found in the majority of patients. which is an important data for genetic counselling. © 2004 Elsevier SAS. All rights reserved. Keywords: Marker chromosome; Ring chromosome 7; Supernumerary chromosome 7; Genetic counselling

1. Introduction Small supernumerary marker chromosomes (SMC) composes a heterogeneous group of extra structurally abnormal chromosomes, the origin and composition of which cannot be resolved using conventional cytogenetic methods. Four fifth of SMC are derived from acrocentric chromosomes, half of which are made of chromosome 15 material [3]. Supernumerary ring chromosomes (SRC) is a smaller group of marker chromosomes accounting for approximately 10% of autosomal markers. Small extra ring chromosomes deriving from regions adjacent to the centromere of non-acrocentric autosomes have an unclear clinical significance but are often associated with a high rate of phenotypic abnormalities [2,8,5,6]. However, clearly defined karyotype/phenotype correlations have not yet emerged for some of these SMCs, mainly because of their scarcity. Description of more patients carrying rare chromosomal markers is thus required for defining accurate karyotype/phenotype correlations and for genetic counselling. Here we report two new cases of de novo mosaic supernumerary ring chromosome 7 that we compare with the seven cases previously reported in the literature [2,10,12,1,13,7]. 2. Clinical report 2.1. Case 1 A 20-month-old Caucasian girl was referred to the laboratory for karyotyping because of mild developmental delay. After a normal pregnancy, she was born at 39,5 weeks of gestation by caesarean section because of a breech delivery. She was the first child of non-consanguineous parents but the father already had a 8 years old healthy girl from a previous union. Maternal and paternal ages were respectively 30 and 29 years. There was no familial history of congenital malformations and/or mental retardation. Birth weight was 2590g, birth length was 45 cm and head circumference was 33cm. Development was considered as normal up to 9 months, the age at which she was referred to neurologist for a motor developmental delay. At 20 months of age, she just said her first words but she was not able to walk alone. Her height and weight were at the 50th percentile except for the head circumference that was 50,5 cm (90th percentile). Physical examination showed a broad forehead, an asymmetrical facial appearance, a plagiocephaly and a short nose with anteverted nostrils. Her extremities were long and slender. Audiograms performed at thirty month revealed a moderate deafness. 2.2. Case 2 This boy was the first child of a 25 years old mother and a 30 years old father. He was born at 34 weeks of gestation after an uneventful pregnancy. Birth weight was 2680g. At the

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age respectively of 16 and 24 months, he was able to walk and to say his first words. When he was 2 years old, he became hyperactive and, at the age of 9, he was referred to the laboratory for cytogenetic investigations because of borderline performance, obesity and hyperactivity with fits of anger. He had also speech difficulties that were partly resolved by speech therapy. Physical examination at the age of 11 showed hypertelorism and down slanting palpebral fissures. At this age, IQ scores were around 80 and school attendance was difficult but possible. Molecular biology test for Prader-Willi disease was negative. 3. Cytogenetic and FISH results In both cases, metaphase chromosome spreads were prepared from PHA stimulated lymphocytes. Chromosome analysis was performed according to routine procedure using RBG and GTG banding. In order to characterise the marker chromosome origin, fluorescence in situ hybridisation (FISH) was carried out either with various alphasatellite probes (15, 13/21, 14/22, 18, 7) for case 1 or directly using spectral karyotyping (Applied Spectral Imaging, Migdal Ha’Emek, Israel) for case 2. After demonstrating that both markers were derived from chromosome 7, FISH study with the Williams Syndrome (WBS) chromosome region probe, coding for elastin (ELN) at 7q11.23, was performed for determining whether the marker was made of q or p arm chromosomal material. 3.1. Case 1 Chromosome analysis after G and R banding showed a supernumerary ring chromosome, slightly smaller than a G group chromosome, in 76% of the metaphases analysed (Fig. 1A). FISH studies of this marker revealed a positive hybridisation signal only with the chromosome 7 specific centromeric probe D7Z1 (Fig. 1B). In 4% of the cells, FISH analysis using the chromosome 7 centromeric probe showed two fluorescent signals on the marker chromosome indicating that this marker was duplicated (Fig. 1C). Thus, it was considered as a ring chromosome, based on the particular behaviour of ring chromosomes during DNA replication. These results were in agreement with the fact that this marker was a ring chromosome. Using a WBS probe mixture, the ring chromosome showed a positive signal with the probe coding for elastin in 7q11.23 but gave negative results with the control probe D7S522 in 7q31 (Fig. 1D). Interestingly, this latter probe gave systematically two opposite signals even though the ring chromosome was not considered to be duplicated because of its size. FISH using an other WBS probe mixture with D7Z1 as control gave the same result and showed two opposite duplicated signals when the ring were duplicated (Fig. 1E). Therefore, according to G and R banding and FISH results, proband’s karyotype was presumed to be: 47,XX,+mar.ish r(7)(p?q?) (D7Z1+,ELN+)[38]/r(7)(D7Z1++,ELN++)[2]/46,XX[12]. Parental karyotypes, established from blood lymphocytes, were normal. 3.2. Case 2 Chromosome analysis after G banding showed, in 50% of the metaphases analysed, a supernumerary ring chromosome, smaller than a G group chromosome and than that

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Fig. 1. Identification of the supernumerary marker chromosome in case I using conventional cytogenetic and FISH methods. A) Cytogenetic aspect after RBG banding. B) Identification by FISH of the marker chromosome as a derivative chromosome 7, using a chromosome 7 centromeric probe, and as a ring chromosome 7 when duplicated (C arrow). D) Presence of the WBS locus on the ring chromosome using a specific probe (ELN). The normal chromosomes 7 show fluorescent signals for both the elastin (ELN) gene and control probes (D7S522 in 7q31). The ring chromosome exhibits two ELN fluorescent signals, probably due to a particular chromatid spreading. E) Aspect of the ring chromosome when duplicated using a different WBS probe mixture with D7Z1 as control: two opposite fluorescent signals are observed for both the centromere and the WBS locus, the latter being duplicated because of chromatid spreading.

observed in case 1. Spectral karyotyping allowed the identification of the marker evidencing that it derived from chromosome 7 (Fig. 2A and 2B). As in case 1, the observation of some rare dicentric images (2% of scored metaphases) by FISH using a centromeric probe indicated that this marker was a ring chromosome 7. A positive signal was obtained only for the elastin gene using a WBS probe mixture containing both the ELN probe and the subtelomeric 7q probe as control (Oncor, Gaithersburgh, USA) (Fig. 2 C). Therefore, according to G banding and FISH results, proband’s karyotype was presumed to be: 47,XY,+mar.ish r(p?q?)(D7Z1+,ELN+)[48]/r(7)(D7Z1++,ELN++)[2]/46,XY[50]. Parental karyotypes, established from blood lymphocytes, were normal.

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Fig. 2. Direct identification of the supernumerary marker chromosome in case II using spectral karyotyping. Cytogenetic aspect after DAPI staining and reverse banding (A) and automatic classification of the marker chromosome as a derivative chromosome 7 (B arrow). Presence of the WBS locus on the ring chromosome using the ELN probe (C).

4. Discussion Supernumerary marker chromosomes (SMCs) occur with a frequency of 0.3/1000 among new-borns, but their incidence is ten folds higher in the mentally subnormal population [4]. Because their usual very small size and the lack of visible banding pattern, the origin of these markers may be difficult to establish and requires often multiple FISH experiments, as in case 1. More direct diagnosis may be achieved by other techniques like spectral karyotyping, as in case 2, or multi-FISH methods as centromere-specificmulticolor FISH (cenM-FISH) or chromosome probe arrays. However, their use is still restricted to the few laboratories which dispose of the specific material. Comparative genomic hybridisation (CGH) would also offer a rapid diagnosis procedure but mosaicism, which is frequently associated with these marker chromosomes, may limit its employment. Once the origin determined, breakpoint identification may be also difficult although, in our cases, FISH results and size difference between the two ring chromosomes suggested a breakpoint in q21.2 for case 1 and in q11.2 for case 2. SMCs not deriving from an acrocentric chromosome contain pericentromeric regions usually appear as ring chromosomes (SRCs). This small ring subgroup is one of the most problematical with regard to their clinical significance. FISH studies have now identified SRCs deriving from each autosome [5,6,9,11] but only seven cases of supernumerary ring

Speech difficulties Facial anomalies

- Triangular face

- Micrognathia - Hypertelorism

Case B (ref.1 and 2)

Case C (ref.12)

M NA 19 years - Neurological findings: syncope, dystonia

Case E (ref.12)

Case F (ref.13)

Case G (ref.7)

F M 4650 4250 4 years 3 years -Developmental - Developdelay mental delay

F Adult - Mother of cases C and D

- Low performance

- Mild mental retardation

- Mild mental retardation

- Low performance

M 2858 12 years - Speech delayDysmorphic features QI69

+

QIV 57, QIP 84 +

+

- Bad articulation + +

M F M NA 2590 2680 7 month 20 months 9 years -Developmental -Developmental - Mild mental delay and the- delay retardation rapy resistant - Unusual face - Obesity seizure - Not evalua- - Not evalua- - Mild mental ted (7 months ted retardation old) (20 months QIV84 old) QIP84 QIG82

- High narrow forehead - Micrognathia - Low set ears - Down slanting palpebral fissures - Dental problem

Case D (ref.12)

- Flat profile

- Flat profile

- High nasal bridge

- High nasal bridge - Prognathia - Simply formed ears

- Prognathia - Simply formed ears

- Down slanting palpebral fissures

- Horizontal palpebral fissures

- Epicanthal fold

- Not evaluated No dysmorphism

Case 1 This paper

- Not evaluated - Asymetrical facial appearance-

- Low set ear

Epicanthal fold

- Dental problem

- High narrow forehead

Case 2 This paper

+ - Down slanting palpebral fissures

(continued on next page)

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Case A (ref. 10) CLINICAL FINDINGS Sex F Birth weight (grs) 1020 (34sa) Age of diagnosis 20 months Cause of test - Intrauterine and postnatal growth retardation Growth retardation + Mental retardation No IQ

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Table 1 Comparison of the clinical (top) and cytogenetic (bottom) findings between previously published cases of supernumerary ring chromosomes 7 and the present cases

Table 1 (continued)

Associated isodisomy

UPD(7) mat

Case B (ref.1 Case C and 2) (ref.12) - Long and slender fingers

Father (35%) No D7Z1 +, Microdissection and FISH: r(7) (q10q11.2) No

Case D (ref.12)

Case E (ref.12)

Case F Case G (ref.13) (ref.7) - Long and slender fingers

Case 1 This Case 2 This paper paper - Long and slender fingers

Mother (50%) ? Yes (50%) Yes (50%) Pericentric probe P7t1 +, WCP(7) +, YAC probe D7S520 (7q11.2) +

De novo No D7Z1 +, WBS (7q11.23) -

De novo No D7Z1 + (minute ring chromosome)

De novo Yes (64%) D7Z1 +, WBS (7q11.23) +

De novo Yes (50%) D7Z1 +, WBS (7q11.23) +

No

?

No

?

?

Comparison of the clinical (top) and cytogenetic (bottom) findings between previously published cases of supernumerary ring chromosomes 7 and the present cases.

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Case A (ref. 10) Extremities - Clinodactyly of the fifth fingers CYTOGENETIC FINDINGS Origin of the r(7) De novo Mosaic Yes (27%) Cytogenetic chaWCP(7) + racterisation

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chromosome 7 have been previously described in the literature. Clinical features and cytogenetic characteristics of these cases and ours are given in Table 1. The first case (case A) was a girl with Silver- Russell syndrome (SRS) who had an additional mosaic ring chromosome 7 in 27% of her cells [10]. This marker was de novo and derived from the paternal chromosome 7. It was associated with a maternal uniparental disomy of chromosome7 (mUPD7). Most of the clinical findings in this girl, which were consistent with SRS, could be due to maternal disomy which is encountered in 10% of SRS cases. Therefore, comparison between this case and other cases of supernumerary ring chromosome 7 is difficult to establish. Comparison of six other cases (B-G) with those we describe [2,1,12,13,7]. allows the identification of several number of clinical features which seem to be characteristic of the existence of a supernumerary ring chromosome 7. Among these cases, three were inherited, one from a phenotypically normal father (B) and two (C, D) from a mother with low performance (E). Two other cases were de novo (F, G,). Moderate facial anomalies were described like down slanting palpebral fissures (4 cases), a flat profile (3 cases in the same family), a high and narrow forehead (2 cases), abnormal ears (2 cases), an epicanthal fold (2 cases) and dental problems (2 cases). Long and slender fingers were found in three patients. No case had visceral anomaly. Mild mental retardation or low performance with speech delay was observed in six cases. The seventh case (G), a 7 month old boy, had a very severe delay and therapy resistant seizures but, curiously, no dysmorphisms [7]. Phenotype severity of these seventh cases was not in agreement with previous cases described above and could be due to other factors. Indeed, because a male cousin was also very delayed and have seizure of similar severity, it is possible that clinical features in case G may have a different and familial origin. Although karyotype-phenotype correlations may be difficult because of a frequent associated mosaicism (6/9 cases), it can be argued that these clinical findings are due to a pure trisomy implicating genes localized in the proximal region of chromosome 7 long arm and/or short arm. However, one cannot exclude that some clinical features may also be due to UPD for normal chromosomes 7. Because cases B, C and D were shown to have a biparental origin of their normal chromosomes 7, although exhibiting characteristic facial anomalies, dysmorphic syndrome in all supernumerary ring chromosomes 7 is unlikely to be due to an UPD phenomenon. This review of previously published cases of supernumerary ring chromosomes 7, and comparison with the present cases, allows to delineate frequent clinical findings. Although this comparison does not allow description of characteristic clinical finding, it reveals that the lack of visceral anomaly and a low range mental performance or mild mental retardation are common findings in most supernumerary ring chromosomes 7. Therefore, unexpected prenatal diagnosis, for maternal age or serum screening, of such a chromosomal abnormality would certainly lead to difficulties in genetic counselling and prognosis.

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