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Maternal uniparental disomy 14 as a cause of intrauterine growth retardation and early onset of puberty
M
Maternal uniparental disomy 14 as a cause of
intrauterine growth retardation and early onset of puberty Siv Fokstuen, MD, Claudia Ginsburg, DiplRerNat, Milo Zachmann, MD, and Albert Schinzel, MD
Uniparental disomy for particular chromosomes is increasingly recognized as a cause of abnormal phenotypes in humans either as a result of imprinted genes or, in the case of isodisomy, homozygosity of mutated recessive alleles. We report on the occurrence of maternal uniparental disomy for chromosome 14 (matUPD 14) in a 25-year-old woman with a normal karyotype, normal intelligence but low birth weight, short stature, small hands, and early onset of puberty. Comparison of her phenotype with those of 15 previously described liveborn patients with matUPD14 gives further evidence for an imprinted gene region on chromosome 14 and highlights the necessity to consider this cause in children with intrauterine growth retardation and early onset of puberty caused by acceleration of skeletal maturation. (J Pediatr 1999;134:689-95)
Uniparental disomy is the presence of the 2 homologs of a chromosome pair derived from only 1 parent in a diploid offspring.1 In isodisomy the uniparental pair is a duplicate of a same chromosome, whereas in heterodisomy the 2 different chromosomes from only 1 parent are present. There are 4 proposed mechanisms by which UPD might arise: (1) postfertilization error: mitotic
From Institut für Medizinische Genetik der Universität Zürich, and Abteilung für pädiatrische Endokrinologie, Universitäts-Kinderklinik Zürich, Zurich, Switzerland.
Supported by Swiss National Foundation Grant 32-42088.94. Submitted for publication Aug 3, 1998; revision received Jan 11, 1999; accepted Feb 16, 1999. Reprint requests: Albert Schinzel, MD, Institut für Medizinische Genetik, Rämistrasse 74, 8001 Zürich, Switzerland. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/97903
loss of 1 homolog of a chromosome pair and reduplication of the remaining one, (2) gamete complementation: fusion of a nullisomic with a gamete disomic for the same chromosome, (3) monosomy duplication: fertilization of a nullisomic with a monosomic gamete and duplication of the latter, and (4) trisomy rescue: loss of a chromosome from a trisomic conceptus. Random loss would theoretically result in a normal zygote with respect to biparental contribution in 2 of 3 cases and in uniparental disomy in 1 of 3. The correction of aneuploidy in a zygote can be expected more often at increased maternal age or secondary to unbalanced meiotic segregation of structural chromosomal rearrangements. Abnormal phenotypes have been associated with UPD for several chromosomes and may be caused by homozygosity for mutated recessive alleles in cases of isodisomy, for example, UPD7 and cystic fibrosis2 and
UPD14 and rod monochromacy (complete congenital achromatopsia).3 Another factor that may contribute to distinct disease phenotypes is parentally imprinted genes on the chromosomes involved. Imprinted genes are a class of mammalian genes that show expression depending on their parental origin. Prader-Willi and Angelman syndromes are the best characterized disorders resulting from imprinting effects and can be caused by maternal and paternal UPD15, respectively.4,5 In addition, Wiedemann-Beckwith syndrome has been associated with paternal UPD11p15 mosaicism6 and some cases of Silver-Russell syndrome or primordial intrauterine growth retardation with maternal UPD7.7 Of particular interest in understanding the phenotypic range of UPD are cases derived from trisomy rescue. In these cases the abnormal phenotype may be due partly to residual trisomy mosaicism in the placenta or the fetus. mat UPD
Maternal Uniparental disomy
To gain further insight into UPD in humans, we have studied a population of 50 individuals who we considered to be at increased risk of UPD through trisomy rescue. Our systematic search included patients with any combination of mental retardation of unknown origin, multiple congenital anomalies, dysmorphic features, or growth retardation born to mothers 35 years or older. The subject of this report, a woman, was found to have maternal 689
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Cytogenetic Studies For chromosomal analysis peripheral blood lymphocyte cultures from the proband were GTG-banded by routine methods at the level of 400 bands.
Molecular Analysis
A
B
Figure. Representative examples of microsatellite analysis at chromosome 14. Marker D14S80 (A) illustrates maternal heterodisomy and marker D14S75 (B) maternal isodisomy.
UPD for chromosome 14. So far, maternal UPD for chromosome 14 has been reported in 16 liveborn patients.3,8-22 The most consistent clinical findings of matUPD14 are low birth weight, short stature, short hands, and early onset of puberty. Comparison of 15 liveborn patients and the 1 patient currently described gives further evidence for an imprinted gene region on chromosome 14 and highlights the necessity to consider matUPD14 as a cause for intrauterine growth retardation and early onset of puberty resulting from acceleration of skeletal maturation.
METHODS Patient Report The proposita, a 25-year-old woman, was referred for genetic counseling because of short stature and early onset of puberty. She is the sixth child of healthy unrelated Swiss parents. The mother was 37 and the father 43 years old at delivery. Pregnancy was complicated by oligohydramnios. She was born at term with a birth weight of 1960 g (<10th percentile), length of 47 cm (<10th percentile), and head circumference of 31.5 cm (<10th percentile). Because of poor sucking, she needed nasogastric tube feeding during the neonatal period. Psychomotor development was normal. She was a healthy child but always remained 690
below the 3rd percentile in length. Her parents and brothers and sisters are of average height. The onset of breast development was uncertain. At 8 years and 11 months she had menarche, and thereafter menstruation occurred regularly. Pediatric consultation at the age of 14 9⁄12 years showed a fully developed female with a weight of 45.6 kg (25th percentile), height of 141.6 cm (<3rd percentile), and head circumference of 53 cm (25th percentile). Apart from short stature and mild obesity, clinical examination was unremarkable. Endocrine evaluation showed follicle-stimulating hormone 2.9 U/L, luteinizing hormone 16.3 U/L, testosterone 2.7 nmol/L, and 17-ketosteroids in 24-hour urine 8.7 mg/d. Metabolic, renal, serum calcium, and phosphorus evaluations were normal. Radiographs demonstrated almost closed epiphyses on the right hand with a bone age of 17 years (Greulich and Pyle). At 25 years of age, the height was 143 cm (<3rd percentile), weight 42 kg (3rd percentile), and head circumference 52.5 cm (3 to 10th percentile). The hand length was 14.5 cm (<3rd percentile), middle finger length 6.2 cm (<3rd percentile), and foot length 19.5 cm (<3rd percentile). She had bilateral hyperextensible joints and fifth finger clinodactyly. Otherwise her physical appearance was unremarkable. She attended regular school and had no learning disabilities or behavior problems.
Genomic DNA from the patient and her parents was extracted from peripheral blood samples with standard techniques. Parental origin of the patient’s chromosomes was determined by amplification of highly polymorphic microsatellite markers with standard polymerase chain reaction amplification. The fragment products were analyzed by polyacrylamide/urea gel electrophoresis. A total of 14 markers spanning the whole long arm of chromosome 14 were tested. The microsatellite polymorphisms and their approximate chromosomal localization are shown in Table I. Paternity was investigated with microsatellite markers from all other autosomes.
RESULTS Chromosome analysis revealed a normal female karyotype. Molecular studies showed that the proband inherited 2 chromosomes 14 from her mother and none from her father, a result consistent with maternal UPD14. Seven markers revealed maternal heterodisomy, whereas reduction to homozygosity was shown on 3 markers. These results suggest several recombination events on the maternal chromosomes 14 during meiosis I (Table I). Fig 1 gives representative examples for markers showing maternal heterodisomy and isodisomy, respectively. The results of polymorphic loci from all other autosomes were consistent with biparental inheritance and correct paternity.
DISCUSSION Tables II and III summarize the cytogenetic and clinical findings of the 16
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 6 Table I. Genotypes of microsatellites in the proposita and her parents
Marker
Chromosome localization
Patient
Mother
Father
Interpretation
D14S72 D14S261 D14S264 D14MYH6 D14S70 D14S80
14q11.1-q11.2 14q11.1-q11.2 14q11.1-q12 14q11.2-q13 14q11-q12 14q11-q12
ab ab ab ad ab bc
ab ab ab ad ab bc
bc aa cd bc cd ad
Uninformative* Uninformative* Maternal heterodisomy Maternal heterodisomy Maternal heterodisomy Maternal heterodisomy
D14S75 D14S306 D14S288
14q12-q13 14q12-q13 14q13-q21
aa bb cc
ab ab cd
bb bc ab
Maternal isodisomy Uninformative Maternal isodisomy
D14S77 D14PI-1 D14S51 D14S267
14q24 14q32.1 14q32.1-q32.2 14q32.1-q32.2
bc cd bc ab
bc cd bc ab
ad ab ab cd
Maternal heterodisomy Maternal heterodisomy Uninformative* Maternal heterodisomy
D14S260
14q32.2-q32.3
aa
ab
cc
Maternal isodisomy
The 3 lines indicate meiotic recombination events. *Markers of the proposita show heterodisomy, but they are uninformative for the parental origin.
(including our proband) reported liveborn patients with proven matUPD14. Cases published as abstracts11,16-19,22 often lack detailed clinical information. The interpretation of matUPD14 in 1 report14 must be questioned. The father was not available for analysis, and matUPD14 was suggested on only 2 markers. The absence of a paternal control and homozygosity for only 2 markers do not allow the diagnosis of matUPD14 with certainty.23 Therefore we excluded this case from our review. In 10 patients the investigated markers showed mainly heterodisomy (Table II). In 6 patients all investigated markers were isodisomic (Table III). Most cases of matUPD14 were found in carriers of familial or de novo Robertsonian translocations der(13;14)(q10;q10) or der(14;14)(q10;q10). Our proposita is the first postpubertal patient with matUPD14 and a normal karyotype. In 4 cases low-level mosaicism was described either as confined placental mosaicism11,19 or as proven mosaicism in blood lymphocytes of the proband.9,17 Maternal ages at delivery of the 2 cases with confined placental mosaicism were 40 and 41 years, respectively, and the
karyotypes of both probands were 46,XX. The karyotype of our proposita also was 46,XX, and maternal age at delivery was 37 years. The most likely mechanism leading to matUPD14 in our case was correction of an initial trisomy caused by maternal meiotic nondisjunction associated with advanced maternal age. A similar observation was reported by Sirchia et al,24 who described matUPD14 in an aborted fetus with mosaicism 47,XX,+14/46,XX in amniocytes and fetal blood whose mother was 36 years old at delivery. Except for the proposita of Morichon-Delvallez et al,11 who was described as a normal newborn, all liveborn patients disclosed quite distinct clinical features. The major documented clinical findings of matUPD14 are summarized on Table IV. The most consistent features were early onset of puberty (8 of 8), advanced bone age (3 of 3), short stature (11 of 12), small hands (10 of 11), normal intelligence (8 of 10), and low birth weight (9 of 11). Two patients with birth weight within the normal range were born at 32 weeks of gestation.8,9 It is not known whether they would have been
small for dates at term delivery. The third subject with normal birth weight is Morichon-Delvallez et al’s normal newborn patient. They did not give any clinical details in their abstract, and the patient was too young to assess. Follow-up will show whether she will have some of the characteristic findings of matUPD14. The only patient who did not fit into the expectation of short stature and small hands was the patient reported by Tomkins et al.15 However, the patient’s middle finger length was significantly reduced, and given his sexual maturity at 12 years of age, he may already have attained his adult height, which would be close to the 10th percentile and consistent with a low postpubertal height. One patient had hypogonadism followed by early onset of puberty.16 All other patients who were old enough to assess puberty had early onset with normal endocrinologic evaluations. It seems that early onset of puberty in patients with matUPD14 is the result of acceleration of skeletal maturation.8,18 The fact that low birth weight, short stature, short hands, and early onset of puberty are present in cases with ei691
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Table II. Liveborn patients with maternal UPD 14 (heterodisomy)
Age Maternal age (y) Gestation (wk) Birth weight (g) Hypotonia Hydrocephalus Short stature Developmental delay Intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty (y) Advanced bone age Recurrent otitis media Hypercholesterolemia Others
Temple et al8
Antonarakis et al9
Healey et al10
Morichon et al (abstract)11
Coviello et al13
17 y
9y 24 32-33 1759 (P50) + + + Mild Normal + + + 9
4y 30 38 2000 (
Newborn 40
15 mo
+ + Dysmorphic features
+ + Dysmorphic features
32 1430 (P25) – + + – Normal + – + 10 + + – Bifid uvula Dysmorphic features
+ + –
40 +
Motor Normal + +
Karyotypes are as follows. Temple et al8: 45, XY, der(13:14) (q10;q10)mat. Antonarakis et al9: 45, XX, der(13;14) (q10;q10)/46, XX, –13, +der(13;14) (q10;q10) de novo. Healey et al10: 45, XX, der(13;14) (q10;q10) de novo. Morichon et al11: CPM for trisomy 14, AC: 46, XX. Coviello et al13: PD: 45, XX, der(13;14) (q10;q10) de novo. Link et al16: 45, XY, der (13;14) (q10;q10)mat. Désilets et al18: 45, XX, der(13;14) (q10;q10)mat. Miyoshi et al: 45, XY, i(14) (q10), de novo. Harrison et al22: 45, XY, der(13;14) (q10;q10)mat. Proposita: 46, XX. PD, Prenatal diagnosis; AC, amniocentesis; CPM, confined placental mosaicism; +, feature present; –, feature absent.
Table III. Liveborn patients with maternal UPD 14 (isodisomy)
Age (y) Maternal age (y) Gestation (wk) Birth weight (g) Hypotonia Hydrocephalus Short stature Developmental delay Intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty (y) Advanced bone age Recurrent otitis media Hypercholesterolemia Others
Pentao et al3
Robinson et al12
Tomkins et al15
20 24 40 2216 (
2 9/12
12 24 40 2590 (
+ – Rod monochromacy
36 1900 (
– – Dysmorphic features
+ – L/W/HC >P97 Dysmorphic features
Barton et al (abstract)17
Cleft palate Retrognathia
Karyotypes are as follows. Pentao et al3: 45, XX, der(14:14) (q10;q10) de novo. Robinson et al12: 45, XY, der(14;14) (q10;q10) de novo. Tomkins et al15: 45, XY, der(14;14) (q10;q10) de novo. Barton et al17 45, XX, der(13;14) (q10;q10)/46, XX, –13, +der(13;14) (q10;q10) de novo. Walgenbach et al19: CPM: 47, XX, +14, blood: 46, XX. Splitt et al20: 45, XX, der(14;14) (q10;q10) de novo. L, Length; W, weight; HC, head circumference; +, feature present; –, feature absent; IUGR, intrauterine growth retardation.
692
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Link et al (abstract)16
Désilets et al (abstract)18
Miyoshi et al21
Harrison et al (abstract)22
12 y
13 y
9 mo 37 40 634 (<3P) + – + +
3y
+ – + Motor Normal +
+
Low + – + – Normal + + – + + – –
+
Hypogonadism
Walgenbach et al (abstract)19
One of triplets
Splitt et al20
Newborn 41
26
IUGR + –
2000 (
Poor suck-swallow coordination
+ + + +
– + Migraine Cubitus valgus
Dysmorphic features
Proposita 25 y 37 40 1960(
ther heterodisomy or isodisomy suggests that these findings are due to imprinted genes on chromosome 14 rather than to homozygosity of mutated recessive alleles or cryptic mosaicisms. Further evidence for imprinting on chromosome 14 comes from the observation that paternal UPD14 results in a very different phenotype. So far 4 patients with paternal UPD14 have been reported.14,25-27 The main clinical findings were polyhydramnios, characteristic facial anomalies, mental retardation, and skeletal anomalies including a small thorax, abnormal ribs, and short limbs. The proximal part of human chromosome 14 (14cen-q12) is homologous to chromosome 14 in mice, whereas the distal part (14q13qter) is homologous to mouse chromosome 12.28 Maternal and paternal UPD for mouse chromosome 14 have no phenotypic effect; however, mouse chromosome 12 is thought to contain
imprinted genes.29 Thus the phenotypes of maternal and paternal UPD14 in humans might be due to altered expression of imprinted genes in the region 14q13-qter. So far no imprinted genes have been found in this region. Further studies are required to define the exact region of chromosome 14 that is imprinted and to identify genes within the region that are involved in regulation of growth and development. The variable other clinical findings of matUPD14 could be due to homozygosity for mutated recessive alleles in regions of isodisomy, to undetected mosaicism for trisomy 14, or to complications during labor. Although hydrocephalus and hyperextensible joints are not common findings of mosaic trisomy 14, they could be associated with cryptic trisomy 14 mosaicism, because they were reported only in cases with heterodisomy. In heterodisomy there are 2 different maternal chromosomes 14, suggesting that there could have been initially 3 chromosomes 14. Hypotonia and mild, mainly motor developmental delay are other rather common features. However, it is important to note that despite a stormy neonatal or infant course, most patients caught up and attained normal intelligence (8 of 10). This observation suggests that matUPD14 is compatible with normal intellectual development. Rare associated findings such as bifid uvula or cleft palate may be coincidental. Further reports will prove whether these rare phenotypic anomalies are caused by or are associated by chance with matUPD14. In conclusion, the observation of an adult patient together with the previously reported subjects suggests the need for molecular studies for matUDP14 in patients with idiopathic intrauterine growth retardation and early onset of puberty caused by acceleration of skeletal maturation. For children or adults with a clinical phenotype of matUPD14, a karyotype should precede molecular investigations to exclude a possible sex chromosome aber693
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Table IV. Major documented clinical findings of maternal UPD14
Clinical findings
Heterodisomy
Isodisomy
Total
4/6 6/9 4/8 8/8 6/9 6/6 7/7 5/6 3/6 5/5 3/3 3/5 2/5
5/5 4/4 0/5 3/4 3/4 2/4 3/4 0/3 1/4 3/3 0/0 2/4 1/4
9/11 10/13 4/13 11/12 9/13 8/10 10/11 5/9 4/10 8/8 3/3 5/9 3/9
Low birth weight Hypotonia Hydrocephalus Short stature Mild developmental delay Normal intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty Advanced bone age Recurrent otitis media Hypercholesterolemia
11.
12.
13.
Clinical findings in bold: features that were present in at least 80% of the cases reported.
14.
ration. The finding of a balanced familial or de novo Robertsonian translocation der(13;14)(q10;q10) or der(14;14)(q10;q10) should prompt a subsequent study for UPD14. In the absence of any structural chromosomal aberration, advanced maternal age at the delivery or confined placental mosaicism for trisomy 14 may give indications to look for matUPD14. In these situations maternal age-related nondisjunction events and trisomy rescue might be assumed. The diagnosis of matUPD14 in a patient is important not only to recognize the cause of his or her problems but also to offer appropriate genetic counseling. In the case of a normal karyotype, there is no increased recurrence risk for UPD14 for the siblings or for the offspring of the patient.
4.
5.
6.
7.
8.
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Patel PI, Lupski JR. Maternal uniparental disomy of chromosome 14: association with autosomal recessive rod monochromacy. Am J Hum Genet 1992;50:690-9. Nicholls RD, Knoll JHM, Butler MG, Karam S, Lalande M. Genetic imprinting suggested by maternal heterodisomy in non deletion Prader-Willi syndrome. Nature 1989;342:281-5. Malcom S, Clayton-Smith J, Nichols M, Robb S, Webb T, Armour JAL, et al. Uniparental paternal disomy in Angelman’s syndrome. Lancet 1991;337:694-7. Henry I, Puesch A, Riesewijk A, Ahnine L, Mannens M, Beldjord C, et al. Somatic mosaicism for partial paternal isodisomy in Wiedemann-Beckwith syndrome: a post fertilisation event. Eur J Hum Genet 1993;1:19-29. Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H, et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet 1995;4:583-7. Temple IK, Cockwell A, Hassold T, Pettay D, Jacobs P. Maternal uniparental disomy for chromosome 14. J Med Genet 1991;28:511-4. Antonarakis SE, Blouin JL, Maher J, Avramopoulos D, Thomas G, Talbot Jr CC. Maternal uniparental disomy for human chromosome 14, due to loss of a chromosome 14 from somatic cells with t(13;14) trisomy 14. Am J Hum Genet 1993;52:1145-52. Healey S, Powell F, Battersby M, Chenevix-Trench G, McGill J. Distinct
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phenotype in maternal uniparental disomy of chromosome 14. Am J Med Genet 1994;51:147-9. Morichon-Delvallez N, Seques B, Pinson MP, Bérubé D, Dommerques M, Aubry MC, et al. Maternal uniparental disomy for chromosome 14 by secondary nondisjunction of an initial trisomy [abstract]. Am J Hum Genet 1994;55(Suppl):2224. Robinson WP, Bernasconi F, Basaran S, Yüksel-Apak M, Neri G, Serville F, et al. A somatic origin of homologous Robertsonian translocations and isochromosomes. Am J Hum Genet 1994;54:290-302. Coviello DA, Panucci E, Mantero MM, Perfumo C, Guelfi M, Borronco C, et al. Maternal uniparental disomy for chromosome 14. Acta Geneticae et Gemellologiae 1996;45(1-2):169-72. Papenhausen PR, Mueller OT, Johnson VP, Sutcliffe M, Diamond TM, Kousseff BG. Uniparental disomy of chromosome 14 in two cases: an abnormal child and a normal adult. Am J Med Genet 1995;59:271-5. Tomkins DJ, Roux A-F, Waye J, Freeman VCP, Cox DW, Whelan DT. Maternal uniparental isodisomy of human chromosome 14 associated with a paternal t(13q14q) and precocious puberty. Eur J Hum Genet 1996;4:153-9. Link L, McMilin K, Popovich B, Magenis RE. Maternal uniparental disomy for chromosome 14 (abstract). Am J Hum Genet 1996;59(Suppl):687. Barton DE, McQuaid S, Stallings R, Griffin E, Geraghty M. Further evidence for an emerging maternal uniparental disomy chromosome 14 syndrome: analysis of a phenotypically abnormal de novo Robertsonian translocation t(13;14) carrier (abstract). Am J Hum Genet 1996;59 (Suppl):698. Désilets VA, Yong SL, Kalousek DK, Pantzar TJ, Kwong LC, Siemens C, et al. Maternal uniparental disomy for chromosome 14 [abstract]. Am J Hum Genet 1997;61(Suppl):691. Walgenbach DD, Yang SP, McCaskill C, Shaffer LG, Towner DR. Maternal uniparental disomy of chromosome 14 in an infant with mild dysmorphology and confined placental mosaicism {abstract]. Am J Hum Genet 1997;61 (Suppl):2222. Splitt MP, Goodship JA. Another case of maternal uniparental disomy chromosome 14 syndrome. Am J Med Genet 1997;72:239-40. Miyoshi O, Hayashi S, Fujimoto M,
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uniparental disomy in the euploid cell line of a fetus with mosaic 46,XX/ 47,XX,+14 karyotype. Hum Genet 1994;94:355-8. 25. Cotter PD, Kaffe S, McCurdy LD, Jhaveri M, Willner JP, Hirschhorn K. Paternal uniparental disomy for chromosome 14: a case report and review. Am J Med Genet 1997;70:74-9. 26. Wang JC, Passage MB, Yen PH, Shapiro LJ, Mohandas TK. Uniparental heterodisomy for chromosome 14 in a phenotypically abnormal familial balanced 13/14 Robertsonian translocation carrier. Am J Hum Genet 1991;48:1069-74. 27. Walter ChA, Shaffer LG, Kaye CI, Huff RW, Ghidoni PD, McCaskill C,
et al. Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45, XY,idic(14)(p11). Am J Med Genet 1996;65:259-65. 28. Cox DW, Gedde-Dahl T, Menon AG, Nygaard TG, Tomlinson IM, Peters J, et al. Report of the second international workshop on human chromosome 14 mapping 1994. Cytogenet Cell Genet 1996;69:159-74. 29. Cattanach BM, Barr J, Jones J. Use of chromosome rearrangements for investigations into imprinting in the mouse. In: Ohlsson R, Hall K, Ritzen M, editors. Genomic imprinting, causes and consequences. Cambridge: Cambridge University Press; 1995. p. 327-41.
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695
Maternal uniparental disomy 14 as a cause of
intrauterine growth retardation and early onset of puberty Siv Fokstuen, MD, Claudia Ginsburg, DiplRerNat, Milo Zachmann, MD, and Albert Schinzel, MD
Uniparental disomy for particular chromosomes is increasingly recognized as a cause of abnormal phenotypes in humans either as a result of imprinted genes or, in the case of isodisomy, homozygosity of mutated recessive alleles. We report on the occurrence of maternal uniparental disomy for chromosome 14 (matUPD 14) in a 25-year-old woman with a normal karyotype, normal intelligence but low birth weight, short stature, small hands, and early onset of puberty. Comparison of her phenotype with those of 15 previously described liveborn patients with matUPD14 gives further evidence for an imprinted gene region on chromosome 14 and highlights the necessity to consider this cause in children with intrauterine growth retardation and early onset of puberty caused by acceleration of skeletal maturation. (J Pediatr 1999;134:689-95)
Uniparental disomy is the presence of the 2 homologs of a chromosome pair derived from only 1 parent in a diploid offspring.1 In isodisomy the uniparental pair is a duplicate of a same chromosome, whereas in heterodisomy the 2 different chromosomes from only 1 parent are present. There are 4 proposed mechanisms by which UPD might arise: (1) postfertilization error: mitotic
From Institut für Medizinische Genetik der Universität Zürich, and Abteilung für pädiatrische Endokrinologie, Universitäts-Kinderklinik Zürich, Zurich, Switzerland.
Supported by Swiss National Foundation Grant 32-42088.94. Submitted for publication Aug 3, 1998; revision received Jan 11, 1999; accepted Feb 16, 1999. Reprint requests: Albert Schinzel, MD, Institut für Medizinische Genetik, Rämistrasse 74, 8001 Zürich, Switzerland. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/97903
loss of 1 homolog of a chromosome pair and reduplication of the remaining one, (2) gamete complementation: fusion of a nullisomic with a gamete disomic for the same chromosome, (3) monosomy duplication: fertilization of a nullisomic with a monosomic gamete and duplication of the latter, and (4) trisomy rescue: loss of a chromosome from a trisomic conceptus. Random loss would theoretically result in a normal zygote with respect to biparental contribution in 2 of 3 cases and in uniparental disomy in 1 of 3. The correction of aneuploidy in a zygote can be expected more often at increased maternal age or secondary to unbalanced meiotic segregation of structural chromosomal rearrangements. Abnormal phenotypes have been associated with UPD for several chromosomes and may be caused by homozygosity for mutated recessive alleles in cases of isodisomy, for example, UPD7 and cystic fibrosis2 and
UPD14 and rod monochromacy (complete congenital achromatopsia).3 Another factor that may contribute to distinct disease phenotypes is parentally imprinted genes on the chromosomes involved. Imprinted genes are a class of mammalian genes that show expression depending on their parental origin. Prader-Willi and Angelman syndromes are the best characterized disorders resulting from imprinting effects and can be caused by maternal and paternal UPD15, respectively.4,5 In addition, Wiedemann-Beckwith syndrome has been associated with paternal UPD11p15 mosaicism6 and some cases of Silver-Russell syndrome or primordial intrauterine growth retardation with maternal UPD7.7 Of particular interest in understanding the phenotypic range of UPD are cases derived from trisomy rescue. In these cases the abnormal phenotype may be due partly to residual trisomy mosaicism in the placenta or the fetus. mat UPD
Maternal Uniparental disomy
To gain further insight into UPD in humans, we have studied a population of 50 individuals who we considered to be at increased risk of UPD through trisomy rescue. Our systematic search included patients with any combination of mental retardation of unknown origin, multiple congenital anomalies, dysmorphic features, or growth retardation born to mothers 35 years or older. The subject of this report, a woman, was found to have maternal 689
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Cytogenetic Studies For chromosomal analysis peripheral blood lymphocyte cultures from the proband were GTG-banded by routine methods at the level of 400 bands.
Molecular Analysis
A
B
Figure. Representative examples of microsatellite analysis at chromosome 14. Marker D14S80 (A) illustrates maternal heterodisomy and marker D14S75 (B) maternal isodisomy.
UPD for chromosome 14. So far, maternal UPD for chromosome 14 has been reported in 16 liveborn patients.3,8-22 The most consistent clinical findings of matUPD14 are low birth weight, short stature, short hands, and early onset of puberty. Comparison of 15 liveborn patients and the 1 patient currently described gives further evidence for an imprinted gene region on chromosome 14 and highlights the necessity to consider matUPD14 as a cause for intrauterine growth retardation and early onset of puberty resulting from acceleration of skeletal maturation.
METHODS Patient Report The proposita, a 25-year-old woman, was referred for genetic counseling because of short stature and early onset of puberty. She is the sixth child of healthy unrelated Swiss parents. The mother was 37 and the father 43 years old at delivery. Pregnancy was complicated by oligohydramnios. She was born at term with a birth weight of 1960 g (<10th percentile), length of 47 cm (<10th percentile), and head circumference of 31.5 cm (<10th percentile). Because of poor sucking, she needed nasogastric tube feeding during the neonatal period. Psychomotor development was normal. She was a healthy child but always remained 690
below the 3rd percentile in length. Her parents and brothers and sisters are of average height. The onset of breast development was uncertain. At 8 years and 11 months she had menarche, and thereafter menstruation occurred regularly. Pediatric consultation at the age of 14 9⁄12 years showed a fully developed female with a weight of 45.6 kg (25th percentile), height of 141.6 cm (<3rd percentile), and head circumference of 53 cm (25th percentile). Apart from short stature and mild obesity, clinical examination was unremarkable. Endocrine evaluation showed follicle-stimulating hormone 2.9 U/L, luteinizing hormone 16.3 U/L, testosterone 2.7 nmol/L, and 17-ketosteroids in 24-hour urine 8.7 mg/d. Metabolic, renal, serum calcium, and phosphorus evaluations were normal. Radiographs demonstrated almost closed epiphyses on the right hand with a bone age of 17 years (Greulich and Pyle). At 25 years of age, the height was 143 cm (<3rd percentile), weight 42 kg (3rd percentile), and head circumference 52.5 cm (3 to 10th percentile). The hand length was 14.5 cm (<3rd percentile), middle finger length 6.2 cm (<3rd percentile), and foot length 19.5 cm (<3rd percentile). She had bilateral hyperextensible joints and fifth finger clinodactyly. Otherwise her physical appearance was unremarkable. She attended regular school and had no learning disabilities or behavior problems.
Genomic DNA from the patient and her parents was extracted from peripheral blood samples with standard techniques. Parental origin of the patient’s chromosomes was determined by amplification of highly polymorphic microsatellite markers with standard polymerase chain reaction amplification. The fragment products were analyzed by polyacrylamide/urea gel electrophoresis. A total of 14 markers spanning the whole long arm of chromosome 14 were tested. The microsatellite polymorphisms and their approximate chromosomal localization are shown in Table I. Paternity was investigated with microsatellite markers from all other autosomes.
RESULTS Chromosome analysis revealed a normal female karyotype. Molecular studies showed that the proband inherited 2 chromosomes 14 from her mother and none from her father, a result consistent with maternal UPD14. Seven markers revealed maternal heterodisomy, whereas reduction to homozygosity was shown on 3 markers. These results suggest several recombination events on the maternal chromosomes 14 during meiosis I (Table I). Fig 1 gives representative examples for markers showing maternal heterodisomy and isodisomy, respectively. The results of polymorphic loci from all other autosomes were consistent with biparental inheritance and correct paternity.
DISCUSSION Tables II and III summarize the cytogenetic and clinical findings of the 16
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Marker
Chromosome localization
Patient
Mother
Father
Interpretation
D14S72 D14S261 D14S264 D14MYH6 D14S70 D14S80
14q11.1-q11.2 14q11.1-q11.2 14q11.1-q12 14q11.2-q13 14q11-q12 14q11-q12
ab ab ab ad ab bc
ab ab ab ad ab bc
bc aa cd bc cd ad
Uninformative* Uninformative* Maternal heterodisomy Maternal heterodisomy Maternal heterodisomy Maternal heterodisomy
D14S75 D14S306 D14S288
14q12-q13 14q12-q13 14q13-q21
aa bb cc
ab ab cd
bb bc ab
Maternal isodisomy Uninformative Maternal isodisomy
D14S77 D14PI-1 D14S51 D14S267
14q24 14q32.1 14q32.1-q32.2 14q32.1-q32.2
bc cd bc ab
bc cd bc ab
ad ab ab cd
Maternal heterodisomy Maternal heterodisomy Uninformative* Maternal heterodisomy
D14S260
14q32.2-q32.3
aa
ab
cc
Maternal isodisomy
The 3 lines indicate meiotic recombination events. *Markers of the proposita show heterodisomy, but they are uninformative for the parental origin.
(including our proband) reported liveborn patients with proven matUPD14. Cases published as abstracts11,16-19,22 often lack detailed clinical information. The interpretation of matUPD14 in 1 report14 must be questioned. The father was not available for analysis, and matUPD14 was suggested on only 2 markers. The absence of a paternal control and homozygosity for only 2 markers do not allow the diagnosis of matUPD14 with certainty.23 Therefore we excluded this case from our review. In 10 patients the investigated markers showed mainly heterodisomy (Table II). In 6 patients all investigated markers were isodisomic (Table III). Most cases of matUPD14 were found in carriers of familial or de novo Robertsonian translocations der(13;14)(q10;q10) or der(14;14)(q10;q10). Our proposita is the first postpubertal patient with matUPD14 and a normal karyotype. In 4 cases low-level mosaicism was described either as confined placental mosaicism11,19 or as proven mosaicism in blood lymphocytes of the proband.9,17 Maternal ages at delivery of the 2 cases with confined placental mosaicism were 40 and 41 years, respectively, and the
karyotypes of both probands were 46,XX. The karyotype of our proposita also was 46,XX, and maternal age at delivery was 37 years. The most likely mechanism leading to matUPD14 in our case was correction of an initial trisomy caused by maternal meiotic nondisjunction associated with advanced maternal age. A similar observation was reported by Sirchia et al,24 who described matUPD14 in an aborted fetus with mosaicism 47,XX,+14/46,XX in amniocytes and fetal blood whose mother was 36 years old at delivery. Except for the proposita of Morichon-Delvallez et al,11 who was described as a normal newborn, all liveborn patients disclosed quite distinct clinical features. The major documented clinical findings of matUPD14 are summarized on Table IV. The most consistent features were early onset of puberty (8 of 8), advanced bone age (3 of 3), short stature (11 of 12), small hands (10 of 11), normal intelligence (8 of 10), and low birth weight (9 of 11). Two patients with birth weight within the normal range were born at 32 weeks of gestation.8,9 It is not known whether they would have been
small for dates at term delivery. The third subject with normal birth weight is Morichon-Delvallez et al’s normal newborn patient. They did not give any clinical details in their abstract, and the patient was too young to assess. Follow-up will show whether she will have some of the characteristic findings of matUPD14. The only patient who did not fit into the expectation of short stature and small hands was the patient reported by Tomkins et al.15 However, the patient’s middle finger length was significantly reduced, and given his sexual maturity at 12 years of age, he may already have attained his adult height, which would be close to the 10th percentile and consistent with a low postpubertal height. One patient had hypogonadism followed by early onset of puberty.16 All other patients who were old enough to assess puberty had early onset with normal endocrinologic evaluations. It seems that early onset of puberty in patients with matUPD14 is the result of acceleration of skeletal maturation.8,18 The fact that low birth weight, short stature, short hands, and early onset of puberty are present in cases with ei691
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Table II. Liveborn patients with maternal UPD 14 (heterodisomy)
Age Maternal age (y) Gestation (wk) Birth weight (g) Hypotonia Hydrocephalus Short stature Developmental delay Intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty (y) Advanced bone age Recurrent otitis media Hypercholesterolemia Others
Temple et al8
Antonarakis et al9
Healey et al10
Morichon et al (abstract)11
Coviello et al13
17 y
9y 24 32-33 1759 (P50) + + + Mild Normal + + + 9
4y 30 38 2000 (
Newborn 40
15 mo
+ + Dysmorphic features
+ + Dysmorphic features
32 1430 (P25) – + + – Normal + – + 10 + + – Bifid uvula Dysmorphic features
+ + –
40 +
Motor Normal + +
Karyotypes are as follows. Temple et al8: 45, XY, der(13:14) (q10;q10)mat. Antonarakis et al9: 45, XX, der(13;14) (q10;q10)/46, XX, –13, +der(13;14) (q10;q10) de novo. Healey et al10: 45, XX, der(13;14) (q10;q10) de novo. Morichon et al11: CPM for trisomy 14, AC: 46, XX. Coviello et al13: PD: 45, XX, der(13;14) (q10;q10) de novo. Link et al16: 45, XY, der (13;14) (q10;q10)mat. Désilets et al18: 45, XX, der(13;14) (q10;q10)mat. Miyoshi et al: 45, XY, i(14) (q10), de novo. Harrison et al22: 45, XY, der(13;14) (q10;q10)mat. Proposita: 46, XX. PD, Prenatal diagnosis; AC, amniocentesis; CPM, confined placental mosaicism; +, feature present; –, feature absent.
Table III. Liveborn patients with maternal UPD 14 (isodisomy)
Age (y) Maternal age (y) Gestation (wk) Birth weight (g) Hypotonia Hydrocephalus Short stature Developmental delay Intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty (y) Advanced bone age Recurrent otitis media Hypercholesterolemia Others
Pentao et al3
Robinson et al12
Tomkins et al15
20 24 40 2216 (
2 9/12
12 24 40 2590 (
+ – Rod monochromacy
36 1900 (
– – Dysmorphic features
+ – L/W/HC >P97 Dysmorphic features
Barton et al (abstract)17
Cleft palate Retrognathia
Karyotypes are as follows. Pentao et al3: 45, XX, der(14:14) (q10;q10) de novo. Robinson et al12: 45, XY, der(14;14) (q10;q10) de novo. Tomkins et al15: 45, XY, der(14;14) (q10;q10) de novo. Barton et al17 45, XX, der(13;14) (q10;q10)/46, XX, –13, +der(13;14) (q10;q10) de novo. Walgenbach et al19: CPM: 47, XX, +14, blood: 46, XX. Splitt et al20: 45, XX, der(14;14) (q10;q10) de novo. L, Length; W, weight; HC, head circumference; +, feature present; –, feature absent; IUGR, intrauterine growth retardation.
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Link et al (abstract)16
Désilets et al (abstract)18
Miyoshi et al21
Harrison et al (abstract)22
12 y
13 y
9 mo 37 40 634 (<3P) + – + +
3y
+ – + Motor Normal +
+
Low + – + – Normal + + – + + – –
+
Hypogonadism
Walgenbach et al (abstract)19
One of triplets
Splitt et al20
Newborn 41
26
IUGR + –
2000 (
Poor suck-swallow coordination
+ + + +
– + Migraine Cubitus valgus
Dysmorphic features
Proposita 25 y 37 40 1960(
ther heterodisomy or isodisomy suggests that these findings are due to imprinted genes on chromosome 14 rather than to homozygosity of mutated recessive alleles or cryptic mosaicisms. Further evidence for imprinting on chromosome 14 comes from the observation that paternal UPD14 results in a very different phenotype. So far 4 patients with paternal UPD14 have been reported.14,25-27 The main clinical findings were polyhydramnios, characteristic facial anomalies, mental retardation, and skeletal anomalies including a small thorax, abnormal ribs, and short limbs. The proximal part of human chromosome 14 (14cen-q12) is homologous to chromosome 14 in mice, whereas the distal part (14q13qter) is homologous to mouse chromosome 12.28 Maternal and paternal UPD for mouse chromosome 14 have no phenotypic effect; however, mouse chromosome 12 is thought to contain
imprinted genes.29 Thus the phenotypes of maternal and paternal UPD14 in humans might be due to altered expression of imprinted genes in the region 14q13-qter. So far no imprinted genes have been found in this region. Further studies are required to define the exact region of chromosome 14 that is imprinted and to identify genes within the region that are involved in regulation of growth and development. The variable other clinical findings of matUPD14 could be due to homozygosity for mutated recessive alleles in regions of isodisomy, to undetected mosaicism for trisomy 14, or to complications during labor. Although hydrocephalus and hyperextensible joints are not common findings of mosaic trisomy 14, they could be associated with cryptic trisomy 14 mosaicism, because they were reported only in cases with heterodisomy. In heterodisomy there are 2 different maternal chromosomes 14, suggesting that there could have been initially 3 chromosomes 14. Hypotonia and mild, mainly motor developmental delay are other rather common features. However, it is important to note that despite a stormy neonatal or infant course, most patients caught up and attained normal intelligence (8 of 10). This observation suggests that matUPD14 is compatible with normal intellectual development. Rare associated findings such as bifid uvula or cleft palate may be coincidental. Further reports will prove whether these rare phenotypic anomalies are caused by or are associated by chance with matUPD14. In conclusion, the observation of an adult patient together with the previously reported subjects suggests the need for molecular studies for matUDP14 in patients with idiopathic intrauterine growth retardation and early onset of puberty caused by acceleration of skeletal maturation. For children or adults with a clinical phenotype of matUPD14, a karyotype should precede molecular investigations to exclude a possible sex chromosome aber693
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Table IV. Major documented clinical findings of maternal UPD14
Clinical findings
Heterodisomy
Isodisomy
Total
4/6 6/9 4/8 8/8 6/9 6/6 7/7 5/6 3/6 5/5 3/3 3/5 2/5
5/5 4/4 0/5 3/4 3/4 2/4 3/4 0/3 1/4 3/3 0/0 2/4 1/4
9/11 10/13 4/13 11/12 9/13 8/10 10/11 5/9 4/10 8/8 3/3 5/9 3/9
Low birth weight Hypotonia Hydrocephalus Short stature Mild developmental delay Normal intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty Advanced bone age Recurrent otitis media Hypercholesterolemia
11.
12.
13.
Clinical findings in bold: features that were present in at least 80% of the cases reported.
14.
ration. The finding of a balanced familial or de novo Robertsonian translocation der(13;14)(q10;q10) or der(14;14)(q10;q10) should prompt a subsequent study for UPD14. In the absence of any structural chromosomal aberration, advanced maternal age at the delivery or confined placental mosaicism for trisomy 14 may give indications to look for matUPD14. In these situations maternal age-related nondisjunction events and trisomy rescue might be assumed. The diagnosis of matUPD14 in a patient is important not only to recognize the cause of his or her problems but also to offer appropriate genetic counseling. In the case of a normal karyotype, there is no increased recurrence risk for UPD14 for the siblings or for the offspring of the patient.
4.
5.
6.
7.
8.
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phenotype in maternal uniparental disomy of chromosome 14. Am J Med Genet 1994;51:147-9. Morichon-Delvallez N, Seques B, Pinson MP, Bérubé D, Dommerques M, Aubry MC, et al. Maternal uniparental disomy for chromosome 14 by secondary nondisjunction of an initial trisomy [abstract]. Am J Hum Genet 1994;55(Suppl):2224. Robinson WP, Bernasconi F, Basaran S, Yüksel-Apak M, Neri G, Serville F, et al. A somatic origin of homologous Robertsonian translocations and isochromosomes. Am J Hum Genet 1994;54:290-302. Coviello DA, Panucci E, Mantero MM, Perfumo C, Guelfi M, Borronco C, et al. Maternal uniparental disomy for chromosome 14. Acta Geneticae et Gemellologiae 1996;45(1-2):169-72. Papenhausen PR, Mueller OT, Johnson VP, Sutcliffe M, Diamond TM, Kousseff BG. Uniparental disomy of chromosome 14 in two cases: an abnormal child and a normal adult. Am J Med Genet 1995;59:271-5. Tomkins DJ, Roux A-F, Waye J, Freeman VCP, Cox DW, Whelan DT. Maternal uniparental isodisomy of human chromosome 14 associated with a paternal t(13q14q) and precocious puberty. Eur J Hum Genet 1996;4:153-9. Link L, McMilin K, Popovich B, Magenis RE. Maternal uniparental disomy for chromosome 14 (abstract). Am J Hum Genet 1996;59(Suppl):687. Barton DE, McQuaid S, Stallings R, Griffin E, Geraghty M. Further evidence for an emerging maternal uniparental disomy chromosome 14 syndrome: analysis of a phenotypically abnormal de novo Robertsonian translocation t(13;14) carrier (abstract). Am J Hum Genet 1996;59 (Suppl):698. Désilets VA, Yong SL, Kalousek DK, Pantzar TJ, Kwong LC, Siemens C, et al. Maternal uniparental disomy for chromosome 14 [abstract]. Am J Hum Genet 1997;61(Suppl):691. Walgenbach DD, Yang SP, McCaskill C, Shaffer LG, Towner DR. Maternal uniparental disomy of chromosome 14 in an infant with mild dysmorphology and confined placental mosaicism {abstract]. Am J Hum Genet 1997;61 (Suppl):2222. Splitt MP, Goodship JA. Another case of maternal uniparental disomy chromosome 14 syndrome. Am J Med Genet 1997;72:239-40. Miyoshi O, Hayashi S, Fujimoto M,
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uniparental disomy in the euploid cell line of a fetus with mosaic 46,XX/ 47,XX,+14 karyotype. Hum Genet 1994;94:355-8. 25. Cotter PD, Kaffe S, McCurdy LD, Jhaveri M, Willner JP, Hirschhorn K. Paternal uniparental disomy for chromosome 14: a case report and review. Am J Med Genet 1997;70:74-9. 26. Wang JC, Passage MB, Yen PH, Shapiro LJ, Mohandas TK. Uniparental heterodisomy for chromosome 14 in a phenotypically abnormal familial balanced 13/14 Robertsonian translocation carrier. Am J Hum Genet 1991;48:1069-74. 27. Walter ChA, Shaffer LG, Kaye CI, Huff RW, Ghidoni PD, McCaskill C,
et al. Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45, XY,idic(14)(p11). Am J Med Genet 1996;65:259-65. 28. Cox DW, Gedde-Dahl T, Menon AG, Nygaard TG, Tomlinson IM, Peters J, et al. Report of the second international workshop on human chromosome 14 mapping 1994. Cytogenet Cell Genet 1996;69:159-74. 29. Cattanach BM, Barr J, Jones J. Use of chromosome rearrangements for investigations into imprinting in the mouse. In: Ohlsson R, Hall K, Ritzen M, editors. Genomic imprinting, causes and consequences. Cambridge: Cambridge University Press; 1995. p. 327-41.
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