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Nonmosaic partial duplication 12p: clinical and cytogenetic findings and review of the literature 12p duplication clinical and cytogenetic description

Eid, Maha M.a; Helal, Suzett I.b; Meguid, Nagwa A.b; Hamad, Sayeda A.a; Gerzawy, Assaada; Kamel, Alaaa

doi: 10.1097/01.MJX.0000457180.04887.77

We report on a male patient with de-novo pure partial trisomy 12p syndrome besides Robertsonian translocation. The patient had characteristic dysmorphic features such as low-set ear, a high forehead, flat occiput, long philtrum, and nystagmus. He also suffers from intellectual disabilities, seizures, hypotonia, and developmental delay. He has normal anthropometric measurements, and normal height, weight, and skull circumference. A cytogenetic study using the G-banding technique showed 45,XY, add (12)(p12.3), t(13;14)(q10q10). Karyotyping of the parents was performed, which indicated a normal result for the father and 45, XX, t(13;14)(q10;q10) for the mother. The fluorescence in-situ hybridization technique was performed for the patient using whole-chromosome paint 12 and subs telomere 12p. It showed that the add segment on chromosome 12p was derived from chromosome 12 and that 12p subtelomere was inverted and duplicated. Thus, the karyotype is 45, XY, dup (12)(p ter-p12.3), t(13;14)(q10q10). Comparison of the clinical and the cytogenetic findings of our patient with previously reported dup (12p) in the literature was carried out for better characterization and understanding of the phenotypic and cytogenetic relationship.

Departments of aHuman Cytogenetics

bChildren with Special Needs, National Research Centre, Cairo, Egypt

Correspondence to Suzette I. Helal, MD, Department of Children with Special Needs, National Research Centre, El-Bohouth Street, Dokki, PO Box 2311, 12311 Cairo, Egypt Tel: +00201001004562; fax: +0020233370931; e-mail:

Received May 15, 2014

Accepted May 25, 2014

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The first case of partial trisomy 12p was reported by Uchida and Lin 1, which occurred as a result of malsegregation of a balanced parental chromosomal rearrangement. The clinical feature of the child included a flat round face with prominent cheeks and forehead, broad nasal epicanthic folds, a short upturned nose, long philtrum, thin upper lip, and broad everted lower lip. Since then, 48 additional cases of trisomy 12p have been described 2. The estimated incidence is one case in 50 000 newborns. Following expansion by mosaicism, variations in chromosome 12p were divided into four types on the basis of the extent of the 12p trisomy and the presence of extrachromosomal regions in addition to chromosome 12p 3,4. On the basis of these criteria, Liang et al. 5 have compared patients with ‘pure’ trisomy 12p and subdivided these into four groups.

According to the orientation of the duplicated segment, duplications may be classified either as tandem or inverted, the former usually associated with deletion of the distal region of the duplicated chromosome 6. The best-studied cases of inverted duplications (inv dup) are the inv dup(8p) 7,8 and bisatellited inv dup(15) 9, which are usually nonmosaic. In contrast, mosaic inverted duplications are derived from different postzygotic mechanisms for which various possible origins have been proposed 10–12. There is also a particular subset of inv dup in which the duplication ends terminally on the chromosome and that are named terminal inv dup 13,14.

The clinical features of duplication 12p may sometimes overlap with those of the Pallister–Killian syndrome (PKS). PKS is typically caused by the presence of a supernumerary isochromosome composed of the short arms of chromosome12, resulting in tetrasomy12p, which is often present in a tissue-limited mosaic state 15. Also, the PKS phenotype has been found in patients with complete or partial duplications of 12p (trisomy 12p); however, some patients with duplication 12p may have features that differ from that of PKS 16,17. Given that the full PKS phenotype can be observed in individuals carrying such duplications, it is likely that a subset of genes on 12p are responsible for the PKS phenotype and that trisomic nonmosaic dosage is equivalent to the tetrasomic mosaic dosage in terms of pathogenicity 18.

In this study, we report a male patient presenting a de-novo karyotyping: 45, XY, dup(12)(pter-p12.3),t(13;14)(q10q10), that is inverted duplication 12p with Robertsonian translocation involving chromosomes 13 and 14 led to partial trisomy 12p (p12.3-pter). The phenotype resulting from the mal-arrangement of the involved chromosomal segments will be discussed.

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Clinical description

Our patient was the first-born male child of nonconsanguineous healthy parents with a history of two previous abortions, followed by no conception for 5 years, and then birth of our patient. He was delivered at term after an uneventful pregnancy. His birth weight was 3.5 kg and there were some neonatal problems such as cyanosis, poor suckling, and neonatal prolonged jaundice. The age at the time of first examination was 1.5 years. The patient had delayed milestones and recurrent involuntary fine movements. A thorough clinical examination, anthropometric measurements, neuroimaging (computed tomography, MRI), electroencephalography (EEG), echo heart, and cytogenetic assessment were performed for the patient.

Clinical examination indicated multiple dysmorphic features in the form of frontal bossing, flat occiput, nystagmus, deep-seated eyes, low-set ears, long philtrum, thick lower lip, high-arched palate, and sparse scalp hair and eye brows (Fig. 1). Also, bilateral incomplete Simian crease, prominent heal and flat feet, hypospadias, and unilateral undescended testis were detected. Anthropometric measurements were within normal ranges.

Fig. 1

Fig. 1

In terms of the neurological findings, the patient had ID affecting cognitive, language, and social development. Apart from intellectual disabilities, the patient was hypotonic and had developmental delay. The main neurological feature was seizures. At age of 1 year, the patient had mild involuntary abnormal movements. However, at the age of 3 years, he developed recurrent attacks of seizures, nocturnal more than diurnal the nocturnal fits were tonic–clonic, whereas the diurnal fits were simple partial seizures. The EEG findings at the age of 1.5 years were normal; however, the EEG that was performed at the age of 3 years showed centrotemporal epileptiform discharge with secondary generalization. Accordingly, Rolandic epilepsy was proposed as the diagnosis. Seizures were controlled by sodium valproate.

However, brain computed tomography showed mild cortical brain atrophy, whereas brain MRI showed mild hypoxic ischemic insult perinatally, with more affection of the posterior white matter tracts bilaterally cerebrally. Echo heart was normal.

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Cytogenetics studies

Cytogenetic studies including the G-banding technique were carried out on peripheral blood lymphocytes according to Verma and Babu 19. The cytogenetic result for the patient was 45, XY, add (12)(p12.3),t(13;14)(q10q10) (Fig. 2). However, the father’s karyotype was normal, but the mother’s karyotype was 45, XX, t(13;14)(q10q10).

Fig. 2

Fig. 2

Accordingly, a fluorescence in-situ hybridization (FISH) study was carried out for the proband aiming to identify the origin of the add segment on 12p. The FISH studies were carried out according to the manufacturer’s instructions using a subtelomere 12p probe and a whole-chromosome painting probe for chromosome 12 (Vysis, Abbott Park, Illinois, USA). The FISH results showed that the add segment of 12p was derived from chromosome 12 and the 12p subtelomere was duplicated and not located terminally on 12p (Fig. 3), that is inverted duplication 12p with Robertsonian translocation involving chromosomes 13 and 14, led to partial trisomy 12p (p12.3-pter). The karyotype of the patient was 45, XY, dup(12)(p ter-p12.3),t(13;14)(q10q10).

Fig. 3

Fig. 3

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Recently, different researches have been carried out attempting to evaluate the karyotype–phenotype correlation for the partial trisomy 12p syndrome 5,17. The partial trisomy 12p syndromes usually occurs as a result of unbalanced segregation of a balanced parental translocation, leading to varying extents of the trisomic 12p segment and missing material of another chromosome 3,20–22.

However, this was not the case in our patient; the abnormality in our patient arose de novo, and the karyotyping for the parents showed normal chromosomes apart from the 13;14 translocation that was detected in the mother, which seems to be irrelevant for the targeted abnormality.

Only a few cases of a de-novo duplication of various segments of the short arm of chromosome 12 are known 16,23–25.

The de-novo cases may present as an inverted tandem duplication, a marker chromosome, a derivative of another chromosome, or a supernumerary isochromosome 26.

The variability in phenotypes in patients with dup 12p depends on the type and the extent of the duplication 27. For purposes of characterization of the phenotype differences, cases of trisomy 12p can be divided into five categories on the basis of the extent of the 12p trisomy and the presence of other chromosomal aneusomies. Thus, complete trisomy 12p is recognized by the presence of a duplication region of 12pll or 12p12–12pter, and pure as having no other aneusomy 3.

Category I was designated as a partial pure trisomy of 12p with a duplication point distal to 12pll and not involving any other chromosome. This group may represent the most benign category. Category II includes cases with 12p trisomy in association with cell-line mosaicism. Patients in category II appear to present the same manifestations as those in category III, but with less uniformity. Category III includes cases with complete and pure 12p trisomy with an additional trisomy or monosomy of the short arm of an acrocentric chromosome. Categories IV and V involve complete 12p trisomy with monosomy or trisomy of non-acrocentric chromosomes other than 12p or trisomic involvement of 12q, respectively 3.

Furthermore, depending on the extent of the duplication, pure 12p duplication is divided into four subgroups: A, B, C, D, group A: complete trisomy 12p for 12pter-p11.1, group B: terminal trisomy for 12pter-p13.1, group C: distal trisomy for 12pter-p12.1, and group D: proximal trisomy for 12p12.3-p11.22 2.

For karyotype–phenotype correlation, it is essential to assign our patient into the proper category. Therefore, according to the above categorization, our patient will fit into category I, which represents the most benign group of dup (12p), and depending on the extent of duplication he will fit into group C.

Review of the literature showed few but significant differences between the categories of 12p duplications. However, two abnormalities that have received particular attention are seizures and hypoplastic left heart. Seizures are generally 3 Hz spike and wave discharges, manifested by generalized convulsions, myoclonic jerks, febrile seizures, or clonic spasm as described by Guerrini et al. 22. Although our patient was assigned to category 1, Qazi et al. 28 have reported the presence of seizures in all categories, except category I; this difference could be attributed to the difference in the break point involved in the duplication.

Some refinements in the karyotype–phenotype correlation of trisomy 12p can be made. Accessory nipples and polydactyly of the toes were only present in a subset of group A patients, suggesting that a segment responsible for these features is confined to the region centromeric to 12p11.22. Similarly, the region important for broad eyebrows and foot deformities may be mapped to a 5-Mb, 12p13.1-p12.3 segment because they were present in patients in groups A and C ‘as in our patient,’ but not in patients in groups B and D. Epicanthal folds, ear anomalies, a short neck, and round face/prominent cheeks were observed in the patients in groups A, B, and C, but not in the patients in group D, suggesting that these features may be associated with a segment telomeric to 12p12.3. Rauch et al. 29 and Tsai et al. 25 suggested that terminal 12p (12p13.3-p13.1) might contain a critical region for the facial features of trisomy 12p syndrome and that proximal 12p might contribute more toward major structural features 5.

Depending on the above refinement, although there are some similarities between the clinical features of our patient and the previously reported patients, there are also differences such as the presence of seizures in our patient; although he was categorized in group I, our case report analysis has supported the hypothesis that the stated phenotypic variability depends on the type and extent of the duplication break point, and also the ischemic insult in the perinatal period might be the cause of the seizures rather than genetics factors.

In addition, many studies have highlighted correlations between the phenotypic variability and the karyotype related to the 12p type and segment. The functional imbalances in chromosomes can lead to dose effects from the duplication of 12p and disruption of gene(s) at inversion breakpoints 2.

Partial duplication of 12p is a well-defined entity, characterized by an increased birth weight, hypotonia, macrocephaly, a high forehead, prominent cheeks, a flat face, large philtrum, a short nose with anteverted nares, a broad everted lower lip, and a short neck. However, pure duplications are rare, and the majority of the reported patients carrying the region for the syndrome seem to be limited to 12p13.2-pter and 12p13.1-p13.3 29.

Among the 25 cases of 12p duplication and one partial 12p triplication, the common facial features include prominent forehead/frontal bossing, full cheeks, epicanthus, low-set ears, a wide/depressed nasal bridge, a short nose, anteverted nares, long/deep philtrum, and everted/thick lower lip. Among 13 cases of partial 12p duplication/triplication, 12p13.31 was the common region involved in the duplication; the frequencies of the above-mentioned facial features were as follows: prominent forehead/frontal bossing (five cases), full cheeks (nine cases), epicanthus (five cases), low-set ears (eight cases), wide/depressed nasal bridge (11 cases), a short nose (nine cases), antiverted nares (nine cases), long/deep philtrum (11 cases), and everted/thick lower lip (nine cases). Developmental delay was a universal feature of 12p duplication including partial 12p duplication 18.

The majority of the cases with partial 12p duplication encompassing 12p13.31 manifested with the typical facial features for 12p duplication/PKS, supporting the hypothesis that12p13.31 harbors genes that play a critical role in the pathogenesis of 12p duplication/PKS 11. Among these genes are ING4, CHD4, and MAGP2, which are responsible for negative growth regulation. Overexpression of ING4 has been shown to result in cell cycle arrest 30,31.

In summary, we describe a case of a rare chromosomal imbalance of partial trisomy 12 arousing de novo on top of Robertsonian translocation. The phenotype–karyotype correlations have shown similarities to previously reported cases apart from the presence of hypospadius and undescended testis. Also, the association of the balanced robertsonian translocation in our patient seems to have no clinical impact on the patient; hence, it is a balanced rearrangement. The detection of such abnormalities could provide useful information for genetic counseling in subsequent pregnancies. Also, on reviewing the literature, the critical region involving 12p31 was suggested to be responsible for the most dysmorphic features in our patient.



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This work was supported by National Research center; Research on Children with Special Needs Department. Special thanks to Dr Ehab R. Abdelraouf.

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Conflicts of interest

There are no conflicts of interest.

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