Balkan Journal of Medical Genetics

DICENTRIC CHROMOSOME 14;18 PLUS TWO ADDITIONAL CNVs IN A GIRL WITH MICROFORM HOLOPROSENCEPHALY AND TURNER STIGMATA
Sireteanu A1, Voloşciuc M2, Grămescu M1, Gorduza EV1, Vulpoi C3, Frunză I4, Rusu C1,*
*Corresponding Author: Cristina Rusu, M.D., Ph.D., “Grigore T. Popa” University of Medicine and Pharmacy, Medical Genetics Department, Stradă Universităţii 16, Iaşi 700115, Romania; Tel./Fax: +40-232-272-754; Mobile: +40-745-432-077; E-mail address: abcrusu@gmail.com
page: 67

DISCUSSION

We describe a female patient with some signs of Turner syndrome, mild dysmorphic face, minor features of holoprosencephaly (HPE), small hands and feet, excessive hair growth on anterior trunk and ID. The karyotype showed an unbalanced translocation between chromosomes 14 and 18 resulting in the formation of a dicentric derivative chromosome. Single nucleotide polymorphism array analysis revealed three abnormalities: an 18p deletion flanked by a duplication, and a 16p11.2 duplication. The translocation is de novo as both parents had a normal karyotypes. Non Robertsonian dicentric autosomes are rare findings, reported in only 26 cases in a review by Lemyre et al. [6]. The majority of cases involve the acrocentric chromosomes, with a short arm breakpoint, followed in frequency by chromosome 18. Most of the heterodicentric autosomes have only one primary constriction on metaphase chromosomes, and the constriction is noticed mostly at the site of the non-acrocentric centromere [6], as in our case. Deletions of p arms of acrocentrics containing nucleolus organizer regions (NOR) regions are not known to be associated with phenotypic anomalies, and have therefore probably not contributed to the phenotype. Also, the 1.15 Mb 18p duplication is not likely to have contributed to the phenotype, since most patients with trisomy 18p have normal or mild phenotypes, and may or may not have ID [7]. Our patient displays some of the features of 18p- syndrome, such as ID, features of the HPE spectrum (mild microcephaly, single central maxillary incisor), and features evocative of Turner syndrome (short stature, mild webbed neck, pectus excavatum, broad trunk and narrow hips) (Table 1). Facial dysmorphism (triangular face, blue sclera, bilateral preauricular sinus) is different from that described for 18p deletion, excepting the oromandibular region. Facial appearance has changed over time, becoming elongated (Figure 2), as described also by Tsukahara et al. [8]. Congenital cardiac defects, present in our case, have been observed in 10.0% of cases of 18p- [9]. Although the phenotype described above is not characteristic for monosomy 18p, the standing position with widespread legs and leaning slightly forward as well as marked slowness in motion and action are very suggestive for this chromosomal syndrome. Recurrent 16p11.2 microduplications were initially associated with phenotypes ranging from normal to ID, autistic spectrum disorders and psychiatric problems [10-13]. Other studies showed that these duplications can manifest with dysmorphic features without a recognizable pattern, microcephaly, congenital anomalies (including torticollis, cleft lip and palate, pectus excavatum, pectus carinatum, mild scoliosis, hypospadias, phimosis, tethered cord, pes planus), and seizures [14]. Jacquemont et al. [15] showed that 16p11.2 duplication is associated with a BMI <18.5 kg per m2 in adults and <-2 SD from the mean in children. Among the features mentioned above, our patient exhibited mild microcephaly, pectus excavatum, mild scoliosis and ID, but these features are also described in 18p deletion. She was underweight during childhood, but recovered later, her BMI being within normal range as an adult. Considering that empiric estimate for penetrance of proximal 16p11.2 duplication established a penetrance of 27.2%, and the likelihood of a normal phenotype is ~73.0% [16], we cannot clearly conclude how this copy number variation (CNV) influences the phenotype. More recently, a patient with thoracolumbar syringomyelia and a 16p11.2 duplication has been described [17]. Although our patient presented kyphoscoliosis and nocturnal enuresis, MRI of the spine showed no changes. In a study of three patients with 18p deletion, Portnoi et al. [18] suggested that there might be a critical region for GH deficiency between 18p11.23 and 18pter. Our patient has a deletion which includes that region, but the level of GH is normal and the craniocerebral CT did not show any pituitary gland anomalies. The critical region for ID has been tentatively mapped between 18p11.1 and 18p11.21 [4]. Our patient has a deletion distal to this point and moderate ID, but this feature may be due to the 16p11.2 microduplication. Brenk et al. [19] proposed round face to map to the distal 1.6 Mb of 18p, and post-natal growth retardation and seizures to the distal 8 Mb. Our patient has a terminal deletion larger than 10 Mb, but she had no history of seizures, and the face was triangular in childhood and elongated in adulthood. Considering that a pointed chin can be noticed in five out of 13 patients with 16p11.2 duplication for which the facial features were presented [10,14], we appreciate that the triangular aspect of the face may be due to this rearrangement. Ptosis and short neck, frequently associated with 18p- [2], were attributed by Brenk et al. [19] to the proximal half of 18p. These features were absent in our patient, in whom the proximal 5.1 Mb of 18p was not deleted. Thus, haploin-sufficiency of genes located in this region may be responsible for these features. Our patient has a microform of HPE, although only 10.0% of patients carrying an 18p deletion (including the TGIF gene) present HPE [3]. Holoprosencephaly is a complex developmental disorder in which multiple genetic and environmental factors can affect the severity of the phenotype [20]. A recent array CGH study of a large group of HPE patients demonstrated a high frequency of submicroscopic anomalies involving known but also novel HPE loci, including 16p11.2 [21]. Therefore, the 16p11.2 micro duplication present in our patient can be a second genetic event contributing to HPE manifestation. In conclusion, we report a female patient with a pseudodicentric 14;18 chromosome that carries two additional CNVs. These CNVs confer phenotypic variability to 18p- syndrome, leading to difficulties in establishing the contribution of each abnormality to the phenotype. Although the phenotype of 18psyndrome is not as typical as for other syndromes, HPE microform and Turner stigmata associated with characteristic posture and marked slowness in motion and action is very suggestive for this syndrome. Microarray analysis of our patient allowed us to define precise molecular characterization of the translocation breakpoints and to uncover two unsuspected cryptic abnormalities, improving genotype-phenotype correlations and management.

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