Ring chromosome 14 syndrome is a rare genetic condition first described by Gilgenkrantz et al. (1971) To date, over 70 cases have been reported in the literature that demonstrate a characteristic common phenotype (Zollino et al., 2012). Ring chromosomes arise from chromosomal breaks occurring on the distal end of both arms, with subsequent rejoining of the broken ends, and are usually associated with loss of a small amount of genetic material (Kosztolányi, 1987). They may also result from fusion of subtelomeric sequences or telomere–telomere fusion without deletion, leading to incomplete ring chromosome formation. The clinical phenotype of patients with ring chromosomes may be related to various factors such as gene haploinsufficiency, duplications, or the instability of the ring (Guilherme et al., 2011). Ring chromosome usually represents distal monosomy 14q32.3 (Hou, 2004).
The phenotypic features of patients with ring 14 were recently reviewed by Zollino et al. (2012) with the purpose of establishing a phenotypic map of the main manifestations of the ring 14 syndrome. Although there is general agreement that consistent clinical manifestations include typical facial appearance and intellectual disability, fine characterization of both the clinical phenotype and the basic genomic defect is still limited. More importantly, pathogenic mechanisms are unknown, with particular regard to the severe, and usually drug resistant, seizure disorder. Most of the clinical features are also observed in 14q linear deletion patients, except for seizures and retinal abnormalities (Van Karnebeek et al., 2002; Schlade Bartusiak et al., 2005; Zollino et al., 2009). Therefore, it seems unlikely that a deletion at a specific locus would predispose to the overlapping clinical features associated with these two disorders (Giovannini et al., 2010). Alternative hypotheses have therefore been proposed to explain the prevalence of seizures in the ring 14 syndrome. These include somatic mosaicism, which may vary in degree among different tissues, and position effect, leading to silencing of genes on the long arm of the chromosome juxtaposed to the short arm (Schlade Bartusiak et al., 2005; Zollino et al., 2009).
Unusual problems that occur in children with chromosome 14 aberrations are the presence of behavioral disorders, such as hyperactivity, and the presence of autistic traits and consequently linguistic delay. A large number of observations support a strong genotype–phenotype correlation for behavioral problems and autistic traits with region 14q32.1q32.3 (Zollino et al., 2009). The present study was conducted to describe a ring chromosome 14 with the rare association of drug-resistant epilepsy with autistic features and to emphasize the importance of the deleted genetic material in autistic patients.
Our patient is an 8-year-old boy born of nonconsanguineous, healthy parents (Fig. 1). He was born at term after an uneventful pregnancy by cesarean section. Parental age was over 35 years. There was a history of neonatal repeated respiratory infections and developmental delay during growth. The patient suffered from seizures that did not respond to drugs and from episodes of hyperactivity. Physical examination showed height below −2 SD, weight below −1 SD, and small head circumference at −3 SD. He had typical facies that included a long face, straight eyebrows, a long philtrum and mouth with downturned corners with characteristic hypertelorism, and low-set ears. Examination of the neurological system showed hypotonia in both lower limbs. Fundus examination showed a mottled macula, which may indicate early macular degeneration. A diagnosis of autism was made using Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR), the Childhood Autism Rating Scale (CARS), and Autism Diagnosis Intervention – Revised (ADI-R). The cognitive ability of the child was assessed using the Stanford Binet scale. He had intellectual deficiency with an intelligence quotient of 55. Comprehensive metabolic screening for amino acids yielded results within normal limits. MRI showed Dandy–Walker variant. Electroencephalography showed bilateral frontotemporal and generalized epileptic activity.
Cytogenetic studies and results
After obtaining informed consent according to the recommendations of the medical research ethics committee of the National Research Center, chromosomal analysis for the child and the parents was carried out according to the standard protocols (Misawa et al., 1986; Verma and Babu, 1995). A total of 20 metaphases were analyzed for the proband and his parents and karyotyped according to the ISCN (2013).
Chromosome analysis of the patient showed 46,XY,r(14)(::p11→q?::) in all analyzed metaphases, whereas fluorescence in-situ hybridization (FISH) analysis, which was carried out according to the manufacturer’s instructions with a subtelomeric (14qter) KREATECH FISH probe, showed ring subtelomeric deletion in all analyzed metaphases (Figs 2 and 3). The ring was stable and there were no rods or double rings. The extent of the deletion could not be identified using conventional methods and FISH with the subtelomeric probe. Parents showed a normal chromosomal complement.
Our patient had ring chromosome 14 with autistic features, psychomotor delay, Dandy–Walker variant, and epilepsy. The terminal deletion of the long arm of chromosome 14, most probably distal to band 14q32, was found to contribute to the manifestations of ring chromosome 14 (Kosztolányi, 1987). Clinical features of ring syndromes typically include prenatal and postnatal growth retardation, psychomotor retardation, persistent respiratory infections, and characteristic facies (Hou, 2004).
Zollino et al. (2012) analyzed a total of 27 personally observed patients with ring 14 syndrome and compared the clinical manifestations with those of 39 patients in the literature with ring 14 syndrome, for whom relevant clinical information was available (Table 1).
Most patients with ring chromosome 14 present with distinctive facial characteristics, including long and sometimes slightly asymmetrical face, full cheeks, high forehead, hypoplastic supraorbital ridges, horizontal eyebrows, deep set and downslanting eyes with short palpebral fissures, and apparent hypertelorism. The nose is short with a bulbous tip, the philtrum is long and the mouth small with downturned corners. However, the peculiar facial appearance of ring chromosome 14 is seen only in patients with a deleted ring and in association with a deletion size greater than 0.65 Mb, but not in patients with 14q terminal deletion smaller than 0.65 Mb or with a nondeleted ring. Other regular clinical signs are muscular hypotonia (72%), microcephaly of postnatal onset (81%), and ocular problems (58%) that included mainly retinal pigmentary anomalies and retinitis pigmentosa. Cataract, strabismus, maculopathy, glaucoma, and myopia are found. Scoliosis and café-au-lait spots are noted in some patients. Major malformations are absent (Zollino et al., 2012). Our patient had typical facies including long face, straight eyebrows, long philtrum, mouth with downturned corners, and hypertelorism. The patient also had hypotonia, severe microcephaly, and ocular anomaly in the form of mottled macula. There was scoliosis but no café-au-lait spots and no major malformations.
White matter hypoplasia, corpus callosum abnormalities, hippocampal dysmorphisms, and cerebellar structural anomalies are noted in a few cases of ring chromosome 14. No consistent cerebral cortex abnormalities have been observed (Zollino et al., 2012). Our patient has cerebellar structural anomalies in the form of Dandy–Walker variant. This type of MRI finding, to our knowledge, is described for the first time in ring 14.
Epilepsy associated with ring chromosome 14 has many features that entail a challenging diagnostic process, in which heterogeneity in presentation of clinical characteristics is probably the most challenging factor of all (Specchio et al., 2012). All patients with ring chromosome 14 experience epilepsy. Seizures at onset are of various types, including generalized tonic-clonic, myoclonic-tonic, and clonic, as well as focal with secondary generalization, mainly originating from the mid-temporal and frontal lobe. Soon after onset, epilepsy shows a particularly severe phenotype. No patient has only one type of seizure. Epileptic manifestations are drug resistant and have a tendency to decrease in late adolescence (Zollino et al., 2012). Our patient suffers from frontotemporal seizures, which shortly after onset become generalized, with no response to treatment.
In ring 14 patients the degree of intellectual delay is, on average, severe. It is independent of the presence and extent of the deletion within the ring, but consistently correlated with the severity of the seizure disorder (Zollino et al., 2012). Other problems that typically occur in children with chromosome 14 aberrations are the presence of behavioral disorders, such as hyperactivity, and the presence of autistic traits, such as motoric stereotypies and echolalia (Zampini et al., 2012). Ring 14 patients are usually good natured, but hyperactive, with occasional bursts of aggressiveness. It is worth noting that patients with a nondeleted ring had nearly normal psychomotor development in early infancy, but almost all experienced regression after seizures (Zollino et al., 2012). A large number of observations supported a strong genotype–phenotype correlation for behavioral problems and autistic traits with region 14q32.1q32.3. Moreover, the presence of autistic traits in children with ring 14 syndrome can negatively affect their language development (Zampini et al., 2012). Our patient suffers from intellectual deficiency. He is hyperactive without bursts of aggressiveness. He also has autistic features. One area in which chromosomal aberrations have been instrumental in the identification of candidate genes and chromosomal regions is autism. Visible cytogenetic abnormalities are detected in more than 5% of affected children, involving many different loci on all chromosomes. High-resolution techniques relying on array comparative genome hybridization have detected de-novo submicroscopic chromosomal aberrations in a significant number of individuals with unexplained autism (Castermans et al., 2008). Merritt et al. (2005) described a patient with the smallest known terminal linear 14q deletion, presenting with severe autism scored by the Childhood Autism Rating Scale. Griswold et al. (2011) identified and validated a de-novo 1.5 Mb microdeletion of 14q23.2–23.3 in an autistic patient. This was the first implication of the 14qter region in the etiology of autism. Vaags et al. (2012) reported that autism spectrum disorder affected individuals who possess rare inherited or de-novo microdeletions at 14q24.3–31.1, and harbor NRXN3 exonic deletions, which advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.
The present study has confirmed the involvement of small deletions in 14qter in the etiology of autism. Moreover, it seems that a smaller amount of deleted material is not necessarily related to a better outcome. However, more detailed molecular analyses are still required to determine the characteristic features of ring 14 chromosome and the extent of the deletion and correlate these to clinical presentation and the associated phenotype.
Conflicts of interest
There are no conflicts of interest.
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