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.
Castermans D, Thienpont B, Volders K, Crepel A, Vermeesch JR, Schrander-Stumpel CT, et al..Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism
.Eur J Human Genet2008;16:1187–1192.
Gilgenkrantz S, Cabrol C, Lausecker C, Hartleyb ME, Bohe B.The Dr syndrome. Study of a further case (46, XX, 14r).Ann Genet1971;14:23–31.
Giovannini S, Frattini D, Scarano A, Fusco C, Bertani G, Della Giustina E, et al..Partial epilepsy
complicated by convulsive and nonconvulsive episodes of status epilepticus in a patient with ring chromosome 14 syndrome.Epileptic Disord2010;12:222–227.
Griswold AJ, Ma D, Sacharow SJ, Robinson JL, Jaworski JM, Wright HH, et al..A de novo 1.5 Mb microdeletion on chromosome 14q23.2–23.3 in a patient with autism
Guilherme RS, Ayres Meloni VF, Kim CA, Pellegrino R, Takeno SS, Spinner NB, et al..Mechanisms of ring chromosome formation, ring instability and clinical consequences.BMC Med Genet2011;12:171.
Hou JW.Mosaic ring chromosome 14 and monosomy 14 presenting with growth retardation, epilepsy
and blepharophimosis.Chang Gung Med J2004;27:373–378.
Shaffer LG, McGowan-Jordan J, Schmid M.An International System for Human Cytogenetic Nomenclature
Kosztolányi G.Does ‘ring syndrome’ exist? An analysis of 207 case reports on patients with a ring autosome.Hum Genet1987;75:174–179.
Merritt JL II, Jalal SM, Barbaresi WJ, Babovic-Vuksanovic D.14q32.3 deletion syndrome with autism
. American journal of medical genetics. Part A.Am J Med Genet A2005;133A:99–100.
Misawa S, Horiike S, Taniwaki M, Abe T, Takino T.Prefixation treatment with ethidium bromide for high resolution banding analysis of chromosomes from cultured human bone marrow cells.Cancer Genet Cytogenet1986;22:319–329.
Schlade Bartusiak K, Costa T, Summers AM, Nowaczyk MJM, Cox DW.FISH-mapping of telomeric 14q32 deletions: search for the cause of seizures.Am J Med Genet2005;138 A:218–224.
Specchio N, Trivisano M, Serino D, Cappelletti S, Carotenuto A, Claps D, et al..Epilepsy
in ring 14
Vaags AK, Lionel AC, Sato D, Goodenberger M, Stein QP, Curran S, et al..Rare deletions at the neurexin 3 locus in autism
spectrum disorder.Am J Hum Genet2012;90:133–141.
Van Karnebeek CDM, Quik S, Sluijter S, Hulsbeek MMF, Hoovers JMN, Hennekam RCM.Further delineation of the chromosome 14q terminal deletion syndrome.Am J Med Genet2002;110:65–72.
Verma RS, Babu A.Human chromosomes: manual of basic techniques1995:(2nd ed.).New York:Pergamon Press.
Zampini L, D’Odorico L, Zanchi P, Zollino M, Neri G.Linguistic and psychomotor development in children with chromosome 14 deletions.Clin Linguist Phon2012;2611–12962–973.
Zollino M, Seminara L, Orteschi D, Gobbi G, Giovannini S, Giustina ED, et al..The ring 14
syndrome: clinical and molecular definition.Am J Med Genet2009;149:1116–1124.
Zollino M, Ponzi E, Gobbi G, Neri G.The ring 14
syndrome.Eur J Med Genet2012;55:374–380.
Keywords:© 2014 Middle East Journal of Medical Genetics
autism; epilepsy; ring 14