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Clinical Vignette
| Clinical Features | Kirchhoff et al. | Su et al. | Lance et al. | Present case |
| | (n=14) | | | |
1 | Break Points | All | 13q34 | 13q33.3 | 13q34 |
2 | Gender | Both | F | F | F |
3 | Low Birth weight | 90.9% | + | + | + |
4 | Microcephaly | All patients with | + | + | + |
terminal deletion | |||||
5 | Intellectual disability | 100% | + | + | + |
6 | Short Stature | 2/9 patients with | + | - | - |
terminal deletion | |||||
7 | Facial Dysmorphism (‘13q facial appearance’ as suggested by Kirchhoff et al. )
| ||||
High forehead | 78.6% | NK | + | - | |
Sloping forehead | 78.6% | + | NK | + | |
Prominent metopic ridge | 71.4% | NK | NK | - | |
Deep set eyes | 64.3% | NK | NK | - | |
Hypertelorism | 100% | + | + | + | |
Inner epicanthic folds | 100% | + | + | + | |
Strabismus | 92.9% | NK | NK | + | |
Ear anomalies | 100% | + | NK | + | |
Broad and prominent | 71.4% | + | + | + | |
nasal bridge | |||||
Prominent columella | 57.1% | Short | NK | + | |
and a short philtrum | philtrum | ||||
Open-mouth appearance | 64.3% | + | NK | + | |
8 | Clinodactyly | 57.1% | NK | NK | + |
9 | Foot anomalies (Club foot, | 57.1% | Club | NK | Pes planus |
Pes cavus, Pes planus) | foot | ||||
10 | Hearing anomalies | 20% | + | NK | - |
11 | Seizures | 14.3% | - | + | + |
Onset | NK | NA | 4Yrs | Day1 | |
Type | NK | NA | GTCS | GTCS | |
Response to treatment | Lasted till | NA | Refractory | Refractory | |
age 3Yrs | |||||
12 | Behavioural changes | 28.6% | - | - | + |
NK - Not Known
GTCS - Generalised Tonic Clonic Seizures
Ring chromosomes present commonly as intellectual disability and dysmorphism which may be obvious or subtle depending on the observation and acumen of the clinician.
Deletion 13q has a wide phenotypic spectrum depending on the location of the break point relative to chromosomal
band 13q32.5 This syndrome has been classified into three groups. Deletions proximal to q32 and including q32 have been
classified under group 1 and 2 respectively, with distinct phenotypes including intellectual disability and growth
deficiency, whereas severe intellectual disability, microcephaly with true hypertelorism, frontal bossing,
protruding upper incisors and large external ears are frequently found in group 3 with breakpoints at 13q33 and
13q34. Recently, Kirchhoff et al. have updated this map by means of high resolution array CGH and have
suggested a ‘‘13q deletion facial appearance’’ based on the common dysmorphic features found in a series of 14
patients, regardless of location and size of their deletions [Table 1].6 Microcephaly is a common feature
of individuals with 13q deletions but polymicrogyria is not common.7 Su et al. have recently reported
a case of mosaic RC13 [Table 1].8 Apart from the CNS manifestations, cardiac, renal and genitourinary
anomalies are also reported with 13q deletion syndromes.9,10,11 Our patient with a deleted band 13q34
presented with early onset epilepsy as the predominant feature. This is a relatively uncommon feature
in group 3. With literature review, we could identify only three other cases of group 3 of 13 q deletion
syndrome with seizures.9,10,11 Two cases reported in the case series by Kirchhoff et al. had seizures which
lasted until the age of 3 years only.6 Our patient continued to have seizures at the age of 10. Treatment
noncompliance could have contributed to this. On the other hand, our patient bears a close similarity to the case
reported by Lance et al. who described an 8 year old female child with microcephaly, moderate to severe
intellectual disability and uncontrolled epilepsy but without major malformations, harbouring a terminal 13q33.3
deletion.11 Both cases have a resembling facial profile [Table 1]. We agree with Lance et al. in suggesting
that the deletion 13q syndrome, group 3 may be more severe than previously indicated and intractable
seizures leading to gross cognitive impairment may be considered as a part of the phenotypic spectrum of this
group.
Clinically, the RC14 syndrome is characterized by a recognizable phenotype of short stature, distinctive facial
appearance, microcephaly, scoliosis, and ocular abnormalities. Almost all patients are intellectually delayed, with
aggressive and hyperactive behaviour in some. Seizures occur in all and are usually drug-resistant and predominantly focal
type.12 The facial characteristics include long and sometimes slightly asymmetric face, full cheeks, high forehead,
hypoplastic supraorbital ridges, horizontal eyebrows, deep set and down- slanting eyes with short palpebral fissures,
hypertelorism, short nose with bulbous tip, long philtrum and small mouth with downturned corners.12 It is considered
that adverse clinical effects like growth retardation, neurologic impairment and facial dysmorphism of RC14 deletions are
more pronounced than those of linear 14qter deletions with similar breakpoints.12,13,14 Deletion of susceptibility genes
during ring formation, position effect of the telomeric end and gene silencing due to spread of inactive state of p
arm DNA to q arm are hypothesized mechanisms explaining the clinical manifestations of RC14.14 One
study mentions that in linear terminal 14q deletion syndrome, epilepsy is not included as its component
manifestations and seizures are more likely to be due to ring formation and not the loss of chromosomal material
per se.14 Exact mechanisms pertaining to the severe and drug-resistant seizure disorder are unknown.
The reported case had microcephaly, developmental delay, epilepsy and dysmorphic features which are
classical presentations of RC14 syndrome but the craniosynostosis seen in the case has not been reported
so far with 14q deletion syndrome, to the best of our knowledge. This feature expands the phenotypic
spectrum associated with ring 14 syndrome. Since he had the breakpoint at q32 band and 14q32 being
the possible region for dysmorphic profile, this unusual trait may be assigned to the 14q32qter region.
However delineation of the exact breakpoint by means of FISH or array CGH could not be attempted in our
patient.
Ring chromosomes are generally sporadic in occurrence and recurrence in the family is usually low. However, patients with normal reproductive ability should be counselled about the possibility of transmission to the next generation. For our first patient, parental origin of ring 13 was excluded. The paternal karyotype of translocated Y on chromosome 15 was incidental. Most carriers of this translocation have not been reported to have phenotypic consequences and association with reproductive abnormalities is still controversial.15 Whether this could predispose to ring chromosome formation is at present unknown. Paternal origin of ring 14 could not be excluded in the second patient. However prenatal testing was offered in subsequent pregnancy and the fetal karyotype was found to be normal. Regular follow up was emphasized for both the patients as it is important to assess the natural history, progression of characteristics, and neurodevelopmental achievement.
We have reported here a case of RC13 with unusual presentation of difficult-to-control seizures and a novel case of RC14 with intractable seizures and craniosynostosis. For children with microcephaly, developmental delay and seizures with or without dysmorphism, possibility of ring chromosomes should be kept in mind and karyotype must be an essential part of their evaluation.
1. Sigurdardottir, S. et al. Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of “complete ring” syndrome. Am J Med Genet 87, 384-390 (1999).
2. Guilherme, RS. et al. Mechanisms of ring chromosome formation, ring instability and clinical consequences. BMC Med Genet 12, 71-178 (2011).
3. Martin, NJ. et al. The ring chromosome 13 syndrome. Hum Genet 61 8-23 (1982).
4. Zollino, M. et al. The ring 14 syndrome. Eur J Med Gen 55, 374-380 (2012).
5. Brown, S. et al. The 13q-syndrome: the molecular definition of a critical deletion region in band 13q32. Am J Med Genet 57, 859-866 (1995).
6. Kirchhoff, M. et al. Phenotype and 244k array-CGH characterization of chromosome 13q deletions: An update of the phenotypic map of 13q21.1-qter. Am J Med Genet Part A 149A, 894-905 (2009).
7. Kogan, JM. et al. Interstitial deletion of 13q associated with polymicrogyria. Am J Med Genet Part A 146A, 910-916 (2008).
8. Su, PH. et al. Smallest critical region for microcephaly in a patient with mosaic ring chromosome 13. Genet Mol Res 12, 1311-1317 (2013).
9. Huang, C. et al. Congenital heart defect and mental retardation in a patient with a 13q33.1-34 deletion. Gene 498, 308-310 (2012).
10. Ballarati, L. et al. 13q Deletion and central nervous system anomalies: further insights from karyotype-phenotype analyses of 14 patients. J Med Genet 44, e60 (2007).
11. Lance, EI. et al. Expansion of the Deletion 13q Syndrome Phenotype: A Case Report. Journal of Child Neurology 22, 1124-1127 (2007).
12. Zollino, M. et al. The ring 14 syndrome: clinical and molecular definition. Am J Med Genet A 149, 1116-1124 (2009).
13. Meschede, D. et al. Submicroscopic deletion in 14q32.3 through a de novo tandem translocation between 14q and 21p. Am J Med Genet 80, 443-447 (1998).
14. İncecik, F et al. Ring chromosome 14 syndrome presenting with intractable epilepsy: a case report. Turk J Pediatr 55, 549-551 (2013).
15. Onrat, ST et al. 46,XX, der(15),t(Y;15)(q12;p11) karyotype in an azoospermic male. Indian J Hum Genet 18, 241-245 (2012).
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