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Ring14 Syndrome


RING14 stands  for an aberration of chromosome 14  which takes a ring  shape  owing  to the fusion of the two ends of the short and long arm.  The fusion takes place from two breaking events, one at the end of the short arm and the other one at the end of the long arm, usually with the consequent partial loss of genetic material at both ends. The anomaly can involve all cells, or it can be in a mosaic state with a cell line which has lost the ring, leaving only one chromosome14 (monosomy 14). The chromosome aberration RING14 is responsible for a syndrome characterized by motor and mental retardation and multiple physical anomalies. The initial diagnosis of RING14 syndrome is usually performed by a simple chromosome analysis.

Partial deletions , translocations
Chromosome 14 can be involved in other structural anomalies, such as interstitial deletions of the long arm and balanced or unbalanced translocations, in which  the chromosome remains linear and  does not rearrange in the shape of a ring. Clinical signs associated with partial deletions include once again motor and mental retardation and multiple physical anomalies,  which are in part similar to the clinical manifestations associated with ring 14.  Also In these cases, the preliminary diagnosis usually arises from a simple chromosome test.  
In other cases,  chromosome 14  anomalies associated with  specific clinical conditions are not structural but functional. We refer here to situations in which chromosome 14-specific  material is fully preserved,  but both chromosomes 14 come from the same parent, causing uniparental disomy for chromosome 14 (UPD(14)), of either maternal or paternal origin. Clinical manifestations are quite different in the two conditions.  In UPD(14) of paternal origin clinical signs include severe growth delay, peculiar conformation of skull and face, thoracic deformity,   anomalies of the abdominal wall, mental retardation and motor delay.  Pregnancy  is often complicated by polyhydramnios.  In  UPD(14) of maternal origin clinical signs are less severe and include hypotonia, feeding problems during the first years of life, mild mental and motor retardation,  short stature, small hands and feet. Typical of this condition is the association of short stature and obesity at the age of 7 – 9 years. The majority of UPD(14) cases ascertained so far are associated with balanced Robertsonian translocations, most frequently  t(13;14) translocations, but an increasing number of cases are being reported in association with normal karyotype. For that reasons, diagnosis cannot be reached  through a simple chromosome analysis, but specific molecular tests are needed. All syndromic conditions caused by structural or functional anomalies of chromosome 14 are rare. However, their frequency is underestimated, most likely, with particular regard to the RING 14 syndrome. In fact, physical anomalies are often very mild and growth delay may be mild or absent. For all these reasons, the chromosome test can be delayed or even missed. The clinical and genetic characterization of all these conditions is possible only by analysing a large series of patients. This analysis can provide important insights in improving not only the general knowledge of these conditions, but also the proper diagnostic procedures and treatment.

As to RING14 syndrome, the most constant symptoms concern the central nervous system and the retina even if they change in numbers and  gravity case by case. The entity of mental and motor retardation and hypotonia is in fact variable  and also microcephaly may  vary.  Also speech,  generally compromised,    may  vary.  The retina may be hyperpigmented and may show small white-yellow stains in the mean periphery, the same stains involve the macula; cataract may appear.
Epilepsy is constant, it appears early (even in the very early weeks/months of life) and consists of generalized or partial seizures, probably of fronto-temporal origin; its pharmacological  control may result difficult and it may have a “moody” course with long periods with only few seizures; status epilepticus, mainly partial, is of frequent occurence.   Dimorphisms include : flat occiput, high forehead with prominent sagittal suture, hild palpebralptosis, ephicantic-folds, elongated face, large root and round tip of nose antiverted nostrils, long philtrum, low set ears with big lobe and prominent antehelix, microretrognatia, short neck; more seldom lyphedema on the back of hands and feet. Intrathoracic and intra-abdominal organs are normally developed.  Hyperpigmented skin spots, like scrub white cofee-coloured,  may be present. An immunoglobylin deficiency  (IgA of surface) has been noted with a high risk of respiratory and, may be, grastrointestinal infections.
Linear partial deletions of chromosome 14, at least those concerning the end part of the long arm, are associated, further to the mental and motor retardation, to physical  outlines smilar to those present in RING14 syndrome; while  “epilepsy” and “hyperpigmented retina” are usually absent.

With respect to the RING14  syndrome, the preliminary genetic test is suggested by the typical clinical manifestations, including typical physical anomalies, early seizures, motor and mental retardation and retinal anomalies.  It is important to notice that, even if all the above mentioned clinical signs cannot immediately  suggest this specific syndromic condition, they are fully consistent with a quantitative chromosome imbalance, leading to the chromosome test.  The “RING14” anomaly can be easily diagnosed by a conventional chromosome analysis,  which can be performed  everywhere. However,  its fine definition at a molecular level needs further genetic tests, that are usually carried  be carried out in specialistic centres. Electroencephalogram (EEG)   is fundamental for epilepsy seizure control, but has no diagnostic function. CAT (Computerized Axial Tomography) scan and MRI (Magnetic Resonance Imaging)  Usually show a normal cerebral structure, but they can reveal some critical focal atrophic anomalies often located in the temporal lobe, a dysplasia-hypoplasia of the corpus callosum, a dilatation of the lateral ventricles. Vitreous body and retina examination tests, even in the periphery, add a relevant diagnostic element. Potential evocates and  electroretinogram ERG resulted always  normal. Ecography examination tests of  internal organs add a relevant diagnostic element. Also the preliminary diagnosis of the remaining structural anomalies of the chromosome 14, including partial deletions, is performed by a conventional chromosome analysis, that is suggested by the association of mental and motor retardation  and physical anomalies. Also in these cases the proper molecular definition needs further analyses in specialistic centres. Clinical signs can vary in individual patients. Accordingly, different diagnostic tests can be needed in different patients.  On the first diagnosis, it is however recommended to perform  a the fundus oculi (expected normal) examination, an EEG and an endoabdominal ultrasound examination.

It is important to notice that the recent molecular cytogenetics techniques, such as telomere analysis and the “microarray-CGH” technique, is improving the genetic diagnosis of constitutional conditions with mental retardation and multiple physical anomalies that are associated with apparently normal chromosomes. Small quantitative chromosome anomalies, including subtle chromosome 14 deletions, can be undetected by a conventional chromosome analysis, which resolution is of about 5 megabases, but they can be detected by molecular cytogenetics techniques only. Therefore, if clinical signs are consistent with a chromosome anomaly but conventional chromosomes are apparently normal, it is recommended to go on with the help of these techniques in specialistic centres.

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