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RING 14 NON-PROFIT ASSOCIATION
HELP AND RESEARCH FOR CHILDREN WITH RARE GENETIC DISEASES

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SYNDROMES OF CHROMOSOME 14

What is the RING14 Syndrome?
RING 14 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, informing material of chromosome 14.

The chromosome anomaly can involve all cells, or acts like a mosaic with a cellular line which has lost a complete chromosome 14 (monosomy 14)

Chromosome aberration RING14 associated to frequent and constant signs and symptoms causes a syndrome designated by motor and mental retardation and multiple phenotopical anomalies.

Ring14 initial diagnosis arises from a simple chromosome test.

Other anomalies of chromosome 14
Partial deletions, translocations
Chromosome 14 can be involved in other structural anomalies like internstitial partial deletions of the long arm, balanced or unbalanced translocations in which the chromosome remains line-shaped and is not rearranged in the shape of a ring.

Signs and symptoms associated to partial line-deletions include once again motor and mental retardation and multiple phenotypical anomalies which are partially like the ones associated to RING14.

In this case too, initial diagnosis arises from a simple chromosome test.

UPD(14)
In other cases chromosome 14 anomalies associated with specific clinical situations are not structural but functional, that’s means situations in which the two chromosomes 14 are perfectly integral but coming both from the same parent, with an uniparental disomia situation for chromosome 14 (UPD(14)) of maternal or paternal origin, if chromosomes 14 are coming both from the mother or both from the father.

The clinical picture is deeply different in the two conditions. In UPD(14) of paternal origin clinical signs are characterized by an important delay in growth, a peculiar conformation of skull and face, a thoracic deformity, anomalies of the abdominal wall and mental and motor retardation; often pregnancy is complicated, with polidramnios. In UPD(14) of maternal origin clinical signs are benigner and characterized by hypotonia, alimentary problems during the first years of life, light mental and motor retardation, short stature, small hands and feet. It is typical the delayed development, towards 7 – 9 years, obesity with hyperfagia such as to configure a clinical situation like the syndrome of Prader-Willi.

The most of UPD(14) cases ascertained up to-day, joined to Robertson translocations perfectly balanced as, for instance, translocation t(13;14), but even with normal cariotype. For that reasons diagnosis cannot be reached only through a simple chromosome test, but specific tests of molecolar genetic are necessary.

All syndrome conditions associated to structural or functional anomalies of chromosome 14 are rare, but it is also probable an underdiagnosis, as regards syndrome Ring14 in particular. In fact, phenotypical anomalies are often light, delay in growth is not so marked or even absent and, just for that reason, sometimes request of chromosome test can escape or be delayed.

The clinical and genetic characterization of all those conditions, possible only by analizing and comparing a wide casuistry, will bring a better knowldge to the families and the specialist doctors allowing at the same time a more efficacious treatment.

Which are the symptoms of RING14? Which are the symptoms of 14q line-deletions?
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.

Line-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.

How can RING14 Syndrome and other structural anomalies of chromosome 14 be diagnosed?
As regards RING14 Syndrome, firstly through a clinical diagnosis based on the typical dimorphism, early epilepsy seizures, motor and mental retardation, retina anomalies.

It is important to notice that even if all above signs and symptoms cannot be immediately associated to that syndrome they can be in any case associated to a chromosome pathology which need a cariotype tests. “RING14” anomaly can be easily diagnosed through a standard chromosome test which can be carried on everywhere, even if its exact molecular definition needs further tests to be carried on in specialist 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 diagnosis of the other structural anomalies of chromosome 14, of partial deletions in particular, is achieved by a simple chromosome test requested in presence of mental and motor retardation associated to physical dimorphisms. Also in these cases the exact molecular definition needs the intervention of specialist centres.

Case by case the individual symptoms will suggest the specific examination tests to be carried on.

On the first diagnosis it is however advisable to execute an examination of the fundus oculi (expected normal), an EEG and an endoabdominal ecography.

“Concealed” chromosome anomalies
It is important to notice that the recent citogenetic molecular technologies, such as the analysis of the telomers of all chromosomes or the technics of “microarray-CGH” used for the diagnosis of mental and motor retardation with cariotype apparently normal, are bringing to the individualization of different “concealed” chromosome anomalies which escape the conventional chromosome test being very small, including some small deletions of chromosome 14.

Therefore, before a clinical situation evocative of chromosome anomaly the normal result of a chromosome test cannot be considered sufficient to exclude a chromosome cause of the pathology and it is advisable to proceed with the citogenetic molecular technics carried on in the specific centres.

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