The chromosopathy “ring(14)” : clinical-genetic study with production of the preliminary results and of the dedicated data-base

**Giovannini S, *Scarano A, * Frattini D, **Filippini M, §Seminara L, *Fusco C, § Zollino M, *Della Giustina E., **Gobbi G., §Neri G.

Complex Structure of Children’s Neuropsychiatry, *Arcispedale S.Maria Nuova (RE) and **Ospedale Maggiore “Pizzardi” (BO), § Institute of Medical Genetic, Catholic University “Sacro Cuore” (RM)

The syndrome “ring of chromosome 14” (ring14) reveals itself mainly by mental and motor delay, epileptic seizures, microcephaly, hypotonicity, retinal anomalies and a particular aspect of the face. It is due to a characteristic rearrangement in ring of one of the two chromosomes 14 generally associated to a deletion of variable exension of the genetic material.

Being a rare pathology, it arose the necessity to have one only file of clinical and instrumental data collecting all the cases actually known all over the word and obtained thanks to the activity of the “International Association Ring14 for the study of the rare neurogenetic diseases”.

It is a multisystemic pathology, even if with prevalent affection of the central nervous system and that’s because the file is structured in different under-chapters touching the different clinical aspects characterizing the syndrome. That allows to make longitudinal evaluations of each patient, to make a comparison among the patients and to apply statistical elaborations on the base, for instance, of different clinical and neuro-physicological signs and specific genetic alterations.

We have therefore realized an electronic data-base, studied in clinical key, compiled and used by medical staff.

The data to be inserted are coming from different sources: 1) Questionnaires sent to the families and to the doctors following the patients, structured for problems/apparatus with open and closed questions, translated in different languages (English, French, Spanish and German). 2) Clinical, genetic and instrumental protocol with tests and visits foreseeing specific anamnesis, genetic visit, genetic tests (standard cariotype, FISH analyses and analyses with probes specific for isolation of chromosome 14 microsatellites), metabolic tests (organic acids, arterial lactic acid, plasmatic and urinary amino-acids, ammonium, anion gap), immunological tests (lymphocytic characterization : CD 4, CD 8, CD 3, CD 19, relation CD 4/8, CD 20 and CD 56, IgA, IgG, IgM, underclasses IgG) and instrumental tests (EEG Holter with neuropsychological tests, PET, ENG/EMG, encephalon RM, FOO, VERs, BAER,s), further to a gastroenteric, neurophysiatric and cardiologic advice.

On the base of the data collected up to-day it is possible to consider 19 patients with Ring14 (5 of them present a complete ring while 14 present a ring with loss of genetic material in extension from 0,65 Mb to 5 Mb), 6 patients with deletions involving the different regions of the long arm of chromosome 14 and 2 patients with different rearrangements (1 patients with trisonomy 14q and monosomy 18q and 1 patient with balanced translocation 10-14).

In the patients with ring of chromosome 14 , the typical clinical manifestations are firstly characterized by face anomalies (94,1%) microcephaly (100%), mental and motor retardation (100%), cognitive retardation (88,9%), in the most of cases mid-serious, and epilepsy (100%) in the most of casesof partial type and treatment resistant, with frequent conditions of epileptic diseases with precocious beginning.

As to relations, even if with dismhogeneous profiles, it prevails the aspect of sociability and hyperactivity in the first infancy with the appearance of aggressive gestures and oppositive behaviour in the adolescent age.

The patients with different rearrangements on chromosome 14 present in the most of cases a heavy cognitive deficit while microcephaly (33%) and epilepsy (25%) are less present.

As regards the patients ring(14), it arose that phenotypical manifestations are very variable in each patient and only a part can be justified by a distal deletion of the long arm of chomosome 14. In order to explain that phenomenon we appeal to position effects, mythotic instability of the ring and concomitant presence of a line with complete monosomy of chromosome 14. Furthermore, the compared analysis of cases with ring(14) and cases with interstitial deletion charging different regions of the long arm of chromosome 14 allowed to define a phenotypical deletion map, for which the closest regions of the long arm of chromosome 14 seem to be responsible for retinal anomalies, epilepsy, microcephaly and, moreover, the loss of genetic material in that region seems to cause lighter form of mental retardation.

On the contrary, the loss of genetic material located in the terminal part of the long arm of chromosome 14 is associated to heavier forms of mental retardation and seems to be responsible for other clinical characteristics generally noticed in patients ring(14), such as behaviour disorders and great susceptibility to infections.

Also the study of the neuroimages (6 patients with RING14 and 5 with terminal deletion of the chromosome) has given elements of reflection compared with the literature data. Particularly, it resulted significant some anomalies such as the anomalous morphology of the hippocampus (displasia ?), the dilatation of ventricular system with or without cystic anomalies in back fossa, the dismorphism of the rough body, hypoplasia and delay in myelinization of the white hemispherical substance and, in one case, the variant synthelencephalic of the holoprosencephaly. On those basis it is possible to probe some correlations with the clinical aspects of epilepsy and mental/cognitive retardation of the patients with cromosomepathy 14.

Work developed with the support of:

“International Association RING14 for the study of rare neurogenetic diseases” –

“Foundation Cassa di Risparmio di Bologna” (Giovannini S.)