Di George's syndrome

A child on 2000 births with Di George's syndrome or micro-deletion 22q11, but underestimated and abandoned, because too complex.

A micro-deletion is the loss of a small segment of chromosome including several genes. In the case of Di George's syndrome (or syndrome cycle-cardio-facial or deletion 22q11), this abnormality affects not less than 30 genes. All the biological functions of the body can be allocated to diverse degrees: immunizing, cardiac, digestive, ENT, endocrinologic, intellectual, psychiatric. The complexity of this micro-deletion and the mosaic of the symptoms which it entails, generate numerous difficulties notably the isolation of the patients, a deficit of scientific and medical knowledge, lack of diagnostic tools and therapeutic answers, the misunderstanding of the professionals of health and the relative indifference of the pharmaceutical industry.

A syndrome, multiple, often crippling but little visible symptoms The problem of Di George's syndrome: its discretion! The children are only little stigmatized physically and the syndrome can pass unnoticed during several years, because the diagnosis is difficult in particular at the infant's. The symptoms most frequently observed are: abnormality of the palate and the ears, arousing difficulties of language and understanding, or deficit of the hearing(audition): 95 % of the cases, the delay in the learning and the deficit of the attention:

98 % of the cases cardiac deformation:

65 % of the cases disturbs immune systems:

78 % of the driving shady cases, hypotony:

90 % of the cases risks mattering of schizophrenia which begins in the childhood or the adolescence:

25 % of the cases to advance, a single solution: to inform, to communicate multiple disciplines are concerned, among which the most frequent are the Genetics, the Cardiac Surgery, THE ENT, The Orthophony, the Psychiatry, the Stomatology, The Endocrinology, The Orthopaedics, The Odontology, the Psychomotricity. In every discipline, there are all over the world limited research programs limited, concerning a gene or the other one, a symptom or the other one. Some people can help in the best understanding and the care of the genetic abnormality in its global nature. So certain researches on the schizophrenia were able to help families to understand better the behavior of their children and to try to anticipate it.

Stay in the listening, keep in touch, communicate to be informed, inform to become an actor referent, here is all the stake in the Foundation. Another stake is to make known and recognize Di George's syndrome and its multiple facets by the medical profession.

So that the children can grow in the best conditions and exploit in best their resources and be joined into the society, they have to benefit at the same moment dune approaches global and completes. So that families can accompany them in the best conditions, Di George's syndrome has to become more visible. Di George's syndrome is a primitive immunizing deficit provoked by an abnormal development of certain cells during the growth and the differentiation of the foetus. The thymus and the function of lymphocytes T can be affected by this abnormality of the development.

DEFINITION

Di George's syndrome is a primitive immunizing deficit provoked by an abnormal development of certain cells and tissues of the neck during the growth and the differentiation of the foetus. We call " cellular lineage " of cells forming tissues the normal foetal development of which depends on a unique group of embryonic cells. Although tissues and organs resulting from the same cellular lineage can seem independent in a completely formed body, these tissues and organs are connected because they develop from the same embryonic or foetal tissues. Most of the patients presenting Di George's syndrome have a small deletion (left missing) of a specific part of the chromosome 22 in position 22q11,2. We also call this disease " syndrome of deletion 22q11,2 ".The " cellular lineage " or the region of the embryo in development which is affected in Di George's syndrome controls the development of the face, the parts of the brain, the thymus, the parathyroïdes, the heart and the aorta. The control of the development of this cellular lineage is situated in a group of cells which result from the back of the neck of the embryo in development. So that the components of the cellular lineage can develop normally, cells have to migrate, during the formation of the foetus, since the neck to zones in development of the face, the thymus, the parathyroïdes and the heart. When it is not the case, the development of these regions is not normally made. The abnormalities observed in Di George's syndrome are the consequence of an abnormal development of this cellular lineage.The affected organs are not all identical at the patients affected by Di George's syndrome. An organ can be unhurt or so little affected that its appearance is normal. The patients with Di George's syndrome can present only a part or the totality of the abnormalities described below.

Appearance of the face

The affected children can present an incurvation of the mouth upward, an underdevelopment of the chin, an abnormality of eyes downward, a low presence of ears and defects down from the lobes of ears. These facial abnormalities are very variable from a child to the other one and are discreet at numerous affected child's.

Abnormalities of parathyroïdes

The affected children can present an insufficient development of the parathyroïdes (hypoparathyroïdie ) which are two small glands situated in the neck near the thyroid gland (where from their name, " parathyroïdes "). Their function is to control the normal metabolism and the rate of calcium in the blood. The children reached(affected) by Di George's syndrome can present confusions of the preservation of a normal rate of calcium in the blood, what can entail tétanies (convulsions). In certain cases, parathyroïdes is little affected or normal. The hypoparathyroïdie can improve in the time.

Cardiac abnormalities

The affected children can present diverse abnormalities of the heart. These abnormalities imply essentially the aorta and its origin at the exit of the heart. As for the other abnormalities of Di George's syndrome, the cardiac infringements vary from a child to the other one. At certain children, they can be good-hearted or absent.

Abnormalities of the thymus

The babies and the affected children can present abnormalities of the thymus. The thymus is a gland normally situated in the top of the front of the breast. During the first three months of development in the womb, the thymus begins to develop at the top of the neck. By developing, the size of the thymus increases and the organ comes down in the breast up to its definitive place, behind the breastbone and over the heart.

The thymus controls the development and the maturation of a type of lymphocytes, lymphocytes T ("T" for "thymus"). Lymphocytes T are essential for the resistance with certain viral infections and mycosiques. Lymphocytes T also help lymphocytes B to be transformed plasmocytes and to produce immunoglobulins or antibody (refer to the part relative to the immune system). The function of lymphocytes T patients affected by Di George's syndrome can be defective, what entails an increase of the susceptibility in the viral infections, mycosiques and bacterial. As for the other abnormalities of Di George's syndrome, the infringement of lymphocytes T varies from a patient to the other one. Besides, the good-hearted deficiencies can improve in the time.

Other clinical appearances

The patients affected by Di George's syndrome can occasionally present the other abnormalities as the Palatine crack, the dysfunction of the palace, the delay of language acquisition, confusions of the chewing and the gulp. Certain patients also have confusions of the learning and suffer from hyperactivity.

DIAGNOSTIC

The diagnosis of Di George's syndrome is generally put on the basis of the signs and the present symptoms in the birth or appearing a bit further.

Certain children can present the characteristic facial abnormalities of Di George's syndrome or still symptoms connected to the hypocalcémie (weak rate of calcium in the blood), due to the hypoparathyroïdie. The examinations of laboratory can reveal the hypocalcémie. The child can be also "wrinkled" or make crises of tétanie (convulsions).

The affected children can also show signs and symptoms of a cardiac abnormality. The auscultation of the heart during an examination of routine can reveal a cardiac breath, the child can show signs of cardiac insufficiency or be become cyanotic (blue) because of the lack of oxygen in the arterial blood. The affected children can also show symptoms of infection connected to an underdevelopment of the thymus and to a fonctio deficitfunctional of the lymphocytes T. Certain children already present signs or symptoms to the birth or from the first days; to others they appear only after some weeks or several months. We notice big variations of the clinical presentation of Di George's syndrome. At certain children, all the organs and the tissues of the field are affected. These children present the characteristic facial abnormalities, the hypocalcémie connected to the hypoparathyroïdie, the cardiac abnormalities and the quantitative and functional deficit of lymphocytes T. At other children, only certain organs and tissues are affected, in variable degrees from a patient to the other one. The variations thus concern organs and affected tissues but also gravity of the abnormalities of organs and affected tissues.

Formerly, we put the diagnosis of Di George's syndrome on the basis of the presence of at least three characteristic abnormalities. Numerous good-hearted cases were not diagnosed. The genetic base of the syndrome was however identified, some years ago. More than 90 % of the patients to whom was put the diagnosis of Di George's syndrome has a small deletion of a partspecific of the chromosome 22 in position 22q11,2. Several techniques allow to reveal the deletion. We use mostly a hybridization by fluorescence in situ ( FISH). The hybridization in situ allowed to make more precise the diagnosis of Di George's syndrome.

TREATMENT

The treatment of Di George's syndrome aims at correcting the abnormalities of organs or affected tissues. The treatment thus depends on the nature and on the gravity of the abnormality.

The treatment of the hypocalcémie and the hypoparathyroïdie can require a treatment by the calcium and the administration of hormone parathyroïdienne of replacement.

An abnormality of the heart can require the administration of medicines to improve the cardiac function or the surgical correction. The type of surgical operation depends on the nature of the cardiac defect. A surgical operation can be practised before the correction of the immunizing deficit. It is however necessary to observe all the precautions generally taken for the children presenting a deficit in lymphocytes T, as to irradiate all the blood products to prevent a reaction of the transplant against the host.

As mentioned higher, the functional immunizing deficit of lymphocytes T varies from a child to the other one. The therapeutic needs also differ thus from a child in the other one. Numerous children presenting Di George's syndrome have a lymphocytaire function T perfectly normal and do not need a treatment for immunodeficiency. Other children present initially a light functional deficiency of lymphocytes T but which improves with the age. This spontaneous improvement and the increase of the performances of lymphocytes T are associated with the growth of a tiny but functional thymus. In most of the cases of Di George's syndrome, the small thymus enlarges finally and allows a lymphocytaire function T adequate. At other children (approximately 25 %), the thymus is completely absent or never gets fat(grows) enough to develop a sufficient(self-important) number of lymphocytes T. The severity of the deficit depends on the mass of tissue thymique that the child develops. At certain children with Di George's syndrome, the deficit of lymphocytes T is so important as lymphocytes B do not produce enough antibodies. Antibodies are indeed produced by lymphocytes B supervised by a specific subgroup of lymphocytes T (refer in left relative to the immune system).

As we saw it, all the children with Di George's syndrome do not need a treatment of the immunizing deficit. For the children for whom a treatment for immunodeficiency is necessary, certain forms of transplantation of normal immunizing tissue can be useful. The immunizing defect of Di George's syndrome implies the thymus and the lymphocytes T. We thus used transplants of thymus at the children with Di George's syndrome. Really, we began to transplant foetal thymuses successfully for Di George's syndrome from 1968. The rate of global success is difficult to determine because of the use of different techniques and because the state of certain transplanted children would have improved anyway spontaneously without transplant. We recently made successfully bone-marrow transplants with compatible donors stemming from the sibship at patients affected by grave abnormalities of lymphocytes T and B. New techniques of transplant of thymus also improved the long-term results.

PRONOSTIC

The future of a child with Di George's syndrome depends on the level of gravity of the present abnormalities. The gravity of the cardiac infringement is generally the most determining factor. As mentioned higher, most of the children have no immunizing deficit or only a temporary deficit. In case of grave and persevering deficit, a corrective treatment is necessary.