Mental and physical deficiency related to a partial deletion of the short arm of chromosome 5

Jérpome Lejeune


Sommaire

Autosomal abnormalities determining clear cut clinical entities are essentially represented by the three well known trisomic syndromes :

Trisomy 21 (1)

Trisomy (17-18) (2)

Trisomy (13-15) (3)

Numerous other instances are known, including translocations of various type, in which the genetic damage is related to an excess of chromosomal material. only three instances of transolcations (4), (5) and (6) lead to the tentative hypothesis of a partial haplosomy.

In the published litterature one instance of apparent loss of material, without obvious transolcation, has been recorded (7). A malformed boy exhibited an abnormal chromosome 18, apparently lacking of the short arm. Personnal communication seems to confirm this abnormality in a second case (8).

The present discussion of what we suspect to be a new syndrome, is based on six instances of congenital abnormality and mental deficiency related to a partial deletion of the short arm of chromosome 5.

The first patient, studied around a year ago, was referred to us by Dr. Vialatte. This poorly developping girl, severly retarded, had few malformation, but as reported by the paediatrician, she had a very peculiar cry, quite similar to the mew of a cat.

physically, this girl was under developped (Birth weight 1.700 g. heig 41 cm), microcephalic (29,5 cm of cranial perimeter) and had a broken round face. The only malformation noted were, marked hypertelorism, epicanthus, slanting eyes, smal mandibule and low set ears, otherwise normal.

the cry was indeed very peculiar : a rather high pitched prolonged and weak sound was emitted by the girl when disturbed. Its plaintive tonality was strickingly similar to the mew of a suffering cat.

The dermatoglyphs showed an equivalent of the simian crease in the right hand a typical transversal crease in the left.

The axial triradius was in the t' position in both palms.

The skin biopsy showed 46 chromosomes apparently normals, but one of the members of the group 4 to 5 was exhibiting a short arm much too short. All the 40 cells examined showed this caracteristic element (see fig. 1 and 2).

on this first case it was difficult to conclude wether this was an exceptionnal abnormality or a caracteristic one, and if the chromosomal change was the cause related to the clinical symptome. Also, the possibility of a translocation, not detectable if it had occured on a big chromosome could not be ruled out.

To clear those three points, the paediatricians of our team were asked to look for children, with physical and mental retardation, showing hypertelorism, epicanthus, slanting eyes, simian crease and emitting the typical "cri du chat". Although this sound had been tape recorded, those instructions were given verbally, the sound being reproduced in the old fashionned manner of the onomatopae.

Nevertheless the result was quite efficient.

The second case was reckognised and diagnosed clinically by Professor lafourcade. the child, a boy, was brought to the consultation by his mother for retarded growth and, as she said, because "il crie comme un chat".

The physical picture was identical : a broad, round face, a flat bridge of the nose, hypertelorism, epicanthus; slanting eyes, smal mandibule and low set ears. The dermatoglyphs showed again bilateral transverse palamr crease and t' position of the axial triradius. The "cri du chat" was obvious.

the chromosomes of this boy showed the same abnormality, a loss of around one half of the short arm of chromosome 5.

this boy had a twin brother apparently normal who is now well developping at 9 months of age. the twins were reported as dichorionic and blood group tests ruled out an eventual monozygotic heterokaryotic gemellity.

The third patient, a girl, was detected by Dr. Berger the same week and the caracteristic abnormalities were reckognised.

Microcephaly and round face, hypertelorism, epicanthus, slanting eyes, low set ears, small mandibule. A frontal angiome was noted.

Dermatoglyps showed transversal crease and t' triradius in both hands.

The chromosomes were identical. One of the member of group 4 to 5 had very reduced small arm.

Those three case were to be published when discussing with Pr. Book of Uppsala be mentionned of a very similar case now published (9), of a microcephalic girl having after the paediatrician "a high pitched prolonged cry" and exhibiting the same loss of the small arm of chromosome 5.

Those four cases were published together last november in the Comptes Rendus de l'Académie des Sciences (10).

Since this time two further cases have been observed.

On was clinically detected by Dr. Gautier in a retarede girl suffering from a severe congenital heart disease.

The head was typical, with a round face and microcephaly, epicanthus, hypertelorism, relatively low set ears and slanting eyes. the cry also was typical.

The dermatogyphs showed an equivalent of the simian crease in the right hand and a classical one in the left. The axial triradius was in t' in the left hand and obnormally located in the right one.

The deletion of part of the short arm of 4 or 5 was obvious.

This case alone was complicated by severe internal maformation, all the others having clinically, radiologically and electro-cardiophically a normal heart.

There was here an atrio-ventricular canal, orifical pulmonar stenosis, transposition of the vessels, and absence of the spleen, realising a Yvemark's syndrome.

No formal relation can be made between this syndrome and the partial deletion of the 5, a previous case of Yvemark syndrome, without the other features, was found chromosomally normal. (I. P. n° 386).

The cyanogenic cardiopathy of this girl was the causis of a hemiplegia occuring at 9 1/2 month. She died of pulmonary infection 12 months after.

The child had also a renal anomaly, absence of the right kidney, the left one showing an ebauche of "horse shoe" type.

The last child has been diagnosed clinically and chromosomically by Dr. Jean de Grouchy who kindly supplied whole information on this case now to be published in the "Anales de génétique".

Here also the facial features show flat bridge of the nose, hypertelorism, epicanthus, salnting eues, low set ears and small mandibule. Palmprints, as usual, reveal transversal crease and axial triradius is the t' position.

The chromosomal set, otherwise normal, exhibit the same deletion of the short arm of a chromosome 4 - 5.

This girl now aged of 3 years, the older one we know about, is severly retarded: she does not walk, she does not speak at all and understand very little. Astonishingly enough she still has the typical "cri du chat" when crying ; in fact Dr. de Grouchy told me he made the diagnostic on the cry, before having examined clinically the child.

Altogether we have now complete records of four personnal cases and two from other laboratories (Pr. Book and Dr. de Grouchy). The typical cry is present in all of them and has impressed all the pediatricians. Also all the children are severly retared both mentally and physically.

The facial features are not very stricking but are constant in the six cases : hypertelorism, epicanthus and flat bridge of the nose in a very round face. The eyes are slanting downward, in an "anti mongoloid" manner. Microcephaly is constant and low set normal ears ans small chin are always found more or less pronouced.

The mental retardation is extremely severe and although the I.Q. has not been measured it is surely below 0,30. the rest of the body is morphologically normal but the growth is extremely retaded and the maturation of the motricity very much delayed. No obvious neurological abnormality have been yet recorded.

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The chromosomal lesion

The constancy of the chromosomal anomaly, lead to the conclusion that the clinical syndrome is produced by the loss of the genetic material normally present on the distal of the short arm of a chromosome 4 to 5.

As it is well known, formal reckognition of the pair 4 from the pair 5 is a very difficult task. Statistical approach is not very hepfull for many reasons, so that, pure matching of the pair was considered the only reliable technique.

on the five cases observed in Paris the best matching was giving the following answer : in two cases the pair correctly matched is slightly shorter than the normal chromosome left alone. then the deletion would interest the biggest pair i.e. the 4th. On the three other cases the reverse situation is found, the correctly matched pair is bigger than the normal chromosome left alone.

The identity of the clinical syndrome leave little doubt that the chromosomal lesion is the same in all cases. So, as we have previously proposed in the case of 21 trisomy, we sould take advantage of this new disease to label definitely those two pairs.

Thus using deliberatly and purposedly a tautological approach we would say the disease is due to the loss of around one half of the short arm of chromosome 5 and, conversly, we would state, by definition, that we call 5 the chromosome in wich the loss of part of the short arm produce the "cri du chat" syndrome.

An alternative denomination would be to call it "Paris 5" or Pa 5, according to the rule proposed in the Denver agreement.

Although possibly rewarding for the fame of the wity this way of denominating abnormal chromosomes seems to carry very little scientific meaning. Beside this lack information another difficulty could arise here. Dr. Hirshhorn remebered me, ina personnal communication (11), that he had previously observed a very similar chromosome in an abnormal child, although the available data do not permit to decide wether the affected child was suffering of the same disease as the one described here.

Everything considered the first way of naming chromosome, i.e; by their phenotypic expression when rearranged seems the most usefull and practical awaiting further progress in cytogenetics.

More important than this problem of nomenclature is the possibility of decinding the very nature of the lesion. A translocation of the fragment can not be ruled out, on pure morphological ground, because, as previously stated, the translocation on a medium sized chromosome will be quite unnoticeable.

Nevertheless the constancy of the loss as welle as the absence of transolcation on a chromosome in wich it would be reckognisable (i.e. any other one except the medium sized 6-12) are strongly in favour of the recurrence of the same type of accident in all 6 cases and a simple deletion seem the most economic explanation.

if this hypothesis is true this deletion of the short arm of the 5th will be the first established instance known in man of a constitutionnal syndrome related to a pure loss of genetic material. of course the deleted 21 found in the chronic granulocytic leukaemia (12) is fairly welle established but it is demonstrated that the lesion is not inborn but acquired later, during the post embryonic life.

The problem of the origin of this particular deletion of the short arm of the 5 is entirely open. Two general hypothesis could be put forward, but neither of them can for the moment be experimentally tested.

on one hand it could be concieved that a preferential breakage occur at "a weak pojnt" of the short arm or the 5th. This weak point could be represented by the secondary constriction sometime noted on this segment.

on the other hand, it could be supposed that random breakage happens, but that the only deletion compatible with embryonic development are those who interest genes not strickly necessary in double examplar. Here, a purely selective mechanism could realize the same morphological consitancy as the mechanical hypothesis.

This "selective hypothesis" could possibly be related to the fact that the 6 deletion reported here do not seems exactly identical and that the worse case (case n° 5 with congenital heart disease) seems to have the biggest loss and the midler case (case n° 6) now aged 3 years and a half, show the smallest loss.

This kind of reasonning could be very much misleading, beacuse measurements are very insafe in so short elements. Also, clinical variations found in trisomics for whole chromosomes makes very doubtfukk such correlation (13).

The genetic conclusion to be drawn from the present data are for the moment very negative. Familial investigations in case 2 an d6 failed to reveal a familial translocation and, for mapping purpose, the study of blood groups lead only to the negative assessment toci of MN, Rh and jK are not on the deleted segment.

s to the biochemical effect of this loss of genetic material, investigations are now under way but preliminary results on case 1 and case 6 do not show any abvious trouble in the electropheretic pattern of serum globoline, proteins and lipids as wella s in the chromatography of the amino acids in urine.

The only particular trouble found in three cases is a shift to the left of the arneth formula. this effect on the lobulation of the nucleus of the granulocytes, first found in mongolism (14) seems to be rather frequent in chromosomal imbalance, but no explanantion for it is now at hand.

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Summary and conclusion

This review of six cases lead to the individualisation od a new syndrome reckonizable on three point of view :

Morphology - Microcephaly, hypertelorism, epicanthus, slanting eyes, flat nose, relatively low set ears, small chin. The dermatogkyphs show transversal palmar crease and axial triradius in t'.

General statuts - Hypotrophy, retarded growth and severe mental deficiency accompanied by a very special cry, the "cri du chat".

Caryotypic feature - loss of part of the short arm of a chromosome 4 to 5, the remmant segment being approximatively of the siez of the short arm of the 17 or 18.

The consistency of the clinical, dermatoglyphical and chromosomal findings lead to the conclusion that this syndrome is a new nosographic entity. No indication on its frequency can be inferred from actually available data, but an order of magnitude of one to 10.000 or even more seems compatible with the relative rapidity with which additive cases have been detected once they were researched for.

One general implication resulting of this relatively late description of this autosomal syndrom could be that the research based on phenotypic inspection is very much biased. The malformative complex of this syndrome is not so impressive, compared to the expected disturbance provoked by a deletion and possibly, other comparable entities are awaiting description.

Antother consideration comes out from the fact that the only commoin symptom, always found in autosomal imbalnce either by excess or by loss of genetic material is mental deficeincy. this constatation is possibly not as a desepreating one as could be first thought of.

Very likely many of those genetic changes are not directly related to the cerebral machinery but are just interferring with its functionning.

If we take the example of a motor car, builded to reach a given top speed, we will observe that any change to the original design will decrease its performances. No matter if the change concern the air epressure of the tires, the precision of the wheel or even the confort of the position of the driver, any impairment wil; always reduce the top-speed even if it does not interfere directly with the engine itself.

Genreally speaking human intelligence is the top-speed of the living thing. Hence any abnormality of the genetic substratum can reduce it, even if it is not intrinsecly related with the normal brain function. this is welle exemplified by the consequencies of metabolic defects like Phenylketonuria and other.

If this image represent a part of reality it would be a little more interesting than a pure academic metaphore. This state of things will leave the hope of searching for the function impaired by the genetic trouble and of trying to correct it once it will have been pointed out.

Then therapeutic action could become for seeble to restore the equilibrium and liberate the victims of the genetic errors from the barriers who prevent them of reching the top speed of humanity a conscious and responsible intelligence.


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