TWENTY-SEVEN MONTHS OF ANTISTRESS DRUG THERAPY

IN A GIRL WITH PARTIAL TRISOMY 22. (Updated to 97 months of treatment)


Renato Cocchi, neurologist and medical psychologist


Summary.

The case of a girl with partial trisomy 22 [47, XX+[der] ( 22 )t( 11-22 ) (q24q12)] treated by an antistress therapy for 97 months is presented. Symptoms of stress improved were: Mental retardation, anger outbursts without reason, spastic constipation, self-aggression, recurrent awakenings during the night, day drooling, rocking, face paleness, cold hands and feet.
Other symptoms improved: Attention, understanding, the mood, irritability, sociability, self-esteem, the relationship with the object, the play, the feeding, the weigh-height growth, the autonomy. The language had poor modification in speaking but some ones in understanding
The antistress drugs used were glutamine, pyridoxine, a benzodiazepine, carbamazepine, then clonidine for treating self-aggression, and finally amantadine for ADHD, on which it had some improvement.

Key words: Partial trisomy 22, stress, symptoms, antistress therapy, positive results, attention, understanding, the mood, irritability, sociability, self-esteem, the relationship with the object, the play, the feeding, the weigh-height growth, the autonomy, hyperkinesis.

 

Other genetic and chromosomal anomalies.

Mental retardation

Drug modulation of stress reactions

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The t(11; 22) is the most common recurrent non-Robertsonian constitutional translocation in humans, having been reported in more than 160 unrelated families. Balanced carriers are at risk of having offspring with the derivative 22 syndrome owing to 3:1 meiotic non-disjunction event. (Hill et al., 2000)

Translocations of the 11th and 22nd chromosome can develop a disorder known most commonly known as partial trisomy 11;22. It is also named as Trisomy 22, Supernumerary der(22) Syndrome, or unbalanced 11;22 translocation. The children

who suffer from this disorder (which is usually inherited from a carrier parent) have a marker chromosome, made up of the upper (p section) and part of the lower

(q section) arms of chromosome 22, and a small portion of the lower (q section) arm of chromosome 11.

Derivative 22 (der[22]) syndrome is though a rare disorder associated with multiple congenital anomalies. It can occur in offspring of carriers of the constitutional t(11; 22)(q23; q11) translocation.(Funke wt al., 1999)

The t(11;22)(q23;q11) translocation is the only recurrent non-Robertsonian rearrangement for which there are a large number of unrelated families, apparently with the same breakpoints (Shaikh et al., 1999). These families most often have been ascertained through an abnormal child with the karyotype 47,XX or XY, +der(22) t(11;22)(q23;q11). (Armstrong et al., 2000).

This tertiary trisomy can occur resulting in abnormal progeny of t(11-22( carriers with the der(22) as the supernumary chromosome. Affected children have a distinct phenotype with multiple anomalies and severe mental retardation. (Dawson et al., 1996).

Carriers are phenotypically normal and often go undetected until diagnosis as a result of infertility investigations or following the birth of chromosomally unbalanced offspring. Efficient diagnostics of t(11;22) is important for children born to carriers of the translocation and for prenatal and pre-implantation diagnosis (Tapia-Paez et al., 2001).

There are a large variety of abnormalities in t(11;22) cases. Cleft palate, heart defects, mental and physical delays, ear abnormalities, hearing loss), small chins, undescended testes( known as criptorchidism), microcephaly, dislocated hips, long philtrums, broad nose, kidney abnormalities, and Imperforate anus are among the most common findings.

There are tumors associated with t(11; 22)(p13; q12) and descriptively designated desmoplastic small round-cell tumor (DSRCT), as distinctive, rare, poorly understood member of this family. (Gerald et al., 1998)

Biederman et al., 1980, reported a case of tertiary trisomy (22q11q) 47, XX, +der(22), (22pter = to 22q13 :: 11q25 = to 11qter) in a child with mental retardation, cleft palate, and congenital heart disease. resulting from 3:1 meiotic nondisjunction in a maternal (11; 22) translocation carrier.

Kessel and Pfeiffer 1977, report of a case of supernumerary extra chromosome der(11; 22)(q23; q12) resulting from a balanced translocation in the mother. The propositus suffers from mental deficiency, deafness and extreme muscular weakness and exhibits cleft palate, a labial lymphangioma and an atrial septum defect.

There was a case with diaphragmatic hernia and Fryns syndrome phenotype in partial trisomy22. (de Beaufort et al., 2000)

A boy with developmental delay and multiple anomalies consistent with the supernumerary der(22) syndrome was also described. The clinical features, including craniofacial dysmorphism, hypotonia, psychomotor retardation, heart defects, and urogenital anomalies. (Hou, 2003).

The case that follows went consultation by passing the word on, the parents having seen interesting results in a neighbour's girl, with severe mental retardation, already considered unmanageable.

 

The case history.

(January, 2000): A girl with 16 years at the moment of the first visit, suffering from severe psychomotor delay following chromosomal anomaly 47, XX+[der] ( 22 )t( 11-22 ) (q24q12) went to my outpatient'. Weigh-high development was absolutely poor as for her age and like to what of a 7-8-old girl. Her face is very unusual and resembles a cat muzzle, and dorsal kyphosis is also present. She did not have menses. In past she was given open-heart surgery for inter-atrium defect and lack of the ventricular septum. Moreover, she had even three-times surgery for cleft palate. She attends a day centre (An Educational-Rehabilitative Centre)

Motility: She walks about, but she doesn't run, does not climb the staircases, does not ride the tricycle, does not use the cutlery to eat. Her hand to take things is the right one.

Speech: Lallation and some single words.

Feeding: She more appreciates the salty things, and meat broth. In her diet there are fewer raw vegetables but abundant fruit, and in the morning is soon hungry. She chews only a few.

Bowel function: She alternates spastic constipation to diarrhea.

Physical health: Scarce colds, hands and cool feet, pale.

Sleep: agitated with some awakenings.

Other symptoms: Self-aggression, day and night rocking, day bruxism (from stress), psychomotor agitation. Insistent drooling for which she has redness around her mouth and her eyes ( She touches them with her wet hand by the saliva).

Therapy (daily doses, by the oral via): Glutamine 125mg, pyridoxine 75mg, 100mg carbamazepine, oxazepam 7.5 mg, clonidine 50mcg.

 

The first checkup (March 2000) after 45 days of drug therapy: She slightly improved, with less psychomotor agitation, less self-aggression, more attention, the bruxism reduced, the rocking reduced. Now, she is eating a little more either at home and at the Centre, and her assistants found her improved. Perhaps she is less drooling. As for speech, she uses better the words she knows. Her hands and feet are less cold. Her bowel function has fewer episodes of diarrhea. No chewing improvement. Perhaps she sleeps better. Sometimes she has colic ache (or, now, she more clearly shows it).

As for her health, she seems to do better.

Therapeutic variation (daily doses, by the oral via): Oxazepam 15mg, glutamine 180mg, carbamazepine 150mg.

 

The second checkup (October 2000): Now she is more calm, with reduced colic aches, but she cries for the pain when she is defecating. However, her bowel function is improved. Self-aggression much reduced. She became tall. Now, she is eating more either at home and at the Centre. She is more attentive. Even in the Centre she looks as improved. The rocking diminished, and no more nighttime rocking, but sometimes in the morning it appears. She sleeps better and bruxism even reduced. Evidently, she slobbers less: She does it more when the weather is changing, because she feels it and slobbers more. She is using only the words she knows but she softly sings. Her voice is stronger. Now her feet are warm, but her hands are cold because she drives them into her mouth, even if a little less than in past. She listens longer. Her father and her grandmother tell that now is much more amenable (She is doing well and the same for her family). Now, she chews some more, mainly fruits. Sometimes, she smiles.

Therapeutic variation: Carbamazepine 200mg; oxazepam 22.5mg, glutamine 250mg.

 

The third checkup (March 2002): She still improved. Now she is more calm, but not in the afternoon. After lunch she is more irritable and cries for about one hour. At night she is quiet. She is normally eating, understands more, and is grown both in weigh and in height, although always under reference limits. She uses better the words that know, but she did not get any new one. Bruxism still diminished and self-aggression greatly reduced. At the Centre assistants found her well, being more autonomous. Less rocking, less drooling. As for her health, she is doing well. She puts less her hands in her mouth, so she has even less redness of the eyes. Usually, she is more attentive to the surrounding. She chews better, eats more, is more serene and looks for the companionship. She moves better, but she is always awkward when walking.

Therapeutic variation (daily doses, by the oral via): Oxazepam 30mg, clonidine 100mcg.

 

The fourth checkup (April 2003): Since she was doing well, the relatives have preferred to postpone the checkup that happened after 13 months. She always took drug therapy.

She understands more, nearly always simple orders (one-action orders), which she does. She has become a little spiteful, but it seems that she wants to provoke. Now, she needs to have psychological support and to receive gratification. Her motion is better. Now, she learned by herself to open the doors. She doesn't succeed to eat by herself, she brings the cutlery to the mouth, but then she throws it away. She has become a little sly dog and the assistants of the Centre tell the same. Perhaps now she has the more cute face. Finally, she permits to comb her and want to change, if she is dirty. She doesn't want to stay so. When the grandmother dresses her, she anticipates the movements. At night she always sleeps. She eats anything, all the raw vegetables and some liver also, but she prefers pasta and bread, chews better, slobbers only sometimes. She sucks her tongue, but the bruxism fully disappeared. Her smile appears more. She one or two new words.

She recognizes more the persons. Hypertonic movements of the arms and of the hands are present. Now is more quiet even in the afternoon, and she doesn't cry after lunch. Menses appeared, even if very irregular (three times in a year). Her face is more rosy. Self-aggression is very rare. The rocking went down from one hour daily to not more than five minutes. Her health did well. When she has high fever, she sleeps much. In this time she had much less her hands in her mouth and nearly missing the redness of the eyes. In the peers' group she shows her preferences: Usually she stays only with fewer children. She walks much better, more harmonious in her movements, with her back more erect. She plays by herself with the teddy bear. Now, she pays more attention to the television, mainly to music and ballet.

Therapy variation (daily doses, by the oral via): Oxazepam stopped, delorazepam 0.3mg, amantadine 100mg, clonidine 75mcg.

The fifth checkup (April 2005). The father did get her to check only after 24 months, because, together, she is going quite well. According her father and her grandmother, there were some further improvements.

Motility: Now she is less clumsy in walking, and less overactive. She does not succeed to use the staircases by herself. She does swim and horse therapy.

Language: She understands more but she inclines to obey not. Now, she tries to speak, and she says some words. Often parents heard her to sing softly by herself.

Behaviour: She became mischievous: She pays attention if the others look at her, then she does what she was told to do not. Now she can drink by herself, then throws down the glass, which sometimes she has broken. She puts less her hands into her mouth. Rocking much diminished. Self-aggression disappeared. She used still hair pulling and when told off, she has outbursts. She uses to get out of the shoes. She searches always to put the hands under the flowing water.

At the Centre that she attends, she is gladly with the others children who are in wheelchairs. She uses to play with the hands of other persons. Now, she plays more by herself, but she did not learn new plays. As for the television, now she watches it with more attention and she is amused seeing the cartoons.

Mood: Now she is more serene and smiles more. As the weather is changing, she is a little agitated. When she is irritated, and somebody caresses her, she becomes calm. Some time she cries, when she has her nose clogged, and she wants to be cleaned.

Sleep, feeding and sphincterial control: At night she sleeps, with rare awakenings, or little walking in the kitchen. When her grandmother, who sleeps with her, gets up, she does it too. Towards 11am, she falls into a doze. The bruxism is nearly missing. Now she is less thin. Now she likes much eating bread, cheeses, and fruits, but only when she is hungry. She chews better. She has shown herself more willingly for the dental treatments, and now she has less drooling, mainly after having her teeth cured. Colic is scarcely present. Bowel function regulated, but the sphincterial control was not reached.

Other: She had no particular problems of health, only some cold. Some time she has some trembling and some lines of fever. She became a little taller. Her facies is more beautiful, even if always a typical facies from a chromosomal anomaly, but more rosy. She understands the danger, but perhaps only if it involves the sense of the depth.

Therapeutic variation (daily doses, by the oral via): Delorazepam 0.2mg.

 

May 2007, the sixth checkup. She comes back to check only after 25 months, because, altogether, as for her father and her grandmother, she is doing enough well. The impression of the current writer could be  of some regressive symptoms.

 

Motility: Her walking is going well. When there is a little obstacle that she could easily overcome, she stops. She minds the danger.

Language: Now, she uses the fewer words she knows, and she did not get  new acquisitions.  She listens more and shows to understand more.  She sings softly, and when there is loud music, she starts dancing. Hyperactivity nearly missed

 

Behaviour: Rocking did not disappear and she used to pull her hair. With her front, she touches the edges of the pieces of furniture. Some  times she shows light head banging. She uses scratching eyes and ears. Now, she puts less her hands in her mouth, and plays with others' hands, and even preferably with herself hands. The fingers of the feet are scratched in the interstice among the fingers. Now, she is less calm.  She does not bear the stockings, for which she has needs to hold the shoes' laces fasten. Currently she feels the changes in the weather. Her habit of throwing things away did not stop.

 

Mood: Her face is less relaxed. She laughs a lot. When she stays alone, some times she looks for the company.

 

Sleeping, feeding and  sphincteral control: She sleeps 7-8 hours. Her bowel  is more regulated, and now she has less colic ache.  She eats more at home that in the Centre that she attends.  Chewing improved, mainly for fruits and the bread.  Now she eats all the vegetables. She drinks by herself from the glass, but  doesn't know how to properly place it  and would throw it away. The oversalivation reduced, but when she suffers from gingivitis, it returns as first. Her height did not grow, her weight equals 29 kg.

 

Other: She did not have any particular health's problems, and she caught only some cold. A left  under-orbital eczema is visible.

 

No therapeutic variation.

 

 

The eighth checkup, on February 2008. As the father and the grandmother say, she is doing well. The first impression of the writer, is not at once positive, but he has to change it.

 

Motility: Deambulation is well, she walks more harmonious and runs. In front of the television,  when there are musical shows, she usually dances and she respects the rhythm.

She brings well the glass to the mouth, but she doesn't always put back it on the table in

suitable way. Hyperkinesis greatly decreased and she can stay sitting. The steps give her always a feeling of danger, but she faces them with increased safety.

 

Behaviour: More cunning and spiteful. There are always stereotypies of the arm.

Rocking is  a little diminished.  She pulls less her hair. With her front face she touches less the edges of the pieces of furniture. Head banging disappeared. She scratches less her eyes  and her ears, and perhaps little less she scratches

the fingers of her feet, in the interstice among the

fingers.  Now, she put less her hands in her mouth. She would want her shoes removed. 

The changes in the weather trouble her lesser.  She plays with the hands of the others and sometimes intentionally scratches them.

 

Language: Now, she listens of more.  She uses as many words she knows ( four at all, as with the grandmother reports) but she has a turn for speaking  of more, even if she has not done news

verbal acquisitions. The parents say her to understand of more. Sometime, she sings softly.

 

Mood: Now, she is lesser irritable, more serene, and she searches for the company.

 

Sleep, feeding and sphincteral control: Sleeping lasts about 7-8 hours. Drooling nearly  stopped. She eats of more ( as an adult person, the grandmother says). She likes much the crumb of the bread and she  chews the little pieces of the meat. Now, she eats  even apples and

oranges. The mozzarella is her preferred cheese, and she eats it with the fork, but to times she eats it even in great morsels. Her bowel function runs better,

with rare colic aches. Growing in height did not happen, her heavy is 30kg.

 

Other: She has not had particular problems of health, only some cold. The underorbital eczema of the left side is intermittent.

 

Therapeutic variation: Amantadine 50mg daily.

 

 

Discussion.

It is reported that the partial trisomy of the chromosome 22 does not have any therapy. That is true, if we think to a some chromosomal rearrangement. That is not true if we want to act on symptoms of the answer to stress, those symptoms that do the phenotypical difference among two same subjects as for the chromosomal anomaly. Such stress symptoms, to a large extent produced from the illness itself as a metabolic internal stress, are not specific reactions to the homeostasis perturbation. This is not the first case with genetic or chromosomal anomalies I treated by drugs.

Beyond the syndrome of the Down, on which I am involved since the 1979 (see: <www.stress-cocchi.org/Down's syndrome>), I prescribed drug therapies in cases of tuberous sclerosis, Cri-du-chat syndrome, Aicardi-Goutieres syndrome, Smith-Magenis syndrome, Hallervorden-Spatz disease. My pharmacological action is not then on the cause - and it would not be this - but on the individual resistance abilities, which can be, in some degrees, modulated.

This case, besides the exact chromosomal diagnosis, had physical features among the more frequent of this syndrome: a cardiac defect (surgically fixed), cleft palate (surgically fixed), mental retardation, delay of body development, delay of the speech, face abnormalities.

In the case here reported the incentive to try a drug therapy was the presence of many symptoms linked to stress reactions. In other terms, the presence of symptoms that are not specific of a partial trisomy 22. We can find them in other mental illnesses, not necessarily genetic or chromosomic ones.

We list now several of them, with the possible neurochemical mechanism involved in brackets:

- mental retardation (GABA - glutamate?);

- speech retardation (GABA - grutamate?)

- anger outbursts without reason (noradrenalin-adrenalin);

- spastic constipation or diarrhea (peripheral acetylcholine);

- poor greediness for sweet things (glutamate - GABA);

- greediness for meat broth (glutamate - GABA)

- self-aggression (adrenalin)

- recurrent awakenings during the night (GABA - adrenaline);

- day drooling (GABA - peripheral acetylcholine);

- hyperkinesis and attention deficit disorder (dopamine - GABA);

- rocking (GABA-glutamate?),

- face paleness (noradrenalin)

- cold hands and feet (GABA-glutamate?)

These are the symptoms I used for choosing the drug regimen acting on GABA (diazepam, carbamazepine, pyridoxine and glutamine), on adrenalin (clonidine), and on dopamine (amantadine).

It is possible that the new balance between the A type, and the B type GABAergic inhibition, indirectly improves serotoninergic and cholinergic pathways besides increasing the stress threshold. Till now, I did not prescribe specific drugs acting in these two neurotransmitters, even because I did not find symptoms of deficit.

Here instead other symptoms modified in better: Attention, understanding, the mood, irritability, sociability, self-esteem, the relationship with the object, the play, the feeding, the weigh-height growth, the autonomy, hyperkinesis.

Speech had poorly improvement in production, but some in understanding.

Of course, since any antistress therapy needs to be tailored to the current case, because stress answers are different in each person, for genetic and acquired factors, the therapy I used here cannot be a standard one.

Some health professionals - it is already happening mainly about Down subjects I treated - maintained that in similar patients this improvement would have happened anyhow, even without any drug therapy.

This girl had however sixteen years at the moment of the first drug prescription, and progresses were fewer till then.

Already ten months after the starting of the therapy the relatives said that the girl was much more manageable, or, in other words, they did much less labours to follow her.

Having in mind the possibilities and the limits of an antistress drug therapy in persons who are carriers of genetic or chromosomal anomalies, even an easy management of this subject by her relatives is always a notable result too.

References

Armstrong J, Goldman AS, Speed RM, Hulten MA. "Meiotic studies of a human male carrier of the common translocation, t(11;22), suggests postzygotic selection rather than preferential 3:1 MI segregation as the cause of liveborn offspring with an unbalanced translocation." Am J Hum Genet 2000, 67: 601-609.

Biederman BM; Lin CC; Lowry RB; Somerville R. Tertiary trisomy (22q11q),47,+der(22),t(11; 22). Hum Genet 1980, 53: 173-177.

Cocchi R. Tuberous sclerosis, in a child with epilepsy, autism and mental retardation; Report of the rehabilitative and drug therapy intervention In: www.stress-cocchi.org/Genetics2.htm

Cocchi R. First months of drug therapy in a Cri-du-chat case. In: www.stress-cocchi.org/genetics3.htm

Cocchi R. Drug therapy in a girl aged ten with Smith-Magenis syndrome (last updating) In: www.stress-cocchi.org/Genetic4.htm

Cocchi R. Drug therapy in Aicardi-Goutieres syndrome: Report of a 37-months folloup In: www.stress-cocchi.org/Genetics5.htm

Cocchi R. Seven months of palliative therapy in two siblings with neural-axonal dystrophy of Hallervorden-Spatz In: www.stress-cocchi.org/Genetics6.htm

Dawson AJ; Mears AJ; Chudley AE; Bech-Hansen T; McDermid H. Der(22)t(11; 22) resulting from a paternal de novo translocation, adjacent 1 segregation, and maternal heterodisomy of chromosome 22. J Med Genet 1996, 33:952-956.

de Beaufort C; Schneider F; Chafai R; Colette JM; Delneste D; Pierquin G. Diaphragmatic hernia and Fryns syndrome phenotype in partial trisomy22. Genet Couns 2000; 11: 181-182

Funke B; Edelmann L; McCain N; Pandita RK; Ferreira J; Merscher S; ohouri M; Cannizzaro L; Shanske A; Morrow BE . Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22q11. Am J Hum Genet 1999, 64:747-758.

Gerald WL; Ladanyi M; de Alava E; Cuatrecasas M; Kushner BH; La Quaglia MP; Rosai J.Clinical, pathologic, and molecular spectrum of tumors associated with t(11; 22)(p13; q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 1998,16: 3028-3036.

Hill AS; Foot NJ; Chaplin TL; Young BD. The most frequent constitutional translocation in humans, the t(11;22)(q23; q11) is due to a highly specific alu-mediated recombination. Hum Mol Genet 2000, 12: 1525-1532.

Hou JW. Supernumerary chromosome marker Der(22)t(11; 22) resulting from a maternal balanced translocation. Chang Gung Med J China 2003, 26:48-52

Kessel E; Pfeiffer RA, 47,XY,+der(11; 22)(q23; q12) following balanced translocation t(11;22)(q23; q12)mat. Remarks on the problem of trisomy 22. Hum Genet 1977, 37: 111-116.

Shaikh TH; Budarf ML; Celle L; Zackai EH; Emanuel BS. Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11; 22) families. Am J Hum Genet 1999, 65: 1595-1607.

Tapia-Paez I; Kost-Alimova M; Hu P; Roe BA; Blennow E; Fedorova L; Imreh S; Dumanski JP. The position of t(11; 22)(q23; q11) constitutional translocation breakpoint is conserved among its carriers. Hum Genet 2001, 109: 167-177.

 

Posted on Internet on April 2003. Copyright by Renato Cocchi, 2003

For more information on partial trisomy 22 see: www.c22c.org 

 

Author's address: Dr Renato COCCHI via Rabbeno, 3

42100 Reggio Emilia (Italy).

renatococchi@libero.it

 

Italian translation // traduzione italiana

Other genetic and chromosomal anomalies

Mental retardation

Drug modulation of stress reactions

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