CLINICAL INFORMATION

Medical d iagnosis: Chromosome 22 deletion syndrome

Medical History:

A 26 yr old female, diagnosed with congenic cardiopathy (was operated for tetralogy of Fallot) delayed motorial learning and speech, cognitive defect, high myopia, facial dysmorphies (narrow rima palpebrarum pointing upwards and externally, tubular nose with hypoplasia of the nostrils, mouth with protruding upper lip, small auricles), ogival palate, hypoplasia of the depressor anguli oris muscle (DAOM), hands with tapering fingers, kyphosis, overweight. Given this is a striking clinical picture for a chromosome 22q11.2 microdeletion syndrome (DiGeorge/ Velocardiofacial Syndrome), it led to closer diagnostic examination by FISH to study the chromosomal region 22q11.2 which confirmed the medical hypothesis.

FISH for the region 22q11.2 carried out on the patient’s parents did not register any anomaly, leading to the deduction that the 22q11.2 microdeletion displayed by the patient´s derived “de novo” from two healthy parents. The patient has a 50% risk of transmitting the 22q11.2 microdeletion with every conception. During pregnancy this anomaly is detectable in amniocentesis by FISH examination with specific probes of the 22q11.2 region.

During adolescence the patient also suffered from complications of a psychiatric type as a result of which she attended mental health centre where the following diagnosis was given: sychotic paranoid/depressive type with catatonic-like displays.

Neuropsychological evaluation results: mini mental 26/30

Memory: limited span and visual memory, limited vertebral curve as regards growth and quantity. Sporadic intrusions are indicated. Delayed and very modest retrieval abilities, no incidental memory

Executive functions: motorial organization at its limits (errors in shifting are corrected), slowed-down Trail A, and Trail B (many errors are corrected), pathologic use of meta-linguistics, minimum learning of word pairs (intrusions, perseverations)

Speech: reduced spontaneous speech made up of sparse sentences with simplified lexicon and syntax, reading and writing are possible, spatial analysis within the norm

Other clinical signs: archaic reflexes are absent.

In conclusion, this exam led to this diagnosis: in a cognitive background at its limits, we point to the presence of attentive-mnesic-executive deficits, likely referable to constitutional difficulties which are exacerbated at the time of the examination both by the pharmacological load as well as the depressive syndrome itself. An attempt is recommended to try and reconstruct the patient’s confidence by making her feel useful, placing her within a social, work and economic context suited to her limits. By contrast, any attempts at the theoretical level seem more marginal, given the age and the reduced introspective abilities connected to the linguistic difficulties mentioned above (the verbal instrument appears per se limited for the implementation of a sufficient self-analysis); they can nonetheless be employed as a form of support.

A short-term hospitalization is indicated for treating moderate pulmonary insufficiency, tetralogy of Fallot which underwent surgical correction.

Finally, the patient was followed by a local psychiatrist and put in therapy with Depakin-chrono. The following analysis was done:

Neurological check-up: focus no-deficit

Psychiatric check-up: the girl approaches the meeting with ease. Her behavior is adequate. She talks about herself and her life. Basic themes emerge which are connected to her sense of loneliness. Her mother expresses her own tiredness and depressive reactions towards the situation.

Evaluation with the rehabilitation therapist: patient displays behavior which is not always adequate to the context. Hindrance is noted in the tests for general dynamic coordination, good understanding of verbal instructions, left-right discernment is acquired, spatial cognition of the body is adequate.

Neuropsychological evaluation: within the scope of total cognitive results that can be deemed as normal, a cognitive profile characterized by drops in lexical production, morpho-syntactic understanding and visual perception skills and visual-motorial integration. Difficulties in verbal memory. The young woman displays a self-devaluating attitude and a low level of self-esteem. It seems important to gratify the patient and allow her to carry out activities that can improve her self-perception. For this purpose it seems important to grant the patient responsibilities both in and out of the house, and allow her carry out transfers and purchases on her own. It seems necessary to place the patient in a work context that could help her forge an adult identity for herself. Bases on these observations, a psychological intervention for the patient and support for her family are suggested.

The patient presents intolerance to antipsychotic medications of a traditional type (haloperidol), and she took Olanzapine and hypno-inducing drugs.

Medical questions referred to Medical Opinion online consultation service:

1) Is the psychiatric pathology connected to the genetic problem?

2) Do you agree with the indications put forward by the Neuropsychologist for the treatment of the psychiatric pathology?

3) Can any pharmacological therapy be suggested?

4) Are there centres of excellence for the treatment of these pathologies?

5) What is the prognosis?

Medical Report of the Online Consultant Doctor

 

Medical diagnosis: Chromosome 22 micro-deletion syndrome (VCFS)

Thank you for the online referral and medical summary. From enclosed documentation it appears that the Patient, now 26 years old, was born suffering of tetrology of fallout. She was hospitalized for moderate pulmonary insufficiency related to her congenital heart defect. She was treated for paranoid/ depressive psychosis with catatonic-like displays.

The patient suffers from being overweight and on PE high myopia, facial dysmorphies, DAOM, tapering fingers and kyphosis. Neurological examination was normal. Psychiatric exam showed borderline cognitive ability, with attentive-amnesic-executive deficits. Her behavior is adequate. Expresses loneliness. Her condition adversely affects her mother.

Chromosonal study with a 22q11.2- specific FISH probe confirmed the clinical diagnosis of velocardiofacial syndrome (VCFS). The patents had normal FISH studies.

She is treated with Olanzapine and hypno-inducing drugs (Benzidiazepins?). Depakinchrono was also used, but it is unclear if it is still prescribed. Her family was advised to place her in a work environment that would help her forge an adult identity. Psychological intervention for the patient and support for her family were also suggested. Intolerance to Haloperidol was reported.

Comment of the online doctor:

The patient suffers from VCFS due to micro deletion in chromosome 22. The majority of patients have a ~3 Mb deletion. The missing chromosomal segment contains ~20 genes, including the gene COMT, involved in catecholamine metabolism in the brain. It is believed that haplo-insufficiency for the slow allele for the gene COMT is associated with preponderance to psychological illness. Likewise, haplo-insufficiency of the gene PRODH also implicated in the psychiatric phenotype.

Many patients with VCFS have transient hypocalcaemia, sometimes resulting in tetany, and convulsions. This tends to exacerbate the illness. Catatonic episodes were possibly related to transient hypocalcaemia rather than the psychiatric cause. In addition many patients have a decreased number of T lymphocyte with propensity to infections. In such instances treatment should be very aggressive. Live vaccines are contra-indicated. Myopia is not a part of this syndrome.

Recent investigations utilizing functional MRI scans revealed significantly reduced posterior brain volumes related to age and sex, with more significant white matter loss in the left occipital and left parietal regions than in the front lobes, which relate to specific cognitive defects in the areas of working memory, executive function, visiospatial skill, language and math performance.

Behavior and temperament observed in some individuals with 22q11.2 deletion syndrome disinhibition and impulsiveness on one hand and shyness and withdrawal on the other. Attention deficit, anxiety, perseveration, difficulty with social interaction, autism and autistic spectrum disorders are also common.

The incident of psychiatric disorders, including schizophrenia, bipolar disorder, anxiety, and depression is increased.

Auto-immune disorders are commonly associated with this syndrome. These include childhood rheumatoid arthritis (JRA), idiopathic thrombocytopenia purpura (ITP), thyroid dysfunction, vitiligo, hemolytic anemia, autoimmune neutropenia, aplastic anemia, and celiac disease. Most patients do not suffer from major medical problems, other than those directly related to the malformation such as cardiac defect.

As to your questions:

1) The psychological pathology is connected to the genetic problem.

2) I agree with the indications given by the neuropsychologists for treatment of the psychiatric pathology.

3) In some patients Metyrosine (Demser) has been effective in treating psychosis.

4) Suggested centre for treatment of these pathologies is the European VCSF network. (A list with detailed contact information was transmitted to the patient).

5) The overall prognosis depends on the cardiopulmonary status. As to the psychiatric problems: the data concerning adults is rather limited, but in my experience some adults with VCSF overcome their initial difficulties and function adequately in society. Should the patient decide to have children there is a 50% risk of transmitting the disease, and prenatal diagnosis or even PGD are indicated.

I would be happy to see this patient in my practice. If I can be of any further help you may contact me through medical opinion.

MD

Head Genetic Counseling Service