Genetic Services in Cyprus

Country Background: Demography, Geography and Infrastructure

Cyprus, an island in the eastern Mediterranean, is approximately 150 miles long and just over 100 miles wide. It gained its independence from British rule in 1960. Intercommunal fighting in December 1963 resulted in the establishment of a United Nations peace-keeping force (UNFICYP) in 1964. There are approx. 580,000 Greek Cypriots (G/C, census 1992). There is some controversy about the total population of the Turkish Cypriot (T/C) community of the island. This was approximately 176,000 in 1992, as calculated by the Turkish Cypriot Department of Statistics. According to the Cuco report of the Council of Europe (1992), the (T/C) population is estimated at 106,000 people, the rest being post-1974 Turkish immigrants brought to the island from Anatolia as well as the Turkish army. The total population of the island is estimated to have exceeded 720,000 by the end of 1993. Furthermore, there is a small ethnic minority of Maronites, Armenians and others (less than 2%).

Since independence in 1960, Cyprus has made significant strides in economic development. The GNP has risen from 94.2 million pounds in 1960 to 3,385.3 million in 1993 at current market prices. The unemployment rate is 2.6% (1993). One of the main sources of income of the island is tourism. Cyprus receives a large number of annual visitors, exceeding three times its population.

Health Service Setting

Health services are provided through the public and private sectors. The public sector includes district hospitals which mainly provide a wide range of primary and secondary health services in paediatrics, general medicine and surgery, as well as gynaecology and obstetrics. In addition, there are rural satellite medical centres in various parts of the island. The private clinics offer uni- or multidisciplinary secondary care. There is no national health system but the majority of the population enjoys free care through the public sector, on the basis of a certificate provided by local officials based on income. Tertiary medical services are scarce, perhaps due to the absence of a medical school, and have only developed in recent years. Examples of recent tertiary units include the cardiac surgery and neurosurgery departments of the Nicosia General Hospital, the Cyprus Surgical and Transplantation Centre in Nicosia as well as the bicommunal Cyprus Institute of Neurology and Genetics. The two last centres are non-profit and non-governmental organisations but partly funded by the Government of Cyprus. Expenditure on health amounts to 4.5% of the GNP.

Primary Care

In Cyprus, the primary health care system (PHC) plays an important role in the implementation of genetic programmes, both in public and private systems. The thalassaemia programme relied heavily on PHC services of the Ministry of Health, especially for health education which was an essential prerequisite for the success of the programme. This project was one of the first that put into practice the concept that genetic prevention can be successfully achieved in the general population, using public health principles and services and making practical use of existing primary care services. Medical and nursing staff of PHC centres were used to disseminate information and explain the meaning of the heterozygote state. They were encouraged, and still are, to refer carrier couples to the Thalassaemia Centre for full genetic counselling. Antenatal clinics have played a significant role in the programmes since 1977, when prenatal diagnosis became available. Initially, the aim was to identify the carrier status of individuals of reproductive age. Public and private antenatal clinics ensured that all women at first attendance were tested for thalassaemia carrier state and, if positive, their husbands were also tested. Positive couples were then referred to the Centre. Subsequently, an efficient nationwide prenatal and school screening programme for thalassaemia was established allowing for premarital carrier diagnosis.

The school health services (SHS), another wing of the primary care system, also played a significant role both in education and in the school screening programme. Currently, these SHS have adopted programmes on a pilot study basis for early intervention in the prevention of heart disease, and have joined the European Network of Health Promoting Schools. In this effort, screening for hypercholesterolaemia and thalassaemia is being carried out. It is planned to include basic genetics in the new programmes as an extension to the existing ones.

Prevention of genetic disease is a recognised goal of the Alma Ata Declaration on Health for All by the Year 2000. In this direction, the Cyprus model has demonstrated convincingly the significance of PHC services in the prevention of thalassaemia, mental retardation and neonatal screening.

Cyprus has a long history of public health programmes. The success of these, and the thalassaemia programmes, demonstrated that the population was open to health education programmes, and would respond to any major drive which would improve their health. This background influenced the decision to embark on general genetic services with a largely preventive character.

The majority of Cypriots benefit from free medical care through the government medical services of the Ministry of Health. The government of Cyprus also supports the genetic services of the Cyprus Institute of Neurology and Genetics and the Centre for the Prevention of Mental Retardation.

History of Medical Genetics

In terms of genetic services, the Thalassaemia Control Programme started in 1972 and the Cyprus Thalassaemia Centre was established in 1982, dedicated to the prevention of the disease in the Cyprus population, the thalassaemia genes having a high prevalence on the island. The Centre was also designed to offer medical care for thalassaemia sufferers. The Control Programme included health education, population screening and prenatal diagnosis. Further genetic services were initiated in the 1980s at the Makarios Hospital in Nicosia, with the creation of initial foci in the cytogenetics, molecular and biochemical genetics laboratories. In addition, a centre for prevention of mental retardation was established in Limassol by ‘Theotokos’, a Limassol charity operating a home for the mentally retarded. This centre originated and further developed a nationwide neonatal screening programme for mental retardation and maternal serum triple test screening for Down syndrome.

In 1990, the Cyprus Institute of Neurology and Genetics was established on a bicommunal basis, with financial assistance from the Government of the United States of America through the Cyprus office of the United Nations High Commissioner for Refugees. The main aims of this bicommunal medical centre are to provide specialised medical care and state-of-the-art preventive programmes in collaboration with other local institutions and to promote research and postgraduate education on the island and in the eastern Mediterranean region.

Dimension 1: Availability

Distribution

The geographical distribution of the services in Cyprus is not a major factor in their availability or population access because of the small size of the country. Efficient mechanisms for sample collection and distribution have been developed in various parts of the island. For thalassaemia, counselling is available in all cities. However, free movement across the ‘green line’ for T/C patients and their families is restricted by the T/C authorities. Genetic services are mostly located in the capital city of Nicosia which offers easy access at a relatively short distance from the remaining primary and secondary health care centres.

Personnel (table 1)

Table 1. Medical genetics staff engaged in providing genetic services

Physicians of various disciplines (mainly paediatrics) are directly involved in the clinical management of patients and preventive programmes in genetic diseases. There is one US-qualified genetic counsellor working with clinicians at the Cyprus Institute of Neurology and Genetics, as well as the Thalassaemia Centre and the prenatal diagnosis unit of the Obstetrics Department of the Makarius Hospital, contributing to a unified approach in genetic counselling.

Obstetricians have fully adopted prenatal diagnosis and, more recently, ultrasound as a tool in antenatal care. They routinely take the history of inherited diseases and ensure that there is no family history of thalassaemia or other disorders; they implement the ‘triple test’ programme and perform routine ultrasound on all pregnancies. All at-risk cases are subsequently referred to the prenatal diagnosis unit of the Makarios Hospital, which provides specialised ultrasound for the detection of abnormalities in utero as well as chorionic villus (CVS), amniotic fluid and fetal blood sampling.

Paediatricians are also sensitised to hereditary and congenital abnormalities and refer, mostly, to the clinical services of the Makarios Hospital for diagnosis and counselling. This attitude must be attributed to the success of the thalassaemia programme which proved the necessity and feasibility of genetic control services.

Despite the prominence of prenatal diagnosis in thalassaemia prevention and its wide acceptance in the population, termination of pregnancy for genetic disorders is not fully authorised by law; nevertheless, practically all affected fetuses are aborted. Legally, abortion is permitted if the life and health of the mother are threatened.

In recent years, efforts have been made to increase psychosocial support for affected families and patients facing screening and prenatal diagnosis. This aspect of services has been the slowest to develop, health authorities being in general hesitant in its funding.

Genetic Counselling Clinics

Thalassaemia Centres. Counselling clinics are available daily at each of the centres for carriers of thalassaemia and of sickle cell disease. Carrier couples of α-thalas-saemia or other combinations which may give rise to significant syndromes are counselled by appointment with one of the doctors of the centres as they are detected. If they have opted for prenatal diagnosis, they have a second counselling session (and a samples taken for mutations and haplotypes) at the Centre in Nicosia. One hundred couples, mostly premarital, are detected each year; 200 tests of prenatal diagnosis for thalassaemia are carried out.

The Makarios III Hospital, Nicosia (Essentially a Mother and Child Hospital). Three general genetic clinics are held per week by a clinical geneticist usually with a genetic counsellor. The counsellor will also see patients on her own. The annual number of visits to this clinic is 1,200. The team sees an average of four out-patients daily and another three to four in-patients. This amounts to about 100 cases per month including the follow-up.

Obstetric (Prenatal Diagnosis) Unit. There are two sessions per week for prenatal diagnosis and fetal ultrasound. Mothers at risk for chromosomal and other disorders are counselled, usually with the help of the genetic counsellor. In 1994 there were 470 prenatals for chromosomal analysis. Apart from these and for thalassaemia, prenatal tests were carried out for other conditions.

The Cyprus Institute of Neurology and Genetics. There are two weekly neurogenetics clinics and one in general genetics. The former mainly targets various forms of muscular dystrophy present on the island and in other eastern Mediterranean countries. These include e.g. Duchenne (DMD) and Duchenne-like muscular dystrophies, inherited polyneuropathies, ataxia syndromes and Huntington disease. In other genetic disorders, patients are seen by a paediatrician trained in clinical genetics together with the genetic counsellor for diseases such as autosomal dominant polycystic kidney disease, Sandhoff disease and inborn errors of metabolism.

Molecular Genetic Laboratories

The Department of Molecular Genetics of the Cyprus Institute of Neurology and Genetics is the only provider of molecular genetic services on the island. There are four units, all having a service/research component as follows.

Molecular Genetic Unit A. Carries out prenatal and postnatal molecular genetic diagnostic tests for thalassaemias, as well as research in these diseases, mainly in gene therapy; 220 prenatal CVS for thalassaemia are done yearly, as well as 400 postnatal diagnoses for α- and β-thalassaemia. Pre- and postnatal diagnoses for dystrophinopathies and other rare genetic disorders, such as Sandhoff disease, which is relatively prevalent among Maronites on the island, are also performed.

Molecular Genetic Unit B. This is the national referral centre for forensic DNA diagnosis. In 1996, this unit was requested to address the issue of the identification of over 1,700 missing people from the 1974 war. From the research point of view, genetic factors in cardiovascular diseases and hypertension are studied.

Molecular Genetic Unit C. This is mainly involved in research in autosomal dominant polycystic kidney disease and other hereditary nephropathies as well as cystic fibrosis.

Molecular Genetic Unit D. This is involved in neuromuscular and other neurogenetic disorders in Cyprus and other countries of the region. Such diseases include inherited polyneuropathies (Charcot-Marie-Tooth disease, familial amyloidotic polyneuropathy), familial infantile myasthenia, autosomal recessive forms of muscular dystrophy, autosomal dominant spinal muscular atrophy, autosomal recessive ataxias (Friedreich and other forms of cerebellar ataxias), neurofibromatosis and Huntington disease.

Cytogenetic Laboratories

There are two laboratories in Cyprus, one located within the Thalassaemia Centre at the Makarios Hospital and the other at the Cyprus Institute of Neurology and Genetics.

Makarios Hospital (Thalassaemia Centre). This unit serves the various departments of the Makarios Hospital, such as the Prenatal Diagnosis Unit, and the Paediatric and Haematology Departments of the hospital. In 1994 its output was 470 prenatal (CVS, amniotic fluid and fetal blood) cases, 215 diagnostic cases and 52 leukaemia cases.

The Cyprus Institute of Neurology and Genetics. The Cytogenetics Department of the Institute covers the rest of the needs of the island, including 750 prenatal tests in 1995 and 280 postnatal tests for chromosomal abnormalities. In addition to Down syndrome and leukaemia, this unit is actively involved in other chromosomal syndromes. In 1996, 80 diagnostic FISH examinations were performed for the detection of chromosomal abnormalities in various types of diseases and cancer as well as syndromes like PRW/AG, DiGeorge, Miller Dicker, Kaliman, Smith Magenis, Elastin Williams. In fragile X syndrome, 2 prenatal and 200 postnatal DNA tests were performed in 1995.

Biochemical Genetics

The main laboratory of biochemical genetics operates at the Cyprus Institute of Neurology and Genetics, in conjunction with the Thalassaemia Centre. The laboratory is involved in the diagnosis of inherited metabolic diseases and neuromuscular diseases. Approximately 300 patients per annum are investigated for the former. The laboratory performed studies of Sandhoff disease in the Maronite community in 1995; 350 amino acid analyses were performed and 150 metabolic urine screenings. In neuromuscular disorders, there were 30 studies for mitochondrial screening, 20 glycolytic enzymes and 15 dystrophin tests.

Genetic Screening

This is the main function of the Centre for the Prevention of Mental Retardation in Limassol. Samples are collected from all neonates (10),500–12,000/year) and tested for PKU and hypothyroidism. A third sample is sent to the Cyprus Institute of Neurology and Genetics (biochemical genetics) for DMD screening for newborn boys (5),000–5,500/year). This centre also performs the ‘triple test’, on a national basis, for the prevention of Down syndrome and neural tube defects.

Co-Ordination and Integration of Primary, Secondary and Tertiary Provision

Co-ordination between the three genetic centres is based on free communication between departments and hospitals and regular meetings and joint clinics of physicians and other scientists. Furthermore, physicians at primary and secondary care levels both of the public and private sectors have been sensitised to using genetic services through educational programmes, initially established for thalassaemia. Both the neonatal screening programme and other genetic services presently cover over 95% of the population.

Long-Term Care Facilities

There are several long-term care facilities, mainly including the following. Thalassaemia Centres, where individuals suffering from α- or β-thalassaemia and sickle cell disease are treated and followed up on a day care basis. Improved survival by optimum care provision has resulted in a young adult population of thalassaemias with very few in the paediatric age group because of selective abortion. The Department of Neurosciences of the Cyprus Institute of Neurology and Genetics provides outpatient and in-patient care for a wide range of neurogenetic disorders, including muscular dystrophy and other genetic and chromosomal disorders. A number of day care centres for various forms of mental retardation operate in the cities and major towns of Cyprus.

Dimension 2: Access

The literacy rate of the G/C population is high: 98% for males and 90% for females (1993). This, we feel, has a direct effect on the response to genetic programmes; 19% of males and 16% of females are college or university graduates (1992).

Genetic services are available to all Cypriots irrespective of ethnic group, religion or language. However, the political situation on an island divided by a ‘green line’ following the 1974 war significantly limits access to the genetic services by T/C patients and families. Access to genetic services for the T/C community is subject to authorisation by their authorities to cross the ‘green line’. There is a T/C Thalassaemia Centre operating a similar control programme to the G/C one.

The thalassaemia programme is funded by the Government of the Republic of Cyprus and this includes screening and prenatal diagnosis which are offered free. It provides an outstanding example of an important facet of access to genetic prevention as the cost of maintaining an affected child falls, at least in part, on the family.

Dimension 3: Life Sustaining

Infant mortality was 25/1,000 in 1970 and dropped to 9/1,000 in 1993. These figures suggest a pattern of improvement of paediatric health care and a good standard of living in Cypriot society. Life expectancy in 1992–1993 was 74.6 years for males and 79.1 years for females.

In the G/C community, the total number of live births per year is about 10,500 and the number of deaths 5,000 (death rate 7.7/1,000 in 1993). The crude birth rate was 16.8/1,000 (1993) and infant mortality rate 9/1,000 (1993). There were 5,999 marriages in 1993 of which 4,401 were ecclesiastical and 1,593 civil. About 5% of marriages are between a Cypriot and a non-Cypriot.

Dimension 4: State of the Art

There have been significant efforts in this direction in recent years, following the creation of the Cyprus Institute of Neurology and Genetics, with financial assistance from the United States. A number of well-trained physicians and scientists were repatriated and state-of-the-art equipment was installed in a purpose-built modern building. Equipment and training of personnel of the Thalassaemia Centre are continually being upgraded.

Several training programmes are organised both locally and abroad by the services of the Ministry of Health and the Cyprus Institute of Neurology and Genetics. These include weekly grand-round seminars at the Cyprus Institute of Neurology and Genetics, short training courses with invited lecturers from Europe and the USA and regular meetings of the Paediatric Society of Cyprus.

State-of-the-art equipment is available in all three genetic centres: HPLC, IEF, and other techniques for thalassaemia; automatic karyotyping stations in cytogenetics; nephelometry, flow cytometry for immunogenetics; PCR, automated DNA sequencers, DGGE and other equipment in molecular biology.

In recent years, state-of-the-art laboratories have been established on the island. These include the laboratories of molecular biology, cytogenetics and genetic biochemistry, actively involved in preventive programmes of inherited diseases (e.g. various forms of muscular dystrophies and other neurogenetic disorders, autosomal dominant polycystic kidney disease) as well as in diseases with genetic susceptibility (e.g. cardiovascular-cerebrovascular diseases and cancer). A national neonatal screening programme for PKU, hypothyroidism and DMD covers practically the whole of the G/C community and screening programmes for Down syndrome are now readily available during pregnancy.

Scientists involved in laboratory activities include the following. (1) Thalassaemia Centre: this has six laboratories each headed by scientists with a postgraduate degree. All technicians have a BSc degree; (2) The Cyprus Institute of Neurology and Genetics includes eight laboratory genetic units, each headed by a PhD scientist. There are 6 postdoctorate assistants and fellows, 11 MSc seientists and 18 technicians with BSc degrees. The majority of scientists are graduates of British, American and French universities; (3) The Centre for the Prevention of Mental Retardation has 2 MSc scientists.

Dimension 5: Non-Harmful

All three genetic centres provide, in all their programmes, extensive information on possible risks both of screening and prenatal diagnosis. The information is both written and oral.

The Cyprus Institute of Neurology and Genetics has strict quality control procedures, both intramural and extramural. Intramural procedures include regular clinical and laboratory meetings on methods, procedures and results. Performance evaluation appraisals for clinical and laboratory staff are carried out yearly. Performance evaluation of group leaders and clinical and laboratory groups is performed every 2 years by site review by a panel of international experts in neurosciences and genetics. The Scientific Council and the Board of Directors of the Institute are responsible for maintenance of standards. Quality control of medical services is not implemented in Cyprus. The Cyprus Institute of Neurology and Genetics is the only institution having mechanisms of quality control, through a yearly medical/scientific audit performed by an international panel of experts.

Dimension 6: Effectiveness

The favourable economic conditions, high level of education and the satisfactory health statistics are all factors which favour the development of genetic services and contribute to the success of genetic prevention programmes. In addition, the small size of the country facilitates delivery of health services and health information. This is a further factor favouring the success of such programmes in Cyprus.

The national programmes such as thalassaemia control, DMD control, Downs syndrome prevention and neonatal screening are subject to a monitoring and evaluation process. The main criteria used are: (1) the number of new affected births compared to the expected births, (2) the number of people screened and subjected to prenatal diagnosis, (3) the cost-effectiveness of prevention (compared to treatment) and (4) the survival and well-being of patients.

In thalassaemia, 98% prevention (compared to expected births) has been achieved since 1985. Premarital screening corresponds to approximately the same number of people as the annual births of the island. Prenatal diagnosis is around 200 cases annually. This represents full coverage of needs, since approximately 60–70 new affected cases are expected annually.

The survival of thalassaemic patients in Cyprus is similar to other European centres (e.g. London and Turin), where an 80% survival by the age of 40 years has been reported. The complication rate, e.g. for chronic active hepatitis, is lower in Cyprus than any other centre except London. The cardiac complication rate is still being studied but remains the major cause of death in thalassaemia major.

Dimension 7: Consumer Satisfaction

The Cypriot population has always responded positively to various genetic programmes, as demonstrated by the success of the programmes and their utilisation by the public, as well as the support given by the public to fundraising activities for the CING, the Thalassaemia Association and the mental retardation programmes.

With respect to prenatal diagnosis, there are still reservations by the church, but uptake by the public has been excellent. Freedom of choice is the firm policy on this matter. Policy makers have given full support to these programmes.