Correspondence:
Dr Shahla Roodpeyma,
Pediatric ward, Taleghani hospital,
Evin, Tehran 1985717413, Iran.
Tel: 0098 - 21 - 22432591
Fax: 0098 - 21 - 22432582
E-mail: roodpeyma_shahla@yahoo.com

Idiopathic dilated cardiomyopathy (DCM) is a disease of the cardiac muscle that is characterized by the presence of ventricular dilatation, systolic and diastolic dysfunction, symptoms of congestive heart failure (CHF), and premature death due to heart failure or arrhythmias⁽¹⁾. As much as 30% of patients have a relative with DCM or LV dilatation which may be an early stage of the disease⁽¹⁾.

There is increasing awareness of the familial nature of DCM⁽²⁾. Familial DCM (FDCM) was defined as the presence of at least one relative with idiopathic DCM⁽¹⁾. The majority of familial and non-familial cases are of unknown cause⁽³⁾. Familial analyses are increasingly showing that DCM has a genetic or inherited basis, but, in the pediatric patients, the incidence and proportion of cases with a familial cause have not been defined and many cases are considered idiopathic. Autosomal dominant inheritances have been most frequently described in the familial forms of DCM, but such kindred affected individuals are rarely identified before the age of 10 years. Autosomal recessive inheritance of DCM has been infrequently described, perhaps because a familial association is more difficult to document⁽⁴⁾. Familial DCM can be categorized by inheritance pattern and clinical phenotype. Nearly two thirds of familial DCM involves autosomal-dominant inheritance. Penetrability is incomplete and age-related. autosomal recessive DCM seems to be less frequent and may be characterized by a significantly younger age of onset and a worse prognosis compared with the dominant form⁽⁵⁾. The age of onset and the clinical course is highly variable in the same family⁽³⁾. Patients with hypertrophic cardiomyopathy are identified in the family study of patients with DCM. This is not strange considering that mutations in the same gene can produce both diseases⁽¹⁾.

The existence of consanguinity suggests the possibility of an autosomal dominant or autosomal recessive inheritance⁽¹⁾. In children of consanguineous marriage it is reasonable to assume that the disease gene is contained in a genetic locus that is homozygous by descent⁽⁴⁾. First-cousin marriage may be a significant risk factor for specific types of congenital heart disease in a consanguineous population. Thus in a population with a high degree of inbreeding, consanguinity may exacerbate underling genetic risk factors, particularly in the offspring of first cousins. There may be a recessive component in the causation of some cardiac defects⁽⁶⁾. An investigation in the United Arab Emirates showed that consanguinity did not result in reproductive wastage, but was found to be an important factor in the causation of specific illnesses in offspring⁽⁷⁾. In a study from Qatar, all cardiomyopathy patients below 50 years of age who were citizens or permanent residents in Qatar were included in the study. DCM was most prevalent (75.8%) in all age groups, and the incidence increased remarkably with age. The consanguinity rate was high among Qatari patients⁽⁸⁾.

The purpose of this study was to review all patients with DCM who presented to the pediatric ward of a university hospital in the previous 10 years. The primary aims of this research were to study the frequency of parental consanguinity in our patients, and to study the prevalence of familial DCM and its effect on outcomes of our cases.

The medical records of patients with discharge diagnosis of cardiomyopathy who were hospitalized in the pediatric ward of Taleghani medical center, Tehran, during 1997 - 2007 were retrospectively reviewed. Cardiomyopathy was defined as a heart muscle disease of unknown cause. Dilated cardiomyopathy was diagnosed on the basis of advanced heart failure, where cardiac dilatation and impaired contractility were recognized in the absence of a known etiology. Secondary cardiomyopathies such as storage disease, Adriamycin toxicity, and transient cardiac dysfunction such as acute myocarditis were excluded. During the study period 52 patients were admitted with a diagnosis of idiopathic cardiomyopathy. There were 4 patients with hypertrophic cardiomyopathy who were excluded. Only 48 patients with DCM were included in the study. The medical histories of the patients were reviewed to determine age, gender, symptoms and signs at presentation. The consanguinity of parents, the history of the same cardiac disease in other family members of patients, or the cause of death in other family members was carefully evaluated. Familial DCM was defined as the history of at least one alive or deceased family member with the same clinical presentation or diagnosis as DCM. Diagnostic tests of patients consisted of chest X-ray examination, 12 leads electrocardiography, and two-dimensional Doppler echocardiography. Cardiac catheterization, endomyocardial biopsy, and autopsy had not been performed on any patients. Heart transplantation was not available to any patient. The control group consisted of 56 healthy, sex and age matched children who came for a regular visit to the outpatient clinic. All the cases in the control group had normal physical examination without any evidence of cardiac disease. The consanguinity of parents and the possible cause of disease or death in other family members were also carefully questioned in the control group.

The data were presented as a mean ± SD. t test analysis and were used to compare the groups. A p value of < 0.05 was considered statistically significant.

There were 23 (47.9%) affected males and 25 (52.1%) affected females. The mean age of patients was 5.7 ± 4.5 years (range 3 months to 15 years). Age distribution of patients was as follows: less than 1 year old - 8 (16.7%) cases, 1-5 years old - 16 (33.3%) cases, 6-10 years old - 11(22.9%) cases, and 11-15 years old - 13(27.1%) cases. The control group consisted of 27 (48.2%) males and 29 (51.8%) females. The mean age of the control group was 5.2 ± 4.3 years (range 2 months to 14.5 years). All the patients at presentation had congestive heart failure and 9 were in cardiogenic shock. Chest X-ray showed cardiomegaly in all patients. The ECG showed low voltage QRS complex (14 patients), left ventricular hypertrophy (12 patients), normal pattern (12 patients), nonspecific ST, T changes (6 patients), and a variety of different cardiac rhythm disturbances were observed in the remainder 4 patients. Echocardiographic examination revealed low ejection fraction (18 to 30 percent) and low shortening fraction (10 to 20 percent) in the majority of patients. Consanguinity between parents was detected in 16 (33.3%) patients. In 12 patients, parents were first degree cousins, and in 4, parents were second degree cousins. All parents were in a good state of health without any evidence of heart disease. Parental consanguineous marriage was noted in 7 of 56 children (12.5%) in the control group. Consanguinity between parents in cases, was significantly higher than that in controls (16 of 48 (33.3%) versus 7 of 56 (12.5%), P = 0.01). DCM had not been reported in any live family member of both patients and control groups. Eight patients had siblings who died of DCM, so the familial occurrence of DCM in our patients was 16.7%. Three patients had one dead sibling, 3 patients had 2 dead siblings, 1 patient had 3 dead siblings, and 1 patient had 4 dead siblings. In total 16 affected siblings of 8 patients with familial DCM died. the control group had no sibling death. Parental consanguinity plus sibling death was noted in 5 patients. Thirteen patients died, 2 cases of familial DCM and 11 cases of non familial DCM. We did not find a significant difference between mortality rate in familial and non familial cases (2 of 8 (25%) versus 11 of 40 (27.5%), P = 0.8). The overall mortality rate was 27%. Table 1 summarizes the results of the relationship between parental consanguinity and familial DCM, death of patients, and death of their siblings. As it is shown in this table, we did not find significant correlation between parental consanguinity and familial DCM (P = 0.05), parental consanguinity and patients' death (P = 0.25), parental consanguinity and siblings' death (P = 0.05).

Consanguineous marriage is a major feature of family systems in Islamic Asian countries. A previous study from Iran reported that in a total sample of 306,343 couples with different ethnic/religious backgrounds the overall rate of consanguineous marriage was 38.6%. First cousin marriages (27.9%) were the most common form of consanguineous union⁽⁹⁾. In the present study parental consanguinity among patients with DCM was significantly higher than that in the control group (33.6% versus 12.5%, P = 0.01). The lower rate of parental consanguinity in the control group may be due to a selection of age and sex matched healthy children. Data showed that the frequency of familial DCM in our patients was 16.7%. In a report from the Sultanate of Oman 770890 (87%) first - degree relatives of 108 families of hospitalized patients with idiopathic DCM were screened. Thirty percent of the patients were born to consanguineous parents. Familial DCM was found in 7 (6.5%) of families, which is lower than the earlier published figures of 20-25%. Patients with idiopathic DCM were younger at presentation and were more often associated with parental consanguinity but the survival rates of familial patients did not differ significantly. Despite the high prevalence of consanguinity, there was a low proportion of familial DCM in the study population (10). In another study from an eastern province of Saudi Arabia 55 consecutive cases of DCM in patients < 10 yr of age were seen during a 5 year interval. Echocardiography was the primary diagnostic modality. The 55 cases represented 20% of the offspring of 41 families. In 19 families (46%) of parents were first cousins. There was no obvious consanguinity in 22 families (54%) (4). In an article by Bilgic et al from Turkey, the clinical and epidemiological characteristics of 137 children with cardiomyopathy were studied. Consanguinity between their parents was more common than the proportion for Turkey as a whole. Most of the patients had DCM (78.9%) and 10.3% died (11). The onset of DCM in relatives occurred at ages ranging from 9 to 75 years, so there does not appear to be a safe age at which screening can be discontinued. Familial DCM has been considered to have a poorer prognosis than non familial DCM. It was also found that the mean age at diagnosis in the familial DCM group was significantly younger than in the non-familial group and its progression was more rapid than in non-familial cases. The possibility cannot be excluded that subsets of familial DCM patients with younger age at onset or patients with x-linked or autosomal recessive inheritance have more severe disease with a worse prognosis⁽⁵⁾. A report by Montserrat et al showed that the prevalence of familial DCM is high in patients who undergo heart transplantation⁽¹⁾. In a report by Michles from USA no significant difference was reported in the 5 year survival, or time to heart transplantation, in an unselected series of 30 patients with familial DCM compared with 71 patients with non-familial DCM⁽³⁾. In research from the Mayo clinic 315 relatives of 59 patients with DCM were screened. Twelve of the 59 index patients (20.3%) or at least one in five of the patients had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with non-familial disease⁽¹²⁾.

Patients with DCM commonly have an affected family member and a high proportion of apparently healthy relatives with minor echocardiographic abnormalities⁽¹³⁾. Counseling of family members should emphasize the heritable nature of the disease, the age-dependent penetrability and the unpredictable clinical course⁽¹⁴⁾. Careful family history with review of medical records identifies more familial cases than merely asking the patients if there is a family history of DCM. However, even such a careful family history does not identify all familial cases. Some familial cases are identified only by echocardiographic investigation of asymptomatic relatives⁽¹⁵⁾.

Based on the careful family history the frequency of familial DCM in our data was 16.7%. We did not find a higher mortality rate in patients with familial DCM. The incidence of familial DCM increased in patients with consanguineous parents more than that in patients with non-consanguineous parents (62.5% versus 27.5%) but the difference was not significant (P = 0.05). The death of multiple offspring was higher in consanguineous parents than that in non-consanguineous couples but the difference was not significant (P = 0.05). Our report is a retrospective study reflecting the clinical experience of a single pediatrics ward with all the inherent deficiencies of such a study. We were not able to interviewparents or apparently unaffected offspring or other relatives including cousins, aunts, or uncles. The follow-up on individuals who recovered or stabilized was insufficient and we do not know if these individuals who were critically ill, recovered but will have similar episodes later in life. We were not able to obtain tissue diagnosis on any of our patients (no endomyocardial biopsy or autopsy). However this study provides an opportunity to learn more about DCM and parental consanguinity that may be difficult to recognize in other patient groups in which consanguineous marriage is uncommon and the number of children per family is small.

In conclusion our results indicated that parental consanguinity is significantly higher in patients with DCM. We did not find significant correlation between parental consanguinity and the familial form of DCM, and the mortality from the familial form was not higher than that of non-familial DCM.

1. Monserrat L, Hermida M, Bouzas B, Mosquera l, Mahan N, Peteiro J, et al. Familial dilated cardiomyopathy in patients transplanted for idiopathic dilated cardiomyopathy. Rev Esp Cardiol 2002; 55(7): 725-732.
   
2. Bilinska ZT, Michalak E, Piatosa B, Grzybowski J, Skwarek M, Deptuch TW, et al. Familial dilated cardiomyopathy: evidence for clinical and immunogenetic heterogeneity. Med Sci Monit 2003: 9(5): 67-74.
   
3. Michels VV, Driscoll DJ, Miller FA, Olson TM, Atkinson EJ, Olswold CL, Schaid DJ. Progression of familial and non-familial dilated cardiomyopathy: long term follow up. Heart 2003; 89(7): 757-761.
   
4. Seliem MA, Mansara KB, Palileo M, Ye X, Zhang Z, Benson DW. Evidence for autosomal recessive inheritance of infantile dilated cardiomyopathy: studies from the eastern province of Saudi Arabia. Pediatr Res 2000; 48(6): 770-5.
   
5. Khositseth A, Michels VV. Familial dilated cardiomyopathy. Cardiovasc Rev Rep 2004; 25(5): 200-202.
   
6. Becker SM, Al Halees Z, Molina C, Paterson RM. Consanguinity and congenital heart disease in Saudi Arabia. Am J Med Genet 2001; 99(1):8-13.
   
7. Abdulrazzaq YM, Bener A, al-Gazali LI, al-Khayat AI, Micallef R, Gaber T. A study of possible deleterious effects of consanguinity. Clin Genet 1997; 51(3): 167-73.
   
8. EL-Menyar AA, Bener A, Numan MT, Morcos S, Taha RY, AL- Suwaidi J. Epidemiology of idiopathic cardiomyopathy in Qatar during 1996-2003. Med Princ Pract 2006; 15(1): 56-61.
   
9. Saadat M, Ansari-Lari M, Farhud DD. Consanguineous marriage in Iran. Ann Hum Biol 2004, 31(2):263-9.
   
10. Venugopalan P, Agarwal AK, de Bono D. Low proportion of familial dilated cardiomyopathy in an Arab population with a high prevalence of consanguineous marriage. Acta Paediatr. 2001; 90(11): 1267-70.
    
11. Bilgic A, Ozbarlas N, Ozkutlu S Ozer S, Ozme S. Cardiomyopathies in children: clinical, epidemiological and prognostic evaluation. Jpn Heart J 1990; 31(6): 789-97.
    
12. Michels VV, Moll PP, Mellor FA. Tajik AJ, Chu JS, Driscoll DJ, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992; 326(2):77-82.
    
13. Keeling PJ, Gang Y, Smith G, Seo H, Bent SE, Murday V, et al. Familial dilated cardiomyopathy in the United Kingdom. Br Heart J 1995; 173(5): 417-21.
    
14. Crispell KA, Wray A, Ni H, Nauman DJ, Hershberger RE. Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol 1999; 34(3): 837-47.
    
15. Goerss JB, Michels VV, Burett J, Driscoll DJ, Miller F, Rodeheffer R, et al. Frequency of familial cardiomyopathy. Eur Heart J 1995; 16 Suppl O: 2-4.