Burden of Congenital and Hereditary Anomalies in Hazara Population of Khyber Pakhtunkhwa, Pakistan

Background and Objectives: In Pakistan, there is high incidence of congenital and hereditary anomalies (CA) which are a leading cause of infant mortality and morbidity. In order to elucidate the burden and biodemographic correlates of CA, this study was aimed to report the prevalence-pattern and phenotypic attributes of CA in the Hazara population of Khyber Pakhtunkhwa, Pakistan. Methods: In a retrospective cross-sectional study, subjects/families with CA were recruited from district hospitals and community centers. Phenotypic and descriptive data were obtained; pedigrees were analyzed and parental and biodemographic attributes were recorded. Results: A total of 1,189 independent subjects and/or families with CA were ascertained. The malformations were grouped into nine major and 95 minor categories. Neurological disorder had the highest representation (n=486; proportion=0.409; 95% CI=0.381-0.437), followed by limb defects (n=292; proportion=0.246, 95% CI=0.221-0.270), musculoskeletal defects, sensorineural/ear defects, blood disorders, eye/visual impairments, ectodermal anomalies, and congenital heart defects. In this cohort, sporadic cases were 65% and familial 35%. Parental consanguinity was significantly higher in isolated cases compared to syndromic, and in familial cases compared to sporadic. Further, speech apraxia and epilepsy were most common associations among the syndromic cases. The assessment of variables like demography, parental consanguinity, familial/sporadic nature, and pedigree structures showed conspicuous heterogeneity among the major and minor categories of CA. Conclusions: The trend of CA and high incidence of sporadic cases observed in this cohort indicate that nongenetic factors may play a significant role in their etiology which could be minimized by improving the healthcare system.


INTRODUCTION
Congenital and hereditary anomalies (CA) are the birth abnormalities of structure, function or metabolism that occur in developmental periods. 1 With the advancement in the control of infectious diseases, improvement of the healthcare system, hygiene and nutrition, CA have emerged as the main source of morbidity and mortality. The global prevalence of CA has been estimated to be 4%-5%. 2,3 The burden of CA is very high in Pakistan due to various reasons including high rate of consanguineous unions, large sibships, low socio-economics and maternal factors. Here, an estimated 6%-9% of perinatal deaths are attributed to CA. [4][5] There are a number of etiological factors underlying CA which could be summarized as genetic, maternal conditions, environmental and unknown factors. 3,[6][7] In Pakistan, the majority of the masses reside in rural areas where the healthcare infrastructure is inadequate. 8 Hence, CA render extra burden on the low-resource healthcare system. Towards this end, a population-based study was carried out in order to elucidate the burden and prevalencepatten of CA in the young and adult Hazara population of Pakistan.
Categorical variables were summarized; Chisquare and Fisher-exact test statistics were applied to check the significance of distribution and P < 0.05 was used as the cutoff for significance. For the CA, proportions and corresponding 95% confidence intervals (CI) were calculated.

Sample characteristics:
A total of 1189 independent index cases were recruited, and the CA classified into nine major categories. Among the index cases, 678 (57%) were males (Table-I). The sporadic occurrence was more prominent compared to the familial nature (n=769 (65%) vs. n=420 (35%); respectively). Among all families, the total number of affected subjects was 2212 (1284 males, 928 females; P=0.0005).
The parental consanguinity in this cohort was estimated to be 66%; it ranged from 60% in limb defects to 81% in congenital heart defects (P=0.07). Consanguinity was significantly higher in the familial cases compared to sporadic (72% vs. 63%, respectively; P=0.004).

DISCUSSION
This is the first study reporting detailed clinical and descriptive epidemiological aspects of CA in the Hazara population of Pakistan. The prevalencepattern of CA is useful implications in guiding resource allocation, management plans and therapeutic interventions.    (12) 55 (11) 138 (11) Punjabi 56 (8) 28 (5) 84 (7) Urdu 39 (6) 34 (7) 73 (6) Others 31 (5) 24 (5) 55 (4)  CA related to the central nervous system (CNS) have been shown to be the most common types in many studies carried out internationally and locally. 2,4,7 In our cohort, neurological disorders were observed to be the most prevalent (41%), followed by limb defects (25%) and musculoskeletal defects (9%). This pattern is also concordant with previous studies conducted in Pakistani populations of Lahore, Peshawar and Kurram Tribal Agency. 4,10,11 In addition to a number of maternal, environmental and non-genetic factors, a likely reason for the high incidence of neurological disorders is that CNS requires an extended period of development and morphogenesis during embryonic development. Among the neurological disorders, intellectual disabilities (ID) were most conspicuous in this cohort. Pakistan has been identified as one of the developing countries with the highest percentage of children with ID. 12 Certain non-genetic factors like advanced maternal age at birth, minimal maternal education, low socioeconomic status, rural origin, less availability of healthcare system, poor antenatal care, maternal malnutrition and infections contribute to the increased rate of ID in developing countries including Pakistan. 1,6 Limb defects were the second largest group of CA in the present cohort (25%). An epidemiological study on CA carried out in Sialkot, Pakistan, reported that limb defects were the most prevalent group (47%). 5 In another study conducted in Kurram Agency of Northwest Pakistan, Zahra et al. reported that limb defects were the third most common types (21%), after neurological disorders (34%) and musculoskeletal defects (23%). 11 Many limb defects are the source of disability, i.e., talipes, transverse limb amputations, leg length discrepancy, constriction band syndrome, thumb hypoplasia/aplasia, fibular hypoplasia, radial hemimelia.

Caste-system
There was a high incidence of sporadic cases compared to the familial (65% vs. 35%). This observation is concordant with a recent epidemiological study carried out in Sialkot, Pakistan. 5 In that study, the authors argued that a high preponderance of sporadic presentations among the limb and neurological disorders and a relatively reduced level of parental consanguinity may suggest a significant involvement of environmental factors in the etiology of these anomalies. Studies have shown that specific nongenetic factors may be involved in the etiology of certain types of CA. Brender and Weyer showed that there was a high risk of limb anomalies among the mothers who were exposed to agricultural compounds in water. 13 The consanguinity rate was calculated to be 66% in our cohort and the highest rate of consanguinity evident in congenital heart defects (81%) and sensorineural/ear defects (77%). These observations are concordant with a study conducted by Zahra et al. who showed that the highest inbred unions were observed in children with congenital heart defects and deaf/mute cases. 11 Furthermore, the familial cases had a significantly higher likelihood of parental consanguinity compared to the sporadic cases (P=0.004), which may suggest the key role of recessive genetic factors. In order to understand the more rational role of consanguinity in various CA types, it would be worthwhile to estimate the background consanguinity in the population (see for instance Rittler et al.). 14

Limitation of the Study:
The current study has also several limitations. For instance, this study does not report the true prevalence or incidence rate of CA, and molecular diagnosis through mutation analyses or chromosomal investigations. Further, various physiological and metabolic disorders may remain unreported.

CONCLUSION
This study presents a comprehensive clinical and descriptive account of CA in the Hazara population of Pakistan. Neurological disorder, limb defects and musculoskeletal defects render the highest burden and comprised 74% of the sample. The pattern of anomalies and the high incidence of sporadic cases may be indicative of nongenetic etiological factors. The burden of these anomalies can be minimized by improving health education, provision of antenatal and perinatal care, premarital counselling, genetic screening and molecular diagnosis of CA, and in general strengthening the healthcare system.