Burden of congenital and hereditary anomalies in the war-affected territory at Pakistan–Afghanistan border

A total of 361 independent participating individuals or families having certain types of anomalies were recruited. The index males were 74% (n = 267). The majority of the participants belonged to rural areas (n = 304; 84%), lived in extended or joint families (n = 288; 80%), and spoke Pashto (100%) (Table 1).

The anomalies were grouped into 8 major groups (Table 2). With respect to their familial nature, the majority of the anomalies (76%) had sporadic presentations compared to 24% of familial cases. However, among the major groups, ectodermal anomalies and blood disorders were more often familial (P = 0.0001). Further, there was a high preponderance of anomalies with isolated presentations (76%), while 24% of cases were syndromic. However, neurological disorders were an exception where 51% of the cases had syndromic presentations (P = 0.0001).

Parental consanguinity was observed in 34% of the cases. Among the major categories, consanguinity was prominent in ectodermal anomalies, blood disorders, and sensorineural defects (54%, 50%, and 47%, respectively) (Table 2). It is pertinent to mention that among the familial cases, the majority of the pedigrees were suggestive of autosomal recessive inheritance patterns (data not shown). The representation of index males was generally higher in the major categories. Further, in all families, the total number of affected participants was estimated to be 613 (males 403; females 210) (Table 3).

Collectively there were at least 72 minor entities of anomalies (Table 4). Among the major categories, neurological disorders had the highest representation (n = 100; proportion: 0.277; 95% CI: 0.231–0.323), followed by sensorineural defects (n = 70; prop.: 0.194; 95% CI: 0.153–0.235), limb defects (n = 60; prop.: 0.166; 95% CI: 0.128–0.205), eye or visual impairments (n = 55; prop.: 0.152; 95% CI: 0.115–0.189), musculoskeletal defects (n = 37; prop.: 0.102; 95% CI: 0.071–0.134), ectodermal anomalies (n = 13; prop.: 0.036; 95% CI: 0.017–0.055), blood disorders (n = 12; prop.: 0.033; 95% CI: 0.015–0.052), and others (n = 14; prop.: 0.039; 95% CI: 0.019–0.059). A detailed distribution of minor entities and their relative proportions is presented in Table 4.

This study presents the broad spectrum of anomalies in the north-west territories at the Pakistan–Afghanistan border. The majority of the anomalies were of severe nature and a cause of disability in the individuals. In this cohort, the category of neurological disorders, including ID, was the most prevalent. This observation is similar to the one drawn in Hussain et al.'s study [3], wherein it was discovered that in a cohort of 226 neonates monitored at a tertiary care hospital in Kharian, Pakistan, the anomalies related to the central nervous system were most common (20%). In a similar study carried out by Perveen and Tyyab [4] in Karachi, Pakistan, neural tube defects were found to be the commonest (66%). Among the participants with ID in our study, the cases with mild ID types were more frequent, followed by moderate and severe ID types. These findings are similar to Koirala et al.'s study [27], in which also a high prevalence of mild ID was reported, followed by moderate, severe, and profound types. Further, the proportion of sensorineural defects was 19% and it constituted the second most prevalent category. In many of the reported epidemiological studies, neurological disorders and sensorineural defects show high representations, which could be because both these organ systems require an extended period during embryonic development and any perturbance during this period may cause morbidity [28].

Limb defects comprised 17% of our cohort. Curiously, among the limb defects, talipes and limb amputations had the highest representations (22% and 20%, respectively). In the experience of Bhatti et al. [29], who conducted an epidemiological study in the population of the Sialkot district of Pakistan, clubfoot and polydactyly types were the most prevalent types of limb defects. However, in a study carried out in Chitral, Pakistan, talipes and limb amputations comprised only 3% each of the total limb or musculoskeletal anomalies, whereas polydactyly was the most common [30]. In another study conducted in the Sindh region of Pakistan, talipes and limb amputations were 2% and 8%, respectively, of the total limb anomalies [31]. A very high preponderance of such defects in our cohort could be a strong indication of nongenetic etiological factors and complications during pregnancy [32].

In the present study, most of the anomalies had sporadic occurrence (76% compared to 24% familial cases). A marked variation, however, was evident in the sporadic or familial presentation among the major categories. Here, the sporadic occurrence was common in neurological disorders, sensorineural defects, limb defects, eye or visual impairments, and musculoskeletal defects, whereas ectodermal anomalies and blood disorders were familial most often. Concordantly, in the experience of Zahra et al. [14] and Bhatti et al. [29], the sporadic occurrence was common in limb defects, neurological disorders, musculoskeletal defects, and sensorineural defects assembled from Kurram and Sialkot, Pakistan.

In the present sample, the parental consanguinity was 34%, which is very low compared to the baseline consanguinity rate of 57%–62% reported for other Pakistani populations [6, 7, 8, 33]. The differences in the distribution of consanguineous and nonconsanguineous unions among the major categories of anomalies were statistically significant (P < 0.0001). The rate of consanguinity was higher in the ectodermal anomalies, blood disorders, and sensorineural defects (54%, 50%, and 47%, respectively). The potentially low rate of parental consanguinity is similar to the observations recorded in Bhatti et al.'s study [29], in which a parental consanguinity rate of 17% was ascertained in a cohort of anomalies assembled from the population of Sialkot, Pakistan. Concordant to our study, Bhatti et al. [29] also observed that the differences in the distribution of consanguineous and nonconsanguineous unions among the major categories of anomalies were statistically significant. Further, the rate of consanguinity was higher in subjects with neuromuscular anomalies and neurological disorders (30% and 21%, respectively), and significantly higher in familial cases compared to sporadic ones. In our data, the low rate of consanguinity may also indicate the potentially high role of nongenetic factors in the etiology of these anomalies.

The current study has several limitations. First, the true prevalence rate of each anomaly has not been established. Due to various reasons, it was not possible to launch a true cluster or stratified sampling encompassing the whole area. We, therefore, primarily relied on a combination of convenience sampling and cluster random sampling, which was facilitated by the local resource persons. Second, the recruited anomalies were generally typable through physical examination and non-invasive medical investigation. The anomalies requiring invasive diagnostic characterization and detailed biochemical tests may be underrepresented in this sample. Further, prenatal and postnatal mortality, maternal morbidities and pregnancy conditions, and potential risk and etiological factors remain to be elucidated. The findings of this study may not be generalizable to the rest of the Pakistani population.

This study has several strengths. It is the first report of anomalies prevalent in the war-affected territory of the upper FATA region. In Pakistan, in general, there is no systematic monitoring and compilation of anomalies and there is currently no national database of anomalies. The surveillance of anomalies is difficult because of inadequate funding, poor infrastructure, and the lack of trained staff and enumerators. It is almost impossible to evaluate the potential risk factors and to implement effective prevention and management services without detailed epidemiological data. In this context, the present study is a pilot effort to record and document anomalies prevalent in the population. These data would be very valuable for assigning priorities, resource allocation, and establishing management systems for these disorders.

The high incidence of neurological, sensorineural, and limb disorders, the preponderance of cases with sporadic nature, and the relatively low level of parental consanguinity may indicate a likely high contribution of environmental factors in the etiology of these anomalies. Further, the high occurrence of talipes and limb amputations among the limb defects may also clue toward the role of nongenetic factors. Further, it is quite likely that continued warfare might have added environmental pollutants, residues from explosives, and heavy metals to the human food chain [34]. Further studies are warranted to understand the role of nongenetic factors in the etiology of anomalies and there is a dire need for the management of the anomalies.