Epidemiological study of congenital limb defects in individuals or families from the interior Sindh region of Pakistan

This study was conducted in seven districts of interior Sindh, Pakistan namely: Tando Allahyar, Umerkot, Sanghar, Mirpur Khas, Khairpur, Hyderabad, and Tando Adam (Fig. 1). Interior Sindh is one of the poorly developed regions of Pakistan with prevailing poverty (about 30% live below poverty level) and low literacy rate. It has an agro-based economy, and the majority of the population resides in rural areas. Interior Sindh is a diverse assemblage of various ethnicities both native and migrated. One of the peculiar features of interior Sindh is the largest minority population of Hindus which are residing here from centuries and are considered to be the old settlers. Major languages are Sindhi, Urdu, Saraiki, Marwari, and Dhatki [6].

Figure 1

After approval by our Institutional Ethical Review Committee (approval No. DAS/10-854), a cross-sectional epidemiological study was conducted from July 2010 to July 2013. Individuals with CLDs were ascertained through door-to-door surveys, and from various public places like schools, community centers and hospitals. Cases were not ascertained from the institutes for the handicapped or special-education. Before recruitment, all the subjects provided documented informed verbal ascent or consent for their voluntary participation in our study, for those participants less than 18 years old or were otherwise incapable of providing consent, their parents or legal guardians provided documented informed verbal consent. Many of those included in the study were illiterate. All the data were obtained according to the ethical principles of the current Declaration of Helsinki. Data from individuals who were not the permanent residents of the study area or the respondents providing incomplete information were excluded. Limb anomalies with clear nongenetic or traumatic nature were not included.

Detailed information regarding sociodemographic variables including origin, ethnicity, language, age, family type, and parental marriage type, was obtained from each participant. Data regarding the clinical variability and associated malformations were also acquired. Photographs of almost all the participants and roentgenographs of the selected individuals were obtained with due respect for their privacy.

Only the index participants (n = 165) were included in the analyses. The limb anomalies were grouped into ten major categories (with further subdivisions): polydactyly, syndactyly, absence deformities, musculoskeletal anomalies, brachydactyly, leg defects, camptodactyly, clubfoot, clinodactyly, and club fingers [1-3,7-10]. Distribution of limb anomalies was established across the sociodemographic variables of study participants. Descriptive summaries were generated and the departure from random distributions was evaluated with a χ² test and Fisher exact test. Proportions of individual malformation types were calculated within the total anomalies. No attempt was made to estimate the prevalence of CLDs in the total population.

CLDs were categorized into 10 major groups (Table 1). Polydactyly was most represented (n = 80; 48.5%), followed by syndactyly (n = 34; 20.6%), absence deformities (n = 13), musculoskeletal defects (n = 11), and brachydactyly (n = 11). The remaining five categories with low representations were leg defects, camptodactyly, clubfoot, clinodactyly, and club finger. The distributions of CLDs with respect to the sex of the index subject and subpopulation are shown in Table 1. The types and distribution of CLDs in the Muslim and Hindu communities were not different (χ² = 5.026; P = 0.83). By contrast, there were more affected males in almost every category (male:female = 4:1).

In the cohort of 165 cases, a total of 315 limbs were affected; the involvement of upper limbs was more common than the lower (172 vs 143, respectively) (Table 2). In the affected upper or lower limbs, there was no significant preference for the involvement of the right or the left limb (Figure 2). However, certain individual CLDs types preferentially affected the upper or the lower limbs (and/or right or left limb). For example, polydactyly affected the upper limbs significantly more commonly than the lower limbs (88 vs 51, respectively; P = 0.03). Absence deformities and camptodactyly also preferentially affected the upper limbs. By contrast, brachydactyly involved the lower limbs more commonly than the upper limbs.

Figure 2

Involvement of only the upper limbs tended to be more frequent than the involvement of only the lower limbs, but the difference was not significant (79 vs 53, respectively; P = 0.14). Involvement of both upper and lower limbs was seen in 33 cases. In majority of the index cases, either one or only two limbs were observed to be affected (n = 67 and 69, respectively) (Table 2 and Figure 2).

To understand the severity of the malformation, CLDs were typed with respect to the affected limb segments (stylopod, zeugopod, autopod, and digits), i.e., the more severe the malformation, the more proximally it ascended the affected limb/segments. Generally, the distal limb segments were more frequently affected than the proximal, and the autopods only were observed to be affected in 176 cases (Figure 3).

Figure 3

In the cohort from Muslim population, there was no specific preference for the involvement of any of the upper or lower limbs; however, in the Hindu subjects, upper limbs tended to be more commonly affected than the lower limbs, but the difference was not significant (82 vs 59, respectively; P < 0.19), (and right limb was the most affected limb) (Table 2). Involvement of only the hands was the most common presentation in both Muslim and Hindu samples. Furthermore, in both communities, either one or two limbs were most often involved in the CLDs. All four limbs were involved in 23 cases, while combinations of any three limbs were seen in only six cases.

CLDs could be further subtyped into 30 entities (Table 3). There were four polydactyly types. Preaxial type I was highest in number (54%), followed by postaxial type A (36%). Among the syndactylies (n = 34), six distinct entities were established, and types Ia and Ic were common (n = 11 each). There were 13 cases of absence deformities, the most prominent of which were constriction rings (n = 4). There were 11 cases of musculoskeletal defects, majority of which (n = 6) had dwarfism, while other types included radial hemimelia (n = 2), and neuromuscular defects (n = 3).

The majority of the CLDs had bilateral presentation (n = 92; 55.8%) (Table 3). Among the five major categories, syndactyly was frequently bilateral (85%), followed by musculoskeletal defects (73%) and brachydactyly (64%). By contrast, absence deformities and polydactyly were generally unilateral (62% and 60%, respectively). Among the bilateral CLDs, 44 (48%) had symmetrical phenotypes. Brachydactyly exhibited symmetrical presentations most often (5/8; 71%), followed by musculoskeletal defects (63%). Polydactyly and syndactyly demonstrated symmetrical phenotypes in 50% and 45% cases, respectively (Table 3).

CLDs had isolated presentations in 85% (n = 140) of cases. There were 25 cases associated with certain type of malformations, majority of which (n = 18) involved the digit defects (data not shown). Furthermore, 31.5% participants with CLDs had a positive family history, while 68.5% cases were sporadic. In the familial cases, most of the anomalies segregated in autosomal dominant fashion (data not shown).

The distributions of CLDs across the key demographic attributes in the gender and subpopulation specific samples were established (Table 4). The differences in the distributions of CLDs among Muslim and Hindu participants were statistically significant with respect to variables including district, age range, occupation, literacy, socioeconomic status, marital status, and family type (P < 0.05).