Prevalence-pattern of congenital and hereditary anomalies in Balochistan Province of Pakistan

Objectives: This study was aimed to report the prevalence-pattern of hereditary and congenital anomalies (CA) in general population of Balochistan province of Pakistan, and to elucidate the familial/sporadic presentations and parental consanguinity of CA. Methods: In a multi-center cross-sectional study, patients with CA were ascertained from various district hospitals and public places throughout Balochistan from 2019 to 2023. Online Mendelian Inheritance in Man (OMIM) and International Classification of Diseases (ICD-10) databases were utilized for uniformity in classification. Descriptive statistics was employed. Results: A cohort of 1185 independent patients diagnosed with CA was recruited and the index males were 71%. The CA were classified into nine major and 118 minor entities. In the major categories, neurological disorders had the highest prevalence (n=317; 27%), followed by limb defects (n=161; 14%), blood-heart defects (n=159; 13%), neuromuscular anomalies (n=156; 13%), sensorineural/ear defects (n=140; 12%), eye/visual impairments (n=90; 8%), musculoskeletal defects (n=83; 7%), ectodermal defects (n=31; 3%), and others (48; 4%). Sixty one percent CA were sporadic in nature and 39% were familial; and parental consanguinity was observed in 51% cases. Several rare CA were witnessed. Conclusions: High preponderance of sporadic presentations in neuromuscular anomalies and musculoskeletal defects and low incidence of parental consanguinity in ectodermal defects and musculoskeletal defects may depict a significant etiological role of non-genetic/environmental factors such as prenatal exposures and maternal conditions. In this context, it is important to increase health education, enhance antenatal and perinatal care, and strengthen the health-care system in Balochistan to reduce the burden of CA


INTRODUCTION
The hereditary and congenital anomalies (CA) are frequently observed in Pakistani communities.The incredibly low.For instance, Balochistan had a neonatal mortality rate of 63 per 1000 live births, significantly higher than the national average of 42 per 1000. 10A recent study revealed that 46% of pregnant women in Balochistan had anemia. 11Compared to 23 out of 100 pregnant women in Punjab, Sindh, and Khyber Pakhtunkhwa, just 5 out of 100 women in Baluchistan used iron supplements for three months. 12Further, Balochistan had a skilled birth attendance rate of 38% compared to 75% in Sindh, 71% in Punjab, and 67% in Khyber Pakhtunkhwa. 13nly 18% of births in Balochistan occur in medical facilities, which makes it difficult to manage pregnancy risks.The prevalence of prenatal care in Pakistan is 86%, with Punjab leading the way with 92% coverage and Balochistan with 56%. 13 Hence, Balochistan population is anticipated to carry heavy burden of CA which may have genetic, maternal, and environmental etiologies.The current clinico-epidemiological investigation is a preliminary step towards bridging this knowledge gap.

METHOD
A multi-center study was conducted in Balochistan, Pakistan from 2019-2023 and patients/families with CA were recruited from Civil Hospital Quetta and District Headquarter Hospitals in Pishin, Zhob, Loralai and Ziarat.In order to have representation of all sociodemographic strata and age segments, patients were also recruited from general populations through mixed method sampling including door-to-door visits, whereas snowball sampling was employed in the rural areas.Detailed pedigrees were constructed for each individual but only the index person from a particular family was included in the analyses.Descriptive summaries were generated, and Chi-square and Fisher-exact tests were employed to check the significance of distribution.For the CA, proportions and corresponding 95% confidence intervals (CI) were calculated.

Sample characteristics:
A total of 1185 index cases, 839 (71%) males and 346 (29%) females, were included in the study (Table-I).There was representation of individuals from all districts of Balochistan and the individuals belonging to Loralai and Quetta districts were 40% and 20%, respectively.Majority of the individuals originated from rural areas (57%), spoke Pashto (78%), and belonged to poor and low socioeconomic quartiles (56%).The individuals between >9-19 years of age had the highest representation (39%).
Among the neuromuscular disorders, cerebral palsy (CP) was most prominent (n=127), followed by  muscle hypotonia (n=19).In cerebral palsy, spastic and athetoid types were most common comprising 55% and 30% cases, respectively.CP was the second most prevalent entity after ID.Among the CP types, spastic cases were n=70, athetoid n=38 and ataxic n=10.

Familial-sporadic nature:
The anomalies with sporadic appearance were more common compared to the familial (61% vs. 39%, respectively; Table-IV), and the differences among the major anomalies were statistically significant.
There was highest representation of sporadic cases in neuromuscular anomalies, followed by musculoskeletal defects, limb defects and neurological disorders (75%, 71%, 66% and 64%, respectively).On the other hand, familial occurrence was more frequent in ectodermal defects and eye/visual defects (74% and 59%, respectively).Among all families, there were a total of 2273 affected individuals, comprising 1531 (67%) males and 742 (33%) females (P=0.0005).The highest proportion of affected females was witnessed in musculoskeletal defects and ectodermal defects (42% and 39%, respectively).Parental consanguinity: Parental consanguinity was present in 51% of cases and the differences among the major categories were statistically not significant (Table-IV).Highest rate of parental consanguinity was observed in ectodermal defects (74%) followed by musculoskeletal defects (61%), whereas limb defects had the lowest consanguinity rate (42%).Geographic and ethnic differences in CA: The differences in the distribution of major categories of CA among the districts were statistically significant (p<0.0001)(Table-V).Detailed analyses showed that neurological disorders were more prevalent in individuals from Quetta (39%), blood-heart disorders and neuromuscular defects in Lo-rali (21% and 19%, respectively), sensorineural defects in Ziarat (20%), eye/visual impairments in Zhob (14%), and musculoskeletal defects were more common in individuals coming from Pishin (15%).Further, with respect to mother tongue, the differences in the distribution of major categories of CA were statistically significant (p<0.0001)(Table-V).These analyses revealed that neurological disorders were more prevalent in individuals speaking Brohvi, limb defects in Balochi speaking, blood-heart disorders in Pashto speaking, neuromuscular defects in Brohvi speaking, and eye/visual impairments were more prevalent in Balochi speaking individuals.

DISCUSSION
This study presents detailed prevalence-pattern and clinical aspects of CA recruited from Balochistan province of Pakistan.This is the first study of such kind which involves a large sample size ascertained through a multi-center study.][17] Previously, Mian and Mushtaq showed that the rate of consanguinity in population of Quetta was 31%. 18In a recent study in Quetta, Ijaz et al, enrolled 105 couples with consanguineous marriages and observed that child mortality and CA were high among the couples with first cousin marriages. 3The authors showed that the common CA included mental retardation (24%), diabetes (10%), deafness (7%), and thalassemia (6.8%).
Neurological disorders had the highest representation in this study.This is similar to other studies carried out in Khyber Pakhtunkhwa, Pakistan. 1,19,20Pakistan bares a substantial burden of ID as compared to other developing countries.Several factors contribute to the high prevalence of ID in developing nations, which include maternal age, education, socioeconomic status, rural upbringing, suboptimal antenatal care, malnutrition, and infections. 21,22n the present cohort, cerebral palsy (CP) was the most common anomaly in neuromuscular disorders (n=127).
CP is a common developmental disorder prevalent in families with socioeconomically deprived strata.In Pakistan, CP is one of the common causes of disability and morbidity.Among the common risk factors of CP are maternal malnutrition, premature birth, poor antenatal care, birth asphyxia and infections of nervous system are the major causes of CP. 23 In the rural areas of Pakistan in general and in Balochistan in particular, there is high ratio

A h e a d o f F i n a l P u b l i c a t i o n
Congenital anomalies in Balochistan Pak J Med Sci October 2024 Vol.40 No. 9 www.pjms.org.pk 9 of maternal malnutrition and anemia, and majority of the deliveries take place at home.Hence, an overwhelmingly high ratio of sporadic cases was observed with CP indicating low contribution of genetic factors.In these data, spastic CP and athetoid CP were most common comprising 55% and 30% of the CP cases, respectively.Nonetheless, among spastic CP, quadriplegia is more prevalent followed by diplegia and hemiplegia.
In present cohort, in the category of eye/visual impairments, blindness types and strabismus were observed in 26 and 18 individuals, respectively.Lakho et al 24 carried out a study on ocular problems prevalent among the school children in Lasbela district of Balochistan.It was observed that 23% children had ocular problems, and conjunctivitis was the most common condition (11%), followed by vitamin-A deficiency disorders (3.3%), and refractive errors (3%).Notably, the ocular problems were more prevalent among children in madrasa (34%) compared to conventional schools (21%), with significant differences seen in conjunctivitis (17% in children from madaris vs. 10% in schools).
Here, the sporadic cases were almost twice as common as compared to familial cases (65% vs. 35%), which is similar to a study carried out in other regions of Pakistan. 17,19Concordantly, Naeem et al. 20 also witnessed high incidence of sporadic cases among the cohort of CA ascertained from north-western territories of Pakistan.The high prevalence of sporadic cases among the limb and neurological disorders, coupled with lower levels of parental consanguinity, may suggest a likely contribution of nongenetic factors in the etiology of these anomalies.
Limitations: This study has several limitations.It does not provide the true prevalence of CA, rather the anomalies ascertained based on convenience sampling were reported.Hence, the rates presented here may by underor over-estimated.The diagnosis of CA is mainly based on the phenotypic presentation and is not supported by molecular genetic methods.The environmental and risk factors which may be involved in the etiology of the CA were not explored in this study.

CONCLUSION
Our research indicates that non-genetic and environmental factors may play a significant role in the development of sizable number of CA, particularly those affecting the neuromuscular and musculoskeletal systems.Given this context in resource deficient region like Balochistan, it is crucial to take several measures to address and reduce the burden of CA.These measures include: 1) increasing health education; 2) enhancing antenatal and perinatal care; 3) provision of premarital counseling and genetic testing; 4) implementing genetic screening programs particularly for common anomalies like thalassemia and metabolic disorders; and strengthening the health-care system.

Table - I
: Demographic distribution of index subjects.
*differences in the distribution were statistically significant.A h e a d o f F i n a l P u b l i c a t i o n

Table -
II: Index cases in major categories of CA, proportions and 95% CI.

Table -
III: Major and minor categories of congenital anomalies.