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Epidemiological study of congenital and hereditary anomalies in Sialkot District of Pakistan revealed a high incidence of limb and neurological disorders


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Spectrum of limb defects and their distribution with respect to familial/sporadic nature and total number of affected family members

Limb defects

Presented in alphabetical order.

Index casesFamilial/sporadicTotal no. of people affected in all families
MaleFemaleTotalFamilialSporadicMaleFemaleTotal
Arthrogryposis82102810818
Brachydactyly, brachymetatarsus IV404318412
Brachydactyly, all fingers02211123
Camptodactyly10110213
Clubfoot19726818301141
Congenital shortening of lower limb40413415
Polydactyly, postaxial type A194231310351651
Polydactyly, postaxial type B50523707
Polydactyly, preaxial type I17421813251338
Polydactyly, preaxial type II01101011
Reduction defects of lower limb20211213
Reduction defects of upper limb516157310
Split-hand/foot10110628
Syndactyly, type II01110123
Syndactyly, type 1a404319110
Syndactyly, type 1c02220639
Total8924113486515369222

Mean parental ages at index subject’s birth

Category Sporadic cases (n = 137)NPaternal age (mean ± SD)Maternal age (mean ± SD)Significance level (P)

T-test statistics were used for comparison between paternal and maternal ages.

Limb defects6233.4 ± 5.027.0 ± 5.2<0.0001
Neurological disorders5632.8 ± 4.826.3 ± 4.6<0.0001
Musculoskeletal defects1435.8 ± 4.929.3 ± 4.70.0014
Neuromuscular anomalies540.0 ± 3.732.8 ± 3.60.0143
Total13733.7 ± 5.127.1 ± 5.0<0.0001
ANOVA, P = 0.910ANOVA, P = 0.726
Familial cases (n = 70)
Limb defects4334.7 ± 7.427.7 ± 6.2<0.0001
Neurological disorders1631.8 ± 5.625.4 ± 4.80.0018
Musculoskeletal defects731.4 ± 5.625.3 ± 5.90.0702
Neuromuscular anomalies436.0 ± 6.829.0 ± 5.00.1469
Total7033.8 ± 6.927.0 ± 5.9<0.0001
ANOVA, P = 0.561ANOVA, P = 0.689

Major and minor categories of congenital/hereditary malformations observed in the studied population

Malformation (major/minor)No. of cases Proportion95% CIICD-10

ICD-10, International Classification of Diseases, Tenth Revision; ^IQ, intelligence quotient

OMIM

OMIM, Online Mendelian Inheritance in Man; ORPHA, #Orphanet database identifiers/Entrez.

ORPHA

Orphanet database identifiers/Entrez.

Limb defects1130.4690.406–0.532
Clubfoot260.1080.069–0.147Q66119800293150, 199315
Polydactyly, postaxial type A230.0950.058–0.133Q69.0;Q69.217420093335
Polydactyly, preaxial type I200.0830.048–0.118Q69.117440093339
Arthrogryposis100.0420.016–0.067Q74.31081201146
Polydactyly, postaxial type B60.0250.005–0.045Q69.0;Q69.217420093335
Reduction defects of upper limb60.0250.005–0.045Q7121710093457
Brachydactyly, 4th toe; brachymetatarsus IV40.0170.001–0.033Q72.8113475294998
Congenital shortening of lower limb40.0170.001–0.033Q72.8295057
Syndactyly, type 1a40.0170.001–0.033Q70.360981593402, 295187
Brachydactyly, all fingers short20.008−0.003 to 0.020Q71.8295130
Reduction defects of lower limb20.008−0.003 to 0.020Q7293457
Syndactyly, type 1c20.008−0.003 to 0.020Q70.1295191
Camptodactyly10.004−0.004 to 0.012114200295016
Polydactyly, preaxial type II10.004−0.004 to 0.012Q74.01745002950, 93336
Split-hand/foot10.004−0.004 to 0.012Q72.71836002440
Syndactyly, type II10.004−0.004 to 0.012Q70.4186000295195
Neurological disorders760.3150.257–0.374
Intellectual disability: mild210.0870.052–0.123F7024950088616
Spastic diplegic cerebral palsy200.0830.048–0.118G80.1
Intellectual disability: severe110.0460.019–0.072F7261109188616
Hereditary neuropathy60.0250.005–0.045G60201300970
Cerebral palsy, unspecified40.0170.001–0.033G80.9605388
Spastic hemiplegic cerebral palsy30.012−0.002 to 0.026G80.2
Spastic quadriplegic cerebral palsy30.012−0.002 to 0.026G80.0603513210141
Ataxic cerebral palsy20.008−0.003 to 0.020G80.4605388
Amyotrophic lateral sclerosis10.004−0.004 to 0.012G12.2105400803
Down syndrome10.004−0.004 to 0.012Q90.9190685870
Hereditary ataxia10.004−0.004 to 0.012G1122930095
Hereditary spastic paraplegia10.004−0.004 to 0.012G11.4270800
Intellectual disability; succinic semialdehyde dehydro- genase deficiency10.004−0.004 to 0.01227198022
Microcephaly, low IQ^10.004−0.004 to 0.012Q022512002512, 52183
Musculoskeletal defects230.0950.058–0.133
Achondroplasia120.0500.022–0.077Q77.410080015
Kyphosis20.008−0.003 to 0.020Q76.4192900
Congenital deformity of forehead10.004−0.004 to 0.012Q75.8
Congenital dislocation of hip10.004−0.004 to 0.012Q65.2142700
Congenital malformation of bony thorax; genu valgum10.004−0.004 to 0.012Q76.9; Q74.1
Congenital scoliosis10.004−0.004 to 0.012Q76.3
Disorder of ligament (leg)10.004−0.004 to 0.012M24.2
Diastrophic dysplasia10.004−0.004 to 0.012Q77.5222600628
Genu valgum10.004−0.004 to 0.012Q44.1137370
Multiple congenital exostoses10.004−0.004 to 0.012Q78.6133700321
Osteochondrodysplasia, unspecified10.004−0.004 to 0.012Q78.9
Neuromuscular anomalies100.0420.016–0.067
Muscular dystrophy80.0330.011–0.056G71.031020098896
Spinal muscular atrophy20.008−0.003 to 0.020G12.125330070, 83330
Others190.0790.045–0.113
Oculocutaneous albinism30.012−0.002 to 0.026E70.320310079431, 352731
Allergic asthma30.012−0.002 to 0.026J45.9
Deaf-mute30.012−0.002 to 0.026H91.3.22029090636
Dysphasia10.004−0.004 to 0.012R47.0600117
Amblyopia10.004−0.004 to 0.012H53.0
Congenital malformation of cardiac septum10.004−0.004 to 0.012Q21.9600001
Deformed ear pinna10.004−0.004 to 0.012H61.9156243
Disorders of fluid, electrolyte, and acid–base balance10.004−0.004 to 0.012E87
High myopia10.004−0.004 to 0.012H52.1160700
Hypertensive heart disease10.004−0.004 to 0.012I11
Intestinal cancer10.004−0.004 to 0.012C17.926106
Night blindness10.004−0.004 to 0.012H53.6257270215
Vitiligo10.004−0.004 to 0.012L80

Phenotypic manifestation of limb defects (n = 113)

Limb defectsNo. ofTotal no. ofUpper limb (n = 87)Lower limb (n = 109)No. of cases with involvement of ….No. of limbs involved
casesaffected limbs
RALARLLLArms onlyLegs onlyBothAny 1Any 2Any 3All 4
Arthrogryposis102267545143412
Brachydactyly, brachyme-4500320403100
tatarsus IV
Brachydactyly, all fingers2422002000200
Camptodactyly1411110010001
Clubfoot2644002321026081800
Congenital shortening of4500410403100
lower limb
Polydactyly, postaxial23501212161039119635
type A
Polydactyly, postaxial5623104104100
type B
Polydactyly, preaxial type I2125101311200119101
Polydactyly, preaxial1110001001000
type II
Reduction defects of2300120201100
lower limb
Reduction defects of6743006005100
upper limb
Split-hand/foot1411110010001
Syndactyly, type II1411110010001
Syndactyly, type 1a4800440400400
Syndactyly, type 1c2422002000200
Total113196424561484351195642411

Major categories of CA, familial/sporadic nature, and total number of affected family members

Congenital anomaliesIndex subjectProportion95% CIFamilial/sporadic nature

Chi-test statistics were statistically highly significant.

Total no. of people affected in all families

Chi-test statistics were statistically highly significant.

MaleFemaleTotalFamilialSporadicMaleFemaleTotal
Limb defects89241130.4690.406–0.532486515369222
Neurological disorders5719760.3150.257–0.37420568335118
Musculoskeletal defects167230.0950.058–0.133815231841
Neuromuscular anomalies91100.0420.016–0.0675521223
Others (n < 6)109190.0790.045–0.113163444993
Total181602411.00097144324173497

Demographic characteristics of index subjects

GenderFamilial/sporadic
Demographic variablesGender MaleFemaleFamilial/sporadic FamilialSporadicTotal
Age category, years
≤92619162945
>9–196728286795
>19–29405222345
>29–39224151126
≥39264161430
Total1816097144241
P = 0.0027P = 0.0187
Rural/urban origin
Rural1484572121193
Urban3315252348
P = 0.2553P = 0.0617
Caste system
Jatt5112323163
Rajput327132639
Arain18791625
Malik139101222
Meher14410818
Others5321235174
P = 0.3207P = 0.1325
Migratory origin

During the 1947 partition.

Native1504276116192
Migrated3118212849
P = 0.0318P = 0.6766
Literacy (age >5 years)
Illiterate98314980129
Literate7121415192
P = 0.8351P = 0.3263
Family type
Nuclear107306770137
Extended74303074104
P = 0.2166P = 0.0017

Combinations of malformations associated with CA

CA category\AssociationBrachydactylyCamptodactylySyndactyly typeClubfootArthrogryposisDeaf- muteCerebral palsyOthers
Achondroplasia11High myopia
ArthrogryposisIII
CamptodactylyFirst toe
ClubfootFourth toe31a
Deaf-mutePolydactyly, postaxial type A
Down syndromeFourth toeSquint eye
Dysphasia1
Hereditary neuropathyThird toeSquint eye
Intellectual disability: mild3210Ataxia
Intellectual disability: severeFourth toe138Cleft lip, overriding toe; polydactyly postaxial type B
KyphosisFourth toe1
Muscular dystrophyCleft lip
Polydactyly, postaxial type A1aClinodactyly
Polydactyly, preaxial type I1Hypoplastic thumb
Reduction defects of lower limb11
Spastic diplegic cerebral palsyThird toe1Cleft palate
Spinal muscular atrophy1
Total75335818

Relationship between consanguinity and different sample types

Parental marriage type, N (%)
CategoryConsanguineous

Inbreeding coefficient F30.0313

NonconsanguineousTotal no. of marriages
Malformation
Limb defects10 (9)103 (91)113
Neurological disorders16 (21)60 (79)76
Musculoskeletal defects4 (17)19 (83)23
Neuromuscular anomalies3 (30)7 (70)10
Others8 (42)11 (58)19
P = 0.003
Familial/sporadic nature
Familial28 (29)69 (71)97
Sporadic13 (9)131 (91)144
Total41 (17)200 (83)241
P < 0.0001
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