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

Bhatti, Nadeem Ahmad; Mumtaz, Sara; Malik, Sajid

doi:10.1515/abm-2019-0040

Figures & Tables

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 cases			Familial/sporadic		Total no. of people affected in all families

	Male	Female	Total	Familial	Sporadic	Male	Female	Total
Arthrogryposis	8	2	10	2	8	10	8	18
Brachydactyly, brachymetatarsus IV	4	0	4	3	1	8	4	12
Brachydactyly, all fingers	0	2	2	1	1	1	2	3
Camptodactyly	1	0	1	1	0	2	1	3
Clubfoot	19	7	26	8	18	30	11	41
Congenital shortening of lower limb	4	0	4	1	3	4	1	5
Polydactyly, postaxial type A	19	4	23	13	10	35	16	51
Polydactyly, postaxial type B	5	0	5	2	3	7	0	7
Polydactyly, preaxial type I	17	4	21	8	13	25	13	38
Polydactyly, preaxial type II	0	1	1	0	1	0	1	1
Reduction defects of lower limb	2	0	2	1	1	2	1	3
Reduction defects of upper limb	5	1	6	1	5	7	3	10
Split-hand/foot	1	0	1	1	0	6	2	8
Syndactyly, type II	0	1	1	1	0	1	2	3
Syndactyly, type 1a	4	0	4	3	1	9	1	10
Syndactyly, type 1c	0	2	2	2	0	6	3	9
Total	89	24	113	48	65	153	69	222

Mean parental ages at index subject’s birth

Category Sporadic cases (n = 137)	N	Paternal age (mean ± SD)	Maternal age (mean ± SD)	Significance level (P) T-test statistics were used for comparison between paternal and maternal ages.
Limb defects	62	33.4 ± 5.0	27.0 ± 5.2	<0.0001
Neurological disorders	56	32.8 ± 4.8	26.3 ± 4.6	<0.0001
Musculoskeletal defects	14	35.8 ± 4.9	29.3 ± 4.7	0.0014
Neuromuscular anomalies	5	40.0 ± 3.7	32.8 ± 3.6	0.0143
Total	137	33.7 ± 5.1	27.1 ± 5.0	<0.0001
		ANOVA, P = 0.910	ANOVA, P = 0.726
Familial cases (n = 70)
Limb defects	43	34.7 ± 7.4	27.7 ± 6.2	<0.0001
Neurological disorders	16	31.8 ± 5.6	25.4 ± 4.8	0.0018
Musculoskeletal defects	7	31.4 ± 5.6	25.3 ± 5.9	0.0702
Neuromuscular anomalies	4	36.0 ± 6.8	29.0 ± 5.0	0.1469
Total	70	33.8 ± 6.9	27.0 ± 5.9	<0.0001
		ANOVA, P = 0.561	ANOVA, P = 0.689

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

Malformation (major/minor)	No. of cases Proportion		95% CI	ICD-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 defects	113	0.469	0.406–0.532
Clubfoot	26	0.108	0.069–0.147	Q66	119800	293150, 199315
Polydactyly, postaxial type A	23	0.095	0.058–0.133	Q69.0;Q69.2	174200	93335
Polydactyly, preaxial type I	20	0.083	0.048–0.118	Q69.1	174400	93339
Arthrogryposis	10	0.042	0.016–0.067	Q74.3	108120	1146
Polydactyly, postaxial type B	6	0.025	0.005–0.045	Q69.0;Q69.2	174200	93335
Reduction defects of upper limb	6	0.025	0.005–0.045	Q71	217100	93457
Brachydactyly, 4th toe; brachymetatarsus IV	4	0.017	0.001–0.033	Q72.8	113475	294998
Congenital shortening of lower limb	4	0.017	0.001–0.033	Q72.8		295057
Syndactyly, type 1a	4	0.017	0.001–0.033	Q70.3	609815	93402, 295187
Brachydactyly, all fingers short	2	0.008	−0.003 to 0.020	Q71.8		295130
Reduction defects of lower limb	2	0.008	−0.003 to 0.020	Q72		93457
Syndactyly, type 1c	2	0.008	−0.003 to 0.020	Q70.1		295191
Camptodactyly	1	0.004	−0.004 to 0.012		114200	295016
Polydactyly, preaxial type II	1	0.004	−0.004 to 0.012	Q74.0	174500	2950, 93336
Split-hand/foot	1	0.004	−0.004 to 0.012	Q72.7	183600	2440
Syndactyly, type II	1	0.004	−0.004 to 0.012	Q70.4	186000	295195
Neurological disorders	76	0.315	0.257–0.374
Intellectual disability: mild	21	0.087	0.052–0.123	F70	249500	88616
Spastic diplegic cerebral palsy	20	0.083	0.048–0.118	G80.1
Intellectual disability: severe	11	0.046	0.019–0.072	F72	611091	88616
Hereditary neuropathy	6	0.025	0.005–0.045	G60	201300	970
Cerebral palsy, unspecified	4	0.017	0.001–0.033	G80.9	605388
Spastic hemiplegic cerebral palsy	3	0.012	−0.002 to 0.026	G80.2
Spastic quadriplegic cerebral palsy	3	0.012	−0.002 to 0.026	G80.0	603513	210141
Ataxic cerebral palsy	2	0.008	−0.003 to 0.020	G80.4	605388
Amyotrophic lateral sclerosis	1	0.004	−0.004 to 0.012	G12.2	105400	803
Down syndrome	1	0.004	−0.004 to 0.012	Q90.9	190685	870
Hereditary ataxia	1	0.004	−0.004 to 0.012	G11	229300	95
Hereditary spastic paraplegia	1	0.004	−0.004 to 0.012	G11.4	270800
Intellectual disability; succinic semialdehyde dehydro- genase deficiency	1	0.004	−0.004 to 0.012		271980	22
Microcephaly, low IQ^	1	0.004	−0.004 to 0.012	Q02	251200	2512, 52183
Musculoskeletal defects	23	0.095	0.058–0.133
Achondroplasia	12	0.050	0.022–0.077	Q77.4	100800	15
Kyphosis	2	0.008	−0.003 to 0.020	Q76.4	192900
Congenital deformity of forehead	1	0.004	−0.004 to 0.012	Q75.8
Congenital dislocation of hip	1	0.004	−0.004 to 0.012	Q65.2	142700
Congenital malformation of bony thorax; genu valgum	1	0.004	−0.004 to 0.012	Q76.9; Q74.1
Congenital scoliosis	1	0.004	−0.004 to 0.012	Q76.3
Disorder of ligament (leg)	1	0.004	−0.004 to 0.012	M24.2
Diastrophic dysplasia	1	0.004	−0.004 to 0.012	Q77.5	222600	628
Genu valgum	1	0.004	−0.004 to 0.012	Q44.1	137370
Multiple congenital exostoses	1	0.004	−0.004 to 0.012	Q78.6	133700	321
Osteochondrodysplasia, unspecified	1	0.004	−0.004 to 0.012	Q78.9
Neuromuscular anomalies	10	0.042	0.016–0.067
Muscular dystrophy	8	0.033	0.011–0.056	G71.0	310200	98896
Spinal muscular atrophy	2	0.008	−0.003 to 0.020	G12.1	253300	70, 83330
Others	19	0.079	0.045–0.113
Oculocutaneous albinism	3	0.012	−0.002 to 0.026	E70.3	203100	79431, 352731
Allergic asthma	3	0.012	−0.002 to 0.026	J45.9
Deaf-mute	3	0.012	−0.002 to 0.026	H91.3.	220290	90636
Dysphasia	1	0.004	−0.004 to 0.012	R47.0	600117
Amblyopia	1	0.004	−0.004 to 0.012	H53.0
Congenital malformation of cardiac septum	1	0.004	−0.004 to 0.012	Q21.9	600001
Deformed ear pinna	1	0.004	−0.004 to 0.012	H61.9		156243
Disorders of fluid, electrolyte, and acid–base balance	1	0.004	−0.004 to 0.012	E87
High myopia	1	0.004	−0.004 to 0.012	H52.1	160700
Hypertensive heart disease	1	0.004	−0.004 to 0.012	I11
Intestinal cancer	1	0.004	−0.004 to 0.012	C17.9	26106
Night blindness	1	0.004	−0.004 to 0.012	H53.6	257270	215
Vitiligo	1	0.004	−0.004 to 0.012	L80

Phenotypic manifestation of limb defects (n = 113)

Limb defects	No. of	Total no. of	Upper limb (n = 87)		Lower limb (n = 109)		No. of cases with involvement of ….				No. of limbs involved
	cases	affected limbs
			RA	LA	RL	LL	Arms only	Legs only	Both	Any 1	Any 2	Any 3	All 4
Arthrogryposis	10	22	6	7	5	4	5	1	4	3	4	1	2
Brachydactyly, brachyme-	4	5	0	0	3	2	0	4	0	3	1	0	0
tatarsus IV
Brachydactyly, all fingers	2	4	2	2	0	0	2	0	0	0	2	0	0
Camptodactyly	1	4	1	1	1	1	0	0	1	0	0	0	1
Clubfoot	26	44	0	0	23	21	0	26	0	8	18	0	0
Congenital shortening of	4	5	0	0	4	1	0	4	0	3	1	0	0
lower limb
Polydactyly, postaxial	23	50	12	12	16	10	3	9	11	9	6	3	5
type A
Polydactyly, postaxial	5	6	2	3	1	0	4	1	0	4	1	0	0
type B
Polydactyly, preaxial type I	21	25	10	13	1	1	20	0	1	19	1	0	1
Polydactyly, preaxial	1	1	1	0	0	0	1	0	0	1	0	0	0
type II
Reduction defects of	2	3	0	0	1	2	0	2	0	1	1	0	0
lower limb
Reduction defects of	6	7	4	3	0	0	6	0	0	5	1	0	0
upper limb
Split-hand/foot	1	4	1	1	1	1	0	0	1	0	0	0	1
Syndactyly, type II	1	4	1	1	1	1	0	0	1	0	0	0	1
Syndactyly, type 1a	4	8	0	0	4	4	0	4	0	0	4	0	0
Syndactyly, type 1c	2	4	2	2	0	0	2	0	0	0	2	0	0
Total	113	196	42	45	61	48	43	51	19	56	42	4	11

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

Congenital anomalies	Index subject			Proportion	95% CI	Familial/sporadic nature Chi-test statistics were statistically highly significant.		Total no. of people affected in all families Chi-test statistics were statistically highly significant.

	Male	Female	Total			Familial	Sporadic	Male	Female	Total
Limb defects	89	24	113	0.469	0.406–0.532	48	65	153	69	222
Neurological disorders	57	19	76	0.315	0.257–0.374	20	56	83	35	118
Musculoskeletal defects	16	7	23	0.095	0.058–0.133	8	15	23	18	41
Neuromuscular anomalies	9	1	10	0.042	0.016–0.067	5	5	21	2	23
Others (n < 6)	10	9	19	0.079	0.045–0.113	16	3	44	49	93
Total	181	60	241	1.000	–	97	144	324	173	497

Demographic characteristics of index subjects

	Gender		Familial/sporadic
Demographic variables	Gender Male	Female	Familial/sporadic Familial	Sporadic	Total
Age category, years
≤9	26	19	16	29	45
>9–19	67	28	28	67	95
>19–29	40	5	22	23	45
>29–39	22	4	15	11	26
≥39	26	4	16	14	30
Total	181	60	97	144	241
	P = 0.0027		P = 0.0187
Rural/urban origin
Rural	148	45	72	121	193
Urban	33	15	25	23	48
		P = 0.2553		P = 0.0617
Caste system
Jatt	51	12	32	31	63
Rajput	32	7	13	26	39
Arain	18	7	9	16	25
Malik	13	9	10	12	22
Meher	14	4	10	8	18
Others	53	21	23	51	74
		P = 0.3207		P = 0.1325
Migratory origin During the 1947 partition.
Native	150	42	76	116	192
Migrated	31	18	21	28	49
		P = 0.0318		P = 0.6766
Literacy (age >5 years)
Illiterate	98	31	49	80	129
Literate	71	21	41	51	92
		P = 0.8351		P = 0.3263
Family type
Nuclear	107	30	67	70	137
Extended	74	30	30	74	104
		P = 0.2166		P = 0.0017

Combinations of malformations associated with CA

CA category\Association	Brachydactyly	Camptodactyly	Syndactyly type	Clubfoot	Arthrogryposis	Deaf- mute	Cerebral palsy	Others
Achondroplasia		1				1		High myopia
Arthrogryposis			III
Camptodactyly	First toe
Clubfoot	Fourth toe	3	1a
Deaf-mute								Polydactyly, postaxial type A
Down syndrome	Fourth toe							Squint eye
Dysphasia					1
Hereditary neuropathy	Third toe							Squint eye
Intellectual disability: mild					3	2	10	Ataxia
Intellectual disability: severe	Fourth toe			1		3	8	Cleft lip, overriding toe; polydactyly postaxial type B
Kyphosis	Fourth toe			1
Muscular dystrophy								Cleft lip
Polydactyly, postaxial type A			1a					Clinodactyly
Polydactyly, preaxial type I		1						Hypoplastic thumb
Reduction defects of lower limb				1	1
Spastic diplegic cerebral palsy	Third toe					1		Cleft palate
Spinal muscular atrophy						1
Total	7	5	3	3	5	8	18

Relationship between consanguinity and different sample types

	Parental marriage type, N (%)
Category	Consanguineous Inbreeding coefficient F³0.0313	Nonconsanguineous	Total no. of marriages
Malformation
Limb defects	10 (9)	103 (91)	113
Neurological disorders	16 (21)	60 (79)	76
Musculoskeletal defects	4 (17)	19 (83)	23
Neuromuscular anomalies	3 (30)	7 (70)	10
Others	8 (42)	11 (58)	19
		P = 0.003
Familial/sporadic nature
Familial	28 (29)	69 (71)	97
Sporadic	13 (9)	131 (91)	144
Total	41 (17)	200 (83)	241
		P < 0.0001

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

Figures & Tables

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

Mean parental ages at index subject’s birth

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

Phenotypic manifestation of limb defects (n = 113)

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

Demographic characteristics of index subjects

Combinations of malformations associated with CA

Relationship between consanguinity and different sample types

Paradigm

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