SEGREGATION ANALYSIS OF PAKISTANI
FAMILIES WITH HERIDITARY ECTODERMAL DYSPLESIA

Ectodermal dysplasia:-

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Ectodermal dysplasia is not a single disorder, but a
group of syndromes all deriving from abnormalities of the ectodermal structures. More than 150
different syndromes have been identified.

Ectodermal dysplasias are described as:

“heritable
conditions in which there are abnormalities of two or more ectodermal
structures such as the hair, teeth, nails, sweat glands, salivary glands, cranial-facial structure, digits and other parts of the
body.”

What
causes ED?

Ectodermal Dysplasias are caused by altered genes. The
altered genes may be inherited or normal genes may become defective (mutate) at
the time of conception. The chances for parents to have affected children
depend on the type of ED that exists in the family.It is important to remember
that a person cannot choose or modify the genes that he or she has.Genetic
counseling is available for families.

One common type of ED affects males more than females
this is the X-linked type of hypohidrotic ED, other types can affect males or
females equally and may be inherited in different ways.Despite some of the
syndromes having different genetic causes the symptoms are sometimes very
similar. Diagnosis is usually by clinical observation often with the assistance
of family medical histories so that it can be determined whether transmission
is autosomal dominant or recessive.

ANALYSIS IN PAKISTANI FAMILIES:-

Three Pakistani families (N, O, P)
displaying different types of ectodermal dysplasias have been investigated.
Affected members in the family N presented a novel combination of abnormalities
of  hair, nails and localized skin
pigmentation. Affected members in the second family O showed features of pure
hair and nail ectodermal dysplasia (PHNED) while those in the family P
exhibited features of hypohidrotic ectodermal dysplasia (HED).

Characterization of a Family
with Abnormalities of Hair, Nail and Skin Pigmentation 

Family N

Subjects and Clinical
features 

Family N was recruited from District Nawabshah, Sindh
Province, Pakistan. This five generation family has six affected individuals
(IV-6, IV-8, IV-9, IV-10, IV-11, V-2) who were 12 to 28 years of age at the
time of the study. All the affected individuals are the product of
consanguineous unions and born at full term of normal pregnancies. The pedigree
showed clear evidence of autosomal recessive mode of inheritance.

Detailed
clinical evaluation revealed following clinical features in the affected individuals
of the family.

Nails:At the time of birth nail
growth was normal. Dystrophy of the nails appeared during second decade of the
patient’s life. Severe onychodystrophy manifested.Other features associated
with nail dystrophy noted in the patients included micronychia (small nails),
transverse melanonychia (dark colored spots on nail plate) and onycholysis
(detachment of the nail from nail bed).

Hairs: Sparse thin scalp hair of
woolly texture, and sparse eyebrows and eyelashes were observed in all the
patients.

Skin: Reticulate pattern of
hyperpigmentation manifested in form of net like dark brown gray patches, was
observed on different parts of the body.Associated condition of guttate
hypopigmentation was noted on some of the body parts.

Sweating
and dentition was found normal in all the patients. No underlying defects in
renal, liver and other organ systems were reported.

Genotype:-

DNA samples from six affected (IV-6, IV-8, IV-9,
IV-10, IV-11, VII-7) and eight unaffected individuals (III1, III-2, III-5,
III-6, IV-4, IV-5, IV-7, IV-12) were subjected to genome wide linkage analysis.
The whole genome-wide scan was performed by genotyping SNPs microarray
analysis. . A single run of homozygous SNP markers spanning about 3.03 Mb on
chromosome 18p11.32p11.31 were detected. candidate region of 3.03 Mb on
chromosome 18p11.32-p11.31, identified in family N, contains 16 protein coding
and one long intergenic non-protein coding RNA gene. . None of these genes were
reported to cause any type of dermatosis phenotype.Subsequently exons, splice
junction sites, 5’untranslated regions (UTR) and polyadenylation site in 3′ UTR
of all 17 genes were screened for potential sequence variants in two affected
and one unaffected individual of the family. Sequence analysis failed to detect
any functional sequence variant which
could be responsible for causing disease phenotypes observed in the family N.

Characterization of a Family with Pure Hair and Nail
Ectodermal Dysplasia (PHNED)

Family O

Subjects and Clinical Features:

A four generation
consanguineous family, segregating an autosomal recessive form of PHNED, was
ascertained from a village in remote region of Sindh province, Pakistan. The
family O comprised of five affected individuals (II-3, III-3, III-4, IV-7,
IV-8) and three of them (III-3, III-4, IV-7) underwent clinical examination.Clinical
examination revealed presence of sparse hairs on scalp, thin eyebrows and
eyelashes, and thin hairs on rest of the body parts. The hairs were fragile and
easily breakable.Dystrophic nails were observed on all fingers of hands and
toes of feet.Heterozygous carriers had normal hairs and nails and were
clinically indistinguishable from genotypically normal individuals. No other associated
abnormality in other ectodermal appendages (teeth, sweat glands) was observed
in any of the three affected subjects of the family. They followed normal
pattern of growth and development.

 

Genotype:-

Initially, the gene KRT85, known  to cause PHNED was screened for potential
sequence variants and they fail to detect sequence variants in KRT85.Recently,two
mutations reported in the gene HOXC13, located in HOXC cluster on chromosome
12p13.11-q21.1,causing PHNED phenotype. Therefore, the same gene was then
sequenced in two affected and one unaffected members of the family O. Primer
sequences, amplified PCR product size, Tm conditions used to amplify HOXC13
and  other genes.Sequence analysis
revealed a novel homozygous 4-bp duplication in exon 1 of the gene HOXC13 in
all three affected individuals of the family. This sequence change resulted in
substitution of amino acid histidine to glutamine at amino acid position 68
resulting in frameshifting leading to premature termination codon.This
duplication mutation was present in heterozygous state in obligate carriers of
the family.

Characterization
of a Family with Hypohidrotic Ectodermal Dysplasia (HED)

Family
P

Subjects
and Clinical Features:

Family P segregating  HED  phenotypes, is inhabitant of an area near
district Bhimbar in Azad Jammu and Kashmir, Pakistan. It is a small family
comprising of only one affected male individual (IV-1) who was of 24 years of
age at the time of study. The patient demonstrated clinical symptoms compatible
with HED clinical picture. The clinical features observed included sparse thin
hypopigmented hairs on scalp, sparse eyebrows and eyelashes, absence of
axillary, pubic and body hairs, missing frontal teeth reduced to absent
sweating,dry and thin skin.

Genotype:-

Initially, genotyping was performed
using microsatellite markers tightly linked to four genes reported earlier to
be involved in causing HED. These included EDAR on chromosome 2q11-q13,EDA on
Xq12-q13,EDARADD on 1q42.2-q43 and TRAF6 on 11p12.Since, the genotyping results
failed to produce convincing linkage to any of the four genes, therefore, all
the four genes (EDAR, EDA, EDARADD, TRAF6) were sequenced in the affected and
one unaffected members of the family. Primer sequences and Tm conditions used
for amplification of PCR products.Sequence analysis, however, failed to detect
disease causing variants in the four genes.

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