الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Skeletal and limb malformations have special attention in the population from pediatric
age group to adult age group.
Limb reduction defects are important skeletal disorders that are classified into isolated
and syndromic forms. Temtamy and McKusick classification depends on genetic and
anatomical considerations thus, was adopted in this work.
SHFM is a type of limb reduction defects, which is genetically and clinically
heterogeneous, the most common mode of inheritance is autosomal dominant but other modes
of inheritance were reported.
Full detailed medical history, three generations pedigree, clinical examination and skeletal
survey were conducted to SHFM cases while molecular tests were conducted to some cases either
isolated or syndromic in the form of gene panel test and whole exome sequencing. Despite of the
clinical identification of SHFM, precise diagnosis is still difficult and challenging.
The study was carried out on 25 cases with limb reduction defects (SHFM) including 15
males and 10 females. The age ranged from 1day to 15 years.
This study was carried out on 25 patients, 60% of them had isolated SHFM while 40%
had syndromic SHFM. Isolated SHFM classified as 12 cases with SHFM only and 3 cases with
SHFML. While syndromic cases listed as eight cases diagnosed as EEC syndrome, one case
diagnosed as SHFM with sensorneural hearing loss and one case diagnosed as HFG syndrome.
The percentage of non-parental consanguinity and positive family history in the present study
was 72% and 52%, respectively. The non paternal consanguinity was observed more common
among isolated and syndromic SHFM. Six patients had positive family history of similar
medical condition while seven cases had positive family history to other medical conditions.
Seven mothers of affected cases had history of prenatal hazards during first trimester such as
vaginal bleeding, hormonal induction, multiple radiological exposure, agriculture setting,
hyperthermia and no history of folic acid intake. This study showed an increased risk of SHFM
among maternal age group (20-25 years) and among paternal age group (31-35 years). In
current study the bilateral limb affection was more common than unilateral limb affection; also
split hand deformity was common among bilateral affection. While SHFM was equal among
both bilateral and unilateral limb affections. The right side was more common than left side. Six
cases were sequenced by miSeq Illumina Next Generation Sequencer, using customized panel
of inheritable genetic diseases related genes (including TP63, DYNCII genes); two cases were
diagnosed as EEC syndrome and had previously reported missense heterozygous mutations in
exon 5 and exon 7 respectively in the TP63 gene and one case; diagnosed as autosomal
dominant SHFM, with novel splice single base exchange mutation in DYNCII gene; the rest
three cases revealed deep intron variations in TP63 and DYNCII genes. Five cases were
investigated by Whole Exome Sequencing (WES), three cases of them were diagnosed as
SHFM-6, SHFM with hearing loss and HFG syndrome with novel mutations within WNT10,
DLX5, HOXA13 genes, respectively. While two other cases revealed heterozygous mutations in
multiple genes and they will need further investigations. The clinical heterogenicity of SHFM
cases necessitates orchestrated serial investigations to identify the causative genetic mutations
and proper genotype phenotype correlation
Summary, Conclusions and Recommendations
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The habilitation of a newborn child with a limb deficiency should begin at the mother’s
bedside and continue as an active educational program. Parental acceptance of the baby and
cooperation with the clinic are necessary prerequisites to a successful habilitation program.
6.2. Recommendations:
The clinical and genetic heterogeneity of SHFM contributes to extremely challenging
and difficult genetic counseling. Awareness of the clinical presentations of SHFM and other
extra limb manifestations that may be associated with this clinical phenotype is important for
proper referral and correct genetic counseling; in addition to molecular diagnosis.
One of the most important diagnostic assessments is providing multi-disciplinary team
from different specialties. Noninvasive prenatal diagnostic procedures as ultrasonography and
fetal MRI are considered as one of helpful diagnostic modalities.
The genetic flow chart which includes cytogenetics and molecular diagnostic tests are
essential in the evaluation of SHFM cases. Array CGH is important in the diagnosis of cases
harboring chromosomal rearrangements and micro-deletions while MLPA is helpful in the
detection of CNV (copy number variants)
Excluding all known disease-causing alterations, molecular diagnostic testing using
next-generation sequencing provides an opportunity to solve unresolved cases (whole-exome
or whole-genome sequencing), contributing to the identification of novel disease-causing
candidate genes associated with SHFM.