Achondroplasia

Centre for Arab Genomic Studies
A Division of Sheikh Hamdan Award for Medical Sciences

The Catalogue for Transmission Genetics in Arabs
CTGA Database



Achondroplasia


Alternative Names
Molecular Genetics
ACH
Achondroplasia is inherited as an autosomal

dominant trait, although most of the cases are
WHO International Classification of Diseases
sporadic, a result of a de novo mutation. This
Congenital malformations, deformations and
disorder comes from the genetic point mutations
chromosomal abnormalities
in the fibroblastic growth factor receptor 3 gene

(FGFR3), which enables abnormal cartilage
OMIM Number
growth-plate differentiation and insufficient
100800
bony development. FGFR3 is a major negative

regulator of linear bone growth, acting to inhibit
Mode of Inheritance
growth plate chondrocyte proliferation and
Autosomal dominant
terminal differentiation. FGFR3 is normally

activated by ligand-induced dimerization that
Gene Map Locus
activates the intrinsic tyrosine kinase activity of
4p16.3
the receptor. This leads to transphosphorylation

of key tyrosine residues in the cytoplasmic
Description
domain of the receptor that serve as docking
Achondroplasia is the most common form of
sites for adaptor proteins and effectors that
human dwarfism with characteristically
propagate FGFR3 signals. Among different
rhizomelic shortening of extremities and
populations, the most common genetic
relative macrocephaly. It follows an autosomal
mutations in this receptor are G-A at position
dominant mode of inheritance and has a
1138 (G1138A), which results in the
frequency of approximatly 1 in 26,000 to 1 in
substitution of glycine to arginine at codon 380.
40,000 births. Achondroplasia is characterized
This is most uncommon in other autosomal
by short-limbed marked short stature
dominant genetic diseases.
(rhizomelic short stature), a relatively

macrocephaly with prominent forehead,

midface hypoplasia, lumbar lordosis, a trident
Epidemiology in the Arab World
configuration of hands and hydrocephalus

during growth development caused by
Lebanon
narrowing of the foramen magnum. Other
Bittar (1998) reported a prospective study of
symptoms caused by narrowing include apnea
3,865 consecutive newborns delivered between
(cessation of breathing) and cervical
1991 and 1993. Major congenital anomalies
myelopathy. In addition to prepubertal growth
(MCA) were found in 64 newborns at incidence
failure, achondroplasia patients show decreased
of 16.5/1000 births. Many of the cases had
pubertal growth spurt.
achondroplasia. Among the malformed infants,

the rate of low birth weight and the rate of
About 80% of affected individuals result from
parental first cousin consanguinity were
sporadic mutations without positive family
significantly higher than corresponding rates
histories. Based on genetic information,
among normal infants in a control group.
molecular genetic testing can provide an exact

diagnosis comparing to radiological and
United Arab Emirates
prenatal ultrasound evaluations.
Al Talabani et al. (1998) studied the pattern of

major congenital malformations in 24,233
consecutive live and stillbirth in Corniche

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hospital, which is the only maternity hospital in
of osteochondrodysplasia in the United Arab
Abu Dhabi, between January 1992 and January
Emirates to be 0.39/10,000. They also noted
1995. A total of 401 babies (16.6/1,000),
that all sporadic cases of achondroplasia
including 289 Arabs, were seen with major
occurred in one year (January-March 1999).
malformation. Single gene disorders accounted
Al-Gazali et al. (2003) also noted that the birth
for 24% of the cases, 21% were due to
prevalence of sporadic ahondroplasia is higher
autosomal dominant disorders. In their study, Al
in the UAE population than those reported for
Talabani et al. (1998) observed four cases of
other populations (0.13-0.64/10,000).
achondroplasia in families from the United Arab

Emirates. Recurrence was not reported in other
References
members of the families. Al Talabani et al.
Al Talabani J, Shubbar AI, Mustafa KE. Major
(1998) concluded that their study was very close
congenital malformations in United Arab
to representing the true incidence of congenital
Emirates (UAE): need for genetic
abnormalities in the United Arab Emirates, as
counselling. Ann Hum Genet. 1998; 62 (Pt
they investigated over 98% of deliveries in Abu
5):411-8.
Dhabi, the capital of United Arab Emirates.
Al-Gazali LI, Bakir M, Hamid Z, Varady E,

Varghes M, Haas D, Bener A, Padmanabhan
Eapen et al. (1998) carried out a screening
R, Abdulrrazzaq YM, Dawadu A,
program among school-going children in Al-
Abdulrrazzzaq YM, Dawodu AK. Birth
Ain, United Arab Emirates, to identify children
prevalence and pattern of
with learning disorders. During the course of
osteochondrodysplasias in an inbred high risk
one academic year, 34 such children were
population. Birth Defects Res Part A Clin
identified. The cause was judged to be prenatal
Mol Teratol. 2003; 67(2):125-32. Erratum in:
in 18 cases (53%). Eight cases exhibited
Birth Defects Res Part A Clin Mol Teratol.
dysmorphic features including a case with
2003; 67(4):276. Abdulrrazzzaq Yeusef M
achondroplasia.
[corrected to Abdulrrazzaq Yousef M];

Dawodu Aden Kula [corrected to Dawadu
In a 5-year prospective study for newborns at Al
Adekunle].
Ain Medical District, Al-Gazali et al. (2003)
Bittar Z. Major congenital malformations
defined the pattern and birth prevalence of the
presenting in the first 24 hours of life in 3865
different types of osteochondrodysplasias in the
consecutive births in south of Beirut.
United Arab Emirates. Among the 38,048
Incidence and pattern. J Med Liban. 1998;
births during the study period, 36 (9.46/10,000
46(5):256-60.
births) had some type of skeletal dysplasia of
Eapen V, al-Gazali LI, Bin-Othman S,
which four had achondroplasia (1.05/10,000
Pramathan T. Learning disorders in school-
births); however, one case was inherited from
going children--detection and diagnosis. J
the affected father, therefore the birth
Trop Pediatr. 1998; 44(4):192-3.
prevalence rate of non-inherited achondroplasia

was 0.78/10,000 births. In three cases,
Contributors
including the inherited form, the parents were
Ghazi O. Tadmouri: 14.8.2006
consanguineous. The mean paternal and
Ghazi O. Tadmouri: 16.4.2006
maternal age for thanatophoric dysplasia were
Ghazi O. Tadmouri: 11.6.2005
36.6 and 28 years, respectively. Al-Gazali et al.
Ghazi O. Tadmouri: 7.5.2005
(2003) calculated the mutation rate of this type
Sarah Al-Haj Ali: 14.3.2005


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