The genetic aspect

of growth and
puberty
dr. Yulia Ariani, Sp.A
Departemen Biologi Kedoktera FKUI

GROWTH

Growth
Growth : gain of body weight (BW),
body height (BH), or head
circumference (HC)
Growth is influenced by environment
and genetic factors
Body height is highly heritable
high genetic contribution, polygenic
and multifactorial
Heritability index for BH 0,6 0,8

A genetic map of the genes affecting height.

 Hundreds of syndrome in OMIM

(Online Mendelian Inheritance in
Men) registry are associated with
growth disturbance
Most cases are delayed growth due
to endocrine abnormality and linked
to growth hormone (GH) deficiency
(isolated or combine with other
hypophyseal hormone deficiencies)
or with a lack of activity

Genes
Mutations of genes expressed along the
somatotropic axis (GH coding gene, its
receptor, etc) and transcription factors
(HESX1, LHX3, LHX4, PROP1, POU1F1,
SOX3, SOX2, etc)
Mutation of genes involved in bone
formation (FGFR3, COLI-A1)
Anomalies of SHOX gene, located in
sex chromosome most frequent

SHOX gene
SHOX gene is located at the tip of
both sex chromosome inside the
telomeric part of pseudoautosomal
region I (PAR I) which comprises
around 2,6Mb
There is no difference between SHOX
(X) dan SHOX (Y)

 This region is a hotspot for very

frequent recombination events
SHOX gene function is dosage
dependent loss of function of one
SHOX allele growth failure

SHOX gene abnormality

Idiopathic short stature
Turner syndrome

Idiopathic short stature

Loss of function of one SHOX allele
due to mutation
Most frequent is deletion of SHOX
gene in a different size account for
around 80% of all mutations
Prevalence of SHOX mutations in
children with idiopathic short stature
is estimated around 2 15%

Turner syndrome
Turner syndrome (TS) is almost always
associated with the loss of one SHOX gene
because of the numerical or structural
aberration of the X chromosome
female with absence of one X chromosome
Incidence: 1 in 1200 2500 females (90%
of them undergo spontaneous abortion)
Short stature (57 inches average)
Hormone therapy may increase height

- Intelligence is often near average, although with severe

deficits in spatial ability and directional sense (perhaps
due to smaller amounts of brain tissue grey & white
matter in parietal lobes; Reiss, 1995).

 Loss of both SHOX alleles causes

complete lack of SHOX and extreme
phenotype called Lange syndrome

 The gain of 1 or 2 additional copies

of SHOX due to structural
abberations can be asociated with
tall stature

Severe growth anomalies

On going studies
Genes are responsible: LH- (-Luteinizing
Hormone), COLI A1(Collagen I A1), VDR
(Vitamin D Receptor), ESR1 (Estrogen
Receptor 1), DRD2 (Dopamine Receptor D2),
IGF-1 (Insulin-like Growth Factor 1), CYP17
(Cytochrome P450c17a), CYP19 (Aromatase),
Y chromosome, PTHR1 (PTH/PTHrP Receptor),
GH1 (Growth Hormone 1), PPAR (Peroxisome
Proliferator-Activated Receptor-)

PUBERTY

Puberty
Puberty corresponds to the activation
of the hypothalamo-hypophysealgonadal function full development
of sexual characteristics, final height,
reproductive function and fertility
Stages in pubertal were classified
according Tanner classification,
focussing on secondary sexual
characterisrics

 First sign of puberty in girls is the

development of breast glands
Average age 10,5-11 y.o
Followed by the growth of pubic and
axillary hair
Ends by the occurrence of menarche,
around the age of 13 (2-2,5 years
after the first sign of puberty)
mean 10 15,5 y.o

 First sign of puberty in boys is an

increase in the volume of the
testicles in average occurs
between 12-13 years of age
Followed by the growth of pubic and
axillary hair, increase in the size of
glans penis

 Genetics factors have contribution in

the occurrence of puberty and
determine the age of onset of puberty
Puberty depends of the reactivation of
gonadotropic axis (around 7-8 years of
age)
The absence of reactivation of this
reactivation is responsible for the
delayed puberty or even the complete
absence of puberty
Acceleration of this reactivation is
responsible for precocious puberty

 It is now established that the onset of puberty

is determined by the events that take place in
the brain leads to a synchronized increase
of GnRH in hypothalamus
The secretion of GnRH stimulates the
synthesis and release of LH and FSH
LH and FSH reach the gonad and regulate
gonad development and secretion on gonad
steroids promote the growth of secondary
sex hormone and trigger the onset of sexual
dimorphisms (distribution of fats, muscle
mass, breast development, tone, voice)

Turner syndrome
Sometimes is undetectable until puberty, as
secondary sex characteristics and
menstruation are not appearing
Ovaries (gonad) do not develop prenatally
leads to high level of FSH and LH in early
childhood hypergonadrotropic
hypogonadism
Hormone therapy may induce menstruation
nevertheless it does not work for pregnancy
purpose

Kallmann syndrome
KS is a combination of congenital hypogonadrotropic
hypogonadism disorder and decrease/absent sense of
smell (anosmia)
Caused by disturbance of intrauterine migration of GnRH
neurons from the olfactory placodes to hypothalamus
insufficient/absent of GnRH insufficient of FSH/LH
hypogonadism
Clinically and genetically heterogenous, most cases are
sporadic (60%)
Genes involved are vary
In familial cases mode of inheritance is vary
(autosomal recessive, autosomal dominant, X-linked
recessive, oligogenic)

KS genes

KAL1 ???
FGFR1 in 10% - 30% of KS cases
FGF8
PROK2
PROKR2
WDR11

KAL 1 gene

FGFR 1 gene

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