The genetic aspect

of growth and puberty

dr. Yulia Ariani, Sp.A

Departemen Biologi Kedoktera FKUI
 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-β (β-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),
PPARγ (Peroxisome Proliferator-Activated
Receptor-γ)
 Puberty
• Puberty corresponds to the activation of the
hypothalamo-hypophyseal-gonadal 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