Type I or type II? Recent developments.

[Guest guest]

Hi everybody,

I read the recent posts about type I and type II BPES and

infertility. I noticed that there are a lot of questions and

uncertainties. Maybe I can clarify one and other. I have a degree in

medicine and although I am now specializing in psychiatry, I am

familiar with general medicine matters. Moreover, recently I spoke

with Dr. Debaere, who's a world expert on genetic research in BPES.

First I'd like to explain something about genetics. Humans have 46

chromosomes. We have 2 Sex chromosomes, XX (female) or XY (male),

and 44 autosomal chromosomes. Each parent Passes 23 chromosomes (22

autosomal and 1 sex chromosome) so you get 23 chromosome " couples " .

Chromosomes consist of DNA. Specific regions on chromosomes are

called genes. There are a lot of genes (eye-colour, hair-colour, ...

etc). In our cells there is a sophisticated system that can

translate the information which is encoded in the DNA, the building

material of genes, and form proteins. So a gene actually stands for

a specific protein (like there is a gene for insulin). How do

genetic disorders arise? Genetic disorders arise when there is a

mutation (change) in the DNA within a specific gene region. This

alters the gene and, thus, alters the protein which is formed. This

is important. For example insulin which is different from normal

insulin might not be able to lower blood sugar levels. Once a

genetic disorder has arisen, which can happen spontaneously, it can

be passed from parents to children. Genetic disorders can

be " dominant " or " recessive " . When a genetic disorder is dominant

only one of the two genes in the gene couple (the one from father or

the one from mother) has to be altered to give rise to the disorder.

When a genetic disorder is recessive both the father and the mother

need to pass an altered gene to give rise to the disorder.

What about BPES? BPES is an autosomal dominant genetic disorder. The

gene is called FOXL2 and is located on chromosome 3. Chromosome 3 is

an autosomal chromosome and the fact that the disorder is dominant

means that you only need to have one altered gene to get the

disorder. The different types (I and II) of BPES were first

described in 1983 (Zlotogora). Type I includes the four major

features (blepharophimosis, ptosis, epicanthus inversus and

telecanthus) and female infertility caused by premature ovarian

failure (POF). Type II includes only the four major features. The

difference between Type I and II is the position on which the DNA,

and thus the gene, is mutated (altered). There are several (at least

21) known mutations of the FOXL2 gene. Depending on the location

these mutations give rise to a shortened protein or an extended

protein. The ones that give rise to a shortened protein cause type I

and the ones that give rise to an extended protein cause type II.

For some mutations it's not clear which type they cause. During a

genetic investigation, which takes about three months, they try to

find a known mutation to see if they are able to tell which type of

BPES the affected person has.

What about the management of POF? Management of POF needs to address

the two major medical issues: hormone replacement therapy (HRT) and

infertility.

HRT: Oestrogen and progesterone replacement therapy is usually

indicated. No comparative data are available to guide estrogen use

in young women as most studies on HRT involve post-menopausal women,

but the advantages often outweigh the possible side-effects.

Infertility: No effective treatment for infertility exists. Adoption

and oocyte (egg) donation are among the available options. However,

more recently there are some new therapies under investigation.

Ovarian tissue and oocyte cryopreservation (freezing in) hold

promise for fertility preservation in the women most likely to

undergo ovarian failure. Adolescent girls with BPES who have a risk

of developing POF could be candidates for ovarian (not necessarily

the complete ovary so it's not necessary to cause surgical

menopause) cryopreservation. This cryopreserved ovarian tissue can

be used in two ways: retransplanting and in vitro stimulation. The

first live birth after retransplantation was reported in 2004 (this

was not a woman with BPES). Note that these techniques are not (yet)

applied on a large scale.

Women with POF often reach menopause when they are 25-30 years old.

In the old days, when women conceived at a younger age, this was not

necessarily a problem. Nowadays most women start a career and think

of children at an older age which makes POF more of an issue.

Endocrinologic and gynecologic follow-up are advised in affected

females in whom the BPES type is unknown or in whom BPES type I is

suspected based on a positive family history or suggestive FOXL2

mutation.

I myself had a blood sample taken one and a half month ago. We are

planning to have more kids and we just want to know which type I

have to be as prepared ad possible. I do not have the result yet. It

takes about three months.

I hope I was of any help. If some things are unclear please ask

questions.

Greetings,

Jeroen.