Open Journal of Genetics, 2013, 3, 1-7 OJGen
http://dx.doi.org/10.4236/ojgen.2013.32A3001 Published Online August 2013 (http://www.scirp.org/journal/ojgen/)
Fraser Syndrome: Two millennia of cryptophthalmos
from Pliny the Elder to FRAS, FREM and GRIP:
A historical perspective
George R. Fraser
Green Templeton College, Oxford, UK
Received 20 May 2013; revised 21 June 2013; accepted 6 July 2013
Copyright © 2013 George R. Fraser. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
From its first description in antiquity, the place of
cryptophthalmos in the history of medical genetics is
briefly set out until, in the twentieth century, this rare
constellation of multiple congenital malformations of
which cryptophthalmos is the most striking, even
though not obligatory, component, was identified as
an inherited autosomal recessive condition. It was
given the name of Fraser syndrome and mutant al-
leles of the genes FRAS1, FREM2 and GRIP1 were
identified as being responsible for a proportion of
cases. In the remainder of cases, it may be supposed
that mutant alleles of other genes, as yet unidentified,
are responsible. In general, this association of multi-
ple disparate malformations in an autosomal reces-
sive condition may be expected to throw light on im-
portant aspects of gene action in embryogenesis. An
aspect of medical genetics, which has become impor-
tant with respect to the condition, is antenatal diag-
nosis with th e p ros pect of abort ion of affected fetuses.
Keywords: Cryptophthalmos; Fraser Syndrome;
Blindness; Deafness; Sublethal Genes; Autosomal
With reference to the title, Gaius Plinius Secundus (2 3 to
24 August 79 AD), better known as Pliny the Elder, was
an outstanding au thor, natural ph ilosoph er, and naval and
military commander who wrote Naturalis Historia .
He believed that “true glory consists of doing what de-
serves to be written, and writing what deserves to be
read”. As Admiral of the Roman Fleet, he perished in 79
AD trying to help survivors of the eruption of Mount
In Book VII of his Naturalis Historia, Chapter XII en-
titled Examples of many who have been very like and
resembled one another, begins with the following sen-
tence. In Lepidorum gente tres, intermisso ordine, ob-
ducto membrana oculo genitos accepimus (We have
heard it stated that three children of a couple belonging
to the clan of the Lepidi, have been born, although not in
uninterrupted succession, with an eye covered with a
membrane of skin). This sentence does not specify whe-
ther reference is being made with one eye or both eyes in
any of the three sibs.
This observation probably represen ts an early report of
cryptophthalmos (hidden eye behind an unopened eyelid)
inherited in an autosomal recessive manner, and it has
been mentioned as such by many authors. Thus, Pliny the
Elder distilled into one sentence the main features of the
condition under discussion, the eye hidden behind un-
opened eyelids and the familial occurrence within a sib-
2. CRYPTOPHTHALMOS BEFORE
THE ERA OF GENETIC MEDICINE
Going fast forward eighteen centuries from the time of
Pliny the Elder to 1872, we come to an outstanding de-
scription of a case of cryptophthalmos by Zehender and
Manz  in a six-month old girl. It is in this paper that
the term cryptophthalmos (hidden eye), or Kryptophthal-
mus in German, was first used. It is of interest to note
that the mother attributed the misfor tune to the fact that a
blind cat terrified her by jumping on to her from a fence.
Every physician who has dealt with families with handi-
capped offspring has heard many stories of this nature.
Zehender and Manz  first pointed out in 1872 that
the malformation is not restricted to the eyes but is gen-
eralized. Thus, in their patient (Figure 1), there was an
umbilical hernia and the external genitalia were abnor-
G. R. Fraser / Open Journal of Genetics 3 (2013) 1-7
mal. The anal and vesical sphincters showed impaired
function. There were variable findings of syndactyly in
both hands and both feet.
Zehender and Manz  who performed a post mortem
examination of the disorganized ocular tissues behind the
unopened eyelids, including detailed histology, described
the child as a “Monstrum”. As long ago as the sixteenth
century, however, in his essay Of a Monstrous Child ,
written in 1580, Michel Eyquem de Montaigne (1533-
1592) wrote: Those that we call monsters are not so to
God, who sees in the immensity of His work the infinite
forms that He has comprehended therein; and it is to be
believed that this figure which astonishes us has relation
to some other figure of the same kind unknown to man.
From His all wisdom nothing but good, common, and
regular proceeds, but we do not discern the disposition
Quod crebro videt, non miratur, etiamsi, cur fiat, ne-
scit. Quod ante non vidit, id, si evenerit, ostentum esse
censet. “What he often sees he does not admire, though
he be ignorant how it comes to pass. When a thing hap-
pens he never saw before, he thinks that it is a portent.”
—Cicero, De Divin, 2. 22].
Whatever falls out contrary to custom we say is con-
trary to nature, but nothing, whatever it be, is contrar y to
her. Let, therefore, this universal and natural reason ex-
pel the error and astonishment that novelty brings along
Figure 1. The striking photograph shown here was taken in
1872, less than fifty years after the advent of photography. The
drastic expedient of chloroform anesthesia was employed in
order to prepare the child for this photograph, taken seven
weeks before the death of the infant at the age of nine months.
In 1902, Golowin wrote a remarkable article  on
cryptophthalmos occurring in his Moscow practice. He
described two cases, the first a healthy 26-year-old mar-
ried, but childless, peasant, and the second a two-month-
old girl who had an affected sister. The man was blind
with total cryptophtha lmos on the right and partial on th e
left. He begged the surgeon to cut through the skin cov-
ering the right eye, since he found the feel of the eye
region and the consequent asymmetry of his face hateful.
The surgeon complied with his request; the patient was
Thus, we find in this report that the condition is com-
patible with healthy surv ival into adu lt life and with mar-
riage. We also find the occurrence of the condition in
sibs, as first described by Pliny the Elder.
In an extensive review of the literature, Golowin 
differentiated cryptophthalmos from forms of anophthal-
mos and microphthalmos. In no case was any functional
remnant of the eye present when the eyelids were surgi-
cally opened. He included cases with consanguineous
parents and mentioned many of the associated malforma-
tions which we now know as part of the syndrome (syn-
dactyly, gender ambiguities, abnormal development of
the nose and auricles, laryngeal stenosis and ossification
defects in the bones of th e skull). He determined that the
cryptophthalmos could be bilateral or unilateral and that
in some unilateral cases the other eye was entirely nor-
Avižonis in 1928  described a case and wrote a
comprehensive review of the literature of the cryptoph-
thalmos syndrome which had already been well deline-
ated by that time. Although many familial cases had been
described, there had not been any mention of the possi-
bility of the hereditary nature of th e condition.
Throughout this period, cases of cryptophthalmos were
reported not only in human beings but also in pheasants,
rabbits, pigeons, and chickens. In 1906, at a Japanese
Ophthalmological Congress, Asayama  reported the
condition in eight out of 50 inbred mice. His findings can
be regarded as the first recorded instance of the blebbing
mutants in mice, which played such a large part in un-
ravelling the molecular biology of Fraser syndrome a
To place the cryptophthalmos syndrome in its chrono-
logical context within the wider historical perspective of
the significance of genetics to medicine, the paper of
Zehender and Manz in 1872  was almost contempo-
raneous with the description by Langdon Down in 1866
 of what he called “mongolism”, a term now super-
seded by “the Down syndrome”. In his paper, Langdon
Down wrote that his findings, leading to his calling the
disease “mongolism”, furnished “some arguments in
favor of the unity of the human species”. Even though
his reasoning was somewhat unorthodox in that he in-
voked the hypothesis that disease is able to break down
Copyright © 2013 SciRes. OPEN ACCESS
G. R. Fraser / Open Journal of Genetics 3 (2013) 1-7 3
the barrier between racial divisions so as to simulate
closely the features of the members of a division other
than that of the patient, his conclusion echoes the senti-
ment, expressed so beautifully and so concisely in the
poetry and music of Schiller and Beethoven, Alle Men-
schen werden Brüder or All mankind will be brothers.
Almost a century after the paper of Langdon Down, in
1959, Lejeune, Gautier and Turpin  discovered the tri-
somy of chromosome 21, which characterizes the Down
It should be noted that the seminal work of Abbot Jo-
hann Gregor Mendel on peas, published in 1866 , was
proceeding in a quiet monastery garden not long before
the discoveries in 1872 of Zehender and Manz  with
respect to cryptophthalmos, even though these authors
could not, of course, have conceived of the vast signifi-
cance of Mendel’s work in connection with the future
elucidation of the chromosomal theory of heredity, nor
have divined the role of heredity by the operation of
autosomal recessive inheritance in the causation of the
It should also be noted that the paper of Langdon
Down  with respect to the Down syndrome which is
associated with a chromosomal anomaly, was published
in the same year (1866) as the work of Mendel , al-
though, of course, Langdon Down could not have been
aware of the significance of Mendel’s work in connec-
tion with his d e scri pt i on of “m ongol i sm”.
These discoveries [2,7,9], published within a brief span
of years between 1866 and 1872, contributed in a re-
markable manner to presaging the advances of the era of
3. CRYPTOPHTHALMOS IN THE
ERA OF GENETIC MEDICINE
In 1962, I wrote a review of the genetic load of our spe-
cies, or the deficit expressed in terms of disease and
premature death caused by less than optimal genotypes
. This is a 28-page paper, and just half a page was
devoted to two pairs of sisters who suffered from the
“syndrome of cryp tophthalmos” whom I h ad seen during
my studies of profound deafness in children over the
preceding five years. Thus, the main features of the “syn-
drome of cryptophthalmos” were described in this very
short section of a long paper dealing with the load of
lethal and detrimental gen e mutations.
This short section was preceded by the following para-
graph based on large studies in Japan, sponsored by the
Atomic Bomb Casualty Commission.
There was a significant increase in major congenital
abnormalities amongst the offspring of first cousin mat-
ings. This suggests that recessive inheritance plays some
part in the causation of these major congenital abnor-
malities, and the tenden cy is especially marked when the
complex anomalies were considered.
I suggested for the first time that the “syndrome of
cryptophthalmos” was an autosomal recessive condition.
I listed the following as malformations forming part of
the syndrome—cryptophthalmos; absent or malformed
lachrymal ducts; middle and outer ear malformations;
high palate; cleavage along the midplane of nares and
tongue; hypertelorism; laryngeal stenosis; syndactyly;
wide separation of symphysis pubis; displacement of um-
bilicus and nipples; primitive mesentery of small bowel;
maldeveloped kidneys; fusion of labia and enlargement
of the clitoris; bicornuate uterus and malformed Fallo-
pian tubes. Many other malformations have been added
to this list since 1962.
In each of the sibships which I described, one sister
was stillborn and the o ther survived. One of the two sur-
viving girls, Michele S, had fully developed bilateral
cryptophthalmo s. When I first met her in 1960 at the age
of five, she was not only blind but also profoundly deaf
in association with malformations of the outer and mid-
dle ears. The other surviving girl, Carol D, did not show
the characteristic feature of cryptophthalmos but could
be identified as a case of Fraser syndrome because she
showed many of the other components of the condition
and because she had a fully affected stillborn sib. She
provides a striking illustration of the fact that every com-
ponent of the syndrome is widely variable in its mani-
festations, giving rise to the anomalous diagnostic label
of “cryptophthalmos syndrome without cryptophthal-
mos”. The condition did not give rise to any educational
handicap in the case of Carol D. Children without educa-
tional handicap have been described in whom the cryp-
tophthalmos was unilateral, the other eye being entirely
Michele S was first ascertained in 1960 during my
studies of 3535 individuals with profound childhood
deafness between 1957 and 1967; she was ascertained
for a second time in 1964 during the course of my studies
of the causes of blindness in 776 children between 1963
and 1965. These studies have been comprehensively de-
scribed in two books [12,13]; both books contain details
It should be noted that the men tal ability of Michele is
potentially normal. In reviews of the pleiotropic nature of
this syndrome leading to widely variable degrees of ma-
nifestation in each of the organs which can be involved,
it is accepted that the mental status can be normal, but
this normality may, of course, be cloaked by sensory de-
privation, especially when both eyes and, in addition,
hearing, are involved, as in Michele’s case. In contrast to
Michele, Carol D who is neither deaf nor blind, has en-
joyed normal mental development.
Since severely affected individuals with this condition
are stillborn or do not survive infancy, the gene con-
cerned may be regarded as being sublethal. The concept
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G. R. Fraser / Open Journal of Genetics 3 (2013) 1-7
of sublethal genes was extensively discussed in 1955 by
Hadorn  who coined the term “Durchbrenner” (es-
capers) for experimental animals who survive even
though they are homozygous for autosomal recessive
sublethal genes responsible for multiple malformations
which are often incompatible with survival beyond in-
fancy. Both Michele S and Carol D may be regarded as
Durchbrenner in this sense although Michele is far more
seriously affected than Carol. The critical threshold with
respect to failure to survive is often associated with ex-
treme degrees of bilateral renal hypoplasia or with bilat-
eral renal aplasia, manifested in both stillborn sibs of the
How did these two paragraphs, a very small part of a
long paper on the genetic load , written 90 years after
the outstanding paper of Zehender and Manz , lead to
the assignment of my name as an eponym with respect to
the Fraser syndrome?
In 1963, Victor McKusick had sent me catalogs in ma-
nuscript form of X-linked and autosomal recessive con-
ditions, asking for comments and using my name as an
eponym with respect to the crypto phthalmos syndrome. I
went through these draft catalogs and sent my comments
to Victor; I quote one of these comments:
I am flattered by the epon ym (Fraser syndrome). How-
ever, copious references to cryptophthalmos (as you in-
dicate on pages 6 - 7 of your addenda) are to be found in
the literature and the presence of many other malforma-
tions has been not ed.
Nevertheless, when these manuscript catalogs came to
fruition in 1966 in the first publish ed edition of the cata-
logs as we know them today , th e eponym was to be
found there. It took some time for it to be generally
adopted. In 1983, Buyse  wrote in an editorial com-
ment on the anomalous phenomenon that the diagnosis
of the “cryptophthalmos syndrome” was being made in
individuals who did not in fact manifest cryptophthalmos
among their multiple malformations: “Dr Feingold brings
up an important issue of nomenclature when he points
out the difficulty of diagnosing a condition th at is named
after a clinical feature not present in the particular pa-
tient with that diagnosis… Perhaps, cryptophthalmos
syndrome should be called Fraser syndrome, an epony-
mic designation under which it is already known. How-
ever, I do not believe this would solve the basic issue of
understanding the pathogenesis of the cryptophthalmos
In 1986, two decades after McKusick’s initial assign-
ment of my name as an eponym, in a letter to the editor
of Clinical Genetics, entitled Cryptophthamos-syndactyly
syndrome without cryptophthalmos, Meinecke  wrote:
“…it has now been proved by an adequately large num-
ber of cases that cryptophthalmos is not an obligatory
feature of the Fraser syndrome. However, since the des-
ignation ‘cryptophthalmos syndrome’ might be prejudi-
cial in implying that cryptophthalmos is part of the syn-
drome, the eponymic designation, ‘Fraser syndrome’, is
per haps to be preferred”.
I had first been told about Michele S at a small hospi-
tal unit for deaf-blind and ineducable children. She had
been sent home as being unmanageable and, as part of
my studies of profound childhood deafness I went to see
her at her home in rural Essex in March 1960.
Her mother has written a small unpublished book
about Michele’s upbringing; this is how she describes
our first meeting.
Henry and I were out in the greenhouse in the garden.
Suddenly two men carrying black briefcases came to-
wards us. At first I thought they were Jehovah’s Wit-
nesses but they introduced themselves as doctors from
the Nuffield Hospital, Grays Inn Road, London. One said,
“We hear that you have a littl e girl who has an ear defect .
We think she might be deaf and would like to see her. Dr
Williams passed your letter on to us”.
More than four decades later, when I read the book, I
tried to persuade Mrs. S that the two Jehovah’s Witnesses
had been just one person, to wit, I myself. Michele was
five years old at the time of our first meeting. I spent the
afternoon with her and with her parents. Michele be-
haved in a very wild manner, almost like a feral child,
reacting with a terrified scream to any attempted ap-
proach. I noticed that she seemed very fond of a large
alarm clock which she continually pressed to her fore-
head. I suspected that there might be a conductive ele-
ment to her deafness. As part of my studies of deafness
in Oxford, I had been seeing groups of children with
malformations of the outer and middle ears. I was col-
laborating in this study with an otorhinolaryngologist,
Gavin Livingstone, who was interested in improving the
hearing of these children by reconstructing the outer and
middle ear. Gavin Livingstone agreed to see Michele; he
reconstructed her outer and middle ears, and Michele
began to hear for the first time at the age of six years. By
the time she was nine, she was keep ing up with the chil-
dren at Condover Hall, a school for the deaf and blind.
She was able to communicate with other children and
with members of the staff, as I was able to confirm when
I saw her for the second time at Condover Hall in 1964
during the course of my studies of the causes of blind-
ness in children.
She has been well looked after for many years in a
home run by a charity called Sense, where I was able to
meet her for the last time at the age of 51 years in 2005,
45 years after our first meeting.
I shall let Michele’s mother continue Michele’s story a
few months after the operations by Gavin Livingstone on
her ears in 1960.
It was at this point Mr Livingstone declared, “This
Copyright © 2013 SciRes. OPEN ACCESS
G. R. Fraser / Open Journal of Genetics 3 (2013) 1-7 5
child must be educated. There is now a new unit which
has been opened by the Royal National Institute for the
Blind in the small village of Condover, Shropshire. It is a
unit for blind and deaf child ren and is called, ‘Pathways’.
The school has been built in the grounds of a large man-
sion, Condover Hall. I will get in touch with them and
Michele must have an assessment. You will hear further
Was I dreaming? Not only could our child hear and
was beginning to use the English language but there was
a hope she would receive an education. Imagine how
Henry and I felt? We were struck dumb with disbelief. We
had just gone through six years of being told Michele
was uneducab le and so mentally ha ndicapped she would
never talk and now realized the diagnosis was wrong.
She had been totally deaf and now had some useful
In 1964, Michele’s mother wrote me a letter after I had
seen her daughter at Condover Hall. I had asked her to
fill in a form which I was using during the course of my
studies of the causes of blindness in children:
Dear Dr Fraser
I hope that the form has been filled in satisfactorily
and that some help m ay be ga i ned from it.
I would like to take this opportunity of thanking you
for being instrumental in the discovery of Michele’s
deafness. The operation proved very successful. She is
now talking very well, is learning Braille and figure work,
and is rapidly becomi n g a n o r mal bl i n d c hi l d.
Thank you for your interest in her.
Later in 1964, on 27 October, Michele’s mother wrote
to me again:
Dear Dr Fraser
We have returned from a four-day assessment at Con-
dover with Michele.
They are most impressed with her and the things she
manages for herself and are taking her for training in the
New Year until her speech is fluent when they will pass
her to Blind School. They th ink once she settles they will
do quite a lot with her. Her vocabulary increases daily
and she always remembers, though perhaps she hasn’t
touched the article, or said the word, for weeks.
The three of us will always be deeply grateful to you,
for making the trip to Great Baddow to see Michele, and
we feel that now she should go ahead. Condover is cer-
tainly a wonderful p lace…
Thank you for all you have done for us and for the in-
terest you have shown in Michele.
Michele has lived a life which I believe to have been
much more tolerable than it would have been without
any hearing. Perhaps this small contribution to the im-
provement in the quality of the life of this girl represents
a greater achievement than that of my name becoming
attached to a syndrome, or even, in abbreviated form as
FRAS1 to a gene. Michele was initially thought to be a
boy because of indeterminate genitalia; sex chromatin
studies at the age of one year showed an XX karyotype,
and she was then raised as a girl.
A breakthrough occurred in the study of the Fraser
syndrome with the publication of two papers by the late
Robin Winter in 1988 and 1990 [18,19]. The first of
these papers was a wide-ranging review of mouse/human
homologies with respect to hereditary malformation syn-
dromes. In this paper, two mouse mutants, bl-blebbed
and my-myencephalic blebs, were suggested as homo-
logs for human mutants giving rise to Fraser syndrome.
The second paper related specifically to this possibility
and raised the very important point that subepidermal
blebs or blisters could play an important role during em-
bryonic development in the pathogenesis of the malfor-
mations seen in the Fraser syndrome.
Robin Winter pointed out that this suggestion of ho-
mology mi ght b e hel p ful fo r t hree reasons.
1) Providing clues for the genetic mapping of Fraser
syndrome by reference to mouse/human homology of
ch romosome segment s.
2) It might point to genetic heterogeneity in view of
the fact that at that time three nonallelic mouse mutants
had been characterized that produce similar phenotypes.
3) It might provide an additional ultrasound marker
when attempting first trimester prenatal diagnosis,
namely subepidermal blebs.
All these three far-seeing predictions have been con-
firmed during the more than twenty years which have
elapsed since the publication of this paper.
Thus, in 1994, Darling and Gossler  wrote a re-
view entitled A mouse model for Fraser syndrome. They
stated that the first mouse bleb mutants were described
by Little and Bagg in 1924 , but, as mention ed above,
Asayama in Japan in 1906  had already described
eight cases of cryptophthalmos among 50 inbred mice.
Chromosome 4 then became the target for the location
of the gene responsible for the Fraser syndrome; some
inconclusive linkage studies were carried out before Pro-
fessor Peter Scambler accepted a PhD student called
Lesley McGregor towards the end of the nineteen-nine-
ties, to work on the topic in the Molecular Medicine Unit
at the Institute of Child Health, University College Lon-
I had reached the age for obligatory retirement in 1997
and I was not aware of these studies. During this period,
I was attending very few professional meetings; it was
the merest chance, fate, serendipity, providence, call it
what you will, which took me to Birmingham for a meet-
ing of the European Society of Human Genetics in May
2003, the main practical consideration being that Bir-
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G. R. Fraser / Open Journal of Genetics 3 (2013) 1-7
mingham is near my home.
4. CRYPTOPHTHALMOS AND
In the opening address, I learned that Professor Scambler
was going to talk three days later in the Late-Breaking
Research Session, a talk not previously announced, about
the Fraser syndrome. And it was in that session that I
first met Peter Scambler and first learned that a mutant
allele of a gene named FRAS1, mapp e d t o c hr o mo s o me 4
(4q21), was responsible for the Fraser/cryptophthalmos
Several articles were published between 2003 and
2005 in Nature Genetics, Proceedings of the National
Academy of Science and Human Molecular Genetics by
Peter Scambler, Ian Smyth and their groups, together
with collaborators in Greece and other countries, con-
cerning the genetics and molecular biology of the syn-
drome. The first of these papers is a condensed version
of Lesley McGregor ’s PhD thesis . Fraser syndrome,
an autosomal recessive condition, was shown to be
cau sed by a mutation in a gene designated as FRAS1 and
located on chromosome 4. This paper was coupled with
another  showing that the corresponding syndrome in
bl/bl blebbed mice was caused by a mutation in a ho-
mologous gene (FRAS1) on c h romosome 5 of the mouse.
This gene, FRAS1, and its homologs exist in Man, in
the mouse, and, as can be confirmed on the ensembl
website (http://www.ensembl.org), in other vertebrate
species. It is one of a group of genes controlling the pro -
duction of proteins which are required for the adhesion
between epidermal basement membrane and the under-
lying dermal connective tissues during embryonic de-
velopment. These proteins have also been shown to play
a crucial role in the initiation and development of the
kidney including assuring the integrity of the renal glo-
meruli  and they may modulate cell signalling.
This group of genes includes FRAS1 on chromosome
4, FREM1 (FREM standing for “FRAS1-related extra-
cellular matrix”) on chromosome 9, FREM2 on chromo-
some 13, FREM3 on chromosome 4, and GRIP1 (GRIP
stands for “glutamate receptor interacting protein”) on
chromosome 12. All these genes have been identified in
most of the vertebrate species whose genomes have been
studied and recorded on the ensemb l website
(http://www.ensembl.org). Mutations giving rise to the
Fraser syndrome have been found in FRAS1, FREM2 and
Slavotinek and Tifft  wrote an extensive article in
2002 reviewing the literature of Fraser syndrome and
cryptophthalmos. A review article by Smyth and Scam-
bler  appeared in 2005 concerning the genetics and
molecular biology of the syndrome, and of its homologs
in the mouse. Two papers by van Haelst and collabora-
tors in 2007 and 2008 [25,29] summarized the knowl-
edge then available about the Fraser syndrome as a result
of the study of 59 cases in 33 families. In 2011, a paper
was published  reviewing two autosomal recessive
syndromes which subsumed components of the Fraser
syndrome. In this paper, Manitoba-oculo-tricho-anal
(MOTA) syndrome and bifid nose, renal agenesis and
anorectal malformations (BNAR) syndrome were found
to be associated with mutations of the FREM1 gene.
It should be noted that the disabilities associated with
the fully expressed form of Fraser syndrome are even
more severe than those associated with the Down syn-
drome, and yet there are families who are bringing up
such children in an atmosphere of harmony and happi-
ness. Thus, recently, antenatal diagnosis of a fully af-
fected female fetus was not followed by an abortion but
rather by surgery involving the trachea, in order to re-
lieve the effects of laryngeal malformation—not gene
therapy in utero as yet, but at least surgical intervention
in fetal life leading to the survival of a fetus suffering
from a potentially fatal autosomal recessive disease .
Thus, the Fraser syndrome can manifest itself at the
very beginning of life in the fetus; it can also be present
throughout the entire gamut of years until extreme old
age. Although the prognosis for survival in individuals
born with this condition is, in general, poor, a case has
been reported  of a woman surviving to the age of 96
years when she died as the result of an accident. This
lady is truly a “Durchbrenner” (escaper) in the sense used
by Hadorn (1955) in the book  which I have already
I acknowledge with gratitude my contacts with two human beings who
were unfortunate in the lottery of the genes. Florina B (24/3/99 to
20/2/2008) and Michele S (born 16/6/1954). These contacts provided
me with moving experiences .
 Gaius Plinius Secundus (Pliny the Elder) (77-79) Natu-
 Zehender, W. and Manz (1872) Eine missgeburt mit hau-
tüberwachsenen augen oder kryptophthalmus. Klinische
Monatsblätter für Augenheilkunde, 4, 225-234.
 Michel Eyquem de Montaigne (1580) Of a monstrous
child. Essays (Second Book, 30).
 Golowin, S. (1902) Beiträge zur anatomie und patho-
genese des kryptophthalmus congenitus. Zeitschrift für
Augenheilkunde, 8,175-212. doi:10.1159/000289955
 Avižonis, P. (1928) Über kryptophthalmus congenitus.
Klinische Monatsblätter für Augenheilkunde, 64, 240-256.
 Asayama (1906) Vererbung von kryptophthalmus. Klinis-
Copyright © 2013 SciRes. OPEN ACCESS
G. R. Fraser / Open Journal of Genetics 3 (2013) 1-7
Copyright © 2013 SciRes.
che Monatsblätter für Augenheilkunde, 44, 346
 Down, J.H.L. (1866) Observations on an ethnic classifi-
cation of idiots. London Hospital Records, 3, 259-262.
 Lejeune, J., Gautier, M. and Turpin, R. (1959) Etude des
chromosomes somatiques de neuf enfants mongoliens.
Comptes Rendus Hebdomadaires des Séances de l’Aca-
démie des Sciences (Paris), 248, 1721-1722.
 Mendel, G. (1866) Versuche über pflanzen-hybriden.
Verhandlungen des Naturforschenden Vereines, Abhand-
lungen, Brünn, 4, 3-47.
 Fraser, G.R. (1962) Our genetical “load”. A review of
some aspects of genetical variation. Annals of Human
Genetics, 25, 38-414.
 Sinclair, W. (1918) A case of cryptophthalmos. Transac-
tions of the Ophthalmological Society UK, 38, 142-144.
 Fraser, G.R. and Friedmann, A.I. (1967) The causes of
blindness in childhood. A study of 776 children with se-
vere visual handicaps (with preface by L. S. Penrose).
Johns Hopkins Press, Baltimore.
 Fraser, G.R. (1976) The causes of profound deafness in
childhood. A study of 3535 individuals with severe hear-
ing loss present at birth or of childhood onset (with fore-
word by V. A. McKusick). Johns Hopkins University
Press, Baltimore and London.
 Hadorn, E. (1955) Letalfaktoren in ihrer bedeutung für
erbpathologie und genphysiologie der entwicklung. Thi-
 McKusick, V.A. (1966) Mendelian inheritance in man:
Catalogs of autosomal dominant, autosomal recessive and
X-linked phenotypes. Johns Hopkins Press, Baltimore.
 Buyse, M.L. (1983) Editorial comment. Journal of Clini-
cal Dysmorphology, 1, 32.
 Meinecke, P. (1986) Cryptophthalmos-syndactyly syn-
drome without cryptophthalmos. Clinical Genetics, 30,
 Winter, R.M. (1988) Malformation syndromes: A review
of mouse/human homology. Journal of Medical Genetics,
25, 480-487. doi:10.1136/jmg.25.7.480
 Winter, R.M. (1990) Fraser syndrome and mouse “bleb”
mutants. Clinical Genetics, 37, 494-495.
 Darling, S.M. and Gossler A. (1994) A mouse model for
Fraser syndrome. Clinical Dysmorphology, 3, 91-95.
 Little, C.C. and Bagg H.J. (1924) The occurrence of four
inheritable morphological variations in mice and their
possible relationship to treatment with X-rays. Journal of
Experimental Zoology, 41, 45-91.
 McGregor, L., Makela, V., Darling, S.M., Vrontou, S.,
Chalepakis, G., Roberts, C., et al. (2003) Fraser syn-
drome and mouse blebbed phenotype caused by muta-
tions in FRAS1/Fras1 encoding a putative extracellular
matrix protein. Nature Genetics, 34, 203-208.
 Vrontou, S., Petrou, P., Meyer, B.I., Galanopoulos, V.K.,
Imai, K., Yanagi, M., et al. (2003) Fras1 deficiency re-
sults in cryptophthalmos, renal agenesis and blebbed phe-
notype in mice. Nature Genetics, 34, 209-214.
 Pitera, J.E., Scambler, P.J. and Woolf, A.S. (2008) Fras1,
a basement membrane-associated protein mutated in Fra-
ser syndrome, mediates both the initiation of the mam-
malian kidney and the integrity of renal glomeruli. Hu-
man Molecular Genetics, 17, 3953-3964.
 van Haelst, M.M., Maiburg, M, Baujat, G, Jadeja, S,
Monti, E., Bland, E., et al. (2008) Molecular study of 33
families with Fraser syndrome: New data and mutation
review. American Journal of Medical Genetics Part A,
146A, 2252-2257. doi:10.1002/ajmg.a.32440
 Vogel, M.J., van Zon, P., Brueton, L., van Gijzen, M.,
van Tuil, M.C., Cox, P., et al. (2012) Mutations in GRIP1
cause Fraser syndrome. Journal of Medical Genetics, 49,
 Slavotinek, A.M. and Tifft, C.J. (2002) Fraser syndrome
and cryptophthalmos: Review of the diagnostic criteria
and evidence for phenotypic modules in complex mal-
formation syndromes. Journal of Medical Genetics, 39,
 Smyth, I. and Scambler, P.J. (2005) The genetics of Fra-
ser syndrome and the blebs mouse mutants. Human Mo-
lecular Genetics, 14, R269-R274.
 van Haelst, M.M., Scambler, P.J., Fraser Syndrome Col-
laborative Group and Hennekam, R.C.M. (2007) Fraser
syndrome: A clinical study of 59 cases and evaluation of
diagnostic criteria. American Journal of Medical Genetics
Part A, 143A, 3194-3203. doi:10.1002/ajmg.a.31951
 Slavotinek, A.M., Baranzini, S.E., Schanze, D., Labelle-
Dumais, C., Short, K.M., Chao, R., et al. (2011) Mani-
toba-oculo-tricho-anal (MOTA) syndrome is caused by
mutations in FREM1. Journal of Medical Genetics, 48,
 Kohl, T., Hering, R., Bauriedel, G., van de Vondel. P.,
Heep, A., Keiner, S., et al. (2006) Percutaneous feto-
scopic and ultrasound-guided decompression of the fetal
trachea permits normalization of fetal hemodynamics in a
human fetus with Fraser syndrome and congenital high
airway obstruction syndrome (CHAOS) from laryngeal
atresia. Ultrasound in Obstetrics and Gynecology, 27, 84-
 Impallomeni, M., Subramanian, D., Mahmood, N. and
Illes, J. (2006) Fraser syndrome in a 96-year-old female.
Age and Ageing, 35, 642-643. doi:10.1093/ageing/afl109
 Yap-Todos, E. and Yap, D. (2007) Michele, Florina, and
George Fraser: The cryptophthalmos story at the human
level. In: Mayo, O. and Leach, C., Eds., Fifty Years of
Human Genetics: A Festschrift and Liber Amicorum to
Celebrate the Life and Work of George Robert Fraser.
Wakefield Press, Kent Town, 299-308.