Smith-Magenis syndrome is a genetic syndrome associated with interstitial
deletions of chromosome 17p11.2. Main features include congenital
anomalies, abnormal behaviour and sleep/wake rhythm abnormalities.[1] The
latter have been shown to result from a reversed circadian rhythm of
melatonin.[2,3] Normally, secretion of melatonin peaks at night and is
minimal during the day. In Smith-Magenis syndrome mel...
Smith-Magenis syndrome is a genetic syndrome associated with interstitial
deletions of chromosome 17p11.2. Main features include congenital
anomalies, abnormal behaviour and sleep/wake rhythm abnormalities.[1] The
latter have been shown to result from a reversed circadian rhythm of
melatonin.[2,3] Normally, secretion of melatonin peaks at night and is
minimal during the day. In Smith-Magenis syndrome melatonin reaches a peak
in the daytime and is lowest during the night.[2,3] This results in early
onset and offset of sleep, frequent waking during the night and
hypersomnia during the day.[1]
The inversion of the circadian rhythm of melatonin in Smith-Magenis
syndrome can be considered as an extremely advanced or an extremely
delayed melatonin rhythm. The therapeutic consequences differ: melatonin
rhythm can maximally be delayed with exogenous melatonin administered 10
hours after endogenous melatonin onset and maximally be advanced by
exogenous melatonin administered 5 hours before endogenous melatonin onset.[4] We hypothesised that sleep disturbances in Smith-Magenis syndrome
result from an extremely advanced melatonin rhythm. Consequently, we
treated a patient with Smith-Magenis syndrome with melatonin, administered
after endogenous melatonin onset.
Case report
A boy with Smith-Magenis syndrome was referred to our outpatient clinic at
age eight years. He had been diagnosed with the syndrome at age three
years, after evaluation for developmental delay. The diagnosis had been
confirmed by demonstration of a 17p11.2 deletion by FISH analysis. At the
time of referral, the boy¡¦s parents reported serious disturbances of both
sleep and behaviour. Mean onset of sleep was at 7.30 pm, with mean waking
at 4.30 am. Moreover, there was frequent nocturnal waking and need for
naps during the day. The main behavioural symptoms experienced were
hyperactivity and tantrums. Because of this uncontrollable behaviour, the
boy had been institutionalised. The boy was treated with a morning regimen
of melatonin alone. Initially, melatonin 3 mg was administered at 4 am.
Over the next weeks, the time of administration was shifted towards 7 am,
and some time later to 8 am. Mean waking was delayed to 7 am, and
disappearance of both night awakenings and the need for naps during the
day were reported. The time of onset of sleep was not influenced by the
treatment. Thus, with treatment mean gain in sleep was two-and-a-half
hours. In addition, behavioural disturbances improved significantly with
this treatment as well. At the time of this report, the boy has been
treated with this regimen for over a year and results have been
consistently positive.
Discussion
Behavioural symptoms and sleep disturbances in Smith-Magenis syndrome have
a major impact on patients and their families. A therapeutic regimen using
beta1-adrenergic antagonists has been reported to improve both behaviour
and sleep disturbances in Smith-Magenis syndrome.[5] More recently,
addition of evening melatonin suppletion to this regimen has been reported
to enhance this positive effect.[6] Nine children were treated with a
combination of morning acebutolol and evening melatonin, which resulted in
a mean delay in sleep onset of 30 minutes and in waking by 60 minutes. The
mean gain in sleep in this report was 30 minutes (rate not mentioned). The
authors do not mention the considerations for administration of melatonin
in the evening. Yet, evening suppletion seems logical, as by this the
melatonin peak is reached at its physiological time at night.
As mentioned, we postulated that sleep disturbances in Smith-Magenis
syndrome result from an extremely advanced melatonin rhythm. From the
observations of the natural sleep-wake rhythm in our patient, we
considered the endogenous melatonin onset to be around 7 p.m. Previous
observations have shown serum melatonin peaks around this time in several
other Smith-Magenis patients.[3,5,6] Consequently, we treated our patient
with melatonin administered several hours after this moment, with the time
of administration gradually being shifted towards a normal waking time.
With this treatment, the boy¡¦s waking time shifted along with the time of
administration. By this, eventual gain in sleep was two-and-a-half hours.
In contrast, De Leersnijder et al. reported a mean gain in sleep of 30
minutes with melatonin and acebutolol, and no gain in sleep as much as two
-and-a-half hours was reached in any of the nine children studied.[6]
This suggests that a treatment regimen with morning melatonin may be more
successful in restoring a normal sleep pattern in Smith-Magenis syndrome
than is treatment with both a beta1-adrenergic antagonist and evening
melatonin. Thus far, our observations have been limited to a single case.
Yet, in our opinion the results of treatment in this case are solid and
may point to a new direction in the search of adequate therapy of sleep
disturbances in Smith-Magenis syndrome.
The observations in this case support our hypothesis that sleep
disturbances in Smith-Magenis syndrome are due to advancement of the
endogenous melatonin rhythm. The circadian disorder in Smith-Magenis
syndrome may well reflect an Advanced Sleep Phase Syndrome, characterised
by an advanced sleep-wake and melatonin rhythm.[7] In this syndrome, a
defect in the Per2 clock gene has been demonstrated,[8] whereas in the
Delayed Sleep Phase Syndrome, characterised by a delayed sleep-wake and
melatonin rhythm, a defective Per3 clock gene has been found.[9] Clock
genes of Smith-Magenis patients are currently under investigation and may
provide further insight in the nature of the underlying sleep syndrome.
References
(1) Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J, Killian J, Murphy
MA, Williamson D, Brown F, Dutton R, McCluggage C, Friedman E, Sulek M,
Lupski JR. Multi-disciplinary clinical study of Smith-Magenis syndrome
(deletion 17p11.2). Am J Med Genet 1996;62(3): 247-54.
(2) Potocki L, Glaze D, Tan DX, Park SS, Kashork CD, Shaffer LG, Reiter RJ,
Lupski JR. Circadian rhythm abnormalities of melatonin in Smith-Magenis
syndrome. J Med Genet 2000;37:428-433.
(3) De Leersnyder H, De Blois, MC, Claustrat B, Romana S, Albrecht U, Von
Kleist-Retzow JC, Delobel B, Viot G, Lyonnet S, Vekemans M, Munnich A.
Inversion of the circadian rhythm of melatonin in the Smith-Magenis
syndrome. J Pediatr 2001;139:111-116.
(4) Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian
rhythm according to a phase-response curve. Chronobiol Int 1992;9(5):380-392.
(5) De Leersnyder H, De Blois MC, Vekemans M, Sidi D, Villain E, Kindermans
C, Munnich A. ƒÒ1-adrenergic antagonists improve sleep and
behavioural disturbances in a circadian disorder, Smith-Magenis syndrome. J Med Genet 2001;38:586-590.
(6) De Leersnyder H, Bresson JL, De Blois MC, Souberbiele JC, Mogenet A,
Delhotal-Landes B, Salefranque F, Munnich A. ƒÒ1-adrenergic
antagonists and melatonin reset the clock and restore sleep in a circadian
disorder, Smith-Magenis syndrome. J Med Genet 2003; 40:74-78.
(7) Wiz-Justice A, Armstrong SM. Melatonin: nature¡¦s soporific? J Sleep Res
1996; 5(2):137-141.
(8) Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH.
An hPer2 phosphorylation site mutation in familial advanced sleep phase
syndrome. Science 2001;291(5506):1040-1043.
(9) Archer NS, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J,
Schantz MV. A length polymorphism in the circadian clock gene Per3 is
linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 2003;26:413-415.
This letter is in reference to the recent article by Zito et al.[1]
This
very interesting article presents evidence for the association
between a frameshift mutation (845-846delTG) in exon 8 of the
RPGR gene and an X-linked syndrome inclusive of retinitis
pigmentosa, impaired hearing and sino-respiratory infections.
We would like to take this opportunity to draw the readers’...
This letter is in reference to the recent article by Zito et al.[1]
This
very interesting article presents evidence for the association
between a frameshift mutation (845-846delTG) in exon 8 of the
RPGR gene and an X-linked syndrome inclusive of retinitis
pigmentosa, impaired hearing and sino-respiratory infections.
We would like to take this opportunity to draw the readers’
attention to our companion paper,[2] forthcoming in the November
issue of the Journal of Medical Genetics, in which we provide
evidence for an American family with an identical phenotype
associated with a missense mutation (G173R) in the RPGR gene.
In our work, we corroborate the clinical conclusion of a plausible
association between this newly characterized syndrome and
defects in RPGR function reached by Zito et al.[1] and our group
by providing immunohistochemical evidence that not only RPGR is
expressed in the human retina, but also along the luminal side of
the epithelial lining of human bronchi and sinuses, and at several
locations within the human and monkey cochlea.[2] The latter
pattern of expression is consistent with the possibility that defective
RPGR function could lead to hearing loss independently of
recurrent otitis as a result of a sensorineural mechanism.
Indeed, the report of Zito et al.[1] and ours [2] follow previous
ones
in which either recurrent infections [3,4] or pure sensorineural
hearing loss [5] had been observed independently in association
with X-linked retinitis pigmentosa and RPGR gene defects. In
addition, in parallel to the work of our groups, Hong et al.[6] have
recently provided corroboration to our human findings by
identifying expression of RPGR also in the epithelial lining of the
mouse trachea.
In summary, these novel findings provide evidence in favor of a
broader phenotypic range in association with RPGR mutations
than previously recognized and suggest an important role for
RPGR also in the respiratory tract and in the cochlea. Even when a
history of infections is present, the observed clinical phenotype
can be easily confused with that of Usher syndrome and, in some
cases, can be indistinguishable from it.[5] The counseling
implications of an incorrect diagnosis of Usher syndrome, which is
transmitted as an autosomal recessive trait, are immediately
evident. Diagnosing this newly recognized clinical entity of X-
linked pseudo-Usher syndrome will require a high degree of
awareness and a high index of suspicion by ophthalmologists,
geneticists, otolaryngologists, and pediatricians alike.
References
(1) Zito I, Downes SM, Patel RJ, Cheetham ME, Ebenezer ND,
Jenkins SA, Bhattacharya SS, Webster AR, Holder GE, Bird AC,
Bamiou DE, and Hardcastle AJ. RPGR mutation associated with
retinitis pigmentosa, impaired hearing, and sinorespiratory
infections. J Med Genet 2003;40:609-615.
(2) Iannaccone A, Breuer DK, Wang XF, Kuo SF, Normando EM,
Filippova E, Baldi A, Hiriyanna S, MacDonald CB, Baldi F,
Cosgrove D, Morton CC, Swaroop A, Jablonski MM. Clinical and
immunohistochemical evidence for an X-linked retinitis
pigmentosa syndrome with recurrent infections and hearing loss in
association with an RPGR mutation. J Med Genet 2003; 40 (in press).
(3) van Dorp DB, Wright AF, Carothers AD, Bleecker-Wagemakers
EM. A family with RP3 type of X-linked retinitis pigmentosa: an
association with ciliary abnormalities. Hum Genet 1992;88:331-4.
(4) Dry KL, Manson FDC, Lennon A, Bergen AAB, van Dorp DB,
Wright AF. Identification of a 5'splice site mutation in the RPGR
gne in a family with X-linked retinitis pigmentosa (RP3). Hum Mutat
1999;13:141-5.
(5) Rosenberg T, Haim M, Hauch A-M, Parving A. The prevalence
of Usher syndrome and other retinal dystrophy-hearing impairment
associations. Clin Genet 1997;51:314-21.
(6) Hong D-H, Pawlyk B, Sokolov M, Strissel KJ, Yang J, Tulloch B,
Wright AF, Arshavsky VY, Li T. RPGR isoforms in photoreceptor
connecting cilia and the transitional zone of motile cilia. Invest Ophthalmol Vis Sci 2003;44:2413–21.
In their letter Ayoub et al. suggest that Peutz-Jeghers Syndrome (PJS)
can be distinguished from Laugier Hunziker Syndrome (LHS) by histological
examination of the pigmented macules[1] and suggest that the
pigmented macules in PJS are histologically lentigos showing increased
numbers of normal melanocytes whereas in LHS the histology shows no
increase in melanocyte numbers. They support their ar...
In their letter Ayoub et al. suggest that Peutz-Jeghers Syndrome (PJS)
can be distinguished from Laugier Hunziker Syndrome (LHS) by histological
examination of the pigmented macules[1] and suggest that the
pigmented macules in PJS are histologically lentigos showing increased
numbers of normal melanocytes whereas in LHS the histology shows no
increase in melanocyte numbers. They support their argument with three
references (Calnan, 1960; Dupre and Viraben, 1990; Ortonne, 1999).[2-4] Based
on a wider assessment of the literature we do not believe that the
histological findings in PJS and LHS are as distinct as Ayoub et al.
suggest.
The following reports have shown no increase in melanocyte numbers in PJS.
Yamada et al. reported three cases of PJS in which they had examined
samples of the pigmented macules with both light and electron microscopy.[5] They found pigmentation in the basal layer of the
epidermis with no differences between the lesions and normal skin in the
number of melanocytes. These findings were consistent at all sites studied
which included the lip, fingers and toes. The dendrites of the melanocytes
in the lesions were longer and more branched than those in normal skin.
Gregory and Ho in their review of the cutaneous manifestations of
gastrointestinal disorders described the pigmented macules of PJS as
showing increased melanin granules in the basal layer keratinocytes and
dermis and either normal or increased numbers of melanocytes.[6] Other articles have reported elevated numbers of melanocytes.[4,7] One is forced to conclude that in PJS there
can either be normal or increased melanocytes in the pigmented macules
compared with normal skin.
In the case of LHS the majority of reports of LHS show normal melanocyte
numbers on histology .[8,9] One
report describes an increase in melanocyte numbers in LHS.(10)
In conclusion in both PJS and LHS there are reports of both normal
and increased numbers of melanocytes within the pigmented macules. We
therefore disagree with Ayoub et al and suggest that at present there is
uncertainty about the nature of the histological appearances of PJS and
LHS. Taken on their own the histological features are not diagnostic and
over-reliance on histology in the diagnosis of these syndromes could lead
to diagnostic error.
We agree that genetic screening is not required routinely in all cases of
suspected LHS. It is interesting to speculate that some of the confusion
alluded to above arises from incorrect clinical diagnosis. In our patient
the diagnosis was made clinically based on the late appearance of
pigmentation, the history of negative GI investigation and on the clinical
dermatological findings.[11] Formal genetic screening was
only performed at the request of the reviewers.
References
(1) Ayoub, N. M. (2003). Dissimilar histological features in Peutz-
Jeghers syndrome and Laugier-Hunziker syndrome. Journal of Medical
Genetics 40, e77.
(2) Calnan CD. The Peutz-Jeghers syndrome. Trans St John'sHosp Dermatol
Soc 1960; 44: 58-64.
(3) Dupre, A., and Viraben, R. (1990). Laugier's disease. Dermatologica
181, 183-6.
(4) Ortonne, J. (1999). Les troubles de la pigmentation cutanee. In
Dermatologie et maladies sexuellment transmissibles, G. E. Saurat JH,
Laugier P, Lachapelle JM, ed. (Paris: Masson), pp. 407-426.
(5) Yamada, K., Matsukawa, A., Hori, Y., and Kukita, A. (1981).
Ultrastructural studies on pigmented macules of Peutz-Jeghers syndrome. J
Dermatol 8, 367-77.
(6) Gregory, B., and Ho, V. C. (1992). Cutaneous manifestations of
gastrointestinal disorders. Part I. J Am Acad Dermatol 26, 153-66.
(7) McKee, P. Pathology of the skin, Second Edition (London: Mosby-
Wolfe).
(8) Kemmett, D., Ellis, J., Spencer, M. J., and Hunter, J. A. (1990). The
Laugier-Hunziker syndrome--a clinical review of six cases. Clin Exp
Dermatol 15, 111-4.
(9) Veraldi, S., Cavicchini, S., Benelli, C., and Gasparini, G. (1991).
Laugier-Hunziker syndrome: a clinical, histopathologic, and
ultrastructural study of four cases and review of the literature. J Am
Acad Dermatol 25, 632-6.
(10) Koch, S. E., LeBoit, P. E., and Odom, R. B. (1987). Laugier-Hunziker
syndrome. J Am Acad Dermatol 16, 431-4.
(11) Lampe, A. K., Hampton, P. J., Woodford-Richens, K., Tomlinson, I.,
Lawrence, C. M., and Douglas, F. S. (2003). Laugier-Hunziker syndrome: an
important differential diagnosis for Peutz-Jeghers syndrome. J Med Genet
40, e77.
We read with attention and interest the eLetter by Been et al.[1] We would like to reply.
We agree with the author that Smith-Magenis syndrome (SMS)
may be may be an extremely advanced sleep phase syndrome. The definition
of this advanced sleep phase syndrome is based actually on clinical
evaluation and melatonin dosages. A mutation of Perclock gene was found
in families with familial...
We read with attention and interest the eLetter by Been et al.[1] We would like to reply.
We agree with the author that Smith-Magenis syndrome (SMS)
may be may be an extremely advanced sleep phase syndrome. The definition
of this advanced sleep phase syndrome is based actually on clinical
evaluation and melatonin dosages. A mutation of Perclock gene was found
in families with familial advances sleep phase syndrome, but there is no
evidence of this mutation in non familial cases and Per gene is not
deleted in SMS.
Following this hypothesis, it is of interest to try a treatment by
melatonin in the morning to reset the melatonin secretion of this hormone
in SMS. That is what the authors of the letter did, with success.
Meanwhile, there is only one case studied, and they have no objective
proof of the results, such as plasmatic melatonin dosages or
polysomnography or actimetry recordings.
In our study, the main purpose was to act on the symptoms and to blockade
the endogenous melatonin secretion to improve day behaviour
(hyperactivity, tantrums, excessive daytime sleepiness) and then reset the
clock by adding melatonin in the evening. Our study in 9 children is
confirmed by melatonin dosages and actimetry recordings.
The mechanism of melatonin phase shift in SMS is not yet known, and
treatment approach acting on the mechanism as L. Bok did is very
interesting and the good results he obtained encourage further studies. In
the same order we could imagine using phototherapy in the morning in SMS.
The difficulty is to have large series of patients of this rare disorder,
and to make double-blind series if possible, with bioethical approved
protocols.
Reference
(1) Been J et al. Improvement of sleep disturbances and behaviour in Smith-Magenis syndrome with morning melatonin [electronic response to de Leersnyder et al. Beta-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome] jmedgenet.com 2003http://jmg.bmjjournals.com/cgi/eletters/40/1/74#30
Wilcken et al, (2003), in “Geographical and ethnic variation of the
677C>T allele of the 5,10 methylenetetrahydrofolate reductase (MTHFR):
finds from over 7000 newborns from 16 areas worldwide” showed that the TT
genotype in Calgary, Alberta was present in 5.8% of newborns as compared
to one previous report from Quebec of 11% [Infante-Rivard et al., 2003].
The authors did not explain why this...
Wilcken et al, (2003), in “Geographical and ethnic variation of the
677C>T allele of the 5,10 methylenetetrahydrofolate reductase (MTHFR):
finds from over 7000 newborns from 16 areas worldwide” showed that the TT
genotype in Calgary, Alberta was present in 5.8% of newborns as compared
to one previous report from Quebec of 11% [Infante-Rivard et al., 2003].
The authors did not explain why this difference was present, but they did
state that the latter study was drawn from a selected population of
infants over the 10th percentile, whereas their own study involved
consecutive newborns.
We suggest that the difference in the frequency seen in Alberta and
Quebec more likely reflects the ethnic origin of Albertans versus the
Quebeçois. Most Quebec residents are descendants of immigrants from France
and the province has a larger proportion of Greeks and Italians compared
to other Canadian jurisdictions. Caucasians in Alberta are generally the
descendants of Northern and Eastern Europeans with 50% of the population
being descendents of immigrants from the UK and Ireland [Population by
ethnic origin,1996]. French, Italy and Greece all have a higher frequency
of C677T MTHFR than eastern and northern European countries. Therefore, it
is not surprising that the Quebeçois also have higher frequencies than
Albertans. There have also been five other C677T MTHFR association studies
in Quebec that included small control groups variously selected with
homozygote frequencies ranging from 11 to 16% [Deloughery et al., 1996,
Christensen et al., 1997, 1999, Delvin 2000, Merouani et al., 2001.]
The largest single study of C677T MTHFR frequency was conducted using
newborn screening filter paper cards here in Manitoba. Mogk et al (2000),
genotyped 977 consecutive Manitoba newborns for the 677 C>T
polymorphism and found the frequency of 677 C>T homozygotes to be 7%.
The percentage of TT genotypes in Manitoba is 7% (36% heterozygotes).
Manitoba has the second largest ethnically French population in Canada and
has a substantial Metis (French/Aboriginal) population. We would therefore
expect the frequency in Manitoba to be intermediate between that of Quebec
and Alberta, as our data indicate. It is our opinion that both the 5.8%
Alberta result and the 11% Quebec result are accurate estimates of the
frequencies of this variant in these two ethnically different Canadian
provinces.
Reference
(1) Population by ethnic origin, 1996 Census, provinces and
territories.2003a. Statistics Canada
(2) Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt
R, Gilfix BM, Rosenblatt DS, Gravel RA, Forbes P, Rozen R.5-21-
1999.Genetic polymorphisms in methylenetetrahydrofolate reductase and
methionine synthase, folate levels in red blood cells, and risk of neural
tube defects. Am J Med Genet 84:151-157.
(3) Christensen B, Frosst P, Lussier-Cacan S, Selhub J, Goyette P,
Rosenblatt DS, Genest J, Jr., Rozen R.1997.Correlation of a common
mutation in the methylenetetrahydrofolate reductase gene with plasma
homocysteine in patients with premature coronary artery disease.
Arterioscler Thromb Vasc Biol 17:569-573.
(4) Deloughery TG, Evans A, Sadeghi A, McWilliams J, Henner WD,
Taylor LM, Jr., Press RD.12-15-1996.Common mutation in
methylenetetrahydrofolate reductase. Correlation with homocysteine
metabolism and late-onset vascular disease. Circulation 94:3074-3078.
(5) Delvin EE, Rozen R, Merouani A, Genest J, Jr., Lambert
M.2000a.Influence of methylenetetrahydrofolate reductase genotype, age,
vitamin B-12, and folate status on plasma homocysteine in children. Am J
Clin Nutr 72:1469-1473.
(6) Infante-Rivard C, Rivard GE, Yotov WV, Genin E, Guiguet M,
Weinberg C, Gauthier R, Feoli-Fonseca JC.7-4-2002.Absence of association
of thrombophilia polymorphisms with intrauterine growth restriction. N
Engl J Med 347:19-25.
(7) Merouani A, Lambert M, Delvin EE, Genest J, Jr., Robitaille P,
Rozen R.2001.Plasma homocysteine concentration in children with chronic
renal failure. Pediatr Nephrol 16:805-811.
(8) Mogk RL, Rothenmund H, Evans JA, Carson N, Dawson AJ.2000b.The
frequency of the C677T substitution in the methylenetetrahydrofolate
reductase gene in Manitoba. Clin Genet 58:406-408.
(9) Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Redlund M, Stoll
C, Alembik Y, Dott B, Czeizel AE, Gelman-Kohan Z, Scarano G, Bianca S,
Ettore G, Tenconi R, Bellato S, Scala I, Mutchinick OM, Lopez MA, de Walle
H, Hofstra R, Joutchenko L, Kavteladze L, Bermejo E, Martinez-Frias ML,
Gallagher M, Erickson JD, Vollset SE, Mastroiacovo P, Andria G, Botto
LD.2003b.Geographical and ethnic variation of the 677C>T allele of 5,10
methylenetetrahydrofolate reductase (MTHFR): findings from over 7000
newborns from 16 areas world wide. J Med Genet 40:619-625.
We read with great interest the report by Sng et al. [1] in which the
authors reported that the BRCA1 frameshift mutation 2845insA could be a
founder mutation in Malay breast or ovarian cancer patients in Singapore.
This mutation results in protein truncation at codon 914.
We would like to take this opportunity to draw the readers’ attention
to our work on BRCA1 mutations among Singapo...
We read with great interest the report by Sng et al. [1] in which the
authors reported that the BRCA1 frameshift mutation 2845insA could be a
founder mutation in Malay breast or ovarian cancer patients in Singapore.
This mutation results in protein truncation at codon 914.
We would like to take this opportunity to draw the readers’ attention
to our work on BRCA1 mutations among Singapore breast cancer patients. In
the initial study comprising 43 women with early-onset breast cancer
(before age 36), the same deleterious mutation as that reported by Sng et
al. was identified in 2 of 7 unrelated Malay women.[2] This led to a
further study on 49 unrelated Malay breast cancer patients, the results of
which were published in Human Mutation in August 2003.[3] Three patients
and three relatives of these patients carried the frameshift mutation.
Haplotype analysis using the microsatellite markers D17S855, D17S1323 and
D17S1325 showed a common haplotype for these cases and their relatives
with the mutation. This common haplotype was not seen in any of the
controls in both studies.[1,3]
In the report by Sng et al. [1], haplotype analysis of family members
of the six patients with the mutation was not done, as samples from
relatives were not available then, but this work is currently underway.
Haplotype analysis of the parents of two of the patients in our study,[3]
showed segregation of haplotypes to the patients, supporting the
suggestion that this may be a founder mutation.
In contrast to the studies on Singaporean Malays, this 2845insA
mutation was not detected in any of the 16 Malay breast cancer patients
from Malaysia.[4] However, this may be due to the small sample size in
that study.
The results of Sng et al. are consistent with ours, which strongly
suggest that the 2845insA mutation is a founder mutation in breast cancer
patients of Malay ethnicity. Indeed, once validated with a larger cohort
of Malays, comprising both breast cancer patients and normal subjects,
these results would facilitate genetic counselling and screening of
Malays.
References
(1) Sng J-H, Ali AB, Lee SC, Wong JEL, Blake V, Sharif A, Cross G,
Iau PTC. BRCA1 c.2845insA is a recurring mutation with a founder effect in
Singapore Malay women with early-onset breast/ovarian cancer. J Med Genet
2003;40:e117.
(2) Ho GH, Phang BH, Ng IS, Law HY, Soo KC, Ng EH. Novel germline
BRCA1 mutations detected in women in Singapore who developed breast
carcinoma before the age of 36 years. Cancer 2000;89:811-6.
(3) Lee ASG, Ho GH, Oh PC, Balram C, Ooi LL, Lim DTH, Wong CY, Hong
GS. Founder mutation in the BRCA1 gene in Lalay breast cancer patients
from Singapore. Hum Mutat 2003;22:178.
(4) Balraj P, Khoo AS, Volpi L, Tan JA, Nair S, Abdullah H. Mutation
analysis of the BRCA1 gene in Malaysian breast cancer patients. Singapore
Med J 2002;43:194-7.
We thank Dr Selvan for his comments [1] on our paper.[2] Cyrillic 3 does indeed use the BRCAPRO and MENDEL models. With regards to our use of BRCAPRO, we would like to draw his attention to the official Cyrillic 3 homepage [3] where it states clearly that the BRCAPRO plug-in calculates risk
based on the “Bayes’ rules of determination of the probability of a mutation, given family history. An estimate of th...
We thank Dr Selvan for his comments [1] on our paper.[2] Cyrillic 3 does indeed use the BRCAPRO and MENDEL models. With regards to our use of BRCAPRO, we would like to draw his attention to the official Cyrillic 3 homepage [3] where it states clearly that the BRCAPRO plug-in calculates risk
based on the “Bayes’ rules of determination of the probability of a mutation, given family history. An estimate of the mutation frequencies in the normal population [4,5] and among Ashkenazi Jews [6] provides the probability of the mutation in the proband, prior to the ascertainment of family history.” In summary, the BRCAPRO software included in Cyrillic 3 gives the option of using three population models on which it bases its results - Claus et al 1994, Ford et al 1998 and Streuwing et al 1997. The guidelines for using BRCAPRO within Cyrillic 3 were followed and we generated results for
unaffected family members using both the Ford and Claus results. As was clearly stated in our paper "Claus and Ford risks were calculated using a plug-in for the Cyrillic 3 package, a software package designed to display family pedigrees for use in clinical genetics and genetic counselling." All results were subsequently described as Claus or Ford. Having to state that they had been derived from a BRCAPRO plug-in every time would have been unwieldy.
In the Study tools section we clearly state: "Computerized risk assessment packages Gail, BRCAPRO (Claus and Ford) and Tyrer-Cuzick were tested on this population". While we were a little ambiguous in the paragraphs before this, we think this sentence is perfectly clear in explaining what we were doing and as the correspondent acknowledges, he is not familiar with Cyrillic 3. We are not sure how much clearer we could have been.
With regard to the rest of the correspondence this appears to be an advert to use the CancerGene software programme. Although Dr Selvan does distinguish between models that merely predict the likelihood of a mutation being present (Myriad I and II, [7]), those that just predict breast cancer risk over time [8,9] and those that purport to do both (BRCAPRO) our paper was only addressing breast cancer risk. Although we did not use a direct download of the BRCAPRO, we have no reason to
believe that the results would have been any different if we had. BRCAPRO appears to underestimate breast cancer risk over time because it assumes that all inherited breast cancer is due to mutations in BRCA1 or BRCA2. The Ford element of this involves the use of the Ford et al [5] penetrance figures in the BRCAPRO algorithm as opposed to those of Claus [8].
References
1. Selvan, M. Breast cancer risk prediction models. Rapid Respone, www.jmedgenet.com.
2. Amir E, Evans DG, Shenton A, Lalloo F, Moran A, Boggis C, Wilson M,
Howell A. Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet. 2003 Nov;40(11):807-14.
3. About BRCAPro in Cyrillic 3. Accessed on: 14th April 2004. Details available at:
http://www.cyrillicsoftware.com/support/cy3brca.htm
4. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic
attributable risk of breast and ovarian cancer. Cancer. 1996;77(11):2318-
24.
5. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop
DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J,
Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S,
Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M
and the Breast Cancer Linkage Consortium. Genetic Heterogeneity and
Penetrance Analysis of the BRCA1 and BRCA2 genes in breast cancer
families. Am J Hum Genet 1998;62:676-89
6. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M,
Timmerman MM, Brody LC, Tucker MA (1997) The risk of cancer associated
with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New
England Journal of Medicine 336:1401-1408
7. Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 mutations in women
attending clinics that evaluate the risk of breast cancer. N Engl J Med
1997; 336:1409-1415.
8. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of
early onset breast cancer:implications for risk prediction. Cancer
1994;73:643-51
9. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized
probabilities of developing breast cancer for white females who are being
examined annually. J Natl Cancer Inst 1989; 81(24):1879-1886.
Berry DA, Parmigiani G, Sanchez J, et al. Probability of carrying a
mutation of breast-ovarian cancer gene BRCA1 based on family history. J
Natl Cancer Inst 1997; 89(3):227-238.
Cyrillic 3.0 pedigree software. Accessed on: March 30th, 2004.
Details available at:
http://www.exetersoftware.com/cat/cyrillic/cyrillic.html
Frank TS, Manley SA, Olopade OI et al. Sequence analysis of BRCA1 and
BRCA2: Correlation of mutations with family history and ovarian cancer
risk. J Clin Oncol 1998; 16:2417-2425.
Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities
for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet
1998; 62(1): 145-158.
Shattuck-Eidens D, Oliphant A, McClure M et al. BRCA1 sequence
analysis in women at high risk for susceptibility mutations. Risk factor
analysis and implications for genetic testing. JAMA 1997; 278:1242-1250.
The University of Texas Southwestern Medical Center at Dallas.
CancerGene. Available at
http://www3.utsouthwestern.edu/cancergene/index.ht
I would like to bring to your attention an error with respect to the
original article by Amir et al.[1]
The paper validated a few available breast cancer risk
prediction models and compared them to the Tyrer-Cuzick model.[2] From the paper by Amir et al., I understand that they used
the Cyrillic plug-in to estimate breast cancer risk (Cyrillic 3.1
Version). Although, I am only fa...
I would like to bring to your attention an error with respect to the
original article by Amir et al.[1]
The paper validated a few available breast cancer risk
prediction models and compared them to the Tyrer-Cuzick model.[2] From the paper by Amir et al., I understand that they used
the Cyrillic plug-in to estimate breast cancer risk (Cyrillic 3.1
Version). Although, I am only familiar with Cyrillic version 2.1,
according to the home page for Cyrillic 3.1, it calculates risk
assessments according to the BRCAPRO and Mendel models. In their paper,
the authors referred to the Ford model [3] and at times to
the Claus models as the BRCAPro model, which is not correct. It will be
good to clarify on this to the research community, as this paper is an
important reference in breast cancer research in perspectives of risk
estimation and model development. BRCAPRO [4,5] is one of the eight models available through the
CancerGene program [6,7] Amir et al.[1] consistently made this mistake in their paper: in the introduction, study
tools section, Table 4, Table 5, Table 9, and in Figure 1. Clarification
of what models were validated for their data is needed.
The risk models most widely used in breast cancer research, and in
clinical and genetic counseling are the Gail model,[8] the
Claus model, [9,10] BRCAPRO,[4,5] Myriad I, also called the Shattuck-Eidens model,[11] Myriad II, also called the Frank model,[12] the Couch model,[13] also known as
the UPenn model, the NCI model,[14] and the Family
History Assessment Tool.[15] Among them, BRCAPRO
estimates the probability of an individual being a carrier of a
deleterious BRCA-1 or -2 mutation, along with estimating the predicted
breast cancer risk, while the Gail and Claus models are empirical models
developed prior to the identification of the BRCA genes. The Myriad and
Couch models are empirical models to estimate the probability of BRCA1 or
BRCA2 mutations. CancerGene,[6,7] is a
software program that incorporates all the aforementioned models into a
single software package. After all the pedigree information and other
epidemiological risk factors required for each of these models have been
entered, CancerGene calculates the risk for each model separately. The
best feature of the program is its ability to calculate an individual
woman’s predicted risk values and outputs from all these models, allowing
an oncologist, genetic counselor, researcher, or physician to compare the
values of predicted risk.
References
1. Amir E, Evans DG, Shenton A, Lalloo F, Moran A, Boggis C, Wilson M,
Howell A. Evaluation of breast cancer risk assessment packages in the
family history evaluation and screening programme. J Med Genet. 2003
Nov;40(11):807-14.
2. Tyrer JP, Duffy SW, Cuzick J. A breast cancer prediction model
incorporating familial and personal risk factors. Statist. Med. 2004;
23:1111–1130
3. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, the Breast Cancer
Linkage Consortium. Risk of cancer in BRCA-1 mutation carriers. Lancet
1994;343:692–5.
4. Berry DA, Parmigiani G, Sanchez J, et al. Probability of carrying a
mutation of breast-ovarian cancer gene BRCA1 based on family history. J
Natl Cancer Inst 1997; 89(3):227-238.
5. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities
for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet
1998; 62(1): 145-158.
6. Euhus DM. Understanding mathematical models for breast cancer risk
assessment and counseling. Breast J 2001; 7(4):224-232.
7. Euhus DM, Smith KC, Robinson L, Stucky A, Olopade OI, Cummings S,
Garber JE, Chittenden A, Mills GB, Rieger P, Esserman L, Crawford B,
Hughes KS, Roche CA, Ganz PA, Seldon J, Fabian CJ, Klemp J, Tomlinson G.
Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the
computer model BRCAPRO. J Natl Cancer Inst 2002; 94(11):844-851.
8. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized
probabilities of developing breast cancer for white females who are being
examined annually. J Natl Cancer Inst 1989; 81(24):1879-1886.
9. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the cancer and steroid hormone study.
Am J Hum Genet. 1991;48(2):232-42.
10. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early onset breast cancer:implications for risk prediction. Cancer 1994;73:643-51
11. Shattuck-Eidens D, Oliphant A, McClure M et al. BRCA1 sequence
analysis in women at high risk for susceptibility mutations. Risk factor
analysis and implications for genetic testing. JAMA 1997; 278:1242-1250.
12. Frank TS, Manley SA, Olopade OI et al. Sequence analysis of BRCA1 and
BRCA2: Correlation of mutations with family history and ovarian cancer
risk. J Clin Oncol 1998; 16:2417-2425.
13. Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 mutations in women
attending clinics that evaluate the risk of breast cancer. N Engl J Med
1997; 336:1409-1415.
14. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. The
prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J
Hum Genet. 1999 Apr;64(4):963-70.
15. Gilpin CA, Carson N, Hunter AG. A preliminary validation of a family
history assessment form to select women at risk for breast or ovarian
cancer for referral to a genetics center. Clin Genet 2000; 58(4):299-308.
We read with interest a recent report in your journal by
Jakkula et al.[1] on two families of multiple epiphyseal
dysplasia (MED) with the recurrent R718W mutation in COMP.
Key points of the report are: 1) In a family (family 1),
two children presented with muscular weakness and all four
family members with R718W showed moderate rise in plasma
creatine kinase...
We read with interest a recent report in your journal by
Jakkula et al.[1] on two families of multiple epiphyseal
dysplasia (MED) with the recurrent R718W mutation in COMP.
Key points of the report are: 1) In a family (family 1),
two children presented with muscular weakness and all four
family members with R718W showed moderate rise in plasma
creatine kinase (CK), indicating possible association of
myopathy; 2) In both families, the skeletal change is more
severe in the knee joint than in the hip joint. This
observation contradicts to the previous assumption of
genotype-phenotype association, i.e. presence of
dysplastic capital femoral epiphyses and severely irregular
acetabuli is suggestive of COMP mutations, while dysplastic
changes in patients with collagen IX mutation are mainly
seen in the knees and the hips are relatively spared.[2,3]
We previously experienced a MED family with three affected
individuals harboring the same R718W mutation.[4] Here we
describe their clinical and radiographic features for
comparison and further discussion.
The proband was a 64-year-old factory laborer who presented
with bilateral coxalgia at aged 56 years that had started 2
years. His height was 152 cm (nearly Ð3 SD), and his
weight 53.5 kg. He had no history of muscle weakness.
Physical examination had no indication of myopathy. His CK
was 67 (normal range: 50-170) U/L, and was kept within the
normal range during the follow-up period. Radiographic
examination showed severe osteoarthritic (OA) changes in
both hip joints (Figure 1A). The OA changes were minimal in
knee, ankle, foot, shoulder, elbow, hand and wrist joints
(Figure 1B and C). Only an episode of transient pain in the left
knee was noted as well as transient pain in the right
elbow, the right shoulder and the left hand. The hip pain
could not be controlled by medication, and he underwent
bilateral total hip replacement at aged 57 years.
Figure 1 Radiographs of the proband aged 56 years.
A) Hip. Terminal
osteoartritic (OA) changes.
B) The left knee. Mild
dysplasia with flattend femoral chondyle and tibial spine.
C) The right hand. Advanced OA of the MP (metacarpo-
phalangeal) and CM (carpo-metacarpal) joints.
The daughter of the proband, a 37-year-old housewife, had
the bilateral knee pain; the right since the age 32 years
and the left since the age 35 years, respectively. She had
no symptom in other joints. Physical examination revealed
no remarkable findings. Her height was 156 cm, and her
weight 51 kg. The son of the proband was a 33-year-old
factory worker. His height was 161 cm, and his weight 57
kg. He was found to have MED when he visited us because of
the injury of the anterior cruciate ligament of the right
knee. He had occasional vague pain in the right knee on
climbing stairs, but had no symptom in other joints. Both
individuals had no sign and symptom of myopathy. Their CK
levels were normal (80 and 123 U/L). Radiographic
examination identified dysplasia of the hip, knee, and the
1st and 2nd metatarsal joints in both patients (Fig. 2).
Hip dysplasias were marked in the son, but minimal in the
daughter, while knee changes were similar and mild.
Figure 2 Radiographs of the affected family members.
A) and C) The
daughter at aged 37 years.
B) D) and E) The son at aged
33 years.
A) and B) FHip joints. Dysplasia was marked in B,
but minimal in A.
C) and D) Knee joints. Dysplasias of the
knee joints were both mild.
Thus, myopathy was clearly absent in our cases. We consider
the association of myopathy with R718W in the JakkulaÕs
case is fortuitous. Although more than 50 COMP mutations
have been reported, they present MED or more severe
pseudoachondroplasia (PSACH) phenotype, but not myopathy.
The family 1 of the JakkulaÕs a report [1] is the only
exception. COMP is expressed in skeletal muscle, but not
abundant. Even the closely-situated mutation, G719D, did
not present myopathy, though it showed severe PSACH
phenotype.[5]
In our family, the skeletal changes were more severe in the
hip joint, which is consistent with the previous assumption
for the phenotype of the COMP mutation.[2,3] Hip changes
in patients with COMP mutations progress with age as
typically seen in PSACH. It is also true in the cases of
Jakkula et al.[1] The inconsistency of their cases with
the previous assumption may result from the patients' age
at observation. Two affected individuals in the family did
develop severe hip OA in adulthood. Alternatively, it may
be another example of phenotypic variation of the same
mutation.
References
1) Jakkula E, Lohiniva J, Capone A, et al. A recurrent
R718W mutation in COMP results in multiple epiphyseal
dysplasia with mild myopathy: clinical and pathogenetic
overlap with collagen IX mutations. J Med Genet 2003;
40:942-8.
3) Briggs MD, Chapman KL. Pseudoachondroplasia and multiple
epiphyseal dysplasia: mutation review, molecular
interactions, and genotype to phenotype correlations. Hum
Mutat 2002; 19:465-78.
4) Mabuchi A, Manabe N, Haga N, et al. Novel types of COMP
mutations and genotype-phenotype association in
pseudoachondroplasia and multiple epiphyseal dysplasia. Hum
Genet 2003; 112:84-90.
5) Mabuchi A, Haga N, Ikeda T, et al. A novel mutation in
exon 18 of the cartilage oligomeric matrix protein gene
causes a severe pseudoachondroplasia. Am J Med Genet 2001;
104:135-9.
Recently, Wang
et al. [1] reported R1193Q mutation of SCN5A in one of the 7 patients with
acquired long QT syndrome (LQTS) and suggested that R1193Q is a functional
mutation that can increase the susceptibility to LQTS. The authors fo...
Recently, Wang
et al. [1] reported R1193Q mutation of SCN5A in one of the 7 patients with
acquired long QT syndrome (LQTS) and suggested that R1193Q is a functional
mutation that can increase the susceptibility to LQTS. The authors found 0.2%
(4 of 2087) of the control subjects (in which more than 90% were whites and
only 0.4% were Asians) also carried the mutation and suggested that it may be a
risk factor for LQTS in the general population. The same mutation has been
reported in a Japanese infant with Brugada syndrome having frequent ventricular
fibrillation episodes [2]. They found none of the 100 control subjects of Asian
descent carried the variant.
We have identified the same R1193Q
mutation by direct DNA sequencing of SCN5A in a four-generation family of
Chinese descent with cardiac conduction abnormalities and several instances of
sudden death. However, the mutation is not associated with the disease or any
ECG abnormalities in this family.
We then screened for the presence
of R1193Q mutation in randomly selected control subjects consisting of Han
Chinese by direct DNA sequencing and SNP genotyping using
high-throughput MALDI-TOF mass spectrometry. R1193Q mutation was present
in 12% (11/94) of the subjects with allele frequency of 6%. One of the carriers
was homozygous for the mutation, and all the others were heterozygous. Clinical
studies were available in nine of the 11 carriers (Table 1). Two of them had
abnormal electrocardiograms (ECGs). No known associated risk factors were
identified in subject no.1 for her frequent ventricular premature complexes
(VPCs). Drug-induced prolonged QT-interval was ruled out in subject no.7.
Table 1. Summary of clinical findings in the
R1193Q carriers
1
2
3
4
5
6
7
8
9
Genotype
R/Q
R/Q
R/Q
R/Q
R/Q
R/Q
R/Q
R/Q
Q/Q
Age/Gender
35, F
32, M
45, F
40, F
71, M
26, M
75, F
46, M
76, M
History
of syncope or arrhythmia
¡V*
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
Family
history of sudden death or arrhythmia
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
ECG findings
Brugada
sign#
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
Prolonged
QTc
¡V
¡V
¡V
¡V
¡V
¡V
+¡±
¡V
¡V
Others
Frequent VPCs
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
*-
indicated negative findings
#
Type 1~3 ST-segment abnormalities in leads V1-V3 (3)
To
investigate whether sequence variants other than R1193Q had effects on the
clinical presentations, we sequenced all the coding regions of SCN5A in all
carriers and compared the sequences to 4 control subjects. Fifteen SNPs
including six novel ones were identified (Table 2). All novel SNPs were either
located within the introns or showed synonymous amino acid changes and thus
suggesting these SNPs are likely to be normal variants. There was no clear
association of any particular SNPs in the carriers with abnormal ECG as
compared to those with normal tracings; including H558R polymorphism which has
been reported to modify the expression of the arrhythmia causing mutation
[4].
Table 2.SNPs identified in the R1193Q carriers
and control subjects
In summary,
R1193Q, a Brugada and long QT mutation found in patients with other ethnic
background, is a common polymorphism in Han Chinese. Further studies will be
needed to determine whether this variant carries an increased risk for
arrhythmia in the Chinese population.
*Institute of Biomedical Sciences,
Academia Sinica, Taipei, Taiwan.
#Dept
Pediatrics, Taipei Veteran General Hospital, Taipei, Taiwan
¡±Department
of Pediatrics, Duke University Medical Center, Durham, NC, USA
Acknowledgements
The research project
was supported by grants from the National Science & Technology Program forGenomic Medicine, National Science Council, Taiwan (National Clinical
Core and National Genotyping Core),and the Genomics and Proteomics
Program, Academia Sinica.
References
(1)
Wang Q, Chen S, Chen Q, Wan X,
Shen J, Hoeltge GA, Timur AA, Keating MT, Kirsch GE. The common SCN5A mutation
R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium
channel. J Med Genet 2004; 41(5):e66.
(2) Vatta M, Dumaine R, Varghese G,
Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G,
Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA. Genetic and biophysical
basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic
to Brugada syndrome. Hum Mol Genet 2002; 11(3): 337-345.
Dear Editor
Smith-Magenis syndrome is a genetic syndrome associated with interstitial deletions of chromosome 17p11.2. Main features include congenital anomalies, abnormal behaviour and sleep/wake rhythm abnormalities.[1] The latter have been shown to result from a reversed circadian rhythm of melatonin.[2,3] Normally, secretion of melatonin peaks at night and is minimal during the day. In Smith-Magenis syndrome mel...
Dear Editor
This letter is in reference to the recent article by Zito et al.[1]
This very interesting article presents evidence for the association between a frameshift mutation (845-846delTG) in exon 8 of the RPGR gene and an X-linked syndrome inclusive of retinitis pigmentosa, impaired hearing and sino-respiratory infections.
We would like to take this opportunity to draw the readers’...
Dear Editor
In their letter Ayoub et al. suggest that Peutz-Jeghers Syndrome (PJS) can be distinguished from Laugier Hunziker Syndrome (LHS) by histological examination of the pigmented macules[1] and suggest that the pigmented macules in PJS are histologically lentigos showing increased numbers of normal melanocytes whereas in LHS the histology shows no increase in melanocyte numbers. They support their ar...
Dear Editor
We read with attention and interest the eLetter by Been et al.[1] We would like to reply.
We agree with the author that Smith-Magenis syndrome (SMS) may be may be an extremely advanced sleep phase syndrome. The definition of this advanced sleep phase syndrome is based actually on clinical evaluation and melatonin dosages. A mutation of Perclock gene was found in families with familial...
Dear Editor
Wilcken et al, (2003), in “Geographical and ethnic variation of the 677C>T allele of the 5,10 methylenetetrahydrofolate reductase (MTHFR): finds from over 7000 newborns from 16 areas worldwide” showed that the TT genotype in Calgary, Alberta was present in 5.8% of newborns as compared to one previous report from Quebec of 11% [Infante-Rivard et al., 2003]. The authors did not explain why this...
Dear Editor
We read with great interest the report by Sng et al. [1] in which the authors reported that the BRCA1 frameshift mutation 2845insA could be a founder mutation in Malay breast or ovarian cancer patients in Singapore. This mutation results in protein truncation at codon 914.
We would like to take this opportunity to draw the readers’ attention to our work on BRCA1 mutations among Singapo...
Dear Editor
We thank Dr Selvan for his comments [1] on our paper.[2] Cyrillic 3 does indeed use the BRCAPRO and MENDEL models. With regards to our use of BRCAPRO, we would like to draw his attention to the official Cyrillic 3 homepage [3] where it states clearly that the BRCAPRO plug-in calculates risk based on the “Bayes’ rules of determination of the probability of a mutation, given family history. An estimate of th...
Dear Editor
I would like to bring to your attention an error with respect to the original article by Amir et al.[1]
The paper validated a few available breast cancer risk prediction models and compared them to the Tyrer-Cuzick model.[2] From the paper by Amir et al., I understand that they used the Cyrillic plug-in to estimate breast cancer risk (Cyrillic 3.1 Version). Although, I am only fa...
Dear Editor
We read with interest a recent report in your journal by Jakkula et al.[1] on two families of multiple epiphyseal dysplasia (MED) with the recurrent R718W mutation in COMP.
Key points of the report are:
1) In a family (family 1), two children presented with muscular weakness and all four family members with R718W showed moderate rise in plasma creatine kinase...
Dear Editor
Recently, Wang et al. [1] reported R1193Q mutation of SCN5A in one of the 7 patients with acquired long QT syndrome (LQTS) and suggested that R1193Q is a functional mutation that can increase the susceptibility to LQTS. The authors fo...
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