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The Committee on Genetics is grateful to the clinicians on the Scientific and Clinical Advisory Committee of the National Fragile X Foundation, clinical leaders of the Fragile X Clinical and Research Consortium (FXCRC), Dr. Hagerman and K. Kessler for providing valuable contributions to the recently published clinical report, "Health Supervision for Children with Fragile X Syndrome " (2011;127(5):994-1006). On the basis of...
The Committee on Genetics is grateful to the clinicians on the Scientific and Clinical Advisory Committee of the National Fragile X Foundation, clinical leaders of the Fragile X Clinical and Research Consortium (FXCRC), Dr. Hagerman and K. Kessler for providing valuable contributions to the recently published clinical report, "Health Supervision for Children with Fragile X Syndrome " (2011;127(5):994-1006). On the basis of recent publications and clinical experience generated from the Fragile X Clinical Research Consortium Clinics, the following corrections, additional observations, and updates to the clinical report are listed below:
A) Revision of Table 1: Risks for Expansion from a Maternal Premutation to a Full Mutation When Transmitted to Offspring based on the CGG repeat Number in the Mother. 
Number of Maternal Premutation CGG Repeats
Expansions to Full Mutations (%)
B) Based on the report from Fernandez-Carvajal et al,  the smallest repeat number to expand to a full mutation in a single generation is 56 CGG repeats, rather than 59 CGG repeats, as reported in the second full paragraph on page 1000. Also, in the same paragraph, in the first sentence, the number of CGG repeats should have read 45 to 54, and not 41 to 58.
C) New neuropathological findings have been described by Greco et al.  These include significant deficits in neuronal migration in the hippocampus and cerebellum, loss of Purkinje cells, and significant deficits in the dendritic arborization of the remaining Purkinje cells in the cerebellum, which adds to the anatomical abnormalities of the brain described in the Neurobiology section on page 996.
D) Clinical observations of the behavioral phenotype in fragile X syndrome described on page 996 can be further enhanced on the basis of input from the Fragile X Clinical and Research Consortium Clinics. They report describing attention-deficit/hyperactivity disorder symptoms in more than 90% of males and more than 50% of females  and anxiety disorders in 86% of males and 77% of females,  with the most commonly observed symptom of anxiety representing social phobia observed in the majority of patients with fragile X syndrome.
E) On page 997, the clinical report describes the clinical manifestations of FXTAS affecting the majority of adult men who carry a premutation but only rarely reported in female premutation carriers. Investigators from the Fragile X Clinical and Research Consortium point out that in their experience, 8% to 16% of older female premutation carriers develop FXTAS as well. [6,7]
F) It is also pointed out by the Fragile X Clinical and Research Consortium that in the Health Supervision section of the clinical report, sleep problems should be included in the first 2 years of life, because they are frequently reported. 
G) The clinical report indicated that males who are of reproductive age and have nonmosaic full mutations are infertile. However, although intellectual disability would make reproduction less likely, as a result of decreased reproductive fitness, we should have stated that males who are of reproductive age with a nonmosaic full mutation may be fertile on the basis of clinical observations in the Fragile X Clinical and Research Consortium.
H) In the last paragraph on page 999, the authors failed to reference the paper by Johannison et al,  describing impairment in spermatogenesis in 2 males with fragile X syndrome.
I) Although the clinical report described the presence of diffuse hyperpigmentation in the Prader-Willi phenotype of males with a full mutation, it has been reported by Nowicki et al  that this finding is rare.
Incorporating these findings with those presented in the clinical report should prove to be valuable to pediatricians caring for patients with fragile X syndrome, maximizing their care in childhood and adolescence.
Joseph H. Hersh, MD, Robert A. Saul, MD, and the Committee on Genetics
1. Nolin SL, Brown WT, Glicksman A, et al. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet. 2003;72(2):454-464
2. Fernandez-Carvajal IP, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn. 2009;11(4):324-329
3. Greco CM, Navarro CS, Hunsaker MR, et al. Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome. Mol Autism. 2011;2(1):2
4. Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. Advances in the treatment of fragile X syndrome. Pediatrics. 2009;123(1):378-390
5. Cordeirio LE, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodev Disord. 2011;3(1):57-67
6. Coffey SM, Cook K, Tartaglia N, et al. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A. 2008;146(8):1009-1016
7. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 2009;17(10):1359-1362
8. Kronk R, Bishop EE, Raspa M, Bickel JO, Mandel DA, Bailey DB Jr. Prevalence, nature, and correlates of sleep problems among children with fragile X syndrome based on a large scale parent survey. Sleep. 2010;33(5):679-687
9. Johannison R, Rehder H, Wendt V, Schwinger E. Spermatogenesis in two patients with the fragile X syndrome. Hum Genet. 1987;76:141-147
10. Nowicki ST, Tassone F, Ono MY, et al. J Dev Behav Pediatr. 2007;28(2):132-138
Response: Health Supervision for Children with Fragile X Syndrome
Randi Hagerman,1 Elizabeth Berry-Kravis,2 Robert Miller,3 Clinical
Committee of the Fragile X Clinical and Research Consortium,3,4 and the
Scientific and Clinical Advisory Committee of the National Fragile X
1UC Davis MIND Institute 2Rush University Medical Center 3National
Fragile X Foundation 4Fragile X Clinical and Researc...
1UC Davis MIND Institute 2Rush University Medical Center 3National
Fragile X Foundation 4Fragile X Clinical and Research Consortium
Re: "Clinical Report: Health Supervision for Children With Fragile X
Syndrome" Committee on Genetics; 127:5 e994-e1006; doi:10.1542/peds.2010-
We read with interest the Clinical Report--Health Supervision for
Children with Fragile X Syndrome published in Pediatrics by Hersh, Saul
and the Committee on Genetics.1 This was a well written and thorough
report that gives pediatricians guidance for the follow-up of children and
their families who have the fragile X mutation. They have done a
remarkable job in covering extensive and complex information for the
spectrum of involvement seen in fragile X syndrome (FXS) and also
disorders associated with the premutation including fragile X-associated
primary ovarian insufficiency (FXPOI) and the fragile X-associated tremor
ataxia syndrome (FXTAS). This is an important report that has also
generated valuable publicity to raise awareness regarding diagnosis and
treatment of Fragile X-associated Disorders.
We represent the clinicians on the Scientific & Clinical Advisory
Committee of the National Fragile X Foundation (NFXF) and the clinical
leaders of the Fragile X Clinical & Research Consortium (FXCRC) that
is composed of 24 clinics throughout the United States and Canada. Our
vast collective clinical experience in working with patients and families
affected with Fragile X-associated Disorders can enlighten some of the
issues addressed in this review of health supervision. There have been
some concerns voiced by both families and professionals to the NFXF that
we wanted to clarify with this letter.
In the phenotypic section of the Hersh et al. paper, the description
of the Prader-Willi phenotype of fragile X syndrome includes diffuse
hyperpigmentation, but this is not the case in our experience. Diffuse
hyperpigmentation is rare in this phenotype.2 We also wanted to call the
reader's attention to a new report regarding the neuropathology changes in
the brain of 3 older individuals with fragile X syndrome.3 This study
demonstrated significant deficits in neuronal migration in the hippocampus
and cerebellum, loss of Purkinji cells and significant deficits in the
dendritic arborization of the remaining Purkinji cells in the cerebellum.
The Hersh et al. paper stated that behavioral problems occur in more
than 50% of affected patients but in reality, almost all boys and the
majority of girls with FXS have at least some behavior problems. In
addition to ADHD symptoms, particularly inattention and impulsivity, which
occur in over 90% of males and over 50% of females,4 anxiety disorders are
very common and 86% of males and 77% of females meet DSM IV criteria for
an anxiety disorder5 with additional patients having symptoms. Although
the report does discuss anxiety disorders, it is important to note the
frequency and severity of this problem in FXS. Most patients have more
than 1 anxiety disorder and social phobia is the most common anxiety
problem seen in the majority of patients with FXS, and this may increase
with age. We want to emphasize the importance of treating these problems
with a selective serotonin reuptake inhibitor (SSRI) when they arise
because patients can be highly dysfunctional from anxiety symptoms and
there are overall behavioral and social interaction benefits from this
In the discussion of FXTAS in premutation carriers (55 to 200 CGG
repeats), the report states that the prevalence in females is rare.
Actually about 8 to 16% of older female carriers develop FXTAS, so it is
not rare in our experience.7-8 Both the maternal grandfather and
grandmother, as well as the mother of affected children with FXS, should
be tested to determine whether they carry a premutation or a full
mutation. The grandparent that is found to have a premutation can be
counseled, evaluated and treated as appropriate, not only for movement
disorders but also for any neurological problems associated with FXTAS or
the premutation in general, including autonomic dysfunction,
hypothyroidism, fibromyalgia, neuropathy, hypertension and
psychopathology.7, 9-12 Mothers with the premutation should be counseled
and treated as necessary for any psychiatric problems or FXPOI.
The report also states that no offspring with a full mutation has
been described with a CGG repeat number less than 59 in the mother.
Actually there has been a report of a full mutation male born to a woman
with 56 repeats, so this is important to recognize for counseling
purposes.13 At one point Hersh et al. mention that 41 to 58 CGG repeats is
the gray zone, but the finding of expansion to the full from 56 repeats
confirms the accepted premutation range as 55 to 200 repeats; therefore 58
is not in the gray zone.
The report states that gray zone alleles "are not considered to be
predisposed to meiotic instability" and although the report later
clarifies that unstable alleles can infrequently be seen in this size
range, the initial statement may be misleading. Clearly "gray zone"
alleles between 45-54 repeats can be unstable and this relates to the
number of AGG triplets interrupting the repeat sequence. Most people have
two of these, around 10 and 20 repeats into the repeat sequence, however
some individuals have 3 or even 4 and some people have 0 or 1. It is the
"gray zone" allele carriers who have only 0 or 1 AGG anchors who tend to
have expansion of the allele when transmitted to the next generation.14-15
Although testing for AGG number and location has been challenging in the
past, new assays are becoming available that will allow mapping of the
number and location of AGGs, and this will impact genetic counseling,
allowing better information about expansion risk to be provided to
individuals with "gray zone" alleles.14-15
Hersh et al. state that "males who are of reproductive age and have
non mosaic full mutations are infertile." This is not true in our
experience. Clearly, intellectual disability makes reproduction less
likely from a standpoint of cognitive and behavioral impairment, and thus
there is reduced reproductive fitness, but in those men with FXS who are
sexually active we often see offspring suggesting that fertility is not
decreased. Indeed there are a number of cases in the literature describing
men with FXS who have had children, including girls with a premutation.
All daughters of a full mutation male will be premutation carriers,
because males with full mutation "non-mosaic" FXS have a premutation in
sperm.16 Because the premutation is present in sperm, males with full
mutation FXS would be expected to have similar fertility to premutation
carrier males, who do not have any obvious reduction in fertility. Hersh
et al. mention one study demonstrating significantly malformed spermatids
and a reduction in normally differentiated spermatids, but it is not cited
and this isolated finding has not been confirmed. We have found only one
paper that describes only 2 cases which have both normally- and abnormally
-shaped spermatids in addition to thickening of tubular lamina propria and
non specific changes in the testicle biopsy consistent with what is seen
in males after vasectomy.17 These males were middle aged and had been
institutionalized from an early age with significant intellectual
disability so it is likely that they were not sexually active. Concerns
about levels of malformed spermatids in males with FXS require further
study both in those who are sexually active and those who are not.
Regarding anticipatory guidance in the first year and second year, we
want to emphasize a high frequency of sleep problems in FXS.18 A
controlled study of melatonin in FXS and autism has demonstrated efficacy
and should be recommended to treat sleep problems.19 Sleep is essential
for normal development and the normal pruning of synaptic connections
occurs in sleep. The absence of FMRP in FXS is associated with a
deficiency of pruning and maturation of these connections. Melatonin is
not only the hormone that induces sleep but it is an antioxidant and it
has also been shown to improve synaptic connections in the mouse model of
FXS when given after birth,20 similar to the effect of other antioxidants
including vitamin E in improving the synaptic connections in these mice.21
This is an exciting time in the treatment of FXS because of the
proliferation of targeted treatments designed to improve behavior and
cognitive function by reversing some of the neurobiological abnormalities
associated with the loss of FMRP. The use of a variety of targeted
treatments such as mGluR5 antagonists, GABA B agonists (arbaclofen), GABA
A agonists (ganaxolone), lithium and minocycline have been shown to
improve aspects of cognition and behavior in the fragile X mouse model.
The preliminary results in patients with FXS regarding behavior are
positive22-27 and controlled trials in FXS are taking place at multiple
centers. It is likely that not only behavior but cognition will be
improved in patients with FXS and some of these medications are likely to
also be helpful for autism without FXS.28-30
We thank Hersh, Saul and the Committee on Genetics for this timely
and excellent review of health maintenance for those with FXS and the
Fragile X-associated Disorders and for clarifying a very complex body of
literature. We recommend that future health maintenance recommendations
for FXS take advantage of the vast clinical experience of clinical experts
at the FXCRC clinics, which follow or consult about the care of the
majority of identified children with FXS in our country.
1. Committee on Genetics. Health supervision for children with
fragile x syndrome. Pediatrics. May 2011;127(5):994-1006.
2. Nowicki ST, Tassone F, Ono MY, et al. The Prader-Willi phenotype of
fragile X syndrome. J Dev Behav Pediatr. Apr 2007;28(2):133-138.
3. Greco CM, Navarro CS, Hunsaker MR, et al. Neuropathologic features in
the hippocampus and cerebellum of three older men with fragile X syndrome.
Mol Autism. 2011;2(1):2.
4. Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. Advances in the
treatment of fragile X syndrome. Pediatrics. Jan 2009;123(1):378-390.
5. Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of
DSM-IV anxiety disorders in fragile X syndrome: prevalence and
characterization. Journal of neurodevelopmental disorders. Mar
6. Berry-Kravis E, Potanos K. Psychopharmacology in fragile X syndrome--
present and future. Ment Retard Dev Disabil Res Rev. 2004;10(1):42-48.
7. Coffey SM, Cook K, Tartaglia N, et al. Expanded clinical phenotype of
women with the FMR1 premutation. American journal of medical genetics. Apr
15 2008;146A(8):1009-1016. .
8. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, et al. Penetrance of
FMR1 premutation associated pathologies in fragile X syndrome families.
Eur J Hum Genet. Oct 2009;17(10):1359-1362.
9. Chonchaiya W, Schneider A, Hagerman RJ. Fragile X: a family of
disorders. Advances in pediatrics. 2009;56:165-186.
10. Chonchaiya W, Tassone F, Ashwood P, et al. Autoimmune disease in
mothers with the FMR1 premutation is associated with seizures in their
children with fragile X syndrome. Hum Genet. Nov 2010;128(5):539-548.
11. Bourgeois JA, Coffey SM, Rivera SM, et al. A review of fragile X
premutation disorders: expanding the psychiatric perspective. J Clin
Psychiatry. Jun 2009;70(6):852-862.
12. Roberts JE, Bailey DB, Jr., Mankowski J, et al. Mood and anxiety
disorders in females with the FMR1 premutation. Am J Med Genet B
Neuropsychiatr Genet. Jan 5 2009;150B(1):130-139.
13. Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ,
Tassone F. Screening for expanded alleles of the FMR1 gene in blood spots
from newborn males in a Spanish population. J Mol Diagn. Jul
14. Nolin S, Glicksman A, Berry-Kravis E, et al. Assessments of the AGG
Structure in More than 1000 Samples Reveals the Risks of Expansion for
Intermediate and Small Premutation Fragile X Alleles. Paper presented at:
American College of Medical Genetics Annual Clinical Genetics Meeting2011;
Vancouver, BC. p. 275; Abstract # 492.
15. Nolin S, Glicksman A, Ding X, et al. Fragile X analysis of 1112
prenatal samples from 1991 to 2010. Prenat Diagn. in press.
16. Reyniers E, Vits L, De Boulle K, et al. The full mutation in the FMR-1
gene of male fragile X patients is absent in their sperm. Nature genetics.
17. Johannisson R, Rehder H, Wendt V, Schwinger E. Spermatogenesis in two
patients with the fragile X syndrome. I. Histology: light and electron
microscopy. Hum Genet. Jun 1987;76(2):141-147.
18. Kronk R, Bishop EE, Raspa M, Bickel JO, Mandel DA, Bailey DB, Jr.
Prevalence, nature, and correlates of sleep problems among children with
fragile X syndrome based on a large scale parent survey. Sleep. May 1
19. Wirojanan J, Jacquemont S, Diaz R, et al. The efficacy of melatonin
for sleep problems in children with autism, fragile X syndrome, or autism
and fragile X syndrome. J Clin Sleep Med. Apr 15 2009;5(2):145-150.
20. Romero-Zerbo Y, Decara J, el Bekay R, et al. Protective effects of
melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic
research model for the fragile X syndrome. J Pineal Res. Mar
21. de Diego-Otero Y, Romero-Zerbo Y, el Bekay R, et al. Alpha-tocopherol
protects against oxidative stress in the fragile X knockout mouse: an
experimental therapeutic approach for the Fmr1 deficiency.
Neuropsychopharmacology. Mar 2009;34(4):1011-1026.
22. Jacquemont S, Curie A, des Portes V, et al. Epigenetic modification of
the FMR1 gene in fragile X syndrome is associated with differential
response to the mGluR5 antagonist AFQ056. Sci Transl Med. Jan 5
23. Paribello C, Tao L, Folino A, et al. Open-label add-on treatment trial
of minocycline in fragile X syndrome. BMC Neurol. 2010;10:91.
24. Utari A, Chonchaiya W, Rivera SM, et al. Is Minocycline a Targeted
Treatment for Fragile X Syndrome? Am J Intellect Dev Disabil.
25. Berry-Kravis E, Sumis A, Hervey C, et al. Open-label treatment trial
of lithium to target the underlying defect in fragile X syndrome. J Dev
Behav Pediatr. Aug 2008;29(4):293-302.
26. Berry-Kravis E, Hessl D, Coffey S, et al. A pilot open label, single
dose trial of fenobam in adults with fragile X syndrome. Journal of
medical genetics. Apr 2009;46(4):266-271.
27. Hagerman R, Rathmell B, Wang L, et al. Effects of STX209 (Arbaclofen)
on Social Function in Fragile X Syndrome: Results of a Randomized,
Controlled, Phase 2 Trial [abstract]. Paper presented at: Pediatric
Academic Societies; April 30 - May 3, 2011; Denver, CO. p. 3844; Abstact
28. Silverman JL, Tolu SS, Barkan CL, Crawley JN. Repetitive self-grooming
behavior in the BTBR mouse model of autism is blocked by the mGluR5
antagonist MPEP. Neuropsychopharmacology. Mar 2010;35(4):976-989.
29. Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for
targeted treatments in autism. Neurotherapeutics. Jul 2010;7(3):264-274.
30. Berry-Kravis E, Knox A, Hervey C. Targeted treatments for fragile X
syndrome. Journal of neurodevelopmental disorders. Feb 19, doi:
Conflict of Interest
Drs Hagerman and Berry-Kravis have received funding from Novartis, Roche, Seaside Therapeutics and Neuropharm for clinical trials in fragile X syndrome. Dr. Berry-Kravis has collaborated with Asuragen on assay validation and research project. Dr Hagerman has also received funding from Seaside Therapeutics, Curemark and Forest for clinical trials in autism. Mr Miller is without conflicts.
The recently published "Clinical Report - Health Supervision for
Children With Fragile X Syndrome" was a comprehensive review of this
common disorder. I appreciate that you have highlighted the variability of
the clinical phenotype and recommend genetic counseling for all family
members who are affected or at risk.
I would like to bring attention to Table 1 that summarizes the risk
of expansion to a full mutat...
I would like to bring attention to Table 1 that summarizes the risk
of expansion to a full mutation based on a mother's premutation size. As
the CGG repeat number increases, so does the risk of expansion to a full
mutation. This was correctly expressed, however, the risks for expansion
quoted in Table 1 are overestimates (1):
CGG Repeat Number (Risk for Expansion %) =
In addition, the report states that the smallest premutation allele
reported to expand to a full mutation allele in a single generation is 59
CGG repeats. There has been a report of a woman with a premutation of 56
CGG repeats having an affected child (2). Any women with 55 CGG repeats
or above should be considered at risk to have a child with a full
(1) Nolin S, et al. Expansion of the Fragile X CGG Repeat in Females
with Premutation or Intermediate Alleles. Am. J. Hum. Genet. 2003;72:454-
(2) Fernandez-Carvajal I, Lopez Posadas B,Pan R,Raske C,Hagerman PJ,and
Tassone F. Expansion of an FMR1 Grey-Zone Allele to a Full Mutation in Two
Generations. J. Mol. Diagn. Jul; 11(4):306-310.
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