Tangier Disease

Tangier disease
Other Names:

High density lipoprotein deficiency, type 1; HDLDT1; High density lipoprotein
deficiency, Tangier type; Analphalipo-proteinemia; Alpha high density
lipoprotein deficiency disease; A-alphalipoprotein neuropathy; Cholesterol
thesaurismosis; Familial high density lipoprotein deficiency disease; Familial
Hypoalphalipo-proteinemia; Hdl lipoprotein deficiency disease See Less
Categories:

Congenital and Genetic Diseases; Endocrine Diseases; Eye diseases; See
More
Summary
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Tangier disease is an inherited disorder characterized by significantly

reduced levels of high-density lipoprotein (HDL) - the 'good cholesterol' - in
the blood. Because people with Tangier disease have very low levels of HDL,
they have a moderately increased risk of cardiovascular disease. Tangier
disease is caused by mutations in the ABCA1 gene. It is inherited in
an autosomal recessive pattern.[1]
Last updated: 8/19/2011
Symptoms
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Tangier disease is characterized by significantly reduced levels of high-

density lipoprotein (HDL) - the "good" cholesterol - in the blood. HDL
transports cholesterol and certain fats called phospholipids from the
body's tissues to the liver, where they are removed from the blood. Because
people with Tangier disease have very low levels of HDL, they have a
moderately increased risk of cardiovascular disease. Additional signs and
symptoms of Tangier disease include a slightly elevated amount of fat in the
blood; disturbances in nerve function; and enlarged, orange-colored tonsils.
Affected individuals often develop atherosclerosis, which is an accumulation
of fatty deposits and scar-like tissue in the lining of the arteries. Other
features of this condition may include an enlarged spleen, an enlarged liver,
clouding of the clear covering of the eye, and type 2 diabetes.[1]
This table lists symptoms that people with this disease may have. For most
diseases, symptoms will vary from person to person. People with the same
disease may not have all the symptoms listed. This information comes from
a database called the Human Phenotype Ontology (HPO) . The HPO collects
information on symptoms that have been described in medical resources.
The HPO is updated regularly. Use the HPO ID to access more in-depth
information about a symptom.
Showing 36 of 36 | View Less
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Medical Terms Other Names
HPO ID
80%-99% of people have these symptoms
Hypertriglyceridemia Increased plasma triglycerides 0002155
[ more ]
Hypocholesterolemia Decreased circulating cholesterol level 0003146
Abdominal pain Pain in stomach 0002027
[ more ]
Accelerated atherosclerosis 0004943
Chronic noninfectious 0002730
lymphadenopathy
Coronary artery stenosis Narrowing of coronary artery 0005145
Distal muscle weakness Weakness of outermost muscles 0002460
Dry skin 0000958
Ectropion Eyelid turned out 0000656
Hepatosplenomegaly Enlarged liver and spleen 0001433
Nail dystrophy Poor nail formation 0008404
Orange discoloured tonsils 0030814
Peripheral axonal neuropathy 0003477
Progressive peripheral neuropathy 0007133
Anemia 0001903
Carotid artery stenosis Narrowing of carotid artery 0100546
Corneal opacity 0007957
Facial diplegia 0001349
Impaired thermal sensitivity 0006901
Left ventricular hypertrophy 0001712
Syringomyelia 0003396
Thrombocytopenia Low platelet count 0001873
Percent of people who have these symptoms is not available through HPO
Learn More:
HPO ID
Autosomal recessive inheritance 0000007
Coronary artery atherosclerosis Plaque build-up in arteries supplying 0001677
blood to heart
Decreased circulating high-density Decreased circulating high-density 0003233
lipoprotein levels lipoprotein cholesterol
[ more ]
Distal amyotrophy Distal muscle wasting 0003693
Hepatomegaly Enlarged liver 0002240
Hyporeflexia 0001265
Impaired pain sensation Decreased pain sensation 0007328
Impaired temperature sensation Abnormality of temperature sensation 0010829
[ more ]
Myocardial infarction Heart attack 0001658
Nail dysplasia 0002164
Opacification of the corneal stroma 0007759
Peripheral demyelination 0011096
Splenomegaly Increased spleen size 0001744
Visual impairment Impaired vision 0000505
[ more ]
Do you have more information about symptoms of this disease? We
want to hear from you.
Cause
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Tangier disease is caused by mutations in the ABCA1 gene. This gene

provides instructions for making a protein that releases cholesterol and
phospholipids from cells. These substances are used to make HDL, which
transports them to the liver. Mutations in the ABCA1 gene prevent the
release of cholesterol and phospholipids from cells. As a result, these
substances accumulate within cells, causing certain body tissues to enlarge
and the tonsils to acquire a yellowish-orange color. A buildup of cholesterol
can be toxic to cells, leading to impaired cell function or cell death. In
addition, the inability to transport cholesterol and phospholipids out of cells
results in very low HDL levels, which increases the risk of cardiovascular
disease. These combined factors cause the signs and symptoms of Tangier
disease.[1]
Inheritance
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Tangier disease is inherited in an autosomal recessive pattern, which means

both copies of the gene in each cell have mutations. The parents of an
individual with an autosomal recessive condition each carry one copy of the
mutated gene, but they typically do not show signs and symptoms of the
condition.[1]
Diagnosis
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GeneTests lists laboratories offering clinical genetic testing for this condition.

Clinical genetic tests are ordered to help diagnose a person or family and to
aid in decisions regarding medical care or reproductive issues.
Orphanet lists international laboratories offering diagnostic testing for this

condition. Click here and scroll down the page to learn more about the
processes of certification, accreditation, and external quality assessment
available to these labs. Click on Orphanet to view the list.
Talk to your health care provider or a genetic professional to learn more

about your testing options.
Testing Resources
 The Genetic Testing Registry (GTR) provides information about the
genetic tests for this condition. The intended audience for the GTR is
health care providers and researchers. Patients and consumers with
specific questions about a genetic test should contact a health care
provider or a genetics professional.
 Orphanet lists international laboratories offering diagnostic testing for
this condition.
Treatment
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To our knowledge there is no specific treatment for Tangier disease. Drugs

known to increase high density lipoprotein levels in unaffected people, such
as estrogens, nicotinic acid, statins, or phenytoin, do not work in people with
Tangier disease.[2]
To reduce the risk for heart and blood vessel disease, people with this
condition should maintain a low fat (especially saturated fat) diet and
overall healthy lifestyle. Heart disease risk factors such as smoking, high
blood pressure, diabetes, obesity, high level of triglycerides and
homocysteine in the blood should receive prompt treatment. Fibrates can be
used to help lower triglycerides.[2]
To date, no treatment has been found to prevent the progression of this
disease, including trials of omega-3-fatty acids, antioxidants, and vitamin E.
[2]
Individuals with Tangier disease may benefit from referral to specialized lipid
centers for advanced management. Consultation with the following
specialists may be required:[3]
 Lipidologist
 Endocrinologist
 Cardiologist
 Vascular specialist
 Cardiovascular surgeon
 Dietitian
Do you have updated information on this disease? We want to hear
from you.
Find a Specialist
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If you need medical advice, you can look for doctors or other healthcare
professionals who have experience with this disease. You may find these
specialists through advocacy organizations, clinical trials, or articles
published in medical journals. You may also want to contact a university or
tertiary medical center in your area, because these centers tend to see more
complex cases and have the latest technology and treatments.
If you can’t find a specialist in your local area, try contacting national or
international specialists. They may be able to refer you to someone they
know through conferences or research efforts. Some specialists may be
willing to consult with you or your local doctors over the phone or by email if
you can't travel to them for care.
You can find more tips in our guide, How to Find a Disease Specialist. We
also encourage you to explore the rest of this page to find resources that can
help you find specialists.
Healthcare Resources
 To find a medical professional who specializes in genetics, you can ask
your doctor for a referral or you can search for one yourself. Online
directories are provided by the American College of Medical Genetics and
the National Society of Genetic Counselors. If you need additional
help, contact a GARD Information Specialist. You can also learn more
about genetic consultations from Genetics Home Reference.
Research
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Research helps us better understand diseases and can lead to advances in

diagnosis and treatment. This section provides resources to help you learn
about medical research and ways to get involved.
Clinical Research Resources

 ClinicalTrials.gov lists trials that are related to Tangier disease. Click
on the link to go to ClinicalTrials.gov to read descriptions of these
studies.
Please note: Studies listed on the ClinicalTrials.gov website are listed

for informational purposes only; being listed does not reflect an
endorsement by GARD or the NIH. We strongly recommend that you talk
with a trusted healthcare provider before choosing to participate in any
clinical study.
 Orphanet lists European clinical trials, research studies, and patient
registries enrolling people with this condition.
 The Research Portfolio Online Reporting Tool (RePORT) provides
access to reports, data, and analyses of research activities at the
National Institutes of Health (NIH), including information on NIH
expenditures and the results of NIH-supported research. Although these
projects may not conduct studies on humans, you may want to contact
the investigators to learn more. To search for studies, enter the disease
name in the "Text Search" box. Then click "Submit Query".
Organizations
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Support and advocacy groups can help you connect with other patients and
families, and they can provide valuable services. Many develop patient-
centered information and are the driving force behind research for better
treatments and possible cures. They can direct you to research, resources,
and services. Many organizations also have experts who serve as medical
advisors or provide lists of doctors/clinics. Visit the group’s website or
contact them to learn about the services they offer. Inclusion on this list is
not an endorsement by GARD.
Organizations Supporting this Disease

 Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Toll-free: 0800 652 3181
Telephone: 0845 241 2173
E-mail: contact@climb.org.uk
Website: http://www.climb.org.uk
 National Tay-Sachs and Allied Diseases Association
2001 Beacon Street
Suite 204
Brighton, MA 02135
Toll-free: 800-90-NTSAD (906-8723)
Telephone: 617-277-4463
Fax: 617-277-0134
E-mail: info@ntsad.org
Website: http://www.ntsad.org
Do you know of an organization? We want to hear from you.
Learn More
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These resources provide more information about this condition or associated

symptoms. The in-depth resources contain medical and scientific language
that may be hard to understand. You may want to review these resources
with a medical professional.
Where to Start
 Genetics Home Reference (GHR) contains information on Tangier
disease. This website is maintained by the National Library of Medicine.
 The National Organization for Rare Disorders (NORD) has a report for
patients and families about this condition. NORD is a patient advocacy
organization for individuals with rare diseases and the organizations that
serve them.
In-Depth Information
 Medscape Reference provides information on this topic. You may need
to register to view the medical textbook, but registration is free.
 MeSH® (Medical Subject Headings) is a terminology tool used by the
National Library of Medicine. Click on the link to view information on this
topic.
 The Monarch Initiative brings together data about this condition from
humans and other species to help physicians and biomedical researchers.
Monarch’s tools are designed to make it easier to compare the signs and
symptoms (phenotypes) of different diseases and discover common
features. This initiative is a collaboration between several academic
institutions across the world and is funded by the National Institutes of
Health. Visit the website to explore the biology of this condition.
 Online Mendelian Inheritance in Man (OMIM) is a catalog of human
genes and genetic disorders. Each entry has a summary of related
medical articles. It is meant for health care professionals and
researchers. OMIM is maintained by Johns Hopkins University School of
Medicine.
 Orphanet is a European reference portal for information on rare
diseases and orphan drugs. Access to this database is free of charge.
 PubMed is a searchable database of medical literature and lists journal
articles that discuss Tangier disease. Click on the link to view a sample
search on this topic.
News & Events

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News
 Caring for Your Patient with a Rare Disease - A New Guide for
Healthcare Professionals
January 31, 2018
 Got a Great Research Idea? ‘All of Us’ Wants to Hear It!
January 18, 2018
 New NCATS Rare Diseases Research Video
December 27, 2017
 Rare Disease Day at NIH on March 1, 2018
December 19, 2017
 IRDiRC Goals 2017-2027: New Rare Disease Research Goals for the
Next Decade
August 10, 2017
GARD Answers
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Questions sent to GARD may be posted here if the information could be

helpful to others. We remove all identifying information when posting a
question to protect your privacy. If you do not want your question posted,
please let us know. Submit a new question
 Where can confirmatory testing for Tangier disease be
performed? How might this condition be treated?
See answer
Have a question? Contact a GARD Information Specialist.
References
1. Tangier disease. Genetics Home Reference (GHR).

2010; http://ghr.nlm.nih.gov/condition/tangier-disease. Accessed
8/19/2011.
2. Assmann G, von Eckardstein A, Brewer HB. Familial
analphalipoproteinemia: Tangier disease. In: Scriver et al.,
eds.. The Metabolic & Molecular Basis of Inherited Disease. 8th Ed.
2001;
3. Singh VN, Citkowitz E. Low HDL Cholesterol
(Hypoalphalipoproteinemia) Treatment & Management. eMedicine.
2009; http://emedicine.medscape.com/article/127943-
treatment#showall. Accessed 8/19/2011.
Hypochondrogenesis
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Description
Hypochondrogenesis is a rare, severe disorder of bone growth. This condition is

characterized by a small body, short limbs, and abnormal bone formation (ossification)
in the spine and pelvis.
Affected infants have short arms and legs, a small chest with short ribs, and
underdeveloped lungs. Bones in the skull develop normally, but the bones of
the spine (vertebrae) and pelvis do not harden (ossify) properly. The face appears flat
and oval-shaped, with widely spaced eyes, a smallchin, and, in some cases, an opening
in the roof of the mouth called a cleft palate. Individuals with hypochondrogenesis have
an enlarged abdomen and may have a condition called hydrops fetalis in which excess
fluid builds up in the body before birth.
As a result of these serious health problems, some affected fetuses do not survive to
term. Infants born with hypochondrogenesis usually die at birth or shortly thereafter from
respiratory failure. Babies who live past the newborn period are usually reclassified as
having spondyloepiphyseal dysplasia congenita, a related but milder disorder that
similarly affects bone development.
Related Information
 What does it mean if a disorder seems to run in my family?
 What is the prognosis of a genetic condition?
 Genetic and Rare Diseases Information Center
Frequency
Hypochondrogenesis and achondrogenesis, type 2 (a similar skeletal disorder) together
affect 1 in 40,000 to 60,000 newborns.
Related Information
 What information about a genetic condition can statistics provide?
 Why are some genetic conditions more common in particular ethnic groups?
Genetic Changes
Hypochondrogenesis is one of the most severe conditions in a spectrum of disorders

caused by mutations in the COL2A1 gene. This gene provides instructions for making a
protein that forms type II collagen. This type of collagen is found mostly in the clear gel
that fills the eyeball (the vitreous) and in cartilage. Cartilage is a tough, flexible tissue
that makes up much of the skeleton during early development. Most cartilage is later
converted to bone, except for the cartilage that continues to cover and protect the ends
of bones and is present in the nose and external ears. Type II collagen is essential for
the normal development of bones and other connective tissues that form the body's
supportive framework. Mutations in the COL2A1 gene interfere with the assembly of
type II collagen molecules, which prevents bones and other connective tissues from
developing properly.
Learn more about the gene associated with hypochondrogenesis
Related Information
 What is a gene?
 What is a gene mutation and how do mutations occur?
 How can gene mutations affect health and development?
 More about Mutations and Health
Inheritance Pattern
Hypochondrogenesis is considered an autosomal dominant disorder because one copy
of the altered gene in each cell is sufficient to cause the condition. It is caused by new
mutations in the COL2A1 gene and occurs in people with no history of the disorder in
their family. This condition is not passed on to the next generation because affected
individuals do not live long enough to have children.
Related Information
 What are the different ways in which a genetic condition can be inherited?
 More about Inheriting Genetic Conditions
Diagnosis & Management Resources
Genetic Testing (2 links)
 Genetic Testing Registry: Achondrogenesis, type II

 Genetic Testing Registry: Hypochondrogenesis
Other Diagnosis and Management Resources (1 link)
General Information from MedlinePlus (5 links)
Related Information
 How are genetic conditions diagnosed?
 How are genetic conditions treated or managed?
 What is genetic testing?
 How can I find a genetics professional in my area?

Other Names for This Condition
 achondrogenesis type II/hypochondrogenesis
Related Information
 How are genetic conditions and genes named?
Additional Information & Resources
MedlinePlus (3 links)
Additional NIH Resources (1 link)
Educational Resources (3 links)
Patient Support and Advocacy Resources (8 links)
Scientific Articles on PubMed (1 link)
OMIM (1 link)
Sources for This Page
 Castori M, Brancati F, Scanderbeg AC, Dallapiccola B. Hypochondrogenesis.

Pediatr Radiol. 2006 May;36(5):460-1. Epub 2006 Jan 24.
Citation on PubMed
 Körkkö J, Cohn DH, Ala-Kokko L, Krakow D, Prockop DJ. Widely distributed
mutations in the COL2A1 gene produce achondrogenesis type
II/hypochondrogenesis. Am J Med Genet. 2000 May 15;92(2):95-100.
Citation on PubMed
 Spranger J, Winterpacht A, Zabel B. The type II collagenopathies: a spectrum of

chondrodysplasias. Eur J Pediatr. 1994 Feb;153(2):56-65. Review.
Citation on PubMed
 Suzumura H, Kohno T, Nishimura G, Watanabe H, Arisaka O. Prenatal diagnosis

of hypochondrogenesis using fetal MRI: a case report. Pediatr Radiol. 2002
May;32(5):373-5. Epub 2002 Mar 9.
Citation on PubMed
ICF syndrome
Other Names:

Immunodeficiency-centromeric instability-facial anomalies syndrome;
Immunodeficiency syndrome, variable; Centromeric instability,
immunodeficiency syndrome; See More
Categories:

Congenital and Genetic Diseases; Immune System Diseases
Summary
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The following summary is from Orphanet, a European reference portal for

information on rare diseases and orphan drugs.
Orpha Number: 2268
Disease definition
The Immunodeficiency, Centromeric region instability, Facial
anomalies syndrome (ICF) is a rare autosomal recessive disease
characterized by immunodeficiency, although B cells are present, and by
characteristic rearrangements in the vicinity of the centromeres (the
juxtacentromeric heterochromatin) of chromosomes 1 and 16 and
sometimes 9.
Epidemiology
ICF has been described in about 50 patients worldwide.
Clinical description
Other variable symptoms of this probably under-diagnosed syndrome include
mild facial dysmorphism, growth retardation, failure to thrive, and
psychomotor retardation. Serum levels of IgG, IgM, IgE, and/or IgA are low,
although the type of immunoglobulin deficiency is variable. Recurrent
infections are the presenting symptom, usually in early childhood.
Etiology
ICF always involves limited hypomethylation of DNA and often arises
from mutations in one of the DNA methyltransferase genes (DNMT3B). Much
of this DNA hypomethylation is in the 1qh, 9qh, and 16qh, regions that are
the site of whole-arm deletions, chromatid and chromosome breaks,
stretching (decondensation), and multiradial chromosome junctions in
mitogen-stimulated lymphocytes. By an unknown mechanism, the DNMT3B
deficiency that causes ICF interferes with lymphogenesis (at a step after
class switching) or lymphocyte activation.
Antenatal diagnosis
With the identification of DNMT3B as the affected gene in a majority of ICF
patients, prenatal diagnosis of ICF is possible. However, given the variety
of DNMT3B mutations, a first-degree affected relative should first have
both alleles of this gene sequenced.
Management and treatment

Treatment almost always includes regular infusions of immunoglobulins,
mostly intravenously. Recently, bone marrow transplantation has been tried.
Visit the Orphanet disease page for more resources.

Symptoms
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Learn More:
HPO ID
Abnormality 0003220
of chromosomestability
Decreased antibody level in blood 0004313
Micrognathia Little lower jaw 0000347
[ more ]
Recurrent respiratory infections Frequent respiratory infections 0002205
[ more ]
Short stature Decreased body height 0004322
[ more ]
Abnormality of neutrophils 0001874
Anemia 0001903
Cellular immunodeficiency 0005374
Communicating hydrocephalus 0001334
Depressed nasal bridge Depressed bridge of nose 0005280
[ more ]
Global developmental delay 0001263
Intellectual disability Mental deficiency 0001249
[ more ]
Lymphopenia Decreased blood lymphocyte number 0001888
Macrocephaly Increased size of skull 0000256
[ more ]
Malabsorption Intestinal malabsorption 0002024
Epicanthus Eye folds 0000286
[ more ]
Flat face Flat facial shape 0012368
Hypertelorism Wide-set eyes 0000316
[ more ]
Low-set ears Low set ears 0000369
[ more ]
Macroglossia Abnormally large tongue 0000158
[ more ]
Learn More:
HPO ID
Protruding tongue Prominent tongue 0010808
[ more ]
Umbilical hernia 0001537
Anteverted nares Nasal tip, upturned 0000463
[ more ]
Bronchiectasis 0002110
Chronic bronchitis 0004469
Decrease in T cell count Low T cell count 0005403
[ more ]
Diarrhea Watery stool 0002014
Failure to thrive Faltering weight 0001508
[ more ]
Immunodeficiency Decreased immune function 0002721
Malar flattening Zygomatic flattening 0000272
Pneumonia 0002090
Sinusitis Sinus inflammation 0000246
from you.
Find a Specialist
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Learn More
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Medicine.
articles that discuss ICF syndrome. Click on the link to view a sample
News & Events

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News
January 31, 2018
January 18, 2018
December 27, 2017
December 19, 2017
Next Decade
August 10, 2017
Related Diseases
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The following diseases are related to ICF syndrome. If you have a question a
bout any of these diseases, youcan contact GARD.
 T cell immunodeficiency primary
GARD Answers
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please let us know
https://rarediseases.info.nih.gov/diseases/2945/icf-syndrome
Immunodeficiency, centromeric region instability, facial anomalies

syndrome (ICF)
Melanie Ehrlich, 1,2
Kelly Jackson,1 and Corry Weemaes3
Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.
Abstract
Go to:
Disease name and synonyms

Immunodeficiency, Centromeric instability, and Facial anomalies syndrome was given the
acronym ICF in 1988 [1]. ICF is an autosomal recessive disease. Note that the instability is not in
the centromere itself, but rather in the region adjacent to the centromere (qh), predominantly in
chromosomes 1 and 16.
Go to:
Definition/diagnostic criteria
ICF (OMIM #24242860) is a rare autosomal recessive disease that involves
agammaglobulinemia or hypoglobulinemia with B cells as well as DNA rearrangements targeted
to the centromere-adjacent heterochromatic region (qh) of chromosomes 1 and/or 16 (and
sometimes 9) in mitogen-stimulated lymphocytes. The frequency of these rearrangements is high
enough to be detected upon routine cytogenetic examination of metaphase chromosomes. These
rearrangement-prone heterochromatic regions exhibit DNA hypomethylation in all examined
ICF cell populations. The three invariant features of ICF are the immunodeficiency despite the
presence of B cells; characteristic rearrangements of chromosome 1 and/or 16 with breakpoints
at 1qh and 16qh in mitogen-stimulated lymphocytes; and hypomethylation of classical satellite 2
and 3 DNA, the main DNA components of 1qh, 16qh, and 9qh [2], in leukocytes, other tissues,
and cell cultures from ICF patients.
Go to:
Epidemiology
ICF is an autosomal recessive disease, with approximately 50 patients reported worldwide since
it was first described in the late 1970's [3,4]. The patients come mostly from Europe. However,
ICF patients are of diverse ethnicity, including European, Turkish, Japanese, and African
American. Some excess of consanguinity has been noted [5-7], although most cases are not
familial. Recently, there has been a sharp increase in the number of diagnosed, non-familial
cases in Europe and Japan, which suggests that this disease is underdiagnosed, especially in the
United States, where only a few cases have been reported [8,9].
Go to:
Etiology
Mutations in DNMT3B coding sequences

The locus for ICF was localized to 20q11-q13 by homozygosity mapping [10]. This led to the
discovery that the DNMT3B gene is often the site of ICF mutations [11-13]. In the 35 ICF
patients analyzed to date for DNMT3B mutations, 57% had mutations in both DNMT3B alleles
(OMIM #602900) within the coding portion [5,14-16]. These mutations are frequently found in
the C-terminal portion of the protein that contains the catalytic domain [17] and are often
missense mutations [11,13,14,18,19]. Although DNMT3B has repressor activity that is
independent of its DNA methyltransferase activity, repression involves the central portion of the
protein, which does not overlap with the methyltransferase domain [20]. DNMT3B also forms a
complex with DNMT1 and with small ubiquitin-like modifier 1, but these interactions involve
the N-terminus of DNMT3B [21,22]. In contrast, many ICF patients have a missense mutation in
one or both of their mutant alleles to give an amino acid substitution in one of ten motifs
conserved among all cytosine-C5 methyltransferases [17]. These findings suggest that it is the
loss of DNA methyltransferase activity, and not some other function of the protein, that is
responsible for the syndrome. The involvement of DNA hypomethylation in the phenotype of
ICF is supported at the cytogenetic level because the ICF-specific rearrangements in mitogen-
treated lymphocytes are the same in frequency, spectrum, and chromosomal specificity as those
found in a normal pro-B lymphoblastoid cell line treated with the DNA methylation inhibitors 5-
azacytidine or 5-azadeoxycytidine [23,24]. Also, biochemical analyses of recombinant proteins
with known ICF mutations [17] and the invariant hypomethylation of certain portions of the
genome from ICF patients [25,26] are consistent with ICF being due to a deficiency in DNA
methylation.
Mutations outside DNMT3B coding sequences

For the ~40% of ICF patients with no mutations discovered in exonic DNA from DNMT3B, there
might be mutations in the promoter or other transcription control elements or mutations affecting
splicing or polyadenylation. However, for several of these ICF patients without
detected DNMT3B mutations, the most common isoform of DNMT3B RNA was still observed
[15], and for the one patient examined in two putative promoter regions of DNMT3B, no
mutations were found [16]. The patients without DNMT3B coding region mutations seem to be
derived from a different subtype of ICF. Lymphocytes or fibroblasts from 9 out of 9 patients in
this category displayed hypomethylation in satellite α (centromeric) DNA while 5 out of 5
patients who had mutations in DNMT3B did not [15]. ICF patients, including those without
demonstrated mutations in DNMT3B, invariantly exhibit hypomethylation in the major DNA
component of 1qh and 16qh (classical satellite 2 DNA) and of 9qh (classical satellite 3 DNA) in
all examined tissues and in B-cell lines. In addition, they display chromosomal anomalies at 1qh
and 16qh in mitogen-stimulated cells [16,25,27,28]. As described below, it is unclear how the
limited amount of DNA demethylation associated with ICF (a 7% decrease in the genomic 5-
methylcytosine level in ICF tissue compared to that in normal tissue [28]) may cause the
immunodeficiency and other variable symptoms associated with the disease.
One other genetic disease, the X-linked α-thalassemia/mental retardation syndrome (ATR-X
linked syndrome), is associated with an apparently Mendelian inheritance of DNA methylation
abnormalities in a small part of the genome [29,30]. This syndrome is accompanied by either
decreases (satellite 1 in Yqh but not in satellites 2 or 3) or increases (ribosomal RNA genes) in
DNA methylation, apparently as a result of mutations in a putative ATP-dependent DNA
helicase. ICF is the only human genetic disease currently known to involve mutations in a DNA
methyltransferase gene. In mice, insertional inactivation of Dnmt3b or of the other two main
DNA methyltransferase genes, Dnmt1 and Dnmt3a, results in prenatal death or (for Dnmt3a)
death several weeks after birth [18]. It is likely that ICF-causing mutations in DNMT3B leave
residual activity, otherwise embryonic lethality would probably result. This is consistent with
analyses of the biochemical effects of ICF-associated mutations on DNMT3B activity in
vitro [17]. Therefore, homozygous null DNMT3B (or DNMT1 or DNMT3A) mutations might
make a small contribution to spontaneous abortions.
Go to:
Clinical description
Immunodeficiency
The immunodeficiency, despite the presence of B cells almost always [31], results in severe
recurrent infections, often seen in early childhood and usually as the presenting finding [32,33].
A review of the literature shows that almost all ICF patients have severe respiratory infections
and more than half have recurrent gastrointestinal infections. Pericarditis, ear infections,
septicemia, and oral Candida infections have also been observed [19,34,35]. The
immunodeficiency in ICF patients ranges from agammaglobulinemia to a mild reduction in
immune response [36]. Most patients have a poor immune response with low amounts or
undetectable levels of IgA, IgG and/or IgM [14], but the exact nature of the immunodeficiency is
variable. For example, in some patients only certain subclasses of IgG display deficiencies
[14,37], while in others, there are very low levels of IgG, IgA, and IgM or just of two of these
three classes of immunoglobulins [26]. Low levels of T-cells are present in about half of the
patients and levels of B cells are also sometimes low, although in some patients only one or the
other type of lymphocyte shows reduced levels [34,35,38].
Facial anomalies
The dysmorphic facial features are variable [31,34] and usually mild; moreover, several patients
did not display them (unpub. data). The typical facial features are a broad flat nasal bridge,
hypertelorism (very widely spaced eyes), and epicanthic folds. Less frequent, but still often
associated with the syndrome, are micrognathia (small jaw), low-set ears, and macroglossia
(protrusion or enlargement of the tongue) [1,5,19,34,39,40].
Psychomotor delay
Mental retardation and neurologic defects have been seen in about one-third and one-fifth of the
patients, respectively [31,34,37], and include slow cognitive and motor development and
psychomotor impairment (ataxic gait and muscle hypotonia) [3,8,31,41]. In one case, delayed
psychomotor development changed into age-appropriate development at 36 months [35].
Other abnormalities
Other congenital abnormalities in ICF are highly variable. Intrauterine growth retardation has
been observed in ICF patients [34,39,40]. Several patients have been described with protruding
abdomens [34,40] and thin arms and legs [34]. At least two patients have been found to have
bipartite nipples [37]. Skin pigment changes have been seen in some patients, with café au
lait spots or irregularly outlined mildly hyperpigmented spots reported [3,6,37]. Scleral
telangiectasias were found in at least one patient [37].
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Diagnostic methods
Peripheral blood karyotype
Chromosomal anomalies
ICF is diagnosed by standard metaphase chromosome analysis of peripheral blood from
paediatric patients (often babies or toddlers) displaying otherwise unexplained recurrent
infections, which are usually severe pulmonary or gastrointestinal infections, despite the
presence of B cells. Metaphases from phytohemagglutinin-stimulated blood cultures exhibit the
following anomalies: whole-arm deletions and pericentromeric breaks of chromosomes 1 and 16
and sometimes 9; multibranched chromosomes containing three or more arms of chromosomes 1
and 16 joined in the vicinity of the centromere (mostly at the 1qh or 16qh region); and occasional
isochromosomes and translocations with breaks in the vicinity of the centromere [3,8,28,34]. In
addition, prominent stretching (decondensation) in the 1qh and 16qh region is seen in
chromosomes 1 and 16. Stimulation of ICF blood cultures with pokeweed mitogen produces
similar anomalies. In most, but not all patients, chromosome 1 is affected more frequently than
chromosome 16.
Although many patients have low in vitro stimulation indices for either phytohemagglutinin or
pokeweed mitogen, this is not an invariant finding and sufficient metaphases accumulate for
cytogenetic analysis. Standard metaphase analysis after incubation of blood with mitogen for 72
or 92 hours allows the development of maximal frequencies of the ICF-associated chromosomal
rearrangements [3,40,42].
Number of metaphases needed to be analysed

Examination of 20 G-banded metaphases is generally adequate to reveal the characteristic
cytogenetic anomalies of ICF because the frequency of chromosomal anomalies at 1qh and or
16qh is so high in mitogen-stimulated T cells from ICF patients, especially at 48-92 hours after
stimulation (compared to examining metaphases 24 hours after stimulation; reviewed in [26]).
However, given the centrality of cytogenetics in the diagnosis of ICF, it would be preferable to
examine 50 metaphases to increase the chance of seeing the ICF-specific multiradial
chromosomes with arms from chromosomes 1 and/or 16 joined in the pericentromeric region.
Sometimes there are rearrangements at 9qh [1,3,7,31,43], but even when they are present,
chromosome 1 or 16 rearrangements predominate. The 9qh DNA consists largely of classical
satellite 3 DNA. Satellite 3 DNA is also hypomethylated in ICF patients [44]. There have been
rare findings of rearrangements at chromosomes 10 and 2 [40,42], both of which have short
heterochromatic juxtacentromeric regions rich in classical satellite 2 [2]. There is no increase in
sister chromatid exchange in ICF samples.
Several ICF patients had aberrations in skin fibroblasts as well as in mitogen-stimulated
lymphocytes [43], and one had the characteristic ICF-type chromosome rearrangements in bone
marrow [8]. However, because bone marrow cells and skin fibroblast cultures from many of the
analyzed patients show little or no recombination at 1qh, 16qh, and 9qh [3,4,6,8,34,43], these
cell types should not be used for diagnosis. Parental chromosomes are generally normal, just as
heterozygous parents show no phenotype.
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Differential diagnosis
Like Bloom syndrome (BS), ataxia-telangiectasia (AT), and Nijmegen breakage syndrome
(NBS), ICF is usually diagnosed in children and involves spontaneous chromosome instability
and immunodeficiency [26,37,45-49]. Growth retardation, psychomotor disturbances, or mental
retardation is seen in some ICF patients as well as in BS and NBS patients. The ICF-specific
cytogenetic abnormalities, which are observed in mitogen-stimulated lymphocytes, consist
predominantly of whole-arm deletions or breaks, multiradial (multibranched) chromosomes, and
decondensation (stretching) involving heterochromatin in the vicinity of the centromeres of
chromosomes 1 and 16 [26,34,43]. These chromosomal anomalies are distinct from those of
other syndromes, e.g., abnormally high levels of rearrangements at the immunoglobulin
superfamily loci of chromosomes 7 and 14, which are found in T cells from AT and NBS
patients [45-47]. Sister chromatid exchange rates are normal in ICF patients [43], distinguishing
ICF from BS, in which elevated rates of sister chromatid exchange are a cytological hallmark of
the disease [49,50]. The multiradial chromosomes in stimulated lymphocytes from ICF patients
have 3 to 10 arms of chromosomes 1 and/or 16, sometimes in combination with chromosome 9;
the region of chromosome fusion is always in the vicinity of the centromere (usually the qh
region) and predominantly in chromosomes 1 and 16 [26,34]. Although stimulated lymphocytes
from BS patients may display multiradial chromosomes, these chromosomal abnormalities are
mostly quadriradials without the strong regional and chromosomal specificity seen in mitogen-
stimulated ICF lymphocytes [49,51]. Facial anomalies in BS (small narrow face with a dwarfed
body) and NBS (bird-like face) and frequent characteristic dermatological abnormalities in AT,
NBS, and BS [46,52,53] also distinguish these syndromes from ICF.
AT, NBS and BS are each associated with greatly increased frequencies of cancer, and an
unusually high frequency is observed in children with NBS [45,50,54]. No cancers have been
reported in ICF patients, who often die during childhood, like NBS patients. However, there was
one recent report of a benign tumor in a 3-year-old ICF patient [16]. ICF, like AT, BS and NBS,
makes cells hypersensitive to certain chemical or physical DNA-damaging agents, although
unlike AT and NBS, cell cycle checkpoints in ICF appear to be normal [46,50,55]. Also, ICF T-
cells in phytohemagglutinin-stimulated peripheral blood samples are more prone to spontaneous
apoptosis than are analogous control cultures [38], which may help prevent tumors forming from
cytogenetically abnormal ICF cells.
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Antenatal diagnosis
Karyotype
Mitogen-stimulated blood samples from unaffected individuals rarely display abnormalities in
the vicinity of the centromeres of chromosomes 1, 16, and 9, in contrast to analogous cultures
from ICF patients. However, 2% of metaphases from random chorionic villus (CV) cultures at
day 8 displayed 1qh or 16qh decondensation and, less frequently, pericentromeric breaks, whole-
arm deletions, quadriradials, or triradials [56]. Furthermore, yet higher frequencies of these types
of chromosomal aberrations have been reported by others in CV cultures [57]. One exceptional
CV sample taken during routine screening exhibited four cells with pericentromeric breaks in
chromosome 1 and seven cells with decondensation of 1qh out of a total of 20 examined
metaphases, even though the amniotic fluid-derived culture was normal and the patient, at almost
2 years of age, appeared normal [56]. Furthermore, high-passage cells in CV or amniotic fluid-
derived (AF) cultures from normal individuals routinely display high frequencies of ICF-like
karyotypic abnormalities, although AF cultures require more passages to display these anomalies
[58]. The chromosomal metaphase anomalies in late-passage AF cultures are largely restricted to
1qh and 16qh decondensation, while those from mid- or late-passage CV cultures exhibit 1qh
and 16qh decondensation and, in addition, whole-arm deletions, chromosome breaks, and
multiradials involving the 1qh or 16qh region. Also, some control B-cell lines after long-term
passage develop ICF-like chromosomal abnormalities, which appear to increase in frequency if
satellite 2 becomes spontaneously demethylated upon prolonged cell culture [59,60], but 1qh
decondensation has been observed even in a control cell line that did not exhibit ICF-like
hypomethylation of satellite 2 (M. Ehrlich, L. Qi, R. Nishiyama, and C. Tuck-Muller, unpub.
data).
Fasth et al. [6] reported on AF cells taken at the time of a cesarean section of a 34-week sibling
of an ICF patient. Five out of 15 metaphases in the AF culture showed decondensation
(despiralization) of the heterochromatic region of chromosome 1. This was also reported in the
bone marrow cells from the affected sibling. At birth, the younger sibling had 90% of
lymphocytes showing despiralization or a break in the juxtacentromeric heterochromatin of
chromosome 1. From the above-mentioned studies, short-term AF cultures are less likely to have
culture-associated chromosomal artifacts than analogous CV cultures. Fetal blood sampling
(cordocentesis) has been successful in at least one family [61].
Linkage analysis
Linkage analysis via CV sampling at 12 weeks of gestation was reported [62]. Linkage markers
from a 9-cM region of chromosome 20, at which the ICF locus had been mapped at that time,
were used. A marker, D20S850, was informative, indicating that the fetus was heterozygous for
the gene. The couple was given a greater than 90% probability that the fetus was not affected
with ICF. Cordocentesis was declined, and postnatal blood chromosome analysis revealed a
normal male karyotype, without juxtacentromeric heterochromatin instability.
DNA sequence analysis

DNA analysis of the DNMT3B gene is also being done on a research basis in some laboratories,
and could be used for diagnosis. However, because of the variety of mutations in DNMT3B that
cause this syndrome [5,15], it is feasible only for analyzing close relatives in ICF families with
known DNMT3B mutations. Therefore, this prenatal diagnosis requires a first-degree affected
relative who had sequenced mutations in both alleles.
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Management including treatment

Intravenous infusion of gammaglobulin has been successful in some ICF patients [35]. In the
Netherlands, nearly all ICF patients receive regular infusions of immunoglobulins, mostly
intravenously (IVIG), and the treatment goal is to reach a serum IgG level of 5 g/l in the child
(C.M.R. Weemaes, unpub. data). Treatment with IVIG reduces the severity and frequency of
infections in most patients. Earlier treatment with IVIG, as can be done if ICF is diagnosed
shortly after birth (such as in the case of younger siblings of known affected patients) can help
prevent the gastrointestinal symptoms in some patients. However, most patients suffer from
some T-cell defect as well. Patients can develop opportunistic infections such as Pneumocystis
carinii (PCP), Cytomegalovirus, and Candida, even if they have normal levels of T-cell
subpopulations. Prophylactic use of trimethoprim-sulfamethoxazole to prevent PCP seems to be
indicated in some patients. Improved anti-microbial therapy for ICF is leading to more ICF
patients reaching adulthood than previously recorded. This may result in other manifestations of
immunodeficiency, such as progressive multifocal leukoencephalopathy, which was recently
described in a 40-year-old ICF patient as a result of infections with Jamestown Canyon
virus (JCV) [63].
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Prognosis
Prognosis varies depending on several factors [43]. Common causes of death are from
opportunistic infections or pulmonary infections. The prognosis is poor in children with
gastrointestinal problems that lead to intractable diarrhea and failure to thrive. In the absence of
combined-type immunodeficiency, the clinical course is often more favorable. Successful bone
marrow transplantation has been performed in two ICF children recently (Weemaes, unpub.
data).
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Discussion and unresolved questions
1. How do mutations in DNMT3B and the resulting deficiency in DNA

methyltransferase activity cause ICF?
It is not clear how DNA hypomethylation in ICF patients may result in the immunodeficiency.
However, it seems likely, as described under "Etiology," that it is the DNA methylation
deficiency, and not some other aspect of impaired DNMT3B activity, that is responsible for the
disease. Hypomethylation in some region(s) of the genome probably changes transcription of one
or more genes that are primary targets for the deficiency in DNMT3B activity.
The immunodeficiency in ICF is manifested as low serum immunoglobulin levels, although there
can be normal B- and T-cell numbers in peripheral blood. The latter finding indicates that the
early stages of lymphocyte differentiation are not abnormal. High percentages of cells in ICF B-
cell lines that have membrane-bound IgM and/or IgD have been observed even in patients with
extremely low levels of IgM. Therefore, class switching was normal for the precursors of these
cells, but there seems to be a defect in lymphocyte maturation or activation [14]. In a comparison
of ICF lymphoblastoid cell lines (B-cell lines with known DNMT3B mutations) and analogous
control cell lines by a microarray expression analysis, only a small number of genes, including
IgG- and IgA-encoding sequences, were found to have ICF-specific differences in RNA levels
[14]. A larger microarray expression analysis, which was followed by quantitative real-time
reverse transcription-polymerase chain reaction (RT-PCR) for selected genes, gave similar
findings (M. Ehrlich, C. Sanchez, C. Shao, R. Kuick, S. Hanash, unpub. data). In the first study,
no ICF-specific differences in promoter methylation were seen, even for genes with elevated
RNA levels in ICF cell lines [14] and similar methylation analyses are underway for selected
genes from the second study. A number of reports of promoter-region hypomethylation in ICF
cells, including in the inactive X chromosome, have revealed inconsistent hypomethylation at
given gene regions among different patients [32,36,64,65]. This finding matches results from a
genome-wide search for consistently hypomethylated DNA sequences in ICF vs. control B-cells
lines by 2-dimensional gel electrophoresis of DNA digested with two restriction endonucleases,
one of which was CpG methylation-sensitive [66]. Only repeated DNA sequences (a
subtelomeric repeat and a repeat from the acrocentric chromosomes) were identified as
hypomethylated specifically in all the ICF samples by this analysis. It has been hypothesized that
in ICF lymphoid cells, hypomethylation of regions of the genome that are normally
constitutively heterochromatic (e.g., 1qh and 16qh) could affect regulation of expression of
genes elsewhere in the genome by altering the postulated normal sequestration of DNA
sequence-specific proteins at this heterochromatin [14,26]. There are precedents for such binding
of transcription factors to centromeric heterochromatin [67,68]. The hypothesis that constitutive
heterochromatin itself can act in trans to modulate gene expression remains to be tested for ICF
cells. Alternatively, there may be only a small number of currently unidentified gene regions
with consistent hypomethylation specific to ICF lymphoid cells that are responsible for ICF-type
immune dysfunction.
2. Which genes are indirectly affected so as to directly cause the

immunodeficiency?
As explained above, the effect of the ICF DNMT3B mutations on immune functions is likely to
be the result of DNA hypomethylation, probably through one or more genes that initiate the
abnormalities in late maturation and activation of lymphoid cells. The above-mentioned
microarray expression analyses [[14], M. Ehrlich, C. Sanchez, C. Shao, R. Kuick, and S. Hanash,
unpub. data] indicate that there are a small number of candidate genes for ICF-specific
alterations in gene expression that might determine the phenotype. These include genes that are
involved in cell signaling, transcription control, or chromatin remodeling. It was suggested that
altered RNA levels in ICF B-cells compared to control cells might simply be a reflection of an
abnormally prevalent immature state of these cells in vivo [26,69]. However, the genes that
displayed ICF-specific differences in RNA levels, other than the immunoglobulin sequences,
were not those predicted to be differentially expressed just because the ICF B-cell lines may
have been derived from less mature cells than is normally the case. More research is needed to
test which of these microarray candidates might be the proximal gene(s) involved in the
lymphogenesis dysregulation in ICF patients as a result of DNMT3B mutations.
3. What is the relationship between DNMT3B mutations and the chromosome
instability of ICF?
No obvious candidate genes for the ICF chromosome instability have been found from the
above-mentioned microarray studies on ICF B-cell lines that exhibit high frequencies of 1qh or
16qh anomalies vs. control cell lines. It is possible that the hypomethylation of the satellite DNA
in these regions in certain types of cells is responsible by itself for these chromosomal
aberrations. However, most early-passage cultures from normal chorionic villi do not display
appreciable numbers of abnormalities in these regions, despite the hypomethylation of 1qh and
16qh DNA in these cells due to the cell's extraembryonic mesodermal origin [56,58]. Therefore,
there must be a cell-type specificity to this chromosome instability, which is in accord with the
lower frequency of chromosomal abnormalities in bone marrow cells and fibroblasts from ICF
patients than that found in stimulated lymphocytes [26]. Moreover, the 1qh satellite DNA
hypomethylation is not required for decondensation in these regions because normal amniotic
fluid-derived cultures at late passage (essentially only embryonic fibroblasts) show high
frequencies of 1qh decondensation despite a very high level of satellite DNA methylation at 1qh
[58]. It is likely that there is a DNA methylation-independent pathway (probably involving
epigenetic chromatin changes) and a DNA methylation-stimulated pathway for decondensation
and rearrangements targeted to the 1qh and 16qh regions. These mechanisms need to be
elucidated. Further studies are also necessary to elucidate why there is a much lower frequency
of these abnormalities in the 9qh region, despite the 9qh region usually being almost as long as
the 1qh region and much longer than the 16qh region. Moreover, 9qh is predominantly composed
of a similar DNA sequence (classical satellite 3; [2]) to that of classical satellite 2 in 1qh and
16qh and, like 1qh, displays ICF-specific DNA hypomethylation of its satellite DNA.
As to the relationship in metaphase between 1qh and 16qh decondensation and 1qh and 16qh
rearrangements, there is evidence that ICF B-cell lines compared to controls show
decondensation in these juxtacentromeric heterochromatin regions even in interphase and that
1qh and 16qh exhibit a significantly increased colocalization [70]. In addition, these regions
colocalize with an aberrantly concentrated focus of heterochromatin proteins 1 (HP1) in G2
phase and with other proteins from promyelocytic leukemia nuclear bodies [71]. Moreover, these
ICF B-cell lines display abnormal looping of pericentromeric sequences at metaphase, formation
of chromosome bridges at anaphase, chromosome 1 and 16 fragmentation at the telophase-
interphase transition, increased apoptosis, and micronuclei with overrepresentation of
chromosome 1 and 16 material [70]. Another source of anaphase bridging in ICF B-cell lines is a
significantly increased frequency of random telomeric associations between chromosomes
[28,70]. These have not been described in stimulated ICF lymphocytes. Extensive karyotype
analysis of ICF B-cell lines suggests that decondensation of 1qh and 16qh often leads to
unresolved Holliday junctions, chromosome breakage, arm missegregation, and the formation of
more stable translocations [28]. The findings that ICF B-cell lines and lymphocytes in vivo are
prone to micronucleus formation and apoptosis [9,70-72] are consistent with the apparently
normal cell cycle checkpoints in ICF B-cell lines [55]. These findings suggest that in stimulated
lymphocytes and B-cell lines from ICF patients there is continuous generation of 1qh and 16qh
chromosome rearrangements followed by removal of most of the cells with these chromosomal
abnormalities, which gives rise to a great variety of rearrangements at 1qh and 16qh and a lack of
clonal abnormalities.
4. Why is the exact nature of the immunodeficiency in ICF so variable and why are
other symptoms of ICF highly variable? What is the location and nature of the
mutations in ICF patients who do not have DNMT3B coding-region mutations?
The diverse collection of mutations in the exons of DNMT3B and the as-yet unmapped other
mutations that cause ICF may explain the variety of symptoms. In addition, it has been proposed
that the polymorphic nature of the length of the 1qh and 16qh region may contribute to the
variety of phenotypes [71]. However, in non-ICF patients, no phenotype has been associated
with the natural length-polymorphism of these constitutive heterochromatic regions.
5. Is there a relationship between the hypomethylation of the

facioscapulohumeral muscular dystrophy (FSHD)-linked D4Z4 repeat in ICF
patients and the much more limited hypomethylation of this repeat in short D4Z4
arrays that cause FSHD?
Curiously, one of the types of DNA repeats found to be strongly hypomethylated in most ICF B-
cell lines compared to controls is the 4q35 and 10q26 D4Z4 repeat [66,73]. Facioscapulohumeral
muscular dystrophy (FSHD) syndrome, a dominant disease, is almost always caused by a
contraction of these copy-number-polymorphic tandem repeats at 4q35 (from 11-100 copies per
locus in unaffected individuals to 1-10 copies in FSHD patients) although the mechanism for
how the array contraction causes the disease is unknown [73]. Evidence has been provided for a
significant reduction in methylation at D4Z4 arrays that have a contracted size [75]. Muscular
dystrophy is not associated with ICF, and so there may not be a causal connection between D4Z4
hypomethylation and FSHD.
6. Is there a relationship between invariant hypomethylation of satellite 2 DNA

sequences in ICF and frequent hypomethylation of these same pericentromeric
repeats in a wide variety of cancers?
There is frequent hypomethylation of satellite 2 at 1qh and 16qh as well as satellite α in the
centromeres of all the chromosomes in various cancers [76,77]. It has been proposed that this
hypomethylation leads to altered gene expression in trans, as has been hypothesized for ICF
lymphoid cells [26,76,77]. While the consequences of satellite 2 hypomethylation in ICF and
cancer require much more study, it is already clear that the causes of satellite 2 hypomethylation
in cancer and in ICF patients with DNMT3B-linked disease probably differ. No significant
association between decreased DNMT RNA levels or increased number of mutations in
the DNMT1 gene has been observed in cancers [78,79]. Furthermore, cancers typically have
hypomethylation in some portions of the genome and hypermethylation in others [76,78], while
no hypermethylated component has been found in the ICF genome (unpub. data). Nonetheless,
the presently unknown cause of the hypomethylation of both satellite 2 and satellite α in the ICF
cases where DNMT3B mutations have not been found [15] might be related to the cause of
hypomethylation of classical satellite 2 and centromeric satellite α in cancer.
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ncontinentia Pigmenti
NORD gratefully acknowledges Michelle Yanik, NORD Editorial Intern from the University of Notre Dame,
and Angela Scheuerle, MD, Department of Pediatrics, Division of Genetics and Metabolism University of
Texas, Southwestern Medical Center, for assistance in the preparation of this report.
Synonyms of Incontinentia Pigmenti

 Bloch-Siemens incontinentia pigmenti melanoblastosis cutis linearis
 Bloch-Sulzberger syndrome
 IP
 pigmented dermatosis, Siemens-Bloch type
General Discussion
Summary
Incontinentia Pigmenti (IP) is a genetic dermatological disorder affecting the skin, hair,
teeth, and central nervous system. Progressive skin changes occur in four stages, the
first of which appear in early infancy or can be present at birth. IP is an X-linked
dominant genetic disorder caused by mutations in the IKBKG gene.
Incontinentia pigmenti is a condition that can affect many body systems, particularly
the skin. This condition occurs much more often in females than in males.
Incontinentia pigmenti is characterized by skin abnormalities that evolve throughout

childhood and young adulthood. Many affected infants have a blistering rash at birth
and in early infancy, which heals and is followed by the development of wart-like skin
growths. In early childhood, the skin develops grey or brown patches
(hyperpigmentation) that occur in a swirled pattern. These patches fade with time, and
adults with incontinentia pigmenti usually have lines of unusually light-colored skin
(hypopigmentation) on their arms and legs.
Other signs and symptoms of incontinentia pigmenti can include hair loss (alopecia)
affecting the scalp and other parts of the body, dental abnormalities (such
as small teeth or few teeth), eyeabnormalities that can lead to vision loss,
and lined or pitted fingernails and toenails. Most people with incontinentia pigmenti have
normal intelligence; however, this condition may affect the brain. Associated problems
can include delayed development or intellectual disability, seizures, and other
neurological problems.
Introduction
IP was named based on the appearance of the skin under the microscope during the
later stages of the condition.
Signs & Symptoms

Skin
The skin changes are the most characteristic and common features in IP. They are
described in four stages. In all the stages, the lesions appear in lines on the arms and
legs or a swirled pattern on the trunk. They can be on the face and scalp.
1) The first stage of IP may be present at birth or appear during early infancy. This
phase consists of redness or inflammation of the skin (erythema), blisters, and boils,
most often affecting the extremities and the scalp, that last a few weeks to a few
months. It can fade and come back again and again for more than a year, commonly
when there is an illness with fever.
2) The second stage may overlap the first and may be present at birth. During this
phase, the blisters develop a raised, wart-like (verrucous) appearance, and the lesions
look like warts. There can be thick crusts or scabs with healing and areas of darkened
skin (increased pigmentation). The extremities are involved almost exclusively in this
stage, which may last for several months but rarely as long as year.
3) The third stage may be present at birth in a small number of affected individuals, but
usually appears between the ages of six and 12 months. In this phase, the skin is
darkened (hyperpigmented). On the trunk, the dark is sometimes described as a
“marble cake” appearance. The hyperpigmentation does not necessarily happen where
the stage I and II rashes happen. The heavy pigmentation tends to fade over time and,
in some cases, the pigmented areas thin and widen, leaving streaky diminished color of
the skin (hypopigmentation).
4) In the fourth stage, which is known as the “atrophic” stage, scarring appears that
often is present before the hyperpigmentation has faded. Scars are seen in adolescents
and adults as pale, hairless patches or streaks. Once the affected individuals reach the
late teens and adulthood, the skin changes may have faded and may not be visible to
the casual observer.
Teeth
Between 50 to 75 percent of individuals with IP have dental abnormalities. These
abnormalities include a delay in the eruption of primary teeth; abnormal contours of
teeth, giving them a peg-like or cone-shaped appearance; or the congenital absence of
both primary and secondary teeth (anodontia); or small teeth, (microdontia).
Nails
Some individuals with IP may have ridged, pitted, thickened (onychogryposis), or
missing nails on the hands and/or feet. In some cases, painful growths may develop
under the nail.
Hair
Approximately 50 percent of individuals with IP may also experience abnormal bald
patches on the scalp (alopecia). This usually happens where the stage one and two
lesions have left scars. The hair generally may be coarse, wiry, and/or lusterless.
Eyes
Nearly one-third of individuals have eye (ocular) abnormalities. The most serious, but
least frequent, is a congenitally small, abnormal eye. In any patient there can be an
abnormality in the growth of blood vessels in the membrane lining the eyes (retina). If it
is going to occur, this typically appears before the age of five. This problem may be
treated if detected early. If left untreated, it may cause retinal detachment leading to
permanent visual impairment or total blindness.
Nervous System
The majority of individuals with IP will have no involvement of the nervous system.
Severe neurologic complications can occasionally occur as a consequence of IP, the
most serious of which is congenital or neonatal strokes. Some affected individuals may
experience episodes of uncontrolled electrical disturbances in the brain (seizures).
About 30 percent of children with IP will have slow motor development, muscle
weakness in one or both sides of the body, intellectual disability, and/or seizures.
Other
Abnormalities in the development of the breast, ranging from extra nipples to complete
absence of the breast, are sometimes seen in individuals with IP.
Causes
IP is an X-linked dominant genetic disorder caused by mutations in the IKBKG gene
(formerly called NEMO). The IKBKG gene is responsible for the production of a protein
that helps regulate other proteins that help protect cells from self-destructing in
response to specific triggers.
X-linked dominant disorders are caused by an abnormal gene on the X chromosome
and occur mostly in females. Females with these rare conditions are affected when they
have an X chromosome with the gene for a particular disease. Males with an abnormal
gene for an X-linked dominant disorder are more severely affected than females and
often do not survive. Affected males who survive may have an IKBKG gene mutation
with relatively mild effects, an IKBKG mutation in only some of the body’s cells
(mosaicism), or an extra copy of the X chromosome in each cell.
Affected Populations
Approximately 1,200 individuals with IP have been reported in the scientific literature.
Most of those affected are female, but several dozen males with IP have also been
reported. Public health birth defect surveillance systems put the birth prevalence at 0.6-
0.7/1,000,000. The female:male ratio is 20:1.
Related Disorders
Symptoms of the following disorders can be similar to IP. Comparisons may be useful
for a differential diagnosis:
Interleukin 1 receptor antagonist deficiency (DIRA) has blistering skin lesions that can
be present at birth but do not follow a linear or swirled pattern. The nails can be
abnormal and biopsy of the skin shares some features with the first stage of IP. Patients
with DIRA have bone abnormalities particularly periosteal elevation. Both sexes are
equally affected. DIRA has a medical treatment.
IP achromians is characterized by diminished skin pigmentations similar only in pattern
to discolorations of IP . The lack of skin coloration is easily contrasted with the excess
discoloration characteristic of IP although diminished skin pigmentations can appear
late in the course of some cases of IP. Associated neurological problems are similar.
This disorder is inherited as an autosomal dominant trait. A variety of other
developmental abnormalities and/or conditions may also occur in conjunction with this
illness. Skin color tends to normalize with aging.
Franceschetti-Jadassohn syndrome is marked by skin pigmentation changes similar to
those of IP, but symptoms begin during adolescence and do not follow inflammatory
skin changes. Additionally, skin may thicken on the hands and/or feet, ability to sweat
may become impaired and yellow mottling of the teeth may occur. This disorder
appears to be inherited as an autosomal dominant trait.
Caffey disease is characterized by discolorations accompanied by soft tissue swellings
over benign bone growths typically capped by cartilage. Fever and irritability may also
occur. Symptoms tend to fluctuate in severity. This disorder, also known as infantile
cortical hyperostosis, primarily affects infants under six months of age and often
resolves with age. It is caused by mutations in the gene for a type of collagen
(COL1A1).
The term hypomelanosis of Ito (HI) encompasses a heterogeneous group of disorders
characterized by hypopigmented whorls and streaks. It may be associated with other
symptoms such as intellectual disability, seizures, a lack of sweating on the areas of
hypopigmentation, crossed eyes (strabismus), nearsightedness, a cleft along the edge
of the eyeball (coloboma), overgrowth of brain tissue, and/or a small head.
Hypomelanosis of Ito may occur sporadically or it may be inherited as an autosomal
dominant trait. (For more information on this disorder, choose “Hypomelanosis of Ito” as
your search term in the Rare Disease Database.)
Diagnosis
The diagnosis of IP is based on clinical evaluation, detailed patient history, and
molecular genetic testing for mutation in the IKBKG gene. IKBKG is the only gene
known to be associated with IP. 65 percent of patients have a specific deletion within
the gene. Another 20 percent or so have mutations found by gene sequencing. A skin
biopsy to confirm the diagnosis in a female is now rarely needed given the widespread
availability and sensitivity of molecular genetic testing. Nonetheless, skin biopsy may be
helpful in confirming the diagnosis in a female with borderline or questionable findings in
whom molecular genetic testing has not identified a disease-causing mutation.
Clinical Testing and Work-Up
It is very important for babies born with IP to have an eye examination by a pediatric
ophthalmologist. This should be done monthly until age four months, then every three
months from age four months to one year, every six months from age one to three
years, and annually after age three years. The eye problems associated with IP can be
severe, but may be effectively managed if recognized early.
The following evaluations may be done to determine the severity of disease in those
affected with IP. physical examination with particular emphasis on the skin, hair, nails,
and neurologic system, electroencephalography (EEG) and magnetic resonance
imaging (MRI) if seizures, other neurologic abnormalities, or retinal abnormalities are
present, magnetic resonance angiography to look for cerebrovascular lesions, and
developmental screening.
Because IP can be very mild, even in infancy, an affected woman may not know that
she has it. It is important that a full evaluation of the mother be done by a geneticist,
dermatologist, or other physician after the birth of a child with IP.
Standard Therapies
Treatment
Skin abnormalities characteristic of IP usually disappear by adolescence or adulthood
without any treatment.
Cryotherapy and laser photocoagulation may be used to treat affected individuals with
retinal neovascularization that predisposes to retinal detachment.
Dental abnormalities can often be treated effectively by dentists who may provide dental
implants in childhood as needed. Also if dental abnormalities interfere with chewing
and/or speech, assistance from a speech pathologist and/or pediatric nutritionist may be
necessary.
Hair problems may require the attention of a dermatologist in some cases, although
they are usually not severe. Neurological symptoms such as seizures, muscle spasms
or mild paralysis may be controlled with various drugs and/or medical devices.
Genetic counseling is recommended for affected individuals and their families. Other
treatment is symptomatic and supportive.
References
Scheuerle AE, Ursini MV. Incontinentia Pigmenti. 1999 Jun 8 [Updated 2015 Feb 12].
In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle
(WA): University of Washington, Seattle; 1993-2016. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1472/ Accessed.April 15, 2016.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University.
Incontinentia Pigmenti; IP. Entry No: 308300. Last Edited December 3, 2015. Available
at: http://omim.org/entry/308300 Accessed April 15, 2016.
Incontinentia Pigmenti. Genetics Home Reference.
https://ghr.nlm.nih.gov/condition/incontinentia-pigmenti Reviewed June 2008. Accessed
April 15, 2016.
ISCHIOCOXOPODOPATELLAR SYNDROME; ICPPS
Alternative titles; symbols
SMALL PATELLA SYNDROME; SPS

PATELLA APLASIA, COXA VARA, AND TARSAL SYNOSTOSIS
ISCHIOPATELLAR DYSPLASIA
COXOPODOPATELLAR SYNDROME
SCOTT-TAOR SYNDROME
Phenotype-Gene Relationships
Phenotype Phenotype Gene/Locus
Location Phenotype MIM number Inheritance mapping key Gene/Locus MIM numbe
17q23.2 Ischiocoxopodopatellar syndrome 147891 AD 3 TBX4 601719
Clinical Synopsis Toggle Dropdown

▼ TEXT
A number sign (#) is used with this entry because ischiocoxopodopatellar syndrome
(ICPPS), also known as small patella syndrome, is caused by heterozygous mutation
in the TBX4 gene (601719) on chromosome 17q23.
▼ Clinical Features
Scott and Taor (1979) described a family in which 12 members in an autosomal
dominant pedigree pattern were found to have small or absent patellas. Seven of
these persons also had abnormalities of the pelvic girdle and upper femurs.
Recurrent dislocation of the patella was a complication in several members of the
family. Familial recurrent dislocation of the patella (169000) and the nail-patella
syndrome (161200) are separate conditions. Renwick (1956) had studied the family
reported by Scott and Taor (1979) while investigating the genetics of the nail-patella
syndrome. Iliac horns are absent in this condition but other changes occur in the
pelvis, the most striking being defective ossification at the ischiopubic
junction. Vanek (1981) reported a second family with affected members in 3
generations and pointed out that there are no changes in the fingernails in this
condition.
Morin et al. (1985) reported a family with 15 affected members under the
designation coxo-podo-patellar syndrome. All 11 patients whose feet had been
examined showed an increased space between the first and second toes. In most of
them, short fourth and fifth toes and flat feet were also noted. Burckhardt
(1988) reported 3 unrelated patients, 1 of whom had a femoropatellar pain
syndrome. Radiographs showed striking hypoplasia of the ischium.
Kozlowski and Nelson (1995) reported 2 sporadic cases thought to represent new
mutations.
Bongers et al. (2001) described 5 cases from 3 previously undescribed families. Based
on the clinical features found in the affected individuals in these families and those
of 46 other individuals and information found in the medical literature, Bongers et
al. (2001) identified diagnostic criteria for this condition. They suggested that aplasia
or hypoplasia of the patellae and absent, delayed, or irregular ossification of the
ischiopubic junctions or infraacetabular axe-cut notches were minimal criteria for
the diagnosis of ischiopatellar syndrome. In addition, major signs were an increased
space between the first and second toes and short fourth and fifth rays of the feet
with pes planus.
Bongers et al. (2005) provided a comprehensive review of human syndromes with
congenital patella anomalies and discussed the underlying gene defects.
Goeminne (2011) suggested that the patients reported by Scott and Taor (1979) had
the same syndrome reported by Goeminne and Dujardin (1970) as 'patella aplasia,
coxa vara, and tarsal synostosis' in 3 members of a family. In addition to absent
patellas, the mother had severe coxa vara, hypoplasia of 'descending parts of the
pubic arches' in the osseous pelvis, talocalcaneal synostosis, and absence of one
metatarsal bilaterally. Her daughter had the full syndrome except for the tarsal
synostosis and her son had only patella aplasia. Goeminne (2011) reviewed other
reported cases and suggested that the syndrome be called familial ischio-coxo-podo-
patellar syndrome (ICPPS).
▼ Mapping
Bongers et al. (2001) carried out haplotype analysis at the 9q34 locus with the
LMX1B gene, mutations in which are responsible for nail-patella syndrome (161200),
and the locus at 17q21-q22, associated with the patella aplasia-hypoplasia
phenotype (168860). Their analysis excluded the 9q34 locus but not the 17q21-q22
locus.
By haplotype analysis, Bongers et al. (2004) identified a critical region of 5.6 cM on
17q22 for small patella syndrome.
▼ Molecular Genetics
In 6 families with small patella syndrome, Bongers et al. (2004) identified
heterozygous loss-of-function mutations in the TBX4 gene (601719). TBX4 encodes a
transcription factor with a strongly conserved DNA-binding T-box domain that
plays a crucial role in lower limb development in chickens and mice. Thus, the
importance of TBX4 was established in the developmental pathways of the lower
limbs and pelvis in humans.
▼ REFERENCES
1. Bongers, E. M. F., Van Bokhoven, H., Van Thienen, M.-N., Kooyman, M. A. P.,
Van Beersum, S. E. C., Boetes, C., Knoers, N. V. A. M., Hamel, B. C. J. The
small patella syndrome: description of five cases from three families and
examination of possible allelism with familial patella aplasia-hypoplasia
and nail-patella syndrome. (Letter) J. Med. Genet. 38: 209-213, 2001.
[PubMed: 11303519, related citations] [Full Text]
2. Bongers, E. M. H. F., Duijf, P. H. G., van Beersum, S. E. M., Schoots, J., van
Kampen, A., Burckhardt, A., Hamel, B. C. J., Losan, F., Hoefsloot, L. H.,
Yntema, H. G., Knoers, N. V. A. M., van Bokhoven, H. Mutations in the
human TBX4 gene cause small patella syndrome. Am. J. Hum. Genet. 74:
1239-1248, 2004. [PubMed: 15106123, images, related citations] [Full Text]
3. Bongers, E. M. H. F., van Kampen, A., van Bokhoven, H., Knoers, N. V. A.
M. Human syndromes with congenital patellar anomalies and the
underlying gene defects. Clin. Genet. 68: 302-319, 2005.
4. Burckhardt, A. Eine Kombination von Knie- und Beckendysplasie. The
small patella syndrome. Z. Orthop. Ihre Grenzgeb. 126: 22-29, 1988.
5. Goeminne, L. Personal Communication. Astene-Deinze, Belgium 2011.
6. Goeminne, L., Dujardin, L. Congenital coxa vara, patella aplasia and tarsal
synostosis: a new inherited syndrome. Acta Genet. Med. Gemellol. 19: 534-
545, 1970. [PubMed: 5512529, related citations]
7. Kozlowski, K., Nelson, J. Small patella syndrome. Am. J. Med. Genet. 57: 558-
561, 1995. [PubMed: 7573128, related citations] [Full Text]
8. Morin, P., Vielpeau, C., Fournier, L., Denizet, D. Le syndrome coxo-podo-
patellaire. J. Radiol. 66: 441-446, 1985. [PubMed: 4045792, related citations]
9. Renwick, J. H. The genetics of the nail-patella syndrome. Ph.D. Thesis: Univ.
of London , 1956.
10. Scott, J. E., Taor, W. S. The 'small patella' syndrome. J. Bone Joint Surg. Br. 61:
172-175, 1979. [PubMed: 438269, related citations] [Full Text]
11. Vanek, J. Ischiopatellare Dysplasie: Syndrom der 'Kleinen Patella' von Scott
und Taor. Rofo 135: 354-356, 1981. [PubMed: 6212344, related citations]
12.
13.
14. Other Names:
15.
16. Scott-Taor syndrome; Coxo-podo-patellar syndrome; Ischiopatellar
dysplasia; Patella aplasia, coxa vara, tarsal synostosis; Congenital coxa vara,
patella aplasia and tarsal synostosis See Less
17. Categories:
18.
19. Congenital and Genetic Diseases; Musculoskeletal Diseases
20. Summary
21.
22. Listen
23. The following summary is from Orphanet, a European reference portal for
information on rare diseases and orphan drugs.
24.
25. Orpha Number: 1509

26. Disease definition
27. Small patella syndrome (SPS) is a very rare benign bone dysplasia
affecting skeletal structures of the lower limb and the pelvis.
28.
29. Epidemiology
30. Less that 50 patients have been reported worldwide.
31.
32. Clinical description
33. The main clinical features include patellar aplasia or hypoplasia,
associated with absent, delayed or irregular ossification of the ischiopubic
junctions and/or the infra-acetabular axe-cut notches. Additional features
found in the majority of reported patients include femur and foot
anomalies (a wide gap between the first and second toes, short fourth
and fifth rays of the feet, and pes planus). Craniofacial anomalies
(micrognathia, cleft palate, flattened nose and prominent forehead) have
been reported occasionally. Intrafamilial variability of the
patellar, pelvic and foot anomalies has been described. Signs and
symptoms vary from pain resulting from gonarthrosis in elderly subjects
to recurrent luxations from infancy, knee pain, and inability to run and
ride a bicycle. However, some cases are asymptomatic.
34.
35. Etiology
36. SPS is caused by mutations in the
human TBX4 gene (chromosome 17q22). TBX4 mutations account
for familial cases with a distinctive facial appearance and those without
facial features. At present, there is no evidence for a genotype-
phenotype correlation.
37.
38. Diagnostic methods
39. Diagnosis is clinical and radiographical.
40.
41. Differential diagnosis
42. SPS should be recognized and differentiated from disorders with
aplastic or hypoplastic patellae, such as isolated familial patella aplasia-
hypoplasia (PTLAH) syndrome and the more severe nail-patella syndrome
(NPS).
43.
44. Genetic counseling
45. SPS is inherited in an autosomal dominant manner.
46.
47. Management and treatment
48. Early surgical treatment, pain relief therapy and supportive
measures should be offered.
49.
50. Visit the Orphanet disease page for more resources.
51. Last updated: 11/30/2006
52. Symptoms
53.
54. Listen
55. This table lists symptoms that people with this disease may have. For
most diseases, symptoms will vary from person to person. People with
the same disease may not have all the symptoms listed. This
information comes from a database called the Human Phenotype
Ontology (HPO) . The HPO collects information on symptoms that have
been described in medical resources. The HPO is updated regularly.
Use the HPO ID to access more in-depth information about a
symptom.
56. Showing 18 of 18 | View Less
Learn More:
HPO ID
Abnormality of epiphysis Abnormal shape of end part of bone 0005930

morphology
Aplasia/Hypoplasia of the patella Absent/small kneecap 0006498

[ more ]
Hip dysplasia 0001385
Autosomal dominant inheritance 0000006
Cleft palate 0000175
Flat capital femoral epiphysis Flat end part of innermost thighbone 0003370
High palate Elevated palate 0000218

[ more ]
Hypoplasia of the lesser trochanter 0008801
Micrognathia Little lower jaw 0000347

[ more ]
Patellar aplasia Absent kneecap 0006443
Patellar dislocation Dislocated kneecap 0002999
Patellar hypoplasia Small kneecap 0003065

[ more ]
Pes planus Flat feet 0001763

[ more ]
Sandal gap Gap between 1st and 2nd toes 0001852

[ more ]
Short femur Short thighbone 0003097
Talocalcaneal synostosis 0005682
Tarsal synostosis Fused ankle bones 0008368

Learn More:
HPO ID
Wide capital femoral epiphyses Wide end part of innermost thighbone 0008784
57. Showing 18 of 18 |
Isodicentric chromosome 15 syndrome

Description
Isodicentric chromosome 15 syndrome is a developmental disorder with a broad

spectrum of features. The signs and symptoms vary among affected individuals.
Poor muscle tone is commonly seen in individuals with isodicentric chromosome 15

syndrome and contributes to delayed development and impairment of motor skills,
including sitting and walking.
Babies with isodicentric chromosome 15 syndrome often have trouble feeding due to

weak facial muscles that impair sucking and swallowing; many also have backflow of
acidic stomach contents into the esophagus (gastroesophageal reflux). These feeding
problems may make it difficult for them to gain weight.
Intellectual disability in isodicentric chromosome 15 syndrome can range from mild to

profound. Speech is usually delayed and often remains absent or impaired. Behavioral
difficulties often associated with isodicentric chromosome 15 syndrome include
hyperactivity, anxiety, and frustration leading to tantrums. Other behaviors resemble
features of autistic spectrum disorders, such as repeating the words of others
(echolalia), difficulty with changes in routine, and problems with social interaction.
About two-thirds of people with isodicentric chromosome 15 syndrome have seizures. In

more than half of affected individuals, the seizures begin in the first year of life.
About 40 percent of individuals with isodicentric chromosome 15 syndrome are born

with eyes that do not look in the same direction (strabismus). Hearing loss in childhood
is common and is usually caused by fluid buildup in the middle ear. This hearing loss is
often temporary. However, if left untreated during early childhood, the hearing loss can
interfere with language development and worsen the speech problems associated with
this disorder.
Other problems associated with isodicentric chromosome 15 syndrome in some

affected individuals include minor genital abnormalities in males such as undescended
testes (cryptorchidism) and a spine that curves to the side (scoliosis).
Related Information
Frequency
Isodicentric chromosome 15 syndrome occurs in about 1 in 30,000 newborns.
Related Information
Genetic Changes
Isodicentric chromosome 15 syndrome results from the presence of an abnormal extra

chromosome, called an isodicentric chromosome 15, in each cell. An isodicentric
chromosome contains mirror-image segments of genetic material and has two
constriction points (centromeres), rather than one centromere as in normal
chromosomes. In isodicentric chromosome 15 syndrome, the isodicentric chromosome
is made up of two extra copies of a segment of genetic material from chromosome 15,
attached end-to-end. Typically this copied genetic material includes a region of the
chromosome called 15q11-q13.
Cells normally have two copies of each chromosome, one inherited from each parent. In
people with isodicentric chromosome 15 syndrome, cells have the usual two copies
of chromosome 15plus the two extra copies of the segment of genetic material in the
isodicentric chromosome. The extra genetic material disrupts the normal course of
development, causing the characteristic features of this disorder. Some individuals with
isodicentric chromosome 15 whose copied genetic material does not include the 15q11-
q13 region do not show signs or symptoms of the condition.
Learn more about the chromosome associated with isodicentric chromosome 15

syndrome
Related Information
 What is a chromosome?
 Can changes in the number of chromosomes affect health and development?
 Can changes in the structure of chromosomes affect health and development?
Inheritance Pattern
Isodicentric chromosome 15 syndrome is usually not inherited. The chromosomal

change that causes the disorder typically occurs as a random event during the
formation of reproductive cells (eggs or sperm) in a parent of the affected individual.
Most affected individuals have no history of the disorder in their family.
 Battaglia A, Parrini B, Tancredi R. The behavioral phenotype of the idic(15)

syndrome. Am J Med Genet C Semin Med Genet. 2010 Nov 15;154C(4):448-55.
doi: 10.1002/ajmg.c.30281.
Citation on PubMed
 Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J
Rare Dis. 2008 Nov 19;3:30. doi: 10.1186/1750-1172-3-30. Review.
Citation on PubMed or Free article on PubMed Central
 Battaglia A. The inv dup(15) or idic(15) syndrome: a clinically recognisable

neurogenetic disorder. Brain Dev. 2005 Aug;27(5):365-9. Epub 2005 Apr 22.
Review.
Citation on PubMed
 Hogart A, Wu D, LaSalle JM, Schanen NC. The comorbidity of autism with the
genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis. 2010
May;38(2):181-91. doi: 10.1016/j.nbd.2008.08.011. Epub 2008 Sep 18. Review.
 Kwasnicka-Crawford DA, Roberts W, Scherer SW. Characterization of an autism-

associated segmental maternal heterodisomy of the chromosome 15q11-13 region.
J Autism Dev Disord. 2007 Apr;37(4):694-702.
Citation on PubMed
 Veenstra-VanderWeele J, Cook EH Jr. Molecular genetics of autism spectrum

disorder. Mol Psychiatry. 2004 Sep;9(9):819-32. Review.
Citation on PubMed
 Wang NJ, Parokonny AS, Thatcher KN, Driscoll J, Malone BM, Dorrani N,
Sigman M, LaSalle JM, Schanen NC. Multiple forms of atypical rearrangements
generating supernumerary derivative chromosome 15. BMC Genet. 2008 Jan
4;9:2. doi: 10.1186/1471-2156-9-2.
 Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA,
Vance JM, Gilbert JR, Abramson RK, Wright HH, Cuccaro ML, Pericak-Vance MA.
Three probands with autistic disorder and isodicentric chromosome 15. Am J Med
Genet. 2000 Jun 12;96(3):365-72. Review.
Isodicentric Chromosome 15
An isodicentric chromosome 15, or idic(15), is an extra chromosome that is made from

two pieces of chromosome 15 that are stuck together end-to-end by their q arms. They
typically have two p arms, one on each end, and the amount of DNA that is included
from the q arm can vary. When an idic(15) is described on a genetic report, the band
numbers are used to give approximate coordinates of the two ends that fused.
Essentially all idic(15) chromosomes that we are aware of are maternally inherited.
This shows two different forms of idic(15). On the left, the idic(15) is carrying two extra
copies of part of chromosome 15, starting at the p - arm and extending down the long
arm to band 15q13.2. When this idic(15) is found in a cell that already has 2 normal
copies of chromosome 15, there are 4 total copies of the genes included on the idic(15).
This would be 2 extra “Core” and “E” pieces. The idic(15) on the right is the most
common type and is asymmetric. On one end, the idic(15) contains part of the q arm
down though 15q13.3, but on the other end, it only goes to 15q13.2. This results in 2
extra “Core” and “E” regions but only 1 extra “e” region.
MOSAICISM
Some children and adults with idic(15) are said to have "mosaicism", meaning that their
idic(15) is not present in all of the cells in their bodies. Mosaicism happens by chance
in this and many other chromosomal disorders.
RECURRENCE
Generally, people with idic(15) do not have other family members with the chromosomal
abnormality. The idic(15) usually forms by chance in one person in the family. Children
with idic(15) are born to parents of every socioeconomic, racial, and ethnic background.
There is no known link between idic(15) and environmental or lifestyle factors. In other
words, there is nothing that parents did before or during pregnancy to cause their child
to be born with idic(15).
This is general information. Families should always seek the advice of a genetics
specialist to discuss their specific situation.
Jackson-Weiss Syndrome
NORD gratefully acknowledges Nathaniel H. Robin, MD, Professor, Department of Genetics, University of
Alabama at Birmingham, for assistance in the preparation of this report.
Synonyms of Jackson-Weiss Syndrome

 craniosynostosis, midfacial hypoplasia, and foot abnormalities
 Jackson-Weiss craniosynostosis
 JWS
General Discussion
Summary
Jackson-Weiss syndrome (JWS) is a rare genetic disorder characterized by distinctive
malformations of the head and facial (craniofacial) area and abnormalities of the feet.
The range and severity of symptoms and findings may be extremely variable, even
among affected members of the same family. Primary findings may include premature
closure of the fibrous joints (cranial sutures) between certain bones of the skull
(craniosynostosis), unusually flat, underdeveloped midfacial regions (midfacial
hypoplasia) abnormally broad great toes, and/or malformation or fusion of certain bones
within the feet. In some patients, JWS is an autosomal dominant genetic condition
caused by a change (mutation) in the FGFR2 gene, although mutations in other genes
(eg, FGFR3) can produce a similar appearing condition.
Introduction
JWS was originally described in 1976 (C.E. Jackson) in a large Amish family (kindred).
Within this kindred, 88 affected individuals were observed and an additional 50 were
known to be affected. Several other families with the disorder have since been
described. In addition, isolated cases have been reported in which there was no known
family history.
JWS is now known to be a member of a group of conditions caused by mutations in
the FGFR genes including Apert syndrome, Crouzon syndrome, Beare-Stevenson
syndrome, FGFR2-related isolated coronal synostosis, Pfeiffer syndrome, Crouzon
syndrome with acanthosis nigricans and Muenke syndrome.
Signs & Symptoms

JWS is typically characterized by craniofacial malformations occurring in association
with skeletal abnormalities of the feet, but some affected individuals have no
craniofacial abnormalities. The range and severity of associated findings may vary
greatly among members of the same or other affected families.
In those with craniofacial abnormalities, such malformations may result in a distinctive
facial appearance. For example, there may be premature closure of the fibrous joints
(cranial sutures) between particular bones of the skull (craniosynostosis), causing the
top of the head to appear pointed or conical (acrocephalic). In some patients,
craniosynostosis may be associated with headaches, disturbances in vision, and
hydrocephalus, a condition in which there is an abnormal accumulation of cerebrospinal
fluid (CSF) in the skull. Hydrocephalus often results in increased fluid pressure and
abnormal enlargement of the cavities (ventricles) within the brain.
Individuals with JWS may also have additional craniofacial abnormalities. These may
include a relatively flat back region of the head (occiput), underdeveloped midfacial
regions (midfacial hypoplasia), and widely spaced eyes (ocular hypertelorism). Affected
individuals may also have downwardly slanting eyelid folds (palpebral fissures),
drooping of the upper eyelids (ptosis), or abnormal deviation of one eye in relation to the
other (strabismus). In some patients, additional features may also be present, such as a
flat nasal bridge, an underdeveloped upper jawbone (maxillary hypoplasia), a highly
arched roof of the mouth (palate), incomplete closure of the palate (cleft palate), and/or
malformed ears.
JWS may also be characterized by various abnormalities of the feet. For example,
affected individuals may have webbed or fused second and third toes (syndactyly)
and/or abnormally short, broad great toes that may bend inward (varus deformities).
There may also be malformation or fusion of certain bones within the body of the feet
(metatarsals), the ankles (tarsal bones), and/or the heels (calcanei). Some individuals
with JWS may also have additional physical abnormalities such as limitation of joint
movements and/or a condition in which the legs are abnormally curved inward, with the
knees close together and the ankles widely separated (genu valgum). In addition,
although most individuals with the disorder have average or above average intelligence
and a normal life span, varying levels of intellectual disability have been reported in a
few patients.
Causes
JWS is an autosomal dominant genetic disorder. Most genetic diseases are determined
by the status of the two copies of a gene, one received from the father and one from the
mother. Dominant genetic disorders occur when only a single copy of an abnormal gene
is necessary to cause a particular disease. The abnormal gene can be inherited from
either parent or can be the result of a new mutation (gene change) in the affected
individual. The risk of passing the abnormal gene from an affected parent to an offspring
is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation
that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from
the parents.
JWS is caused by a mutation in the FGFR2 gene. The FGFR2 gene regulates the
production of a protein known as a fibroblast growth factor receptor (FGFR).Genetic
mutations that disrupt the functioning of such proteins may result in certain
abnormalities during embryonic development, such as premature fusion of the
craniofacial area and the limbs. A number of syndromes have been identified that are
associated with mutations of the FGFR2 gene including Crouzon, Pfeiffer, and Apert
syndromes. (For further information on these disorders, please see the “Related
Disorders” section of this report below.)
Most individuals with a FGFR2 gene mutation associated with JWS will have symptoms
and findings associated with the disorder but range and severity may vary greatly from
person to person).
Affected Populations
JWS appears to affect males and females in equal numbers. The incidence rate is
unknown.
Related Disorders
Symptoms of the following disorders can be similar to those of Jackson-Weiss
syndrome. Comparisons may be useful for a differential diagnosis:
Apert syndrome is a rare disorder inherited as an autosomal dominant genetic trait. This
disorder is characterized by fused or webbed fingers and toes (syndactyly), a pointed
head (acrocephaly or oxycephaly), other skeletal and facial abnormalities, and
intellectual disability. (For more information on this disorder, choose “Apert Syndrome”
as your search term in the Rare Disease Database.)
Carpenter syndrome belongs to a group of rare genetic disorders known as
“acrocephalopolysyndactyly” (ACPS) disorders. All forms of ACPS are characterized by
premature closure of the fibrous joints (cranial sutures) between certain bones of the
skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly);
webbing or fusion (syndactyly) of certain fingers or toes (digits); and/or more than the
normal number of digits (polydactyly). Carpenter syndrome is an autosomal recessive
genetic condition. (For more information on this disorder, choose “Carpenter Syndrome”
as your search term in the Rare Disease Database.)
Saethre-Chotzen syndrome (SCS) is another “acrocephalosyndactyly” disorder. In many
infants with SCS, cranial sutures may fuse unevenly and this may contribute to the head
and face appearing to be dissimilar from one side to the other (craniofacial asymmetry).
SCS is inherited in an autosomal dominant manner. (For more information on this
disorder choose “Saethre Chotzen Syndrome” as your search term, in the Rare Disease
Database.)
Crouzon syndrome is an autosomal dominant genetic condition. Symptoms of this
disorder may be: abnormalities of the skull, face and brain due to premature closure of
the bones of the skull; swelling of the optic disk inside the eye; impaired vision; hearing
loss; a beaked- shaped nose; an underdeveloped lower jaw; and/or a high arched
palate. (For more information on this disorder, choose “Crouzon Syndrome” as your
search term in the Rare Disease Database.)
Pfeiffer syndrome is a rare genetic disorder characterized by premature fusion of certain
skull bones (craniosynostosis), and abnormally broad and medially deviated thumbs
and great toes. Most affected individuals also have differences to their midface
(protruding eyes) and conductive hearing loss. Three forms of Pfeiffer syndrome are
recognized, of which types II and III are the more serious. Pfeiffer syndrome is an
autosomal dominant condition. (For more information on this disorder, choose “Pfeiffer
Syndrome” as your search term in the Rare Disease Database.)
Diagnosis
JWS may be diagnosed or confirmed at birth or during early infancy based upon a
thorough clinical evaluation, identification of characteristic physical findings, and a
variety of specialized tests including advanced imaging techniques. For example,
specialized x-ray imaging studies, such as computerized tomography (CT) scanning or
magnetic resonance imaging (MRI), may help to confirm the presence and/or extent of
certain craniofacial, foot, or other skeletal abnormalities. Molecular genetic testing for
mutations in the FGFR2 gene is available if the diagnosis is uncertain.
In some children, a diagnosis of JWS may be suggested before birth (prenatally) based
upon detection of certain characteristic physical findings during fetal ultrasound.
Standard Therapies
Treatment
The treatment of JWS is directed toward the specific symptoms that are apparent in
each individual. Such treatment may require the coordinated efforts of a team of
medical professionals who may need to systematically and comprehensively plan an
affected child’s treatment. These professionals may include pediatricians; physicians
who specialize in disorders of the skeleton, joints, muscles, and related tissues
(orthopedists), physical therapists; and/or other health care professionals.
Specific therapies for JWS are symptomatic and supportive. In some affected
individuals, craniosynostosis and associated hydrocephalus may result in abnormally
increased pressure within the skull (intracranial pressure) and on the brain. In such
cases, surgery may be advised to correct craniosynostosis and to insert a tube (shunt)
to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of
the body where the CSF can be absorbed. Surgery may also be recommended to
correct other craniofacial and skeletal abnormalities potentially associated with the
disorder. The surgical procedures performed will depend upon the severity of the
anatomical abnormalities, their associated symptoms, and other factors. In some cases,
physical therapy and additional orthopedic and supportive measures may also be
recommended to help improve an affected individual’s mobility.
Early intervention may be important to ensure that children with JWS reach their
potential. Special services that may be beneficial include special education and other
medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. In
addition, thorough clinical evaluations may be important in family members of
diagnosed individuals to detect any findings that may be associated with JWS. Other
treatment for this disorder is symptomatic and supportive.
Investigational Therapies
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.All
studies receiving U.S. government funding, and some supported by private industry, are
posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in
Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-
recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
NORD Member Organizations

 Children’s Craniofacial Association
o 13140 Coit Road
o Suite 517
o Dallas, TX 75240 USA
o Phone: (214) 570-9099
o Toll-free: (800) 535-3643
o Email: contactCCA@ccakids.com
o Website: http://www.ccakids.com
Other Organizations
 AmeriFace
o PO Box 751112
o Las Vegas, NV 89136 USA
o Phone: (702) 769-9264
o Toll-free: (888) 486-1209
o Email: info@ameriface.org
o Website: http://www.ameriface.org
 Cleft Lip and Palate Foundation of Smiles
o 2044 Michael Ave SW
o Wyoming, MI 49509
o Phone: (616) 329-1335
o Email: Rachel@cleftsmile.org
o Website: http://www.cleftsmile.org
 FACES: The National Craniofacial Association
o PO Box 11082
o Chattanooga, TN 37401
o Phone: (423) 266-1632
o Toll-free: (800) 332-2373
o Email: faces@faces-cranio.org
o Website: http://www.faces-cranio.org
 Genetic and Rare Diseases (GARD) Information Center
o PO Box 8126
o Gaithersburg, MD 20898-8126
o Phone: (301) 251-4925
o Toll-free: (888) 205-2311
o Website: http://rarediseases.info.nih.gov/GARD/
References
TEXTBOOKS
Buyse ML. Birth Defects Encyclopedia. Dover, MA; Blackwell Scientific Publications,
Inc.; 1990:467-468.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY; Oxford
University Press; 1990:529-531.
JOURNAL ARTICLES
Park WJ, et al. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes
show allelic heterogeneity and phenotypic variability. Hum Molec Genet. 1995;4:1229-
1233.
Lewanda AF, et al. Genetic heterogeneity among craniosynostosis syndromes: mapping
the Saethre-Chotzen syndrome locus between D7S513 and D7S516 and exclusion of
Jackson-Weiss and Crouzon syndrome loci from 7p. Genomics. 1994;19:115-119.
Jabs EW, et al. Jackson-Weiss and Crouzon syndromes are allelic with mutations in
fibroblast growth factor receptor 2. Nature Genet. 1994; 8:275-279.
Li X, et al. Two craniosynostotic syndrome loci, Crouzon and Jackson-Weiss, map to
chromosome 10q23-q26. Genomics. 1994;22:418-424.
Escobar V, et al. Are the acrocephalosyndactyly syndromes variable expressions of a
single gene defect? Birth Defects Orig Art Ser. 1977;XIII:139-154.
Escobar V, et al. On the classification of the acrocephalosyndactyly syndromes. Clin
Genet. 1977;12:169-178.
Jackson CE, et al. Craniosynostosis, midfacial hypoplasia and foot abnormalities: an
autosomal dominant phenotype in a large Amish kindred. J Pediatr. 1976;88:963-968.
Cross HE, et al. Craniosynostosis in the Amish. J Pediat. 1969;75:1037-1044.
INTERNET
Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-Related Craniosynostosis
Syndromes. 1998 Oct 20 [Updated 2011 Jun 7]. In: Pagon RA, Adam MP, Ardinger HH,
et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington,
Seattle; 1993-2016.Available
from: http://www.ncbi.nlm.nih.gov/books/NBK1455/ Accessed June 29, 2017.
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore,
MD. MIM Number 123150; 09/24/2012. Available
at:. http://omim.org/entry/123150.Accessed June 29, 2017.
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore,
MD. MIM Number 176943; 09/06/2016. Available at: http://omim.org/entry/176943?
search=176943&highlight=176943 Accessed June 29, 2017.
Jackson-Weiss syndrome. Genetics Home Reference.Reviewed January
2017. https://ghr.nlm.nih.gov/condition/jackson-weiss-syndrome. Accessed June 29,
2017.
Jackson-Weiss syndrome. Genetic and Rare Diseases Information Center (GARD).
Last Update 5/14/2011. https://rarediseases.info.nih.gov/gard/6796/jackson-weiss-
syndrome/resources/1. Accessed June 29, 2017.
Joubert syndrome is disorder of brain development that may affect

many parts of the body. It is characterized by the absence or
underdevelopment of the cerebellar vermis (a part of the brain that controls
balance and coordination) and a malformed brain stem (connection between
the brain and spinal cord). Together, these cause the characteristic
appearance of a molar tooth sign on MRI. Signs and symptoms can vary but
commonly include weak muscle tone (hypotonia); abnormal breathing
patterns; abnormal eye movements; ataxia; distinctive facial features;
and intellectual disability.[1][2][3] Various other abnormalities may also be
present. Joubert syndrome may be caused by mutations in any of
many genes. Inheritance is usually autosomal recessive, but rarely it may
be X-linked recessive.[1][4][5] Treatment is supportive and depends on the
symptoms in each person.[1]
Symptoms
Listen
Most infants with Joubert syndrome have weak muscle tone (hypotonia),

which evolves into difficulty coordinating movements (ataxia) in early
childhood.[3] Affected children may have episodes of unusually fast or slow
breathing (hyperpnea), which tends to occur shortly after birth. This may
intensify with emotional stress, but progressively improves with age and
usually disappears around 6 months of age.[3][6]
Abnormal eye movements are also common. Oculomotor apraxia occurs

frequently and causes difficulty moving the eyes from side to side. People
with oculomotor apraxia have to turn their heads to see things in their
peripheral vision.[6]
Developmental abilities, in particular language and motor skills, are delayed

with variable severity. Mild to severe intellectual disability is common, but
some people with Joubert syndrome have normal intellectual abilities.[6]
Distinctive facial features are also characteristic. These include a broad

forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes,
low-set ears, and a triangular-shaped mouth.[3]
Joubert syndrome can cause a wide range of additional signs and symptoms.
The condition is sometimes associated with other eye abnormalities (such as
retinal dystrophy, which can cause vision loss); kidney disease; liver
disease; skeletal abnormalities (such as extra fingers and toes);
and hormone (endocrine) problems. When the characteristic features of
Joubert syndrome occur with one or more of these additional features,
researchers refer to the condition as "Joubert syndrome and related
disorders (JSRD)"[3] or as a subtype of Joubert syndrome.[6]
Learn More:
HPO ID
Apnea 0002104
Ataxia 0001251
Cerebellar vermis hypoplasia 0001320
Episodic tachypnea 0002876
Global developmental delay 0001263
Intellectual disability Mental deficiency 0001249
[ more ]
Muscular hypotonia 0001252
Oculomotor apraxia 0000657
Biparietal narrowing 0004422
Feeding difficulties in infancy 0008872
Gait disturbance Abnormal gait 0001288
[ more ]
Long face Elongation of face 0000276
[ more ]
Nystagmus 0000639
Abnormal form of the vertebral 0003312
bodies
Abnormality of the hypothalamus- 0000864
pituitary axis
Aganglionic megacolon 0002251
Anteverted nares Nasal tip, upturned 0000463
[ more ]
Aplasia/Hypoplasia of the corpus 0007370
callosum
Encephalocele 0002084
Foot polydactyly Duplication of bones of the toes 0001829
Hand polydactyly Extra finger 0001161
Highly arched eyebrow Arched eyebrows 0002553
[ more ]
Hydrocephalus 0000238
Iris coloboma Cat eye 0000612
Low-set ears Low set ears 0000369
[ more ]
Occipital myelomeningocele 0007271
Oral cleft Cleft of the mouth 0000202
Polymicrogyria 0002126
Prominent nasal bridge Elevated nasal bridge 0000426
[ more ]
Learn More:
HPO ID
Ptosis Drooping upper eyelid 0000508
Renal cyst 0000107
Retinal dysplasia 0007973
Scoliosis 0002650
Seizures Seizure 0001250
Situs inversus totalis 0001696
Strabismus Cross-eyed 0000486
[ more ]
Tremor Tremors 0001337
Abnormality of saccadic eye 0000570
movements
Abnormality of the foot Abnormal feet morphology 0001760
[ more ]
Agenesis of cerebellar vermis 0002335
Aggressive behavior Aggression 0000718
[ more ]
Brainstem dysplasia 0002508
Central apnea 0002871
Chorioretinal coloboma 0000567
Dysgenesis of the cerebellar vermis 0002195
Elongated superior cerebellar 0011933
peduncle
Enlarged fossa interpeduncularis 0100951
Epicanthus Eye folds 0000286
[ more ]
Generalized hypotonia Decreased muscle tone 0001290
[ more ]
Hemifacial spasm Spasms on one side of the face 0010828
Hepatic fibrosis 0001395
Hyperactivity 0000752
Hypoplasia of the brainstem Small brainstem 0002365
[ more ]
Impaired smooth pursuit 0007772
Macrocephaly Increased size of skull 0000256
[ more ]
Macroglossia Abnormally large tongue 0000158
[ more ]
Molar tooth sign on MRI 0002419
Neonatal breathing dysregulation Impaired breathing in newborn 0002790
Optic nerve coloboma 0000588
Learn More:
HPO ID
Postaxial hand polydactyly Extra little finger 0001162
[ more ]
Prominent forehead Pronounced forehead 0011220
[ more ]
Protruding tongue Prominent tongue 0010808
[ more ]
Retinal dystrophy 0000556
Self-mutilation Deliberate self-harm 0000742
[ more ]
Triangular-shaped open mouth 0200096
Cause
Listen
Joubert syndrome and related disorders may be caused by changes

(mutations) in any of many genes (some of which are
unknown). The proteins made from these genes are either known or thought
to affect cellstructures called cilia. Cilia are projections on the cell surface
that play a role in signaling. They are important for many cell types,
including neurons, liver cells and kidney cells. Cilia also play a role in the
senses such as sight, hearing, and smell.
Mutations in the genes responsible for Joubert syndrome and related

disorders cause problems with the structure and function of cilia, likely
disrupting important signaling pathways during development. However, it is
still unclear how specific developmental abnormalities result from these
problems.[7]
Inheritance
Listen
Joubert syndrome is predominantly inherited in an autosomal

recessive manner.[4] This means that to be affected, a person must have
a mutation in both copies of the responsible gene in each cell. Affected
people inherit one mutated copy of the gene from each parent, who is
referred to as a carrier. Carriers of an autosomal recessive condition typically
do not have any signs or symptoms (they are unaffected). When 2 carriers
of an autosomal recessive condition have children, each child has a:
 25% chance to be affected
 50% chance to be an unaffected carrier like each parent
 25% chance to be unaffected and not a carrier.
In rare cases, when Joubert syndrome is caused by mutations in
the OFD1 gene on the X chromosome, it is inherited in an X-linked
recessive manner.[5] X-linked recessive conditions usually occur in males,
who only have one X chromosome (and one Y chromosome). Females have
two X chromosomes, so if they have a mutation on one X chromosome, they
still have a working copy of the gene on their other X chromosome and are
typically unaffected. While females can have an X-linked recessive condition,
it is very rare.
If a mother is a carrier of an X-linked recessive condition and the father is

not, the risk to children depends on each child's sex.
 Each male child has a 50% chance to be unaffected, and a 50%

chance to be affected
 Each daughter has a 50% chance to be unaffected, and a 50% chance
to be an unaffected carrier
If a father has the X-linked recessive condition and the mother is not a
carrier, all sons will be unaffected, and all daughters will be unaffected
carriers.
People with specific questions about the inheritance of Joubert

syndrome for themselves or family members are encouraged to
speak with a genetic counselor or other genetics professional. A
genetics professional can help by:
 thoroughly evaluating the family history
 addressing questions and concerns
 assessing recurrence risks
 facilitating genetic testing if desired
 discussing reproductive options
Diagnosis
Listen
The diagnosis of Joubert syndrome is based on the presence of characteristic

clinical features as well as the MRI finding of the molar tooth sign.[8]
The diagnosis of "classic" or “pure” Joubert syndrome is based on the

presence of the following three primary criteria:
 the molar tooth sign on MRI

 hypotonia (weak muscle tone) in infancy with later development
of ataxia
 developmental delays / intellectual disability
Additional features often identified in people with Joubert syndrome include
an abnormal breathing pattern (alternating tachypnea and/or apnea) and
abnormal eye movements.
The term “Joubert syndrome and related disorders” (JSRD) refers to those
with Joubert syndrome who have additional findings such as retinal
dystrophy, renal (kidney) disease, ocular colobomas, occipital encephalocele
(protruding tissue at the back of the skull), fibrosis of the liver, polydactyly,
and/or other abnormalities. A significant proportion of people diagnosed with
classic Joubert syndrome in infancy or early childhood will eventually have
additional findings that represent JSRD.[8]
While mutations in many genes are known to be associated with Joubert
syndrome, they are only identified in about 50% of affected people who
have genetic testing. Therefore, genetic testing is not required for a
diagnosis of Joubert syndrome or JSRD.[8]
Testing Resources
 The Genetic Testing Registry (GTR) provides information about the
genetic tests for this condition. The intended audience for the GTR is
health care providers and researchers. Patients and consumers with
specific questions about a genetic test should contact a health care
provider or a genetics professional.
Treatment
Listen
The resources below provide information about treatment options for this
condition. If you have questions about which treatment is right for you, talk
to your healthcare professional.
Management Guidelines
 Project OrphanAnesthesia is a project whose aim is to create peer-
reviewed, readily accessible guidelines for patients with rare diseases
and for the anesthesiologists caring for them. The project is a
collaborative effort of the German Society of Anesthesiology and
Intensive Care, Orphanet, the European Society of Pediatric Anesthesia,
anesthetists and rare disease experts with the aim to contribute to
patient safety.
from you.
Find a Specialist
Listen
Research
Listen
Research helps us better understand diseases and can lead to advances in

diagnosis and treatment. This section provides resources to help you learn
about medical research and ways to get involved.
Clinical Research Resources

 ClinicalTrials.gov lists trials that are related to Joubert syndrome. Click
on the link to go to ClinicalTrials.gov to read descriptions of these
studies.
Please note: Studies listed on the ClinicalTrials.gov website are listed

for informational purposes only; being listed does not reflect an
endorsement by GARD or the NIH. We strongly recommend that you talk
with a trusted healthcare provider before choosing to participate in any
clinical study.
 The University of Washington's Hindbrain Malformation Research
Program invites individuals with this condition to participate in their
research program. Click on the link for more information on how to
participate in their research study.
Organizations
Listen
Support and advocacy groups can help you connect with other patients and
families, and they can provide valuable services. Many develop patient-
centered information and are the driving force behind research for better
treatments and possible cures. They can direct you to research, resources,
and services. Many organizations also have experts who serve as medical
advisors or provide lists of doctors/clinics. Visit the group’s website or
contact them to learn about the services they offer. Inclusion on this list is
not an endorsement by GARD.
Organizations Supporting this Disease

 Joubert Syndrome and Related Disorders Foundation
1415 West Ave.
Cincinnati, OH 45215
Telephone: (614) 864-1362
Website: http://www.jsrdf.org
Do you know of an organization? We want to hear from you.
Living With
Listen
Living with a genetic or rare disease can impact the daily lives of patients
and families. These resources can help families navigate various aspects of
living with a rare disease.
Financial Resources
 The Social Security Administration has included this condition in their
Compassionate Allowances Initiative. This initiative speeds up the
processing of disability claims for applicants with certain medical
conditions that cause severe disability. More information
about Compassionate Allowances and applying for Social Security
disability is available online.
Learn More
Listen

Where to Start
 Genetics Home Reference (GHR) contains information on Joubert
syndrome. This website is maintained by the National Library of
Medicine.
 The National Institute of Neurological Disorders and Stroke (NINDS)
collects and disseminates research information related to neurological
disorders. Click on the link to view information on this topic.
 The National Organization for Rare Disorders (NORD) has a report for
patients and families about this condition. NORD is a patient advocacy
organization for individuals with rare diseases and the organizations that
serve them.
 The University of Washington's Hindbrain Malformation Research
Program has more information on this condition.
 GeneReviews provides current, expert-authored, peer-reviewed, full-
text articles describing the application of genetic testing to the diagnosis,
management, and genetic counseling of patients with specific inherited
conditions.
Medicine.
articles that discuss Joubert syndrome. Click on the link to view a sample
News & Events

Listen
News
January 31, 2018
January 18, 2018
December 27, 2017
December 19, 2017
Next Decade
August 10, 2017
NCATS Co-Sponsored Conferences
 Gordon Research Conference (GRC): Cilia, Mucus and Mucociliary
Interactions Sunday, February 8, 2015 - Friday, February 13, 2015
Location: Hotel Galvez, Galveston, TX
Description: The aims of the meeting are three fold: (1) To disseminate,
discuss and integrate cutting-edge data related to progress in cilia, mucus
and mucociliary interactions in a forum of world experts and young
scientists. Each area will embrace advances in fundamental cell and
molecular biology, development, novel imaging techniques, new animal
models, and genetic discovery. Attendees will be able to use this information
to improve their own understanding to advance their own work, teaching
and to be stimulated for new discoveries in these areas. (2) To provide a
forum that will link fundamental scientific knowledge related to cilia, mucus,
and mucociliary interactions to human disease and avenues for diagnosis
and therapies. Thereby, drive new collaborations, technologies and
interactions among basic, translational, and clinical researchers related to
gene function in diseases of cilia, mucins, mucosal immunity, disease
diagnosis and treatment. (3) To promote involvement and advancement of
trainees, women and under-represented groups in the study of cilia, mucus
and mucociliary interactions. To assure a strong and equitable
representation of women, minorities, young investigators (junior faculty,
pre-doctoral, post-doctoral trainees) and those with disabilities through
sound proactive planning and organization, we will invite and feature young
investigators and trainees. The meeting format is designed to enhance the
interaction of trainees and senior investigators.
Contact: Robert A. Smith, Ph.D.,(301) 435-0202, robert.smith4@nih.gov
Co-funding Institute(s): National Heart, Lung, and Blood Institute, Office
of Rare Diseases Research
Other Conferences
 Joubert Syndrome & Related Disorders Foundation
10th Biennial Conference
July 13-16, 2011
Orlando Florida
GARD Answers
Listen

please let us know. Submit a new question
 I suspect my 32 year old daughter may have Joubert syndrome. Do
both my husband and I have to be carriers? Her father's relatives were
French Canadians who lived near Quebec, and I have read that there is a
large incidence from this area. See answer
 I am trying for a baby with my partner. From a previous relationship
my partner has a son with Joubert syndrome. Is there a risk I could have
a baby with Joubert syndrome too? Should I get tested? Also, my partner
has previously taken steroids. Do these cause risks of having a Joubert
syndrome child? See answer
 My grandson has Joubert syndrome, autism, and ADHD. Is autism
related to Joubert syndrome? See answer
Have a question? Contact a GARD Information Specialist.
References
1. NINDS Joubert Syndrome Information Page. NINDS. January 21,

2016; http://www.ninds.nih.gov/disorders/joubert/joubert.htm.
2. Overview. Joubert Syndrome & Related Disorders Foundation.
2016; http://jsrdf.org/what-is-js/.
3. Joubert syndrome. Genetics Home Reference. January
2011; http://ghr.nlm.nih.gov/condition/joubert-syndrome.
4. What is Joubert Syndrome?. Hindbrain Malformation Research
Program.
2016; http://depts.washington.edu/joubert/joubertsyndrome.php.
5. Cassandra L. Kniffin. JOUBERT SYNDROME 10; JBTS10. OMIM.
December 2, 2015; http://www.omim.org/entry/300804.
6. Brancati, Francesco, et.al.. Joubert Syndrome and related
disorders. Orphanet Journal of Rare Diseases. July
2010; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913941/pdf
/1750-1172-5-20.pdf.
7. Joubert syndrome. Genetics Home Reference. January,
2011; http://ghr.nlm.nih.gov/condition/joubert-syndrome.
8. Melissa Parisi and Ian Glass. Joubert Syndrome and Related
Disorders. GeneReviews. April 11,
2013; http://www.ncbi.nlm.nih.gov/books/NBK1325/.
Joubert syndrome
Description
Joubert syndrome is a disorder that affects many parts of the body. The signs and
symptoms of this condition vary among affected individuals, even among members of
the same family.
The hallmark feature of Joubert syndrome is a combination of brain abnormalities that

together are known as the molar tooth sign, which can be seen on brain imaging studies
such as magnetic resonance imaging (MRI). This sign results from the abnormal
development of structures near the back of the brain, including the cerebellar vermis
and the brainstem. The molar tooth sign got its name because the characteristic brain
abnormalities resemble the cross-section of a molar tooth when seen on an MRI.
Most infants with Joubert syndrome have low muscle tone (hypotonia) in infancy, which
contributes to difficulty coordinating movements (ataxia) in early childhood. Other
characteristic features of the condition include episodes of unusually fast (hyperpnea) or
slow (apnea) breathing in infancy, and abnormal eye movements (ocular motor
apraxia). Most affected individuals have delayed development and intellectual disability,
which can range from mild to severe. Distinctive facial features can also occur
in Joubert syndrome; these include a broad forehead, archedeyebrows, droopy eyelids
(ptosis), widely spaced eyes (hypertelorism), low-set ears, and a triangle-shaped mouth.
Joubert syndrome can include a broad range of additional signs and symptoms. The
condition is sometimes associated with other eye abnormalities (such as retinal
dystrophy, which can cause vision loss, and coloboma, which is a gap or split in a
structure of the eye), kidney disease (including polycystic kidney
disease and nephronophthisis), liver disease, skeletal abnormalities (such as the
presence of extra fingers and toes), or hormone (endocrine) problems. A combination of
the characteristic features of Joubert syndrome and one or more of these additional
signs and symptoms once characterized several separate disorders. Together, those
disorders were referred to as Joubert syndrome and related disorders (JSRD). Now,
however, any instances that involve the molar tooth sign, including those with these
additional signs and symptoms, are usually considered Joubert syndrome.
Related Information
Frequency
Joubert syndrome is estimated to affect between 1 in 80,000 and 1 in 100,000

newborns. However, this estimate may be too low because Joubert syndrome has such
a large range of possible features and is likely underdiagnosed. Particular genetic
mutations that cause this condition are more common in certain ethnic groups, such as
Ashkenazi Jewish, French-Canadian, and Hutterite populations.
Related Information
Genetic Changes
Joubert syndrome can be caused by mutations in more than 30 genes. The proteins

produced from these genes are known or suspected to play roles in cell structures
called primary cilia. Primary cilia are microscopic, finger-like projections that stick out
from the surface of cells and are involved in sensing the physical environment and in
chemical signaling. Primary cilia are important for the structure and function of many
types of cells, including brain cells (neurons) and certain cells in the kidneys and liver.
Primary cilia are also necessary for the perception of sensory input, which is interpreted
by the brain for sight, hearing, and smell.
Mutations in the genes associated with Joubert syndrome lead to problems with the
structure and function of primary cilia. Defects in these cell structures can disrupt
important chemical signaling pathways during development. Although researchers
believe that defective primary cilia are responsible for most of the features of these
disorders, it is not completely understood how they lead to specific developmental
abnormalities.
Mutations in the genes known to be associated with Joubert syndrome account for

about 60 to 90 percent of all cases of this condition. In the remaining cases, the genetic
cause is unknown.
Learn more about the genes associated with Joubert syndrome
Related Information
 What is a gene?
Inheritance Pattern
Joubert syndrome typically has an autosomal recessive pattern of inheritance, which

means both copies of a gene in each cell have mutations. The parents of an individual
with an autosomal recessive condition each carry one copy of the mutated gene, but
they usually do not show signs and symptoms of the condition.
Rare cases of Joubert syndrome are inherited in an X-linked recessive pattern. In these

cases, the causative gene is located on the X chromosome, which is one of the
two sex chromosomes. In males (who have only one X chromosome), one altered copy
of the gene in each cell is sufficient to cause the condition. In females (who have two X
chromosomes), a mutation would have to occur in both copies of the gene to cause the
disorder. Because it is unlikely that females will have two altered copies of this gene,
males are affected by X-linked recessive disorders much more frequently than females.
A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their
sons.
Related Information
 agenesis of cerebellar vermis

 cerebello-oculo-renal syndrome
 cerebellooculorenal syndrome 1
 CORS
 familial aplasia of the vermis
 JBTS
 Joubert-Bolthauser syndrome
Related Information
 How are genetic conditions and genes named?
 Brancati F, Dallapiccola B, Valente EM. Joubert Syndrome and related disorders.

Orphanet J Rare Dis. 2010 Jul 8;5:20. doi: 10.1186/1750-1172-5-20. Review.
 Doherty D. Joubert syndrome: insights into brain development, cilium biology,

and complex disease. Semin Pediatr Neurol. 2009 Sep;16(3):143-54. doi:
10.1016/j.spen.2009.06.002. Review.
 Maria BL, Quisling RG, Rosainz LC, Yachnis AT, Gitten J, Dede D, Fennell E.
Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic
significance. J Child Neurol. 1999 Jun;14(6):368-76.
Citation on PubMed
 Parisi M, Glass I. Joubert Syndrome. 2003 Jul 9 [updated 2017 Jun 29]. In:
Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD,
Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available
from http://www.ncbi.nlm.nih.gov/books/NBK1325/
Citation on PubMed
 Parisi MA. Clinical and molecular features of Joubert syndrome and related
disorders. Am J Med Genet C Semin Med Genet. 2009 Nov 15;151C(4):326-40.
doi: 10.1002/ajmg.c.30229. Review.
 Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar

ataxia with the molar tooth. Lancet Neurol. 2013 Sep;12(9):894-905. doi:
10.1016/S1474-4422(13)70136-4. Epub 2013 Jul 17. Review.
 Valente EM, Dallapiccola B, Bertini E. Joubert syndrome and related disorders.

Handb Clin Neurol. 2013;113:1879-88. doi: 10.1016/B978-0-444-59565-2.00058-7.
Review.
Citation on PubMed
Juvenile primary lateral sclerosis

Description
Juvenile primary lateral sclerosis is a rare disorder characterized by progressive

weakness and tightness (spasticity) of muscles in the arms, legs, and face. The features
of this disorder are caused by damage to motor neurons, which are specialized nerve
cells in the brain and spinal cord that control muscle movement.
Symptoms of juvenile primary lateral sclerosis begin in early childhood and progress

slowly over many years. Early symptoms include clumsiness, muscle weakness and
spasticity in the legs, and difficulty with balance. As symptoms progress, the spasticity
spreads to the arms and hands and individuals develop slurred speech, drooling,
difficulty swallowing, and an inability to walk.
Related Information
Frequency
Juvenile primary lateral sclerosis is a rare disorder, with few reported cases.
Related Information
Genetic Changes
Mutations in the ALS2 gene cause most cases of juvenile primary lateral sclerosis. This
gene provides instructions for making a protein called alsin. Alsin is abundant
in motor neurons, but its function is not fully understood. Mutations in the ALS2 gene
alter the instructions for producing alsin. As a result, alsin is unstable and is quickly
broken down, or it cannot function properly. It is unclear how the loss of functional alsin
protein damages motor neurons and causes juvenile primary lateral sclerosis.
Learn more about the genes associated with juvenile primary lateral sclerosis
Related Information
 What is a gene?
Inheritance Pattern
When caused by mutations in the ALS2 gene, juvenile primary lateral sclerosis is

inherited in an autosomal recessive pattern, which means both copies of the gene in
each cell have mutations. The parents of an individual with an autosomal recessive
condition each carry one copy of the mutated gene, but they typically do not show signs
and symptoms of the condition.
Related Information

 Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE. Molecular and

cellular function of ALS2/alsin: implication of membrane dynamics in neuronal
development and degeneration. Neurochem Int. 2007 Jul-Sep;51(2-4):74-84. Epub
2007 May 4. Review.
Citation on PubMed
 Mintchev N, Zamba-Papanicolaou E, Kleopa KA, Christodoulou K. A novel ALS2

splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family.
Neurology. 2009 Jan 6;72(1):28-32. doi: 10.1212/01.wnl.0000338530.77394.60.
Citation on PubMed
 Orrell RW. ALS2-Related Disorders. 2005 Oct 21 [updated 2016 Jan 28]. In:
Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD,
Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available
from http://www.ncbi.nlm.nih.gov/books/NBK1243/
Citation on PubMed
 Panzeri C, De Palma C, Martinuzzi A, Daga A, De Polo G, Bresolin N, Miller CC,

Tudor EL, Clementi E, Bassi MT. The first ALS2 missense mutation associated with
JPLS reveals new aspects of alsin biological function. Brain. 2006 Jul;129(Pt
7):1710-9. Epub 2006 May 2.
Citation on PubMed
 Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY,
Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M,
Pericak-Vance M, Hentati F, Siddique T. The gene encoding alsin, a protein with
three guanine-nucleotide exchange factor domains, is mutated in a form of
recessive amyotrophic lateral sclerosis. Nat Genet. 2001 Oct;29(2):160-5.
Citation on PubMed
PRIMARY LATERAL SCLEROSIS, JUVENILE; PLSJ
▼ TEXT
A number sign (#) is used with this entry because of evidence that juvenile primary
lateral sclerosis (PLSJ) is caused by homozygous mutation in the gene encoding
alsin (ALS2; 606352) on chromosome 2q33.
Juvenile amyotrophic lateral sclerosis-2 (205100) and infantile-onset ascending
spastic paralysis (IAHSP; 607225) are allelic disorders with overlapping phenotypes.
See also adult-onset PLS (611637), which occurs sporadically or shows autosomal
dominant inheritance.
▼ Description
Although primary lateral sclerosis is similar to amyotrophic lateral sclerosis

(ALS; 105400), they are considered to be clinically distinct progressive paralytic
neurodegenerative disorders. Following a period of diagnostic confusion, the
clinical distinction between ALS and PLS became clear and diagnostic criteria
established (Pringle et al., 1992). PLS is characterized by degeneration of the upper
motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a
more severe disorder characterized by degeneration of both the upper and lower
motor neurons. A diagnosis of PLS is essentially one of exclusion (Sotaniemi and
Myllyla, 1985; Younger et al., 1988; Yang et al., 2001).
▼ Clinical Features
Stark and Moersch (1945) defined primary lateral sclerosis as a disease of lateral
columns of the spinal cord, the corticospinal tracts. In a review of 60 cases, including
17 familial cases, the authors concluded that it was a slowly progressive disorder
restricted to involvement of the pyramidal tracts and clinically characterized
primarily by spasticity, hyperreflexia, and extensor plantar responses.
Lerman-Sagie et al. (1996) reported a consanguineous Kuwaiti family in which 3
sons developed progressive spastic paralysis of the lower extremities in infancy with
subsequent involvement of the upper extremities and bulbar muscles. Cognition
was spared. The authors noted the phenotypic overlap with hereditary spastic
paraplegia, but concluded that the disorder in this family was consistent with
primary lateral sclerosis. Shaw (2001) classified this family as having primary lateral
sclerosis because of the lack of evidence of denervation.
Mintchev et al. (2009) reported a consanguineous Cypriot family in which 3
members had juvenile primary lateral sclerosis. Onset was at age 2 years in all
patients, with leg spasticity, bulbar paresis, and prominent saccadic gaze paresis.
One patient became wheelchair-bound at age 50 years, the second never achieved
ambulation, and the third remained ambulatory at age 16. Lower motor neuron
symptoms were not apparent.
▼ Inheritance
PLS is usually a sporadic disorder of adult middle age. However, it has been
described in children, and is then referred to as juvenile PLS, and in families in a
pattern consistent with autosomal recessive inheritance (Gascon et al., 1995; Lerman-
Sagie et al., 1996).
▼ Molecular Genetics
In affected members of the Kuwaiti family reported by Lerman-Sagie et al.
(1996), Hadano et al. (2001) identified a homozygous mutation in the ALS2 gene
(606352.0004).
Yang et al. (2001) identified a homozygous deletion in the ALS2 gene (606353.0002)
in 3 affected members of a consanguineous Saudi Arabian family with PLSJ.
In affected members of a consanguineous Cypriot family with juvenile-onset
PLS, Mintchev et al. (2009) identified a homozygous mutation in the ALS2 gene
(606353.0013).
▼ See Also:
Grunnet et al. (1989)
▼ REFERENCES
1. Gascon, G. G., Chavis, P., Yaghmour, A., Stigsby, B., Shums, A., Ozand, P.,
Siddique, T.Familial childhood primary lateral sclerosis with associated
gaze paresis. Neuropediatrics 26: 313-319, 1995. [PubMed: 8719747, related
citations] [Full Text]
2. Grunnet, M. L., Leicher, C., Zimmerman, A., Zalneraitis, E., Barwick,
M. Primary lateral sclerosis in a child. Neurology 39: 1530-1532, 1989.
[PubMed: 2812336, related citations]
3. Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S.,
Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D.
A., Kwiatkowski, T., and 9 others.A gene encoding a putative GTPase
regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature
Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001.
4. Lerman-Sagie, T., Filiano, J., Smith, D. W., Korson, M. Infantile onset of
hereditary ascending spastic paralysis with bulbar involvement. J. Child.
Neurol. 11: 54-57, 1996. [PubMed: 8745388, related citations] [Full Text]
5. Mintchev, N., Zamba-Papanicolaou, E., Kleopa, K. A., Christodoulou, K. A
novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral
sclerosis family. Neurology 72: 28-32, 2009. [PubMed: 19122027, related
6. Pringle, C. E., Hudson, A. J., Munoz, D. G., Kiernan, J. A., Brown, W. F.,
Ebers, G. C. Primary lateral sclerosis: clinical features, neuropathology and
diagnostic criteria. Brain 115: 495-520, 1992. [PubMed: 1606479, related
citations]
7. Shaw, P. J. Genetic inroads in familial ALS. Nature Genet. 29: 103-104, 2001.
8. Sotaniemi, K. A., Myllyla, V. V. Primary lateral sclerosis: a debated
entity. Acta Neurol. Scand. 71: 334-336, 1985. [PubMed: 4003039, related
9. Stark, F. M., Moersch, F. P. Primary lateral sclerosis: a distinct clinical
entity. J. Nerv. Ment. Dis. 102: 332-337, 1945.
10. Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung,
W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A.,
Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. The gene
encoding alsin, a protein with three guanine-nucleotide exchange factor
domains, is mutated in a form of recessive amyotrophic lateral
sclerosis.Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29:
352 only, 2001. [PubMed: 11586297, related citations] [Full Text]
11. Younger, D. S., Chou, S., Hays, A. P., Lange, D. J., Emerson, R., Brin, M.,
Thompson, H., Jr., Rowland, L. P. Primary lateral sclerosis: a clinical
diagnosis reemerges. Arch. Neurol. 45: 1304-1307, 1988.

Tangier Disease

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Tangier Disease

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Tangier disease

Tangier disease is an inherited disorder characterized by significantly

Tangier disease is characterized by significantly reduced levels of high-

Tangier disease is caused by mutations in the ABCA1 gene. This gene

Tangier disease is inherited in an autosomal recessive pattern, which means

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1. Tangier disease. Genetics Home Reference (GHR).

Hypochondrogenesis is a rare, severe disorder of bone growth. This condition is

 What does it mean if a disorder seems to run in my family?

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Hypochondrogenesis is one of the most severe conditions in a spectrum of disorders

Learn more about the gene associated with hypochondrogenesis

 What is a gene mutation and how do mutations occur?

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 Castori M, Brancati F, Scanderbeg AC, Dallapiccola B. Hypochondrogenesis.

 Spranger J, Winterpacht A, Zabel B. The type II collagenopathies: a spectrum of

 Suzumura H, Kohno T, Nishimura G, Watanabe H, Arisaka O. Prenatal diagnosis

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Immunodeficiency, centromeric region instability, facial anomalies

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Disease name and synonyms

Mutations in DNMT3B coding sequences

Mutations outside DNMT3B coding sequences

Peripheral blood karyotype

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