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Disease Profile

Nijmegen breakage syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

Q87.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Berlin Breakage syndrome; Ataxia-Telangiectasia variant V1; Microcephaly with normal intelligence immunodeficiency and lymphoreticular malignancies;

Categories

Congenital and Genetic Diseases; Immune System Diseases; Rare Cancers

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
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Orpha Number: 647

Definition
Nijmegen breakage syndrome is a rare genetic disease presenting at birth with microcephaly, dysmorphic facial features, becoming more noticeable with age, growth delay, and later-onset complications such as malignancies and infections.

Epidemiology
Prevalence and incidence are not known. 150 patients have been reported in the literature but many more are recorded in patient registries. The disease seems to occur worldwide, but has a much higher prevalence among Central and Eastern European Slavic populations due to a founder mutation.

Clinical description
Clinical manifestations are not pathognomonic and may vary in severity. The main signs are microcephaly, present at birth and progressing with age, dysmorphic facial features (prominent midface emphasized by a sloping forehead and receding mandible). Other facial characteristics are more subtle and diverse, e.g. upwardly slanted palpebral fissures, long and beaked nose or short nose with anteverted upturned nostrils. In a few patients, cleft lip/palate or choanal atresia have been described. Mild growth retardation, and, in females, premature ovarian insufficiency are common. Minor skeletal anomalies, such as clinodactyly of the 5th fingers and partial syndactyly of the 2nd and 3rd toes are found (50% of patients). Delayed speech development is common. Café au lait spots and/or vitiligo spots are observed (50-70%). Hair in NBS is usually thin and sparse in infancy but improves with age. Hair greying can appear as early as in the 2nd or 3rd decade. Congenital renal anomalies (hypoplasia/aplasia, horseshoe or double kidney, ectopic/dystopic kidneys) are relatively frequent. Hypospadias, cryptorchidism, urethro-anal fistula are also found. Immune deficiency with recurrent respiratory tract infections that may be life-threatening and a strong predisposition to malignancies (predominantly lymphoid) and radiosensitivity are other integral manifestations. By age 20, over 40% of patients develop a malignant disease.

Etiology
NBS is caused by mutations in the NBN gene (8q21-q24) which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks.

Diagnostic methods
Diagnosis is based on the clinical manifestations, chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, mutations in both alleles of the NBN gene, and complete absence of full-length nibrin. Early diagnosis is very important to avoid severe recurrent infections, unnecessary exposure to radiation for diagnostic purposes, and adverse effects of radiotherapy for treatment of tumors. Analysis of the family pedigree can also support diagnosis (malignancies, microcephaly or hydrocephaly, early death of a sibling). Molecular testing confirms diagnosis.

Differential diagnosis
Differential diagnosis includes Fanconi anemia, Bloom syndrome, NBS-like disorder, ataxia-telangectasia-like disorder, LIG4 syndrome, NHEJ1 syndrome and Seckel syndrome (see these terms).

Antenatal diagnosis
Affected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known.

Genetic counseling
Parents of an affected child are obligate carriers of NBN mutations (25% risk for each pregnancy). Parents should be offered monitoring for cancer. NBS follows an autosomal recessive pattern of inheritance.

Management and treatment
There is no specific therapy for NBS. Due to the specific defect underlying immune deficiency and sensitivity to IR radiation, patients require multidisciplinary management and long term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females).

Prognosis
Prognosis is poor, with malignancy as the major cause of death.

Visit the Orphanet disease page for more resources.

Symptoms

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.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal hair quantity
0011362
Abnormality of chromosome stability
0003220
Anal atresia
Absent anus
0002023
Anal stenosis
Narrowing of anal opening
0002025
Attention deficit hyperactivity disorder
Attention deficit
Attention deficit disorder
Attention deficit-hyperactivity disorder
Attention deficits
Childhood attention deficit/hyperactivity disorder

[ more ]

0007018
Autoimmune hemolytic anemia
0001890
Cachexia
Wasting syndrome
0004326
Chronic diarrhea
0002028
Convex nasal ridge
Beaked nose
Beaklike protrusion
Hooked nose
Polly beak nasal deformity

[ more ]

0000444
Deep philtrum
0002002
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Hearing abnormality
Abnormal hearing
0000364
Low anterior hairline
Low frontal hairline
Low-set frontal hairline

[ more ]

0000294
Macrotia
Large ears
0000400
Mental deterioration
Cognitive decline
Cognitive decline, progressive
Intellectual deterioration
Progressive cognitive decline

[ more ]

0001268
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Prominent nasal bridge
Elevated nasal bridge
High nasal bridge
Prominent bridge of nose
Prominent nasal root
Protruding bridge of nose
Protruding nasal bridge

[ more ]

0000426
Prominent nose
Big nose
Disproportionately large nose
Increased nasal size
Increased size of nose
Large nose
Pronounced nose

[ more ]

0000448
Recurrent pneumonia
0006532
Recurrent sinopulmonary infections
Recurrent sinus and lung infections
0005425
Retrognathia
Receding chin
Receding lower jaw
Weak chin
Weak jaw

[ more ]

0000278
Short neck
Decreased length of neck
0000470
Short stature
Decreased body height
Small stature

[ more ]

0004322
Sloping forehead
Inclined forehead
Receding forehead

[ more ]

0000340
Thrombocytopenia
Low platelet count
0001873
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
30%-79% of people have these symptoms
Pollakisuria
Frequent urination
0100515
5%-29% of people have these symptoms
Abnormality of neuronal migration
0002269
Acute leukemia
0002488
Bcell lymphoma
0012191
Cleft palate
Cleft roof of mouth
0000175
Cutaneous photosensitivity
Photosensitive skin
Photosensitive skin rashes
Photosensitivity
Sensitivity to sunlight
Skin photosensitivity
Sun sensitivity

[ more ]

0000992
Freckling
0001480
Glioma
0009733
Muscle weakness
Muscular weakness
0001324
Non-midline cleft lip
0100335
Respiratory failure
0002878
Rhabdomyosarcoma
0002859
Skeletal muscle atrophy
Muscle degeneration
Muscle wasting

[ more ]

0003202
T-cell lymphoma
0012190
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
B lymphocytopenia
Low B cell count
0010976
Bronchiectasis
Permanent enlargement of the airways of the lungs
0002110
Cafe-au-lait spot
0000957
Choanal atresia
Blockage of the rear opening of the nasal cavity
Obstruction of the rear opening of the nasal cavity

[ more ]

0000453
Cleft upper lip
Harelip
0000204
Diarrhea
Watery stool
0002014
Dysgammaglobulinemia
0002961
Hydronephrosis
0000126
Hyperactivity
More active than typical
0000752
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation

[ more ]

0001511
Long nose
Elongated nose
Increased height of nose
Increased length of nose
Increased nasal height
Increased nasal length
Nasal elongation

[ more ]

0003189
Lymphoma
Cancer of lymphatic system
0002665
Malar prominence
0010620
Mastoiditis
0000265
Medulloblastoma

Learn more

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 Nijmegen breakage syndrome. This website is maintained by the National Library of Medicine.

In-Depth Information

  • 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.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • 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 Nijmegen breakage syndrome. Click on the link to view a sample search on this topic.

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