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Microcephaly, normal intelligence and immunodeficiency(NBS)

MedGen UID:
140771
Concept ID:
C0398791
Disease or Syndrome
Synonyms: Ataxia telangiectasia variant V1; Berlin Breakage syndrome; Immunodeficiency, microcephaly with normal intelligence; IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY; Microcephaly with normal intelligence immunodeficiency and lymphoreticular malignancies; NBS; Nijmegen breakage syndrome; Nonsyndromal microcephaly autosomal recessive with normal intelligence; Seemanova syndrome 2; SEEMANOVA SYNDROME II
SNOMED CT: Microcephaly, normal intelligence and immunodeficiency (234638009); Nijmegen breakage syndrome (234638009); NBS - Nijmegen breakage syndrome (234638009); Seemanova syndrome II (234638009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): NBN (8q21.3)
 
Monarch Initiative: MONDO:0009623
OMIM®: 251260
Orphanet: ORPHA647

Disease characteristics

Excerpted from the GeneReview: Nijmegen Breakage Syndrome
Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma). [from GeneReviews]
Authors:
Raymonda Varon  |  Ilja Demuth  |  Krystyna H Chrzanowska   view full author information

Additional descriptions

From OMIM
The Nijmegen breakage syndrome (NBS) and the phenotypically indistinguishable Berlin breakage syndrome (BBS) are autosomal recessive chromosomal instability syndromes characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome and AT variant-2 is the designation for the Berlin breakage syndrome, which differ only in complementation studies. Cells from NBS/BBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from those of ataxia-telangiectasia (AT; 208900), but NBS/BBS patients have a distinct clinical phenotype. The clinical features of LIG4 syndrome (606593), caused by mutation in the LIG4 gene (601837), resemble those of NBS.  http://www.omim.org/entry/251260
From MedlinePlus Genetics
Nijmegen breakage syndrome is a condition characterized by short stature, an unusually small head size (microcephaly), distinctive facial features, recurrent respiratory tract infections, an increased risk of cancer, intellectual disability, and other health problems.

People with this condition typically grow slowly during infancy and early childhood. After this period of slow growth, affected individuals grow at a normal rate but remain shorter than their peers. Microcephaly is apparent from birth in the majority of affected individuals. The head does not grow at the same rate as the rest of the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Individuals with Nijmegen breakage syndrome have distinctive facial features that include a sloping forehead, a prominent nose, large ears, a small jaw, and outside corners of the eyes that point upward (upslanting palpebral fissures). These facial features typically become apparent by age 3.

People with Nijmegen breakage syndrome have a malfunctioning immune system (immunodeficiency) with abnormally low levels of immune system proteins called immunoglobulin G (IgG) and immunoglobulin A (IgA). Affected individuals also have a shortage of immune system cells called T cells. The immune system abnormalities increase susceptibility to recurrent infections, such as bronchitis, pneumonia, sinusitis, and other infections affecting the upper respiratory tract and lungs.

Individuals with Nijmegen breakage syndrome have an increased risk of developing cancer, most commonly a cancer of immune system cells called non-Hodgkin lymphoma. About half of individuals with Nijmegen breakage syndrome develop non-Hodgkin lymphoma, usually before age 15. Other cancers seen in people with Nijmegen breakage syndrome include brain tumors such as medulloblastoma and glioma, and a cancer of muscle tissue called rhabdomyosarcoma. People with Nijmegen breakage syndrome are 50 times more likely to develop cancer than people without this condition.

Intellectual development is normal in most people with this condition for the first year or two of life, but then development becomes delayed. Skills decline over time, and most affected children and adults have mild to moderate intellectual disability.

Most affected woman have premature ovarian failure and do not begin menstruation by age 16 (primary amenorrhea) or have infrequent menstrual periods. Most women with Nijmegen breakage syndrome are unable to have biological children (infertile).  https://medlineplus.gov/genetics/condition/nijmegen-breakage-syndrome

Clinical features

From HPO
Lymphoma
MedGen UID:
44223
Concept ID:
C0024299
Neoplastic Process
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
Rhabdomyosarcoma
MedGen UID:
20561
Concept ID:
C0035412
Neoplastic Process
A malignant soft tissue tumor which develops from cells of striated muscle. It is the most common form of tumor found in children and adolescents.
Hydronephrosis
MedGen UID:
42531
Concept ID:
C0020295
Disease or Syndrome
Severe distention of the kidney with dilation of the renal pelvis and calices.
Premature ovarian insufficiency
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Amenorrhea due to loss of ovarian function before the age of 40. Primary ovarian inssuficiency (POI) is a state of female hypergonadotropic hypogonadism. It can manifest as primary amenorrhea with onset before menarche or secondary amenorrhea.
Recurrent urinary tract infections
MedGen UID:
120466
Concept ID:
C0262655
Disease or Syndrome
Repeated infections of the urinary tract.
Sandal gap
MedGen UID:
374376
Concept ID:
C1840069
Finding
A widely spaced gap between the first toe (the great toe) and the second toe.
2-3 toe syndactyly
MedGen UID:
1645640
Concept ID:
C4551570
Congenital Abnormality
Syndactyly with fusion of toes two and three.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Imperforate anus
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Anal stenosis
MedGen UID:
82644
Concept ID:
C0262374
Anatomical Abnormality
Abnormal narrowing of the anal opening.
Recurrent infection of the gastrointestinal tract
MedGen UID:
343135
Concept ID:
C1854495
Disease or Syndrome
Recurrent infection of the gastrointestinal tract.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Glioma
MedGen UID:
9030
Concept ID:
C0017638
Neoplastic Process
The presence of a glioma, which is a neoplasm of the central nervous system originating from a glial cell (astrocytes or oligodendrocytes).
Medulloblastoma
MedGen UID:
7517
Concept ID:
C0025149
Neoplastic Process
Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (see 276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007). Millard and De Braganca (2016) reviewed the histopathologic variants and molecular subgroups of medulloblastoma. Pretreatment prognosis of medulloblastoma has been refined by histopathologic subclassification into the following variants: large-cell medulloblastoma, anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity (MBEN). The latter 2 groups have been shown to have a significantly superior prognosis as compared to the large cell and anaplastic groups in young children. At the molecular level, medulloblastomas have been categorized into the following subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Each subgroup is characterized by a unique set of genetics and gene expression as well as demographic and clinical features.
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Progressive loss of neural cells and tissue.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Mastoiditis
MedGen UID:
7480
Concept ID:
C0024904
Disease or Syndrome
Inflammation of the mucosal lining of the mastoid antrum and mastoid air cell system of the mastoid process.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Malar prominence
MedGen UID:
346975
Concept ID:
C1858732
Finding
Prominence of the malar process of the maxilla and infraorbital area appreciated in profile and from in front of the face.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Recurrent bronchitis
MedGen UID:
148159
Concept ID:
C0741796
Disease or Syndrome
An increased susceptibility to bronchitis as manifested by a history of recurrent bronchitis.
Autoimmune hemolytic anemia
MedGen UID:
1918
Concept ID:
C0002880
Disease or Syndrome
An autoimmune form of hemolytic anemia.
Dysgammaglobulinemia
MedGen UID:
41679
Concept ID:
C0013374
Disease or Syndrome
Selective deficiency of one or more, but not all, classes of immunoglobulins.
Sinusitis
MedGen UID:
20772
Concept ID:
C0037199
Disease or Syndrome
Inflammation of the paranasal sinuses owing to a viral, bacterial, or fungal infection, allergy, or an autoimmune reaction.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
B lymphocytopenia
MedGen UID:
340780
Concept ID:
C1855067
Finding
An abnormal decrease from the normal count of B cells.
T lymphocytopenia
MedGen UID:
419385
Concept ID:
C2931322
Finding
An abnormally low count of T cells.
Choanal atresia
MedGen UID:
3395
Concept ID:
C0008297
Congenital Abnormality
Absence or abnormal closure of the choana (the posterior nasal aperture). Most embryologists believe that posterior choanal atresia results from a failure of rupture between the 35th and 38th day of fetal life of the partition which separates the bucconasal or buccopharyngeal membranes. The resultant choanal atresia may be unilateral or bilateral, bony or membranous, complete or incomplete. In over 90 per cent of cases the obstruction is bony, while in the remainder it is membranous. The bony type of atresia is commonly located 1-2 mm. anterior to the posterior edge of the hard palate, and the osseous septum varies in thickness from 1 to 10 mm. In the membranous form of choanal atresia the obstruction usually occurs further posteriorly. In approximately one third of cases the atresia is bilateral.
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap or groove in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Deep philtrum
MedGen UID:
374311
Concept ID:
C1839797
Finding
Accentuated, prominent philtral ridges giving rise to an exaggerated groove in the midline between the nasal base and upper vermillion border.
Long nose
MedGen UID:
326583
Concept ID:
C1839798
Finding
Distance from nasion to subnasale more than two standard deviations above the mean, or alternatively, an apparently increased length from the nasal root to the nasal base.
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children.
Conjunctival telangiectasia
MedGen UID:
66780
Concept ID:
C0239105
Disease or Syndrome
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Progressive vitiligo
MedGen UID:
812758
Concept ID:
C3806428
Finding
Retinal pigment epithelial mottling
MedGen UID:
347513
Concept ID:
C1857644
Finding
Mottling (spots or blotches with different shades) of the retinal pigment epithelium, i.e., localized or generalized fundal pigment granularity associated with processes at the level of the retinal pigment epithelium.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMicrocephaly, normal intelligence and immunodeficiency
Follow this link to review classifications for Microcephaly, normal intelligence and immunodeficiency in Orphanet.

Professional guidelines

PubMed

Strauss TS, Boniferro E, Brockhoff E, Johnson A, Schneider E, Grubman O, Cole D, Hussain F, Ashmead G, Al-Ibraheemi Z, Brustman L
Am J Obstet Gynecol MFM 2023 Mar;5(3):100820. Epub 2022 Nov 28 doi: 10.1016/j.ajogmf.2022.100820. PMID: 36455867
Zhen JT, Syed J, Nguyen KA, Leapman MS, Agarwal N, Brierley K, Llor X, Hofstatter E, Shuch B
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Blood 2012 Mar 15;119(11):2552-5. Epub 2011 Nov 30 doi: 10.1182/blood-2011-08-371021. PMID: 22130802

Recent clinical studies

Etiology

Kose H, Karali Z, Bodur M, Cekic S, Kilic SS
Allergol Immunopathol (Madr) 2024;52(1):85-92. Epub 2024 Jan 1 doi: 10.15586/aei.v52i1.961. PMID: 38186198
Pastorczak A, Szczepanski T, Mlynarski W; International Berlin-Frankfurt-Munster (I-BFM) ALL host genetic variation working group
Eur J Med Genet 2016 Mar;59(3):126-32. Epub 2016 Jan 27 doi: 10.1016/j.ejmg.2016.01.007. PMID: 26826318
Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M
Orphanet J Rare Dis 2012 Feb 28;7:13. doi: 10.1186/1750-1172-7-13. PMID: 22373003Free PMC Article
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Taylor AM
Best Pract Res Clin Haematol 2001 Sep;14(3):631-44. doi: 10.1053/beha.2001.0158. PMID: 11640873

Diagnosis

Takagi M, Hoshino A, Bousset K, Röddecke J, Martin HL, Folcut I, Tomomasa D, Yang X, Kobayashi J, Sakata N, Yoshida K, Miyano S, Ogawa S, Kojima S, Morio T, Dörk T, Kanegane H
J Clin Immunol 2023 Nov;43(8):2136-2145. Epub 2023 Oct 5 doi: 10.1007/s10875-023-01591-8. PMID: 37794136
Pac M, Casanova JL, Reisli I, Maródi L
Front Immunol 2021;12:667727. Epub 2021 May 14 doi: 10.3389/fimmu.2021.667727. PMID: 34084169Free PMC Article
Taylor AMR, Rothblum-Oviatt C, Ellis NA, Hickson ID, Meyer S, Crawford TO, Smogorzewska A, Pietrucha B, Weemaes C, Stewart GS
Nat Rev Dis Primers 2019 Sep 19;5(1):64. doi: 10.1038/s41572-019-0113-0. PMID: 31537806Free PMC Article
Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M
Orphanet J Rare Dis 2012 Feb 28;7:13. doi: 10.1186/1750-1172-7-13. PMID: 22373003Free PMC Article
van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C
J Med Genet 1996 Feb;33(2):153-6. doi: 10.1136/jmg.33.2.153. PMID: 8929954Free PMC Article

Therapy

Ramadurai S, Andrews C, Cheema S, Thomas R, Wagner CL, Sen S
Clin Ther 2022 Jul;44(7):998-1009. Epub 2022 Jul 29 doi: 10.1016/j.clinthera.2022.06.003. PMID: 35909001
Pastorczak A, Szczepanski T, Mlynarski W; International Berlin-Frankfurt-Munster (I-BFM) ALL host genetic variation working group
Eur J Med Genet 2016 Mar;59(3):126-32. Epub 2016 Jan 27 doi: 10.1016/j.ejmg.2016.01.007. PMID: 26826318
Schütte P, Möricke A, Zimmermann M, Bleckmann K, Reismüller B, Attarbaschi A, Mann G, Bodmer N, Niggli F, Schrappe M, Stanulla M, Kratz CP
Eur J Med Genet 2016 Mar;59(3):143-51. Epub 2015 Dec 28 doi: 10.1016/j.ejmg.2015.12.008. PMID: 26732628
Niehues T, Schellong G, Dörffel W, Bucsky P, Mann G, Körholz D, Göbel U
Klin Padiatr 2003 Nov-Dec;215(6):315-20. doi: 10.1055/s-2003-45498. PMID: 14677095
Gatti RA
Acta Oncol 2001;40(6):702-11. doi: 10.1080/02841860152619115. PMID: 11765064

Prognosis

Reuss DE, Downing SM, Camacho CV, Wang YD, Piro RM, Herold-Mende C, Wang ZQ, Hofmann TG, Sahm F, von Deimling A, McKinnon PJ, Frappart PO
Neuropathol Appl Neurobiol 2023 Aug;49(4):e12915. doi: 10.1111/nan.12915. PMID: 37296499
Pac M, Casanova JL, Reisli I, Maródi L
Front Immunol 2021;12:667727. Epub 2021 May 14 doi: 10.3389/fimmu.2021.667727. PMID: 34084169Free PMC Article
Story MD, Durante M
Med Phys 2018 Nov;45(11):e1111-e1122. doi: 10.1002/mp.13064. PMID: 30421807
Pastorczak A, Szczepanski T, Mlynarski W; International Berlin-Frankfurt-Munster (I-BFM) ALL host genetic variation working group
Eur J Med Genet 2016 Mar;59(3):126-32. Epub 2016 Jan 27 doi: 10.1016/j.ejmg.2016.01.007. PMID: 26826318
Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M
Orphanet J Rare Dis 2012 Feb 28;7:13. doi: 10.1186/1750-1172-7-13. PMID: 22373003Free PMC Article

Clinical prediction guides

Murni IK, Kato T, Wirawan MT, Arafuri N, Hermawan K, Hartopo AB, Anggrahini DW, Nugroho S, Noormanto N, Emoto N, Dinarti LK
BMC Pediatr 2023 Jun 10;23(1):288. doi: 10.1186/s12887-023-04102-1. PMID: 37301836Free PMC Article
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Lancet Neurol 2022 Oct;21(10):899-910. doi: 10.1016/S1474-4422(22)00299-X. PMID: 36115362
Story MD, Durante M
Med Phys 2018 Nov;45(11):e1111-e1122. doi: 10.1002/mp.13064. PMID: 30421807
Schütte P, Möricke A, Zimmermann M, Bleckmann K, Reismüller B, Attarbaschi A, Mann G, Bodmer N, Niggli F, Schrappe M, Stanulla M, Kratz CP
Eur J Med Genet 2016 Mar;59(3):143-51. Epub 2015 Dec 28 doi: 10.1016/j.ejmg.2015.12.008. PMID: 26732628
Carney JP
Curr Opin Immunol 1999 Aug;11(4):443-7. doi: 10.1016/S0952-7915(99)80074-0. PMID: 10448147

Recent systematic reviews

Wang L, Cheng J, Gao J, Wang J, Liu X, Xiong L
Mol Biol Rep 2013 Mar;40(3):2711-5. Epub 2012 Dec 29 doi: 10.1007/s11033-012-2358-5. PMID: 23275190

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