Diagnostic Considerations

Table 1.Syndromes to be Considered in the Differential Diagnosis of Nijmegen Breakage Syndrome (Open Table in a new window)

Clinical and Cellular Phenotype	Nijmegen Breakage Syndrome	Nijmegen Breakage Syndrome‒Like Disorder ^{[39, 77]}	DNA LIG4 Deficiency ^{[37, 38, 78]}	NHEJ1 Syndrome ^{[40, 41]}	XRCC4 Deficiency ^{[42, 43]}	Fanconi Anemia ^{[47, 48, 79]}	Warsaw Breakage Syndrome ^{[80, 81]}	Bloom Syndrome ^{[82, 83]}
Online Mendelian Inheritance in Man (OMIM)	251260	604040	606593	611291	616541	227650	613398	210900
Gene	NBN	RAD50	DNA LIG4	NHEJ1	XRCC4	FANC^a	DDX11	RECQL3
Microcephaly	Severe, disproportionate	Severe	Severe	Severe	Severe	In ~30%	Severe, disproportionate	Severe, proportionate
Growth Deficiency	Mild to moderate	Severe	Moderate to severe	Severe	Severe, disproportionate	Mild to moderate	Severe	Severe
Congenital Malformations	Heart, kidney, polydactyly	Not reported	Polydactyly, syndactyly	Polydactyly	Not reported	Heart, kidney radial bone defects (~50%)	Heart	Kidney, polydactyly
Puberty and Fertility	Primary amenorrhea (hypergonadotropic hypogonadism)	Normal puberty	Amenorrhea	Not reported	Primary amenorrhea	Males, infertility; females, early menopause	Normal puberty	Males, infertility; females, early menopause
Other Endocrinologic Problems	Not reported	Not reported	Hypothyroidism, type 2 diabetes	Not reported	Early-onset metabolic syndrome	Type 2 diabetes mellitus	Not reported	Type 2 diabetes mellitus
Recurrent Infections	Yes	No	Rare	Yes	No	No	No	Yes
Immunodeficiency	Combined (B- and T-cell)	No	Combined (B- and T-cell)	Combined (B- and T-cell)	No	No	No	B-cell type
Hematologic Findings	Myelodysplastic syndrome (incidentally)	Not reported	Pancytopenia, myelodysplastic syndrome	Pancytopenia, myelodysplastic syndrome	Thrombocytopenia, pancytopenia	Progressive bone marrow failure, myelodysplastic syndrome	Not reported	Myelodysplastic syndrome
Malignancy Type	Predominantly lymphoid origin	Not reported	Predominantly lymphoid origin	Not reported	Tumor	Acute myeloid leukemia, solid tumors (early onset)	Not reported	Lymphoid origin, acute myeloid leukemia, solid tumors
Chromosomal Instability	Breakages, including 7/14 rearrangements	Breakages, 7/14 rearrangements	Breakages, no 7/14 rearrangements	Breakages, not specified	Not reported	Breakages, figures (asymmetric)	Breakages and cohesinopathy	Breakages, figures (symmetric), high sister chromatid exchange rate
Sensitivity to Damaging Agents (in vitro)	Ionizing radiation, bleomycin; mitomycin C and diepoxybutane, mild	Ionizing radiation, bleomycin	Ionizing radiation, bleomycin	Ionizing radiation (variable)	Ionizing radiation (extreme)	Mitomycin C and diepoxybutane; ionizing radiation, mild	Mitomycin C, camptothecin	Ultraviolet
Mental Retardation	Mild to moderate	Moderate	Mild to moderate	Yes, not defined	Moderate to severe	Moderate to severe	Moderate to severe	Normal to mild
^aFANC: Genetic and phenotypic heterogeneity; 19 genes known (OMIM).

Also consider the following:

Autosomal recessive primary microcephaly (MCPH), genetic and phenotypic heterogeneity (OMIM 17 entries): Defined by primary microcephaly over -3 standard deviations below the mean and various neurological problems (eg, spasticity, motor disability, mental retardation)
Seckel syndrome spectrum disorders (SCKS), genetic and phenotypic heterogeneity (OMIM 10 entries): Defined by severe primary microcephaly, severe prenatal and postnatal growth restriction, multiple various congenital malformations, and/or metabolic/biochemical features
Pediatric severe combined immunodeficiency

Differential Diagnoses

Bloom Syndrome (Congenital Telangiectatic Erythema)
DNA ligase4 deficiency
Fanconi Anemia
NBS-like disorder
NHEJ1 syndrome
Warsaw breakage syndrome
XRCC4 deficiency

Workup

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Media Gallery

A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.
Lateral facial features with sloping forehead and receding mandible are shown in a 6-month-old infant.
Typical facial features in a 9-year-old girl with Nijmegen breakage syndrome. Note the markedly upward-slanting palpebral features.
Lateral profile. This view shows a relatively long nose and receding mandible.
Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.
Vitiligo spots in a patient with Nijmegen breakage syndrome.
Progressive vitiligo in a patient with Nijmegen breakage syndrome.
Café au lait–like spots in a patient with Nijmegen breakage syndrome.
Preaxial polydactyly of the hand in a patient with Nijmegen breakage syndrome.
MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the partial defect of the corpus callosum. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.

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Table 1.Syndromes to be Considered in the Differential Diagnosis of Nijmegen Breakage Syndrome

Clinical and Cellular Phenotype	Nijmegen Breakage Syndrome	Nijmegen Breakage Syndrome‒Like Disorder ^{[39, 77]}	DNA LIG4 Deficiency ^{[37, 38, 78]}	NHEJ1 Syndrome ^{[40, 41]}	XRCC4 Deficiency ^{[42, 43]}	Fanconi Anemia ^{[47, 48, 79]}	Warsaw Breakage Syndrome ^{[80, 81]}	Bloom Syndrome ^{[82, 83]}
Online Mendelian Inheritance in Man (OMIM)	251260	604040	606593	611291	616541	227650	613398	210900
Gene	NBN	RAD50	DNA LIG4	NHEJ1	XRCC4	FANC^a	DDX11	RECQL3
Microcephaly	Severe, disproportionate	Severe	Severe	Severe	Severe	In ~30%	Severe, disproportionate	Severe, proportionate
Growth Deficiency	Mild to moderate	Severe	Moderate to severe	Severe	Severe, disproportionate	Mild to moderate	Severe	Severe
Congenital Malformations	Heart, kidney, polydactyly	Not reported	Polydactyly, syndactyly	Polydactyly	Not reported	Heart, kidney radial bone defects (~50%)	Heart	Kidney, polydactyly
Puberty and Fertility	Primary amenorrhea (hypergonadotropic hypogonadism)	Normal puberty	Amenorrhea	Not reported	Primary amenorrhea	Males, infertility; females, early menopause	Normal puberty	Males, infertility; females, early menopause
Other Endocrinologic Problems	Not reported	Not reported	Hypothyroidism, type 2 diabetes	Not reported	Early-onset metabolic syndrome	Type 2 diabetes mellitus	Not reported	Type 2 diabetes mellitus
Recurrent Infections	Yes	No	Rare	Yes	No	No	No	Yes
Immunodeficiency	Combined (B- and T-cell)	No	Combined (B- and T-cell)	Combined (B- and T-cell)	No	No	No	B-cell type
Hematologic Findings	Myelodysplastic syndrome (incidentally)	Not reported	Pancytopenia, myelodysplastic syndrome	Pancytopenia, myelodysplastic syndrome	Thrombocytopenia, pancytopenia	Progressive bone marrow failure, myelodysplastic syndrome	Not reported	Myelodysplastic syndrome
Malignancy Type	Predominantly lymphoid origin	Not reported	Predominantly lymphoid origin	Not reported	Tumor	Acute myeloid leukemia, solid tumors (early onset)	Not reported	Lymphoid origin, acute myeloid leukemia, solid tumors
Chromosomal Instability	Breakages, including 7/14 rearrangements	Breakages, 7/14 rearrangements	Breakages, no 7/14 rearrangements	Breakages, not specified	Not reported	Breakages, figures (asymmetric)	Breakages and cohesinopathy	Breakages, figures (symmetric), high sister chromatid exchange rate
Sensitivity to Damaging Agents (in vitro)	Ionizing radiation, bleomycin; mitomycin C and diepoxybutane, mild	Ionizing radiation, bleomycin	Ionizing radiation, bleomycin	Ionizing radiation (variable)	Ionizing radiation (extreme)	Mitomycin C and diepoxybutane; ionizing radiation, mild	Mitomycin C, camptothecin	Ultraviolet
Mental Retardation	Mild to moderate	Moderate	Mild to moderate	Yes, not defined	Moderate to severe	Moderate to severe	Moderate to severe	Normal to mild
^aFANC: Genetic and phenotypic heterogeneity; 19 genes known (OMIM).

Table 2. Selected NBN Gene Pathogenic Molecular Variants

Mutation	Exon	Mutation Type	Change in Protein	Number of Families and Origin	Allelic Status
c.643C>T	6	Missense	R215W	1^a Czech	He^b
c.657_661del5 (657del5)	6	Frameshift	Truncated protein (233 aa)	>90% Slavic founder mutation	Ho^c (He)
c.681delT	6	Frameshift	Truncated protein (229 aa)	1 Russian	He
c.698_701del4 (698del4)	6	Frameshift	Truncated protein (236 aa)	2 English	Ho He
c.742_743insGG (742insGG)	7	Frameshift	Truncated protein (251 aa)	1 Italian	Ho
c.835_838del4 (835del4)	7	Frameshift	Truncated protein (279 aa)	1 Italian	Ho
c.842_843insT (842insT)	7	Frameshift	Truncated protein (283 aa)	1 Mexican	Ho
c.900_924del25 (900del25)	8	Frameshift	Truncated protein (305 aa)	1 Moroccan	Ho
c.976C>T	8	Nonsense	Q326X	1 Dutch	Ho
c.1089C>A	9	Nonsense	Y363X	3^d Pakistani	Ho
c.1142delC	10	Frameshift	Truncated protein (402 aa)	2 Canadian	He
^aMonozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.^[86] ^bHe - Heterozygous (compound with 657del5). ^cHo - Homozygous. ^dThree nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).^{[47, 48]}

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Author

Krystyna H Chrzanowska, MD, PhD Professor and Head of Genetic Counseling Unit, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland

Krystyna H Chrzanowska, MD, PhD is a member of the following medical societies: European Association for Cancer Research, European Society of Human Genetics, Polish Academy of Sciences, Polish Genetics Society, Polish Pediatric Society, Polish Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Noah S Scheinfeld, JD, MD, FAAD † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Nijmegen Breakage Syndrome Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

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