RIDDLE syndrome and other radiosensitivities with immunodeficiency

Recommended panel testing at Breda Genetics for this condition:

RIDDLE syndrome and other radiosensitivities with immunodeficiency (incl. Nijmegen breakage syndrome, ataxia-telengectasia, severe combined immunodeficiency with Cernunnos, severe combined immunodeficiency Athabascan type, Immunodeficiency 26, LIG4 syndrome and X-linked agammaglobulinemia) (RNF168, NBN, ATM, NHEJ1, DCLRE1C, PRKDC, LIG4, BTK)

If negative, the following ADD-ON PANEL may be considered:

Fanconi anemia (BRCA1, BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51A, RAD51C, RFWD3, SLX4, UBE2T, XRCC2)

RIDDLE syndrome: a disorder with radiosensitivity

RIDDLE is an acronym for Radiosensitivity, ImmunoDeficiency Dysmorphic features and LEarning difficulties. RIDDLE syndrome was first described by Stewart et al (2007) in a patient with increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. Other clinical signs of RIDDLE syndrome may include mild ataxia,  microcephaly, normal intelligence, conjunctival telangiectasia, recurrent sinus infections, decreased serum IgA, increased alpha-fetoprotein and late onset of pulmonary fibrosis. Patients’ cells are radiosensitive and show defects in the repair of DNA double-strand breakage. RIDDLE syndrome appears therefore to partially overlap with ataxia telangectasia syndrome.

The genetic cause of RIDDLE syndrome

In the few patients so far described sequencing has detected homozygosity or compound heterozygosity for truncating mutations in the RNF168 gene. RIDDLE syndrome is therefore transmitted in an autosomal recessive fashion.

Other syndromes with radiosensitivity

Radiosensitivity is also seen in ataxia telangectasia (which may show some clinical overlap with RNF168-related radiosensitivity because of mild ataxia, telangectasia and elevated serum concentration of alphafetoprotein), Nijmegen breakage syndrome, severe combined immunodeficiency with Cernunnos, Artemis deficiency, DNA-PKcs deficiency, LIG4 syndrome, Fanconi anemia and X-linked agammaglobulinemia.

Nijmegen breakage syndrome is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, an increased risk for cancer, and premature ovarian failure in females. Diagnosis is based on molecular genetic testing of NBN, the only gene known to be associated with Nijmegen breakage syndrome.

Severe combined immunodeficiency with Cernunnos (also known as Severe Combined ImmunoDeficiency – SCID – with microcephaly, growth retardation, and sensitivity to ionizing radiation) is caused by a mutation in the NHEJ1 gene. A milder form without microcephaly or growth retardation, may be cause by a hypomorphic mutation (hypomorphic allele) in the same gene.

Artemis deficiency (also known as Severe Combined ImmunoDeficiency – SCID – Athabascan type) is caused by mutation in the gene encoding Artemis (DCLRE1C). Patients’ cells show increased sensitivity to ionizing radiation. Clinical signs may include oral thrush, diarrhea, fever, pneumonia, failure to thrive, lymphopenia, hypogammaglobulinemia, and absent tonsils and lymph nodes.

Immunodeficiency 26 (also known as DNA-PKcs deficiency) is caused by homozygous or compound heterozygous mutation in the PRKDC gene. Signs and symptoms may include intrauterine growth retardation, recurrent oral and perineal candidiasis, lower respiratory tract infections, oral aphthous lesion, absent circulating B and T cells and normal NK cells, microcephaly and other dysmorphic features, including prominent forehead, wide nasal bridge, deep-set eyes, long philtrum with thin upper lip, small chin, low-set ears, overlapping fingers, and postaxial polysyndactyly of the right foot. Brain MRI signs may also be present.

LIG4 syndrome is caused by homozygous or compound heterozygous mutation in the LIG4 gene and may closely resemble Nijmegen breakage syndrome.  The clinical features include immunodeficiency, developmental and growth delay, unusual facial features, microcephaly, pancytopenia and various skin abnormalities (although dysmorphic features or neurologic abnormalities may allso be absent). Chromosomal breakage studies show a high rate of breakage in fibroblasts and radiosensitivity may be greater than is typically seen in Nijmegen breakage syndrome.

X-linked agammaglobulinemia is due to a mutation in the BTK gene (previously known also as BPK or ATK gene) and represents the majority (85%) of all agammaglobulinemias. The disease is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is very frequent, but conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also commonly seen. Patients may later develop life-threatening infections leading to generalized sepsis like meningitis, pneumonia, cellulitis, empyema or septic arthritis.

Also Fanconi anemia is associated wth radiosensitivity, even if the physical abnormalities (present in 60%-75% of affected individuals) may help to better differentiate this disorder at the very beginning.

References

Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Devgan SS, Sanal O, Doil C, Nakamura K, Nahas SA, Pettijohn K, Bartek J, Lukas C, Lukas J, Gatti RA. Cell Death Differ. 2011 Sep;18(9):1500-6. PMID: 21394101

The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D. Cell. 2009 Feb 6;136(3):420-34. PMID: 19203578

RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Stewart GS, Stankovic T, Byrd PJ, Wechsler T, Miller ES, Huissoon A, Drayson MT, West SC, Elledge SJ, Taylor AM. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16910-5. PMID: 17940005

X-Linked Agammaglobulinemia. Smith CIE, Berglöf A. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2001 Apr 5 [updated 2016 Aug 4]. PMID: 20301626

Ataxia-Telangiectasia. Gatti R, Perlman S. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 1999 Mar 19 [updated 2016 Oct 27]. PMID: 20301790

Nijmegen Breakage Syndrome. Varon R, Demuth I, Chrzanowska KH. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 1999 May 17 [updated 2017 Feb 2]. PMID: 20301355

OMIM: 300755,  606593615966, 602450, 611291.

Recommended panel testing at Breda Genetics for this condition:

RIDDLE syndrome and other radiosensitivities with immunodeficiency (incl. Nijmegen breakage syndrome, ataxia-telengectasia, severe combined immunodeficiency with Cernunnos, severe combined immunodeficiency Athabascan type, Immunodeficiency 26, LIG4 syndrome and X-linked agammaglobulinemia) (RNF168, NBN, ATM, NHEJ1, DCLRE1C, PRKDC, LIG4, BTK)

If negative, the following ADD-ON PANEL may be considered:

Fanconi anemia (BRCA1, BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51A, RAD51C, RFWD3, SLX4, UBE2T, XRCC2)