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CDAGS syndrome

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  • Comment: Notable , however needs many more references, thank you Ozzie10aaaa (talk) 14:38, 13 July 2024 (UTC)
CDAGS syndrome
SpecialtyMedical genetics

CDAGS syndrome is a very rare syndrome characterized by craniosynostosis and other cranial defects, delayed closure of the fontanelles, deafness, anal anomalies, genitourinary malformations and skin eruption.[1] CDAGS is caused by heterozygotic compound variants in the RNU12 gene, which disrupts the function of the minor spliceosome.[2] Only 14 cases are known worldwide.[3][4][1][5][6][7][8][2][9]

Signs and symptoms

The clinical picture is very complex and there is some degree of variation in presentation amongst the patients.[citation needed]

Most CDAGS patients are born with bicoronal craniosynostosis. Other cranial defects can also be present. At birth the anterior and posterior fontanelles are wide open and will be delayed in their closure. CDAGS is also associated with microcephaly, which is more pronounced in some patients than others.[citation needed]

Almost all patients are born with anal anomalies. Often anus imperforatus or a rectovestibular fistula. In at least one patient no anal anomalies were present at birth.[8]

All patients suffer from skin eruption. With some patients the lesions are described as psoriasiform[3], however in most patients they are described as porokeratosis-like. The lesions typically consist of hyperkeratotic rings with fragile, damaged skin in the middle. The lesions manifest themselves in a typical symmetrical pattern where the face and extremities are the most affected regions of the skin. In general the lesions are not painful, though patients may feel itching and mild burning.[6]

Male patients are affected by genito-urinary malformations. Hypospadia is a common symptom.[citation needed]

Many patients have hearing loss. Some are completely deaf, others only have partial hearing loss.[1]

Mental delay is seen in about half of the patients. Often this will already be notable in infancy[1], where developmental milestones will not be reached in time. Sometimes it will only get noticed at age 5-7 when patients perform below average in school[5][8]. Normal intelligence has also been reported.[4]

Many patients have no collarbones or they are underdeveloped, which can cause hightened mobility of the shoulders.[3][1]

Many patients have dental defects like enamel dysplasia.[7]

Cleft palate has been reported in some cases.[1][7]

Overlapping toes have been described in one patient.[7]

All patients suffer some form of alopecia. Newborns will typically have alopecia totalis. During infancy the hair on the scalp will set in at a later time than normal, but eventually will typically appear normal.[5][8] Some patient's scalp hair will remain thin.[4] Eyelashes will be sparse and will typically remain that way. Eyebrows are typically completely absent.[1] Body hair as well will be very sparse or even completely absent.[2]

Genetics

CDAGS is a spliceosomal syndrome. Because of a defect on the minor spliceosome alternative splicing events are seen in 120 genes and gene expression is dysregulated. The expression is most affected in the skin, which explains the skin eruptions. The biological processes impacted most are morfogenesis and forebrain development. This explains the skeletal defects and mental delay seen in some patients.[2]

Diagnosis

Clinical diagnosis is typically made on the basis of the typical skin eruption pattern in combination with bicoronal craniosynostosis and anal atresia. Sequencing of the RNU12 gene can genetically confirm the diagnosis.[citation needed]

Treatment

The cranial defects, genetourinary malformations and anal anomalies can be surgically corrected and will typically have a good prognosis.[citation needed]

Hearing aids can be prescribed for hearing loss.[citation needed]

There is no real cure for the skin eruption. Treatment mainly consists of the regular application of emmolients. Opportunistic bacterial infections can be treated with either topical or systemic antibiotics or a combination of both. Retinoids in combination with corticosteroids are used in some patients.[6] Elinol is used as well. At a later age pulsed dye laser treatment is possible to reduce the scars left by the lesions. As the skin eruption is very difficult to manage, it can have a big impact on the quality of life of the patients.[citation needed]

Mental and motor development need to be monitored after birth, so therapy can start early enough if development is delayed.[citation needed]

Epidemiology

14 cases are known worldwide in 10 families. Based on genetic data it is estimated that CDAGS occurs in about 1 in 40 millions births.[citation needed]

History

The first known patients are a Japanese brother and sister reported in 1981.[10] It was already clear the affliction was hereditary as it affected both siblings. Researchers at the time were wondering if this was a new undiscovered syndrome.[citation needed]

In 1990 an Irish patient was reported.[11] The link with the Japanese cases was not made. When a similarly affected brother was born in 1998 it became clear that they were dealing with a hereditary syndrome. The syndrome was called CAP-syndrome, short for: craniosynostosis, anal anomalies and porokeratosis.[12]

In 2005 Mendoza-Londono discovered 3 new American cases in 2 families. He also connected his cases to the Irish and Japanese cases. As it now became clear that the name CAP-syndrome didn't fully cover the load anymore he decided on a new name: CDAGS. The abbreviation "CDAGS" was chosen because summarizes the most prominent features of the disorder: "C" stands for craniosynostosis and clavicular hypoplasia; "D" for delayed closure of the fontanel, cranial defects, and, in some patients, deafness; "A" for anal anomalies, including anterior placement of the anus and imperforate anus; "G" for genitourinary malformations; and "S" for skin eruption.[1]

In 2013 3 new patients were reported in 2 new families: 2 sisters in Lebanon[5] and 1 girl in the United States.[6]

In 2017 the first Mexican case was reported. She is the first -and only- case where overlapping toes have been reported.[7]

In 2020 the first French case was reported: a 7-year old girl.[8]

In 2021 a new American case was reported: a 2-year old boy.[2]

In 2022 the first Belgian case was born.[9]

Through the years multiple attempts were made to find the genetic cause. In 2005 Mendoza-Londono determined the genetic cause to be located on 22q12-q13.[1] 16 years later, in 2021, Dr. Xing discovered that biallelic variants in RNU12 cause CDAGS syndrome.[2]

References

  1. ^ a b c d e f g h i Mendoza-Londono, Roberto; Lammer, Edward; Watson, Rosemarie; Harper, John; Hatamochi, Atsushi; Hatamochi-Hayashi, Saori; Napierala, Dobrawa; Hermanns, Pia; Collins, Sinead; Roa, Benjamin B.; Hedge, Madhuri R.; Wakui, Keiko; Nguyen, Diep; Stockton, David W.; Lee, Brendan (July 13, 2005). "Characterization of a New Syndrome That Associates Craniosynostosis, Delayed Fontanel Closure, Parietal Foramina, Imperforate Anus, and Skin Eruption: CDAGS". The American Journal of Human Genetics. 77 (1): 161–168. doi:10.1086/431654. PMC 1226190. PMID 15924278.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c d e f Xing, Chao; Kanchwala, Mohammed; Rios, Jonathan J.; Hyatt, Tommy; Wang, Richard C.; Tran, An; Dougherty, Irene; Tovar‐Garza, Andrea; Purnadi, Christy; Kumar, Monique G.; Berk, David; Shinawi, Marwan; Irvine, Alan D.; Toledo‐Bahena, Mirna; Agim, Nnenna G.; Glass, Donald A. (August 13, 2021). "Biallelic variants in RNU12 cause CDAGS syndrome". Human Mutation. 42 (8): 1042–1052. doi:10.1002/humu.24239 – via CrossRef.
  3. ^ a b c Watanabe, K.; Hatamochi, A.; Arakawa, M.; Ueki, H.; Nomura, S.; Osawa, G.; Hata, T. (October 7, 2009). "Congenital Psoriasiform Erythrokeratodermia with Cleidocranial Dysplasia, Urogenital Anomalies and Atresia ani". Dermatology. 192 (4): 368–372. doi:10.1159/000246416 – via Silverchair.
  4. ^ a b c Flanagan, N.; Boyadjiev, S. A.; Harper, J.; Kyne, L.; Earley, M.; Watson, R.; Jabs, E. W.; Geraghty, M. T. (September 1, 1998). "Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome". Journal of Medical Genetics. 35 (9): 763–766. doi:10.1136/jmg.35.9.763. PMC 1051430. PMID 9733036 – via jmg.bmj.com.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ a b c d Chouery, Eliane; Guissart, Claire; Mégarbané, Hala; Aral, Bernard; Nassif, Charbel; Thauvin-Robinet, Christel; Faivre, Laurence; Mégarbané, André (December 13, 2013). "Craniosynostosis, anal anomalies, and porokeratosis (CDAGS syndrome): Case report and literature review". European Journal of Medical Genetics. 56 (12): 674–677. doi:10.1016/j.ejmg.2013.09.012.
  6. ^ a b c d Taylor, April; Nguyen, Roselynn H.; Glass, Donald A.; Agim, Nnenna G. (May 13, 2013). "Annular plaques and craniosynostosis". Journal of the American Academy of Dermatology. 68 (5): 881–884. doi:10.1016/j.jaad.2011.12.005.
  7. ^ a b c d e Pastrana‐Ayala, Rodrigo; Peña‐Castro, Gretty L.; Valencia‐Herrera, Adriana M.; Mena‐Cedillos, Carlos A.; Toussaint‐Caire, Sonia; Akaki‐Carreño, Yumiko I.; García‐Delgado, Constanza; Morán‐Barroso, Veronica F.; Toledo‐Bahena, Mirna (April 13, 2017). "Craniosynostosis, delayed closure of the fontanelle, anal, genitourinary, and skin abnormalities ( CDAGS syndrome): first report in a Mexican patient and review of the literature". International Journal of Dermatology. 56 (4): 435–439. doi:10.1111/ijd.13504 – via CrossRef.
  8. ^ a b c d e Cohen-Sors, R.; Devauchelle, B.; Vabres, P.; Jain, M.; Demeer, B.; Carmi, E. (December 13, 2020). "Syndrome CDAGS (craniosténose, surdité, anomalie anale et génito-urinaire avec éruption cutanée)". Annales de Dermatologie et de Vénéréologie. 147 (12): 868–872. doi:10.1016/j.annder.2020.10.016.
  9. ^ a b Praeter, Dr Mania De (February 28, 2024). ""Na veel onzekerheid voelde de diagnose als een opluchting"". magUZA.
  10. ^ Fukuda, K.; Miyanomae, T.; Nakata, E.; Tanaka, M.; Tanaka, Y.; Usui, T. (March 1, 1981). "Two siblings with cleidocranial dysplasia associated with atresia ani and psoriasis-like lesions: A new syndrome?". European Journal of Pediatrics. 136 (1): 109–111. doi:10.1007/BF00441723 – via Springer Link.
  11. ^ JUDGE, M.R.; MICHAELS, M.; SAMS, V.R.; DAVID, T.J.; HARPER, J.I. (August 13, 1990). "Disseminated porokeratosis in an infant with craniosynostosis". British Journal of Dermatology. 123 (2): 249–254. doi:10.1111/j.1365-2133.1990.tb01855.x.
  12. ^ Flanagan, N.; Boyadjiev, S. A.; Harper, J.; Kyne, L.; Earley, M.; Watson, R.; Jabs, E. W.; Geraghty, M. T. (September 1, 1998). "Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome". Journal of Medical Genetics. 35 (9): 763–766. doi:10.1136/jmg.35.9.763. PMID 9733036 – via jmg.bmj.com.
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