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De Lange syndrome(CDLS)

MedGen UID:
78752
Concept ID:
C0270972
Disease or Syndrome
Synonyms: CDL; CDLS; Cornelia de Lange syndrome
SNOMED CT: Degenerative amstelodamensis typus (40354009); Degenerative amsterodamensis typus (40354009); Typus degenerativus amstelodamensis (40354009); Bruck-de Lange syndrome (40354009); De Lange syndrome (40354009); Cornelia de Lange syndrome (40354009); Brachmann-de Lange syndrome (40354009); Amsterdam dwarf (40354009)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Genes (locations): BRD4 (19p13.12); HDAC8 (Xq13.1); RAD21 (8q24.11)
Related genes: NIPBL, SMC3, SMC1A
 
Monarch Initiative: MONDO:0016033
OMIM®: 122470
OMIM® Phenotypic series: PS122470
Orphanet: ORPHA199

Disease characteristics

Excerpted from the GeneReview: Cornelia de Lange Syndrome
Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. [from GeneReviews]
Authors:
Matthew A Deardorff  |  Sarah E Noon  |  Ian D Krantz   view full author information

Additional descriptions

From OMIM
The Cornelia de Lange syndrome (CDLS) is a multisystem malformation syndrome recognized primarily on the basis of characteristic facial dysmorphism, including low anterior hairline, arched eyebrows, synophrys, anteverted nares, maxillary prognathism, long philtrum, thin lips, and 'carp' mouth, in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies. However, there is wide clinical variability in this disorder, with milder phenotypes that may be difficult to ascertain on the basis of physical features (summary by Rohatgi et al., 2010). Boyle et al. (2015) provided a detailed review of CDLS, including clinical features, diagnosis, and genetic counseling. Genetic Heterogeneity of Cornelia de Lange Syndrome CDLS1, caused by mutation in the NIPBL gene, accounts for about 50 to 60% of CDLS cases (Musio et al., 2006; Rohatgi et al., 2010). X-linked CDLS2 (300590), caused by mutation in the SMC1A gene (300040), accounts for about 5% of cases. CDLS3 (610759) is caused by mutation in the SMC3 gene (606062), and CDLS4 (614701) is caused by mutation in the RAD21 gene (606462). All 4 genes, NIPBL, SMC1A, SMC3, and RAD21, encode components of the cohesin complex. Another X-linked form, CDLS5 (300882), is caused by mutation in the HDAC8 gene (300269), the vertebrate histone deacetylase of SMC3. CDLS6 (620568) is caused by mutation in the BRD4 gene (608749).  http://www.omim.org/entry/122470
From MedlinePlus Genetics
Cornelia de Lange syndrome is a developmental disorder that affects many parts of the body. The features of this disorder vary widely among affected individuals and range from relatively mild to severe.

Cornelia de Lange syndrome is characterized by slow growth before and after birth leading to short stature; intellectual disability that is usually moderate to severe; and abnormalities of bones in the arms, hands, and fingers. Most people with Cornelia de Lange syndrome also have distinctive facial features, including arched eyebrows that often meet in the middle (synophrys), long eyelashes, low-set ears, small and widely spaced teeth, and a small and upturned nose. Many affected individuals also have features similar to autism spectrum disorder, a developmental condition that affects communication and social interaction.

Additional signs and symptoms of Cornelia de Lange syndrome can include excessive body hair (hypertrichosis), an unusually small head (microcephaly), hearing loss, and problems with the digestive tract. Some people with this condition are born with an opening in the roof of the mouth called a cleft palate.  Seizures, heart defects, and eye problems have also been reported in people with this condition.  https://medlineplus.gov/genetics/condition/cornelia-de-lange-syndrome

Professional guidelines

PubMed

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Sabus A, Feinstein J, Romani P, Goldson E, Blackmer A
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Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, Ishman SL, Kerr LM, Levin AV, Mulder PA, Ramos FJ, Wierzba J, Ajmone PF, Axtell D, Blagowidow N, Cereda A, Costantino A, Cormier-Daire V, FitzPatrick D, Grados M, Groves L, Guthrie W, Huisman S, Kaiser FJ, Koekkoek G, Levis M, Mariani M, McCleery JP, Menke LA, Metrena A, O'Connor J, Oliver C, Pie J, Piening S, Potter CJ, Quaglio AL, Redeker E, Richman D, Rigamonti C, Shi A, Tümer Z, Van Balkom IDC, Hennekam RC
Nat Rev Genet 2018 Oct;19(10):649-666. doi: 10.1038/s41576-018-0031-0. PMID: 29995837Free PMC Article

Recent clinical studies

Etiology

Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, Kao CY, Wang Y, Xia F, Eng CM, Benn P
Ultrasound Obstet Gynecol 2022 Jan;59(1):33-39. doi: 10.1002/uog.23756. PMID: 34358384Free PMC Article
Gupta VS, Khan AM, Ebanks AH, Lally PA, Lally KP, Harting MT; Congenital Diaphragmatic Hernia Study Group
J Pediatr Surg 2021 Apr;56(4):697-699. Epub 2020 Jun 11 doi: 10.1016/j.jpedsurg.2020.06.003. PMID: 32762940
Sabus A, Feinstein J, Romani P, Goldson E, Blackmer A
Pharmacotherapy 2019 Jun;39(6):645-664. Epub 2019 Mar 27 doi: 10.1002/phar.2238. PMID: 30793794Free PMC Article
Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, Ishman SL, Kerr LM, Levin AV, Mulder PA, Ramos FJ, Wierzba J, Ajmone PF, Axtell D, Blagowidow N, Cereda A, Costantino A, Cormier-Daire V, FitzPatrick D, Grados M, Groves L, Guthrie W, Huisman S, Kaiser FJ, Koekkoek G, Levis M, Mariani M, McCleery JP, Menke LA, Metrena A, O'Connor J, Oliver C, Pie J, Piening S, Potter CJ, Quaglio AL, Redeker E, Richman D, Rigamonti C, Shi A, Tümer Z, Van Balkom IDC, Hennekam RC
Nat Rev Genet 2018 Oct;19(10):649-666. doi: 10.1038/s41576-018-0031-0. PMID: 29995837Free PMC Article
Avagliano L, Bulfamante GP, Massa V
Birth Defects Res 2017 Jun 1;109(10):771-777. Epub 2017 May 22 doi: 10.1002/bdr2.1045. PMID: 28544538

Diagnosis

Castiglioni S, Di Fede E, Bernardelli C, Lettieri A, Parodi C, Grazioli P, Colombo EA, Ancona S, Milani D, Ottaviano E, Borghi E, Massa V, Ghelma F, Vignoli A, Lesma E, Gervasini C
Genes (Basel) 2022 Mar 15;13(3) doi: 10.3390/genes13030514. PMID: 35328068Free PMC Article
Parenti I, Mallozzi MB, Hüning I, Gervasini C, Kuechler A, Agolini E, Albrecht B, Baquero-Montoya C, Bohring A, Bramswig NC, Busche A, Dalski A, Guo Y, Hanker B, Hellenbroich Y, Horn D, Innes AM, Leoni C, Li YR, Lynch SA, Mariani M, Medne L, Mikat B, Milani D, Onesimo R, Ortiz-Gonzalez X, Prott EC, Reutter H, Rossier E, Selicorni A, Wieacker P, Wilkens A, Wieczorek D, Zackai EH, Zampino G, Zirn B, Hakonarson H, Deardorff MA, Gillessen-Kaesbach G, Kaiser FJ
Clin Genet 2021 Aug;100(2):187-200. Epub 2021 May 14 doi: 10.1111/cge.13977. PMID: 33955014
Sarogni P, Pallotta MM, Musio A
J Med Genet 2020 May;57(5):289-295. Epub 2019 Nov 8 doi: 10.1136/jmedgenet-2019-106277. PMID: 31704779Free PMC Article
Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, Ishman SL, Kerr LM, Levin AV, Mulder PA, Ramos FJ, Wierzba J, Ajmone PF, Axtell D, Blagowidow N, Cereda A, Costantino A, Cormier-Daire V, FitzPatrick D, Grados M, Groves L, Guthrie W, Huisman S, Kaiser FJ, Koekkoek G, Levis M, Mariani M, McCleery JP, Menke LA, Metrena A, O'Connor J, Oliver C, Pie J, Piening S, Potter CJ, Quaglio AL, Redeker E, Richman D, Rigamonti C, Shi A, Tümer Z, Van Balkom IDC, Hennekam RC
Nat Rev Genet 2018 Oct;19(10):649-666. doi: 10.1038/s41576-018-0031-0. PMID: 29995837Free PMC Article
Boyle MI, Jespersgaard C, Brøndum-Nielsen K, Bisgaard AM, Tümer Z
Clin Genet 2015 Jul;88(1):1-12. Epub 2014 Oct 28 doi: 10.1111/cge.12499. PMID: 25209348

Therapy

Sanchez AC, Thren ED, Iovine MK, Skibbens RV
Cell Cycle 2022 Mar;21(5):501-513. Epub 2022 Jan 6 doi: 10.1080/15384101.2021.2023304. PMID: 34989322Free PMC Article
Hu Y, Caldwell KJ, Onciu M, Federico SM, Salek M, Lewis S, Lei S, Zhang J, Nichols KE, Takemoto CM, Triplett BM, Farrar JE, Rubnitz JE, Ribeiro RC, Wlodarski MW
Blood Adv 2022 Jan 25;6(2):521-527. doi: 10.1182/bloodadvances.2021006139. PMID: 34710216Free PMC Article
Sabus A, Feinstein J, Romani P, Goldson E, Blackmer A
Pharmacotherapy 2019 Jun;39(6):645-664. Epub 2019 Mar 27 doi: 10.1002/phar.2238. PMID: 30793794Free PMC Article
de Graaf M, Kant SG, Wit JM, Willem Redeker EJ, Eduard Santen GW, Henriëtta Verkerk AJM, Uitterlinden AG, Losekoot M, Oostdijk W
J Clin Res Pediatr Endocrinol 2017 Dec 15;9(4):366-370. Epub 2017 Jun 7 doi: 10.4274/jcrpe.4349. PMID: 28588001Free PMC Article
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Trends Pharmacol Sci 2015 Jul;36(7):481-92. Epub 2015 May 23 doi: 10.1016/j.tips.2015.04.013. PMID: 26013035

Prognosis

Gupta VS, Khan AM, Ebanks AH, Lally PA, Lally KP, Harting MT; Congenital Diaphragmatic Hernia Study Group
J Pediatr Surg 2021 Apr;56(4):697-699. Epub 2020 Jun 11 doi: 10.1016/j.jpedsurg.2020.06.003. PMID: 32762940
Zhang J, Li J, Saucier JB, Feng Y, Jiang Y, Sinson J, McCombs AK, Schmitt ES, Peacock S, Chen S, Dai H, Ge X, Wang G, Shaw CA, Mei H, Breman A, Xia F, Yang Y, Purgason A, Pourpak A, Chen Z, Wang X, Wang Y, Kulkarni S, Choy KW, Wapner RJ, Van den Veyver IB, Beaudet A, Parmar S, Wong LJ, Eng CM
Nat Med 2019 Mar;25(3):439-447. Epub 2019 Jan 28 doi: 10.1038/s41591-018-0334-x. PMID: 30692697
Ayerza Casas A, Puisac Uriol B, Teresa Rodrigo ME, Hernández Marcos M, Ramos Fuentes FJ, Pie Juste J
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Opitz JM
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Clinical prediction guides

Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, Kao CY, Wang Y, Xia F, Eng CM, Benn P
Ultrasound Obstet Gynecol 2022 Jan;59(1):33-39. doi: 10.1002/uog.23756. PMID: 34358384Free PMC Article
Gupta VS, Khan AM, Ebanks AH, Lally PA, Lally KP, Harting MT; Congenital Diaphragmatic Hernia Study Group
J Pediatr Surg 2021 Apr;56(4):697-699. Epub 2020 Jun 11 doi: 10.1016/j.jpedsurg.2020.06.003. PMID: 32762940
Piché J, Van Vliet PP, Pucéat M, Andelfinger G
Cell Cycle 2019 Nov;18(21):2828-2848. Epub 2019 Sep 13 doi: 10.1080/15384101.2019.1658476. PMID: 31516082Free PMC Article
Zhang J, Li J, Saucier JB, Feng Y, Jiang Y, Sinson J, McCombs AK, Schmitt ES, Peacock S, Chen S, Dai H, Ge X, Wang G, Shaw CA, Mei H, Breman A, Xia F, Yang Y, Purgason A, Pourpak A, Chen Z, Wang X, Wang Y, Kulkarni S, Choy KW, Wapner RJ, Van den Veyver IB, Beaudet A, Parmar S, Wong LJ, Eng CM
Nat Med 2019 Mar;25(3):439-447. Epub 2019 Jan 28 doi: 10.1038/s41591-018-0334-x. PMID: 30692697
Grados MA, Alvi MH, Srivastava S
Curr Opin Psychiatry 2017 Mar;30(2):92-96. doi: 10.1097/YCO.0000000000000311. PMID: 28125439Free PMC Article

Recent systematic reviews

Giani L, Michelini G, Nobile M, Ajmone PF, Vizziello PG, Scaini S
J Affect Disord 2022 Feb 15;299:636-643. Epub 2021 Dec 23 doi: 10.1016/j.jad.2021.12.099. PMID: 34953928
Hutchison DM, Duffens A, Yale K, Park A, Cardenas K, Mesinkovska NA
J Eur Acad Dermatol Venereol 2022 Apr;36(4):536-546. Epub 2021 Dec 31 doi: 10.1111/jdv.17877. PMID: 34919300
Bergeron M, Chang K, Ishman SL
Laryngoscope 2020 Apr;130(4):E122-E133. Epub 2019 Jul 13 doi: 10.1002/lary.28169. PMID: 31301187
Miura da Costa K, Saxena AK
Acta Paediatr 2018 Dec;107(12):2054-2058. Epub 2018 Jul 20 doi: 10.1111/apa.14476. PMID: 29949184
Mulder PA, Huisman SA, Hennekam RC, Oliver C, van Balkom ID, Piening S
Dev Med Child Neurol 2017 Apr;59(4):361-366. Epub 2016 Dec 18 doi: 10.1111/dmcn.13361. PMID: 27988966

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