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2000-02-16-18 Cornelia de Lange syndrome © Jeanty

Cornelia de Lange syndrome

Philippe Jeanty, MD, PhD

Definition:  This syndrome associates abnormal facial characteristics such as abnormal capillary findings (synophrys, long eyelashes, low anterior and posterior hairline), upturned nose, prognathism, long philtrum, down turned mouth angles with prenatal growth retardation (postnatal too), mental retardation and common (but not obligatory) upper limb anomalies.

Synonyms: Brachmann-De Lange Syndrome; Brachmann made the first description in 1916[1]

BDLS (the initials for the really lazy writers or for the medical students wanting to impose their knowledge during rounds).

History: Brachmann described a hypotrophic newborn (1600g) with microcephaly, brachycephaly, sloped forehead, micrognathia, beaked nose, small arms with hypoplastic forearms, flexed at elbows, antecubital web, symmetrical monodactyly with 2 phalanges, cervical ribs, hirsutism. He concentrated most on the upper limb reduction defects and less on the facial appearance. In 1933, Dr. Cornelia de Lange, a Dutch pediatrician from Amsterdam (and the person preceding Ellis van Crevelt in the department), described two children with similar features, one 17 months and the other 6 months, who were admitted within weeks of each other to Emma Children"s Hospital[2],[3].

I cannot resist reporting the following cute anecdote: Milton Alter once wrote: “Perhaps one method of assuring continued use of eponyms in medicine is to assign a difficult, and rather meaningless, Latin label to a clinical entity. This was done by de Lange in 1933. She described a syndrome which was called “typus degenerativus Amstelodamensis”.” [4]. He must have been correct: most of us know the syndrome by the lead author’s name and reserve the information about Amstelodamensis (the Latin name of Amsterdam) for it’s namesake Amstel product.

Incidence: 0.15-0.3:10,000; M1=F1.3.

Recurrence:: [5].

Etiology: Unknown. Recent articles have suspected anomalous human chordin gene (CHRD), THPO (thrombopoietin), CLCN2 (a voltage-gated chloride-channel gene) and EIF4G1 (a eukaryotic translation-initiation-factor-gamma gene) which maps within a gene cluster at 3q27[6]  and SHOT an homeobox gene[7]. But others have suggested mitochondrial DNA deletions[8] (which would go with a more common transmission of the disorder from mother[9] to children then from father[10] to children).

Diagnosis: Prenatal findings: growth retardation, microcephaly + brachycephaly, micrognathia, long eyelashes, hypertrichosis/hirsutism, cardiac anomalies including atrial and ventricular septal defects, hypoplastic left ventricle, anomalous systemic venous drainage, overriding aorta, fibroelastosis, polycystic and ectopic kidneys, and limb anomalies in about a quarter[11],[12],5. Several prenatal diagnoses have been made[13],[14],[15],[16],[17],[18],[19],[20],[21],[22].

Ultrasound images.

Possibly recognizable on 3D examinations: unusual palpebral fissures, low set ears, anteverted nostrils, prominent philtrum, thin upper lip, broad and/or depressed nasal bridge, down turned angles of mouth.

Postnatal findings: low hairline, synophrys, high arched palate, delayed eruption of teeth, brain malformations[23], malrotation of the gut[24], duplications, splenic-pancreatic fusion anomalies, renal anomalies[25] many ocular anomalies. Although normal IQ exist[26],[27], developmental delayed ranging from borderline (10%), through mild (8%), moderate (18%), and severe (20%) to profound (43%)[28],[29] is more common.

Genetic anomalies: Several authors have suggested an autosomal dominant inheritance[30],[31],[32]. A pair of dizygotic twins[33] and a pair monozygotic twins with discordant feature have been reported[34] in Brazil and restudied 20 years later[35]. There are other reports though on affected sibs with no parents affected[36].

Differential diagnosis: Partial trisomy 3q[37].

Associated anomalies:  See Diagnosis.

Prognosis: Mostly affected by the intellectual achievement of those children (and related problems of self-mutilations…), orthopedic and respiratory complications also occur. Several parents of kids with the disorders have created web sites well worth visiting Baylee’ Web suite ; Jessica"s Place ; Amanda"s Room ; Baylee"s Home Page ; Geoff"s Stuff-- The Successes of One Unique Guy ; Kayla"s (Svendson) Home Page ; Kayla"s (Prink) Web Site ; Maddy"s Farm.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation the pregnancy is opted for. Confirmation of diagnosis after birth is important for genetic counseling.

Support organizations:

Cornelia de Lange Foundation Outreach

Other references on the Web


[1] Brachmann, W. : Ein fall von symmetrischer monodaktylie durch Ulnadefekt, mit symmetrischer flughautbildung in den ellenbeugen, sowie anderen abnormitaten (zwerghaftogkeit, halsrippen, behaarung). Jarb. Kinder. Phys. Erzie. 84: 225-235, 1916.

[2] de Lange, C. : Sur un type nouveau de dégénerescence (typus Amstelodamensis). Arch. Med. Enfants 36: 713-719, 1933.

[3] Wolland AM, Lindback T: Cornelia de Lange syndrome and the woman behind the syndrome. Tidsskr Nor Laegeforen 1995 Dec 10;115(30):3724-6

[4] Alter M: Dermatoglyphics in birth defects in Birth Defects original article series March 1969 Vol V #3 Published byt eh March of Dimes, p 116

[5] Jackson L, Kline AD, Barr MA, Koch S de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet 1993 Nov 15;47(7):940-6

[6] Smith M, Herrell S, Lusher M, Lako L, Simpson C, Wiestner A, Skoda R, Ireland M, Strachan T Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes. Hum Genet 1999 Jul-Aug;105(1-2):104-11

[7] Blaschke RJ, Monaghan AP, Schiller S, Schechinger B, Rao E, Padilla-Nash H, Ried T, Rappold GA SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development. Proc Natl Acad Sci U S A 1998 Mar 3;95(5):2406-11

[8] Melegh B, Bock I, Gati I, Mehes K Multiple mitochondrial DNA deletions and persistent hyperthermia in a patient with Brachmann-de Lange phenotype. Am J Med Genet 1996 Oct 2;65(1):82-8

[9] de Die-Smulders C, Schrander-Stumpel C, Fryns JP, Theunissen P Exclusively maternal transmission of autosomal dominant Brachmann-de Lange syndrome. Am J Med Genet 1994 Sep 1;52(3):363

[10] Chodirker BN, Chudley AE Male-to-male transmission of mild Brachmann-de Lange syndrome. Am J Med Genet 1994 Sep 1;52(3):331-3

[11] Boog G, Sagot F, Winer N, David A, Nomballais MF: Brachmann-de Lange syndrome: a cause of early symmetric fetal growth delay. Eur J Obstet Gynecol Reprod Biol 1999 Aug;85(2):173-7

[12] Ranzini AC, Day-Salvatore D, Farren-Chavez D, McLean DA, Greco R Prenatal diagnosis of de Lange syndrome. J Ultrasound Med 1997 Nov;16(11):755-8

[13] Boog G, Sagot F, Winer N, David A, Nomballais MF.   Brachmann-de Lange syndrome: a cause of early symmetric fetal growth delay. Eur J Obstet Gynecol Reprod Biol. 1999 Aug;85(2):173-7.

[14] Ranzini AC, Day-Salvatore D, Farren-Chavez D, McLean DA, Greco R.   Prenatal diagnosis of de Lange syndrome. J Ultrasound Med. 1997 Nov;16(11):755-8.

[15] Ackerman J, Gilbert-Barness E.   Brachmann-de Lange syndrome. Am J Med Genet. 1997 Jan 31;68(3):367-8.

[16] Manouvrier S, Espinasse M, Vaast P, Boute O, Farre I, Dupont F, Puech F, Gosselin B, Farriaux JP.   Brachmann-de Lange syndrome: pre- and postnatal findings. Am J Med Genet. 1996 Mar 29;62(3):268-73.

[17] Golsby LM, McNamara MF, Anderson CF, Quinn DL, Reed KL.   Case of the day. Brachman-De Lange syndrome. J Ultrasound Med. 1995 Apr;14(4):325-6.

[18] Van Allen MI, Filippi G, Siegel-Bartelt J, Yong SL, McGillivray B, Zuker RM, Smith CR, Magee JF, Ritchie S, Toi A, et al.   Clinical variability within Brachmann-de Lange syndrome: a proposed classification system. Am J Med Genet. 1993 Nov 15;47(7):947-58.

[19] Kliewer MA, Kahler SG, Hertzberg BS, Bowie JD.   Fetal biometry in the Brachmann-de Lange syndrome. Am J Med Genet. 1993 Nov 15;47(7):1035-41.

[20] Jelsema RD, Isada NB, Kazzi NJ, Sargent K, Harrison MR, Johnson MP, Evans MI.   Prenatal diagnosis of congenital diaphragmatic hernia not amenable to prenatal or neonatal repair: Brachmann-de Lange syndrome. Am J Med Genet. 1993 Nov 15;47(7):1022-3.

[21] Drolshagen LF, Durmon G, Berumen M, Burks DD.   Prenatal ultrasonographic appearance of "Cornelia de Lange" syndrome. J Clin Ultrasound. 1992 Sep;20(7):470-4.

[22] Bruner JP, Hsia YE.   Prenatal findings in Brachmann-de Lange syndrome.

Obstet Gynecol. 1990 Nov;76(5 Pt 2):966-8.

[23] Hayashi M, Sakamoto K, Kurata K, Nagata J, Satoh J, Morimatsu Y Septo-optic dysplasia with cerebellar hypoplasia in Cornelia de Lange syndrome. Acta Neuropathol (Berl) 1996 Dec;92(6):625-30

[24] Holthusen J, Rottingen JA Cecal volvulus as a complication in Cornelia de Lange syndrome. A case report and literature review. Tidsskr Nor Laegeforen 1998 Apr 20;118(10):1559-60

[25] Charles AK, Porter HJ, Sams V, Lunt P Nephrogenic rests and renal abnormalities in Brachmann-de Lange syndrome. Pediatr Pathol Lab Med 1997 Mar-Apr;17(2):209-19

[26] Saal HM, Samango-Sprouse CA, Rodnan LA, Rosenbaum KN, Custer DA Brachmann-de Lange syndrome with normal IQ. Am J Med Genet 1993 Nov 15;47(7):995-8

[27] Clericuzio CL Mild mental retardation with classic somatic phenotype in the Brachmann-de Lange syndrome. Am J Med Genet 1993 Nov 15;47(7):992-4

[28] Berney TP, Ireland M, Burn J Behavioural phenotype of Cornelia de Lange syndrome. Arch Dis Child 1999 Oct;81(4):333-6

[29] Kousseff BG, Newkirk P, Root AW Brachmann-de Lange syndrome. 1994 update. Arch Pediatr Adolesc Med 1994 Jul;148(7):749-55

[30] McKenney RR, Elder FF, Garcia J, Northrup H Brachmann-de Lange syndrome: autosomal dominant inheritance and male-to-male transmission. Am J Med Genet 1996 Dec 30;66(4):449-52

[31] Kozma C Autosomal dominant inheritance of Brachmann-de Lange syndrome. Am J Med Genet 1996 Dec 30;66(4):445-8

[32] Feingold M, Lin AE Familial Brachmann-de Lange syndrome: further evidence for autosomal dominant inheritance and review of the literature. Am J Med Genet 1993 Nov 15;47(7):1064-7

[33] Stevenson, R. E.; Scott, C. I., Jr. Discordance for Cornelia de Lange syndrome in twins. J. Med. Genet. 13: 402-404, 1976.

[34] Carakushansky, G.; Berthier, C. : The de Lange syndrome in one of twins. J. Med. Genet. 13: 404-406, 1976.

[35] Carakushansky, G.; Aguiar, M. B.; Goncalves, M. R.; Berthier, C. O.; Kahn, E.; Carakushansky, M.; Pena, S. D. J.: Identical twin discordance for the Brachmann-de Lange syndrome revisited. Am. J. Med. Genet. 63: 458-460, 1996.

[36] Krajewska-Walasek M, Chrzanowska K, Tylki-Szymanska A, Bialecka M A further report of Brachmann-de Lange syndrome in two sibs with normal parents. Clin Genet 1995 Jun;47(6):324-7

[37] Holder SE, Grimsley LM, Palmer RW, Butler LJ, Baraitser M Partial trisomy 3q causing mild Cornelia de Lange phenotype. J Med Genet 1994 Feb;31(2):150-2

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