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2006-12-21-12 Cornelia de Lange syndrome © Cuillier www.thefetus.net/


Cornelia de Lange syndrome  

Fabrice Cuillier, MD*, M. S. Avignon, MD**, J. L.  Alessandri, MD***K. Comalli Dillon, BA, RDMS****

*

Gynecologist, Hôpital Félix Guyon, 97400  Saint-Denis, Ile de la Réunion, France. Telephone: 0262 90 55 22; fax: 0262 90 77 30;

**

Neonatologist, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France;

***

Gynecologist, Sainte-Clothilde Clinic, 97400 Saint-Denis, Ile de la Réunion, France;

****

Diagnostic Medical Sonographer, Editor, Translator, Novato, California.

 

Definition

Cornelia de Lange syndrome is a rare syndrome characterized by these associations:
 
1. Abnormal facies, featuring:

a. abnormal hairs; 
b. synophrysis  (hypertrophy and midline fusion of the eyebrows);
c. long curved eyelashes;  low anterior and posterior hairline);
d. upturned nose and downturned mouth corners;
e. dysgnathia (prognathia or mandibular protrusion; micrognathia) and a long philtrum.

2. Various upper limb anomalies; and
3. Intrauterine growth restriction.
 
In effect, Cornelia de Lange syndrome is characterized by short stature with intrauterine growth restriction (IUGR); very specific craniofacial anomalies with  micro-brachycephaly; and cognitive impairment with mental  retardation.  Various musculoskeletal malformations (essentially limb anomalies) and visceral anomalies may be associated as well.
 
Synonyms

Brachmann De Lange syndrome.
 
Case report

A 25-year-old patient was referred at 22 weeks GA to our prenatal unit for assessment of suspected IUGR with facial anomalies (abnormal fetal biometry on our patient’s 22-week sonogram brought her case to our attention).  Her family history was noncontributive.
 
At 12 weeks, the initial sonographic exam was considered normal. Maternal plasma markers (taken at 16 weeks GA) assessed the risk of Down syndrome at 1/1000.
 
At 22 weeks, the second routine prenatal sonogram showed IUGR with micrognathia. The patient was seen in our prenatal unit, and we discovered the following:

  • Cholecystomegaly (Figure 1);

  • Bilateral upper limb defects, with bilateral ulnar hypoplasia; abnormal number of left digits (Figures 2A--2G); and abnormal right digits (Figures 3A--3F). The feet were normal (Figures 4A, 4B);

  • A large ventriculoseptal defect with transposition of the  great vessels (Figures 5A--5D).

Cornelia de Lange syndrome was the suspected diagnosis because of the association of  micrognathia (Figure 6), IUGR (Figure 8A, 8B), cardiac anomalies,  and upper limb anomalies. A micropenis was seen as well  (Figure 7). The parents chose to interrupt the pregnancy at 24 weeks GA. Fetal karyotype was normal (46 XY). The fetus presented the typical facial dysmorphia, with synophrysis, long curved eyelashes, a depressed nasal bone with anteverted nostrils, a long philtrum and micrognathia (Figure 8A). Postnatal  radiography of the upper limbs confirmed ulnar hypoplasia with multiple digital anomalies (Figure 8B, 9).

Figures 1 and 2A. 1 - Ultrasound examination at 22 weeks GA showing marked cholecystomegaly (transverse abdominal view).  2A - 2D view of the left hand.

 

Figures 2B, 2C. 2D views of the left hand with oligodactyly.

 

Figures 2D, 2E. 2D views of the left hand.

 

Figures 2F, 2G. 3D and 2D views of the left hand.

 

Figures 3A, 3B. 2D views of the right hand.

 

Figures 3C, 3D. 2D views of the right hand.

 

Figures 3E, 3F. 3D views of the right hand.

 

Figures 4A, 4B. 2D and 3D view of the feet.
 
 

Figures 5A, 5B. At 22weeks GA, 2D Doppler view showing the ventriculoseptal defect and the transposition of  the great vessels.
 
 

Figures 5C, 5D. At 22weeks GA, 2D Doppler view showing the ventriculoseptal defect and the transposition of  the great vessels.

 

Figures 6, 7. 2D view of the fetal profile and 2D view of the fetal micropenis.
 
 

Figures 8A, 8B. Image showing characteristic facies and the malformation of  the arms and the hand.
 
 

Figure 9. Radiography of the fetus.

History

Brachmann and De Lange first described this syndrome, also known as Cornelia de Lange syndrome.
 
Brachmann (1916) observed a hypotrophic newborn with microcephaly, sloping forehead, micrognathia, beaked nose, small arms with  hypoplastic forearms, and fixed elbow flexion. There was also antecubital webbing and symmetrical monodactyly with only two phalanges. There were also cervical ribs and hirsutism.
 
De Lange syndrome was described in 1933 by Cornelia de Lange, MD, professor of Pediatrics at the University of Amsterdam. She described two Dutch children with a strange syndrome, both presenting with similar characteristics, including a small nose with upturned  nostrils, a thin, turned-down mouth, synophrysis, long curly eyelashes,  short stature, limb malformations, and mental retardation. At this time, Dr. de Lange did not know Brachmann had described the same entity in 1916.
 
 
Prevalence

Beck (Denmark, 1976) estimated of the prevalence of Cornelia de Lange syndrome at 0.05:10,000.
 
Incidence 
 
The incidence of these is approximately 0.2:10,000, according  to Caksen et al. The incidence varies from 1:10,000 in USA to 0.2:10,000 in Denmark. The recurrence risk of the Cornelia de Lange syndrome is in the range of one to three per cent. The recurrence risk was calculated to be less than 1%. Jackson estimated the recurrence risks at 2 to 5% or higher. The recurrence risk within sibling relationships can be explained by germline mosaicism.
 
Etiology

The cause and genetic basis Cornelia de Lange syndrome are unknown; however, chromosome 3q is suggested as the gene responsible for the syndrome. To date, according to Kozma, no specific microdeletion or duplication has been found with high-resolution banding. The complete phenotypic spectrum, etiology, and genetic transmission of this syndrome are not really known. Nevertheless, studies of maternal serum have found lowered pregnancy-associated plasma protein A to be a possible marker of Cornelia de Lange syndrome in the fetus.

Pathogenesis

The paucity of familial cases of Cornelia de Lange syndrome studied prevents from understanding the exact genetic mechanism of the syndrome. Some authors have suggested autosomal-dominant familial inheritance, but most cases (> 99%) are sporadic in families, with variable expressivity. Feingold et al (1993) described a case of familial Cornelia de Lange syndrome, a mother and daughter. Kozma (1996) described one case with a mother with a mild phenotype and her son, who was severely affected. Some publications report an autosomal-dominant trait with male-to-male, female-to-female, and female-to-male transmission. According to Die-Smulders et al, a de novo autosomal-dominant mutation causes the most severe form of Cornelia de Lange syndrome. Nonetheless, Naguib et al described one case of Cornelia de Lange syndrome siblings from consanguineous parents, so suggesting autosomal-recessive transmission.  
Therefore, although most cases of Cornelia de Lange syndrome are sporadic, a careful evaluation of parents of affected children is important for appropriate genetic counseling.
 
Sonographic findings

As the accurate diagnosis of Cornelia de Lange syndrome continues to be based solely on the characteristic phenotype, its accurate and early recognition is essential if prognosis, management, and genetic counseling are to be effective. Misdiagnosis of major forms of Cornelia de Lange syndrome is not uncommon.  Indeed, in classic cases of Cornelia de Lange syndrome, there is rarely any difficulty in making the diagnosis, but for mildly affected cases, it is very difficult to arrive at diagnosis, in particular during the prenatal period.
 
Limb anomalies are often asymmetric. Long-bone abnormalities include ulnar hypoplasia or dysplasia of the radial head, sometimes seen with fusion of the elbow.  In Jackson"s study of 310 cases, only 27% had the upper-extremity abnormalities commonly associated with Cornelia de Lange syndrome. Upper extremity anomalies are a classic Cornelia de Lange syndrome sign, most commonly: 

  • irreducible flexion of the elbows;
  • aplasia or sometimes agenesis of the cubital bones; 
  • oligodactyly; and
  • clinodactyly.

When there is hemimelia of the forarm, fusion at the elbow and oligodactyly are often present, so it is often difficult to determine which bone, the radius or the ulna, is absent. Limitation of elbow extension with radiologic features is an objective observation and is less commonly found in normal children or those with other syndromes.

The limb abnormalities usually associated with Cornelia de Lange syndrome are only present in 27% of affected children.
 
Limb abnormalities, though striking when present, are seen in cases where other clinical manifestations are similarly severe, so do not significantly contribute to the diagnostic process.
 
Cornelia de Lange syndrome manifestations in the hands are some or several of the following: acheiria; oligodactyly; hypoplasia of the thumb and first metacarpal; clinodactyly of the fifth finger; and ectrodactyly. The hands, if there are normal, and the feet are always strikingly small.
 
Other radiologic manifestations include thirteen ribs with precocious sternal fusion.
 
IUGR is nearly always associated with Cornelia de Lange syndrome syndrome; it is a classic sign. Jackson’s study of 377 cases demonstrated a higher proportion of patients affected mildly; IUGR was seen frequently among them.
 
Facial anomalies: Prefrontal edema, prominent eyelashes, nasal hypoplasia with prominent philtrum, and low-set ears are classic. The low-set ears are usually not striking during sonography; and the presentation of widely spaced teeth and a short neck are variable and subject to interpretation. Microcephaly, brachycephaly, and micrognathia are frequently seen.  However, hypertrichosis, synophrys, hirsutism, and long eyelashes can be seen in utero.
 
Cardiac abnormalities are frequently present. Virtually all cardiac anomalies can be found among Cornelia de Lange syndrome cases. Ventriculoseptal or atrioseptal defects, hypoplastic left ventricle, anomalous venous return, and coarctation of the aorta are the most frequently seen cardiac anomalies.
 
Renal anomalies: Polycystic kidneys or pyelectasia are possible.
 
Genital anomalies: Cryptorchidism, micropenis, hypospadias, or abnormally small labia majora can be seen.
 
Other anomalies have been reported, such as, occasionally, bilateral diaphragmatic hernia. The association of diaphragmatic hernia with upper-extremity malformations is characteristic of Cornelia de Lange syndrome.
 
Implications for targeted ultrasound examination

During the first trimester, nuchal translucency is usually abnormal; however, this parameter was normal in our case.

Upper extremities can be abnormal, most commonly featuring ulnaraplasia, and can therefore be detected on endovaginal ultrasonography.
 
During the second trimester, according to Le Vaillant et al, prenatal diagnosis of Cornelia de Lange syndrome is extremely rare, with only six cases diagnosed in utero (2004). In the literature, few observations of prenatal diagnosis have been reported, but these reports concerned only "major" forms of the syndrome, following prenatal detection of significant IUGR, with important upper-extremity anomalies,  associated often with other skeletal abnormalities and sometimes  diaphragmatic hernia. Otherwise, skeletal anomalies for Cornelia de Lange syndrome are rare, but are often the major means of detection, as in the case we present here. These anomalies concern the distal upper limbs in an asymmetric way. Classical limb abnormalities include micromelia, oligodactyly and terminal transverse hemimelia. Ulnar aplasia is frequent. At the level of the fingers, short metacarpals, syndactyly and phalangeal absence or hypoplasia are frequent.
 
Doppler interrogation of the uterine artery, and the Pourcelot index yields a normal result in Cornelia de Lange syndrome.

Differential diagnosis

Diagnosis can be confirmed with analysis of placental protein (PAPP- A) in maternal serum and by 5-hydroxy, indole-3 acetic acid in amniotic fluid, according to Boog. It is ovious to confirm the diagnosis via necropsy after interruption of pregnancy, because this syndrome is sporadic.

3q duplication syndrome (Dup 3q): Patients with Cornelia de Lange syndrome show some resemblance to individuals with 3q duplication syndrome. Features of Cornelia de Lange syndrome have some clinical overlap and present phenotypic similarities with the dup (3q) syndrome (partial trisomy 3q), which more commonly has renal, palatal, ocular, and cardiac abnormalities. So, current findings suggest that the gene responsible for Cornelia De Lange syndrome is located in the distal 3q region, probably between 3q25.1 and 3q26.3 locus.  Nevertheless, it is unclear whether the full phenotype is the result of a submicroscopic chromosomal duplication, deletion of a single gene, or a continuous gene syndrome.
Despite the phenotypic ambiguity, one can eliminate the diagnosis of Dup 3q, since in the latter, one finds an association of craniosynostosis, cleft palate, and urinary tract abnormalities, which are not found in Cornelia de Lange syndrome.
 
Chromosomal abnormalities: Prenatal karyotyping is imperative, to rule out chromosomal abnormalities such as trisomy 18 and Pallister-Killian syndrome (tetrasomy 12p).
 
Heart-hand syndrome is easily ruled out, as is Holt-Oram syndrome, because in these conditions there is radial aplasia and cardiac abnormalities. Thrombocytopenia-Absent Radius syndrome is easily eliminated as well.
 
Fryns syndrome: If there is any combination of facial abnormalities with diaphragmatic hernia and limb abnormalities, Fryns syndrome and Pallister-Killian syndrome may be eliminated as well. Fryns syndrome is the association of diaphragmatic hernia with abnormal facies. 

Other syndromes: Cornelia De Lange syndrome can sometimes resemble Angelman syndrome or Beckwith-Wiedemann syndrome.
 
Associated anomalies

  • Maternal alpha-fetoprotein levels are abnormally low, probably due to abnormal fetal liver function.
  • Ophthalmologic signs are possible. The most frequent ocular findings  include
    • Synophrysis
    • Long curved eyelashes
    • Hypertrichosis of lashes and eyebrows.
  • Ocular surface and anterior-segment signs are occasionally described in the literature.

Prognosis

It is important to diagnose Cornelia de Lange syndrome prenatally due to the severity of the prognosis which is poor. These patients have increased mortality rates: 20% of affected children die during the first few years of life. Its postnatal course is usually marked by initial hypertonicity, a low-pitched weak cry, feeding problems, and behavior problems. In many case, the child can live; but the intellectual level is always very low. Only eight cases of Cornelia De Lange syndrome with normal intellect have been described having according to Saal et al.

Conclusion

Prenatal diagnosis of Cornelia de Lange syndrome is of highest importance so that parents can choose early whether or not to continue pregnancy, and so that if continuation is chosen, they can prepare to care for an affected child.   Early diagnosis is increasingly possible with higher-resolution ultrasound and especially with awareness of Cornelia de Lange syndrome and its associations.

References

1

Le Vaillant C, Quere MP, David A, Berlivet M, Boog G.

 

 

Prenatal diagnosis of a "minor" form of Brachmann-de Lange syndrome by three-dimensional sonography and three-dimensional computed tomography.

Fetal Diagn Ther. 2004 Mar-Apr;19(2):155-9. Review.

PMID: 14764961 [PubMed - indexed for MEDLINE]

2

Lee WB, Brandt JD, Mannis MJ, Huang CQ, Rabin GJ.

 

 

Aniridia and Brachmann-de Lange syndrome: a review of ocular surface and anterior segment findings.

Cornea. 2003 Mar;22(2):178-80. Review.

PMID: 12605058 [PubMed - indexed for MEDLINE]

3

Kotzot D.

 

 

Review and meta-analysis of systematic searches for uniparental disomy (UPD) other than UPD 15.

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4

Caksen H, Kurtoglu S, Cesur Y, Ozturk A.

 

 

An analysis of seven infants with Brachmann-de Lange syndrome, of whom two identical twin sisters.

Genet Couns. 2001;12(4):373-7. Review.

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5

Tsukahara M.

 

 

[Brachmann-de Lange syndrome]

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6

Enns GM, Cox VA, Goldstein RB, Gibbs DL, Harrison MR, Golabi M.

 

 

Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review.

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PMID: 9788565 [PubMed - indexed for MEDLINE]

7

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. Review.

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8

Kozma C.

 

 

Autosomal dominant inheritance of Brachmann-de Lange syndrome.

Am J Med Genet. 1996 Dec 30;66(4):445-8. Review.

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9

Bozner P, Blackburn W, Cooley NR Jr.

 

 

Bilateral ulnar agenesis: case report and review of the literature.

Pediatr Pathol Lab Med. 1995 Nov-Dec;15(6):895-913. Review.

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10

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. Review.

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11

Kousseff BG, Newkirk P, Root AW.

 

 

Brachmann-de Lange syndrome. 1994 update.

Arch Pediatr Adolesc Med. 1994 Jul;148(7):749-55. Review.

PMID: 8019632 [PubMed - indexed for MEDLINE]

12

Saal HM, Samango-Sprouse CA, Rodnan LA, Rosenbaum KN, Custer DA.

 

 

Brachmann-de Lange syndrome with normal IQ.

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13

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. Review.

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14

Braddock SR, Lachman RS, Stoppenhagen CC, Carey JC, Ireland M, Moeschler JB, Cunniff C, Graham JM Jr.

 

 

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15

Opitz JM, Holt MC.

 

 

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Opitz JM.

 

 

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