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:
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
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Maternal alpha-fetoprotein levels are abnormally low, probably due to abnormal fetal liver function.
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Ophthalmologic signs are possible. The most frequent ocular findings include
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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.
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