Cornelia de Lange syndrome is a rare developmental malformation syndrome characterized by learning disability, short stature, limb abnormalities, and distinctive craniofacial features. Diagnosis is made clinically and relies on medical history and examination. The disorder is genetically heterogeneous with three different causative genes identified; NIPBL, SMC1A and SMC3. Mutations in one of these genes (most commonly NIPBL) can be detected in about half of cases with a definite clinical diagnosis. Within Cornelia de Lange syndrome there is a wide spectrum of severity. At the most severe end are severely growth retarded infants with congenital diaphragmatic hernia and/or severe limb reduction defects and global cognitive impairment with little or no speech. Mildly affected individuals may have no major malformations and close to normal intelligence, and are able to live independently and reproduce.
The eponymous title of this chapter was chosen because it is used by the family support organizations in the UK and North America. It honors the Dutch pediatrician Cornelia de Lange, who described 2 children whom she believed had a new and distinct pattern of malformations (de Lange, 1933 Refs). She later described another similar case and post-mortem results of one of the two original cases (de Lange, 1938 Refs). The syndrome is also called Brachmann-de Lange syndrome in recognition of a German doctor who described an earlier case (Brachmann, 1916 Refs). Recently, an even earlier case has come to light, described by Vrolik, a Dutch anatomist working in Amsterdam in the late nineteenth century (Oostra et al., 1994 Refs). The first cases appeared in the English literature in 1963, and there are now many hundreds of reported cases (PTACEK et al., 1963 Refs). The terms Amsterdam dwarfism and Typus Degenerativus Amstelodamenis have been used historically but have been discarded for obvious reasons.
The published estimates of incidence for Cornelia de Lange syndrome vary from 1 in 10,000 to 1 in 200,000 live births (Barisic et al., 2008; Beck, 1976; Opitz, 1985 Refs). A complete ascertainment of all known cases of Cornelia de Lange syndrome in Denmark over a five year period demonstrated an incidence of 1 in 50,000 (Beck and Fenger, 1985 Refs); from the European Surveillance of Congenital Anomalies database, a prevalence of the more severe cases was found to be 1 in 81,000 births (Barisic et al., 2008 Refs). An unpublished study of the entire phenotypic spectrum in the north of England found an incidence of Cornelia de Lange syndrome of 1 in 37,000 (Dr. M. Ireland, personal communication). It is suspected that there are many mildly affected individuals who remain undiagnosed.
Diagnosis is made on a clinical basis, although a pathogenic mutation in one of the three known associated genes provides useful confirmation of the clinical diagnosis. The facial gestalt is the most widely accepted criterion for the diagnosis of Cornelia de Lange syndrome (Figure -.1). The facial features are so striking that they usually override the features that are commonly associated with the genetic and ethnic background of the individual. Affected individuals have microbrachycephaly with a short neck and a low anterior and posterior hairline. The eyebrows are neat and arched with synophrys; bushy eyebrows are not characteristic. The eyes are usually normally set but occasionally can be down-slanting. The eyelashes are often long, lush and curled. Ptosis of the upper eyelids is common and results in a compensatory backward tilt of the head in many cases. The ears may be normally set or posteriorly angulated and low set. The ears may have a thickened helix and appear large in relation to the face. At birth the nasal bridge is usually broad and depressed and the nares anteverted. With increasing age the nasal bridge becomes more prominent and the nares less anteverted. The philtrum is usually long, smooth and prominent. The lips are usually thin with a small central cupid's bow on the upper lip. The mouth is small and crescent-shaped with the outer corners turned down. The mandible is usually smaller than expected for the size of the face and some individuals can have severe micrognathia. The palate is often high-arched and, in a significant minority of cases, cleft or incompletely fused. Teeth may be widely spaced or absent. The supraorbital ridges and zygomatic arches are poorly developed.
Growth, development and behavior are major criteria for diagnosis. Typically all growth parameters are below the fifth percentile for age with the head circumference being below the second percentile for age, although there are individuals whose parameters fall within the normal range. Global developmental delays or mental handicap are common, but there are individuals who have intelligence in the normal range but this is associated with specific learning difficulties. Behavioral probelms are highly characteristic and can range from severe self-injurious behaviour, aggression and autistic-like features to extreme shyness and obsessive-compulsive tendencies.
The characteristic pattern of malformation and/or dysmorphism of the distal upper limbs is also very helpful in the diagnosis. The hands and feet are relatively small, proximally placed thumbs, single palmar crease and brachyclinodactyly. On radiological examination a short first metacarpal with relatively long third and fourth metacarpals in the presence of rounding and subluxation of the radial head is a useful diagnostic finding (Peeters, 1975 Refs). A discriminative score based on the metacarpophalangeal profile have been devised (Halal and Preus, 1979 Refs). Phocomelia and oligodactyly are less commonly seen but very characteristic when present. Limited extension of the elbows, pectus excavatum, hip dislocation, and partial syndactyly of toes 2 and 3 are other common musculoskeletal features. Bunion, scoliosis or hip dysplasia may develop.
The neurosensory system and other major body systems are helpful minor diagnostic criteria. Eye findings, hearing loss, seizures, generalized hypertrichosis and cutis marmarata are included in the neurosensory system findings. The presence of gastrointestinal malformation, diaphragmatic hernia, cleft palate and genitourinary anomalies, as well as the highly prevalent gastroesophageal reflux are included in the other systems. Without positive molecular testing, facial features plus two major system criteria, or one major and two or more minor body system criteria, are enough to make the diagnosis. Molecular testing tends to be reserved for diagnostic dilemmas or if relevant for prenatal diagnostic or other familial purposes.
A recent publication (Kline et al., 2007b Refs) describes a consensus of diagnostic criteria that is summarized in Table 1 as a checklist. Several other authors have considered minimal diagnostic criteria for Cornelia de Lange syndrome. Preus and Rex (Preus and Rex, 1983 Refs) sought to define the syndrome more accurately using numerical taxonomy. They evaluated 207 different clinical characteristics in 48 individuals who had been referred with a possible diagnosis of Cornelia de Lange syndrome using cluster analysis to identify 30 discriminative characteristics. Ireland and colleagues considered four craniofacial features to be most specific to the syndrome: the characteristic eyebrows, the long, smooth philtrum, thin lips, and crescent-shaped mouth. Those features that were felt to be nonspecific were hypertrichosis, synophrys, and bushy eyebrows. Jackson et al. (Jackson et al., 1993 Refs) stated that the facial features and limb anomalies, particularly small hands and feet, were most useful for accurate diagnosis, although no diagnostic criteria suffice for certainty of diagnosis.
Pathogenic mutations have been identified in three genes in Cornelia de Lange syndrome; NIPBL (5p13.2), SMC1A (Xp11.22) and SMC3 (10q25). The proteins encoded by these genes strongly implicate dysfunction of the cohesin complex as the molecular basis of Cornelia de Lange syndrome. The cohesin complex was identified and characterised through the genetic and biochemical analysis of mutations affecting chromosome segregation in yeast. In Saccharomyces cerevisiae the cohesin complex exists as a heterotetrameric ring structure consisting of Smc1 (human ortholog: SMC1A), Smc3 (SMC3), Scc1 (RAD21) and Scc3 (STAG1/2/3). NIPBL is the human ortholog of yeast Scc2 which is part of a complex that load cohesin onto metaphase chromosomes. In higher eukaryotes cohesin has multiple functions in addition to chromosome cohesion, including regulation of gene expression, and DNA repair (Deardorff et al., 2007; Krantz et al., 2004; Misulovin et al., 2008; Strachan, 2005; Tonkin et al., 2004 Refs).
40-50% of Cornelia de Lange syndrome cases have mutations in NIPBL. This is a large gene with 46 coding exons and no specific hotspots for mutations have been identified. Most NIPBL mutations are de novo, heterozygous and loss-of-function mutations caused by frameshift, truncating or splice site changes in the open reading frame. Missense mutations in NIPBL tend to cause a less severe phenotype than (Bhuiyan et al., 2006; Gillis et al., 2004; Selicorni et al., 2007 Refs). Although the majority of NIPBL mutations are de novo, familial cases are described and in these families the condition is inherited in an autosomal dominant fashion. Parental gonosomal mosaicism has been documented in NIPBL mutations. It is likely that parental mosaicism may explain a proportion of the 1.5% empiric sibling recurrence risk that was calculated for counselling parents with no evidence of Cornelia de Lange syndrome themselves.
The genes SMC1A and SMC3, both encode proteins that are subunits of the cohesin complex. ~5% of patients with Cornelia de Lange syndrome have mutations in SMC1A. SMC1A mutations positive cases tend to normal somatic growth, normal hands, fairly atypical facial features and some degree of cognitive impairment (Borck et al., 2007; Deardorff et al., 2007; Musio et al., 2006 Refs). Identification of a SMC1A mutation has significant implications for the family as this is an X-linked disorder Only one patient with a mutation in SMC3 has been reported(Deardorff et al., 2007 Refs) with atypical facial features and a mild phenotype. It is clear that other loci for Cornelia de Lange syndrome remain to be found since over 40% of affected individuals do not have a detectable mutation. Linkage analysis has given suggestive peaks on chromosomes 2 (D2S125, 260cM), 5 (D5S426, 52cM, probably NIPBL), 10 (D10S1643, 40cM) and 14 (D14S74, 87cM).
Molecular testing is available in both North America and Europe, and, if positive, is diagnostic. The clinical diagnosis rests on recognition of the characteristic pattern of delayed growth and development, associated abnormalities of limb development and, in particular, the craniofacial features. However, individuals with atypical features are not uncommon and an objective test can be helpful if positive. This is particularly true with regard to prenatal diagnosis, which currently relies on detailed ultrasonography looking for structural abnormalities such as a cystic hygroma, limb reduction defect, diaphragmatic hernia, heart abnormality, or the characteristic facial profile. The facial profile consists of severe micrognathia with a long, bulging philtrum and small nose and is well illustrated in a publication that shows scan pictures of the fetal face at 33 weeks of gestation
In 1983 Westergaard and colleagues (Westergaard et al., 1983 Refs) reported the total absence of pregnancy associated plasma protein-A (PAPP-A) in serial serum samples from a pregnant women who later gave birth to a child with Cornelia de Lange syndrome. Aitken et al. (Aitken et al., 1999 Refs) confirmed a reduction in PAPP-A and produced a table of likelihood ratios based on retrospective analysis of 19 second-trimester maternal serum samples. PAPP-A testing is no longer offered in the second trimester, although levels from the first trimster may prove to be a valuable additional marker for "high-risk" pregnancies. Detailed ultrasonography remains the most appropriate basis for prediction of affected status during fetal life (Kliewer et al., 1993 Refs) if molecular diagnosis is unavailable.
The most important differential diagnosis is a chromosome disorder and, in particular, a relatively consistent syndrome associated with partial duplication of the long arm of chromosome 3. This is characterized by learning disability and failure to thrive, although usually with normal birth weight and length (Tranebjaerg et al., 1987 Refs). Facially there is a resemblance to Cornelia de Lange syndrome in that hair extends over the forehead, the eyelashes may be prominent, the nasal bridge is depressed, and the nares are anteverted (Anneren and Gustavson, 1984; Fineman et al., 1978 Refs). The philtrum is usually long and prominent, although, unlike Cornelia de Lange syndrome, it continues to show a central philtral groove. Micrognathia is also common, but it is unusual for the lips to be thin or the mouth crescent shaped. The facial features that differentiate duplication 3q syndrome from Cornelia de Lange syndrome are a sloping forehead, bushy eyebrows, hypertelorism, upward slanting palpebral fissures, epicanthal folds, a rather broad nose, maxillary prognathism, and relatively normal lips. Eye abnormalities including congenital cataract and glaucoma are common in duplication 3q syndrome and are only rarely seen in Cornelia de Lange syndrome (Fear and Briggs, 1979 Refs). Malformations common in duplication 3q syndrome include central nervous system, cardiac, and renal abnormalities, cleft palate, and genital hypoplasia. Craniosynostosis, camptodactyly, and talipes are the most commonly associated skeletal abnormalities. Occasionally, polydactyly of the hands or syndactyly of the toes is seen. Rhizomelic shortening of the limbs has been described in a number of cases. Chromosomal analysis of the affected child will confirm the diagnosis.
The most severe cases of Cornelia de Lange syndrome share features with Fryns syndrome, an autosomal recessive disorder characterized by a coarse face, diaphragmatic hernia (85%), cleft palate (30%), and distal limb hypoplasia (75%) (Fryns et al., 1979 Refs). Hypertrichosis, narrow palpebral fissures, flat nasal bridge, upturned nose, micrognathia, cardiac, renal, and genital abnormalities are common in both conditions. Fryns syndrome is distinguished by a short upper lip and macrostomia. In addition, polyhydramnios and premature labor are common in Fryns syndrome and birth weight, length, and head circumference are usually normal for gestation.
Fetal alcohol syndrome (see Chapter -) is characterized by intrauterine growth retardation, failure to thrive, and mild to severe developmental abnormalities. Craniofacial features overlap with those seen in Cornelia de Lange syndrome, especially microcephaly, short palpebral fissures, a short, upturned nose, a smooth underdeveloped philtrum, and a thin upper lip (Clarren and Smith, 1978 Refs). Cardiac defects similar to those seen in Cornelia de Lange syndrome are also well recognized in fetal alcohol syndrome, but the hands and feet are not small, although small distal phalanges are common. Speech is affected much more in Cornelia de Lange syndrome than in fetal alcohol syndrome, and children with the latter are only likely to be confused with milder Cornelia de Lange syndrome.
Family history, details of the pregnancy, and birth weight aid in making the diagnosis of Cornelia de Lange syndrome. Chromosomal analysis, ophthalmologic assessment, and assessment of facial and extremity anomalies by a physician experienced in dysmorphology will allow the discrimination of these entities from Cornelia de Lange syndrome.
Affected individuals have a prenatal onset growth failure manifest by a significantly low birth weight (mean approximately 2300g), short stature and poor growth velocity throughout childhood. Growth hormone therapy is not usually indicated. Kousseff et al. (Kousseff et al., 1993 Refs) found evidence of growth hormone deficiency in 4 of the 12 cases and end-organ resistance to growth hormone in one other individual. However, the authors concluded that the therapeutic use of human growth hormone was not warranted in Cornelia de Lange syndrome unless there was evidence of persistent hypoglycaemia.
Feeding difficulties are present from birth, and it is not uncommon for affected infants to require nasogastric tube feeding with subsequent insertion of a gastrostomy tube. The role of gastrostomy feeding in improving nutritional intake and growth in Cornelia de Lange syndrome has not been formally studied. However, there is a general clinical impression that affected children who are gastrostomy fed may have better growth velocity than those who are not. However, this effect is not marked as individuals with Cornelia de Lange syndrome seem to grow at their own rate regardless of additional caloric intake. Gastroesophageal reflux is common (see below), and contributes to feeding problems and failure to thrive. Lack of coordination of oral musculature, small mouth and jaw, poor bowel motility, and difficulty in chewing may also play a part (Kline et al., 1993 Refs).
Reported IQ's in Cornelia de Lange syndrome have ranged from 30 to 102, with the majority of individuals classified as having moderate to severe global learning disability (Kline et al., 1993 Refs).
Problems with communication and expressive language are of great concern to caregivers and health-care professionals. There are many reports in the literature of speech being absent in individuals with Cornelia de Lange syndrome. In a study of 116 affected individuals the indicators of poor prognosis for the development of speech included: birth weight less than 2.27 kg, moderate to severe hearing impairment, upper limb malformations, poor social interactions, and severe motor delay (Goodban, 1993 Refs) . Of those over the age of four years, 53% could construct sentences of two or more words, whereas 33% had up to two words. Four percent of individuals were thought to have language skills in the normal or low-normal range. Overall, the study found that expressive language was inferior to comprehension and that individuals with highly developed vocabularies often had poor syntactic skills. Individuals were usually quiet and rarely talked even if they had well-developed vocabularies. This suggested that speech and language skills may be underestimated in Cornelia de Lange syndrome. In a small study of nine individuals aged 5-30 years with relatively mild Cornelia de Lange syndrome, Harland and Bowden (Harland and Bowden, 1998 Refs) found no discrepancy between comprehension and expression. Syntactic skills were restricted and utterances telegraphic. Poor eye contact, restricted facial expression, and limited attempts at initiation of speech were also noted. Although no systematic study of the use of sign language in Cornelia de Lange syndrome is available, many parents report marked improvement in communication and behavior using this approach.
A low-pitched growling cry is characteristic of the syndrome in infancy (Fraser and Campbell, 1978 Refs).
Behavioral disturbance is common throughout life in Cornelia de Lange syndrome and is correlated closely with the presence of autistic spectrum disorder and the degree of mental retardation (Berney et al., 1999 Refs) . The autistic features include lack of social relatedness and impassivity, rejection of physical contact, rigidity, and inflexibility to change. A wide variety of abnormal behavior was reported in a study of 49 individuals with Cornelia de Lange syndrome including hyperactivity (40%), self-injury (44%), daily aggression (49%), and sleep disturbance (55%) . Attention deficit disorder has also been noted. In another study of 56 individuals with Cornelia de Lange syndrome, the variability of behavioral characteristics was found to correlate with clinical and functional aspects of the individuals, including age, cognitive level and clinical findings (Basile et al., 2007 Refs), as based on maternal questionnaires, with the behavioral characteristics including hyperactivity, attention disorder, anxiety, compulsive disorders, self-injurious behavior and autistic-like features. Another study described the range of self-injurious behavior seen in Cornelia de Lange syndrome and found a significant association between self-injury and self-restraint along with a higher incidence of compulsive behavior (Hyman et al., 2002 Refs) . Self-injury has also been associated with particular environmental events (Moss et al., 2005 Refs) and can be affected by environmental factors (Arron et al., 2006 Refs). Individuals with Cornelia de Lange syndrome exhibit socially motivated attention-soliciting behaviors, important in the consideration of behavioral management. In infancy, low frequency of eye contact was thought to be a risk factor based on video observations (Sarimski, 2007 Refs).
The prognosis for management of behavior problems is improved if an underlying medical problem, particularly gastroesophageal reflux, is recognized and treated. Difficulties in communication often exacerbate the situation (see above) and the early use of sign language can be helpful. In the absence of such underlying problems, however, behavior remains a difficult management issue for families and care providers. Furthermore, behavioral problems worsen during adolescence (Kline and Audette, 2002 Refs). With aging specific psychiatric diagnoses, include self-injury, anxiety, attention-deficit disorder, autistic features, depression, and obsessive-compulsive behavior can become apparent (Kline et al., 2007a Refs).
Some degree of hearing impairment is present in over 90% of individuals with Cornelia de Lange syndrome (Sataloff et al., 1990 Refs). This has now been shown to be sensorineural in origin and usually bilateral (Sakai et al., 2002; Sataloff et al., 1990 Refs), although conductive hearing loss due to middle ear effusion alone or in combination with sensorineural deficit has also been reported (Marchisio et al., 2008 Refs). Early diagnosis with use of hearing aids should improve compliance and optimize development of language (Sakai et al., 2002 Refs). Otitis media and chronic middle ear disease with conductive deafness are common and can be difficult to diagnose because of the narrow external auditory canals found in many individuals with Cornelia de Lange syndrome. Middle ear disease is less of a problem later in childhood and in adulthood, although chronic sinusitis is noted in 39% of older individuals, and nasal polyps may be seen (Kline et al., 2007a Refs).
Cleft palate occurs in 20% of individuals with Cornelia de Lange syndrome. Cleft lip does not occur, or is unrelated. Submucous cleft palate also occurs and may be under-reported (Yamamoto et al., 1987 Refs); in a study of 49 patients, submucous cleft palate was found in 14%, most undetected before evaluation in that study (Kline et al., 2007a Refs). In a study of nine people with of Cornelia de Lange syndrome, five had hypernasality with nasal escape, one had a submucous cleft palate, and the other 8 had an unusual midline ridge of the soft palate (Harland and Bowden, 1998 Refs). The prognosis for those with cleft palate is usually good, although affected individuals are less likely to develop speech than those with a normal palate. Micrognathia, microstomia and dental crowding are very commonly associated, as are small or absent teeth. There is poor oral hygiene and dental caries may be problematic (Kline et al., 2007a Refs). With aging, periodontal disease may occur.
A wide spectrum of limb abnormalities is seen in Cornelia de Lange syndrome. The most commonly observed pattern includes small hands with short digits, proximally placed thumbs, single palmar creases, and clinodactyly of the fifth fingers (Barr et al., 1971 Refs). A characteristic pattern is observed on the metacarpophalangeal index and has been detailed in the section on Diagnostic Criteria above. Dermatoglyphic abnormalities are common with an increased frequency of radial loops and arches and a decrease in the number of whorls. The total finger ridge count is low, and interdigital triradii are also common (Abraham and Russell, 1968; Filippi, 1989 Refs).
Severe reduction deformities with missing hands and forearms occur in 14-27% of individuals (Berg et al., 1970 Refs). Even with severe limb reduction defects many individuals have remarkably good fine motor skills. Flexion contractures of the elbows are common and are secondary to deformation of the proximal metaphysis of the radius, which is usually subluxed. Syndactyly, polydactyly and duplication of the nail bed have been reported in Cornelia de Lange syndrome but are rare malformations (Beck and Fenger, 1985 Refs). Rare upper limb anomalies have included absent hand and ulnar hemimelia (Roposch et al., 2004 Refs). It is interesting that the vast majority of severe reduction defects involve the upper limbs only. A few major lower limb defects have been reported, including absent toes with clefting of the foot, talipes equinovarus, absence of the tibia, bowed fibula, hallux valgus and bifid femur (Grant et al., 1997 Refs). Scoliosis, leg length discrepancy and Legg-Calve-Perthes disease may be acquired (Kline et al., 2007a; Roposch et al., 2004 Refs). Decreased bone density has been seen with aging.
Gastroesophageal reflux disease is by far the most common gastrointestinal problem in Cornelia de Lange syndrome (Bull et al., 1993; Cates et al., 1989; Rosenbach et al., 1992 Refs). Untreated, it can lead to significant morbidity and mortality. The acquisition of esophageal stenosis and other sequelae of gastroesophageal reflux disease is common. Barrett esophagus has been reported in 10% of an aging population (Kline et al., 2007a Refs), and the development of adenocarcinoma of the esophagus has been documented (DuVall and Walden, 1996 Refs). Gastroesophageal reflux can present with failure to thrive, reduced growth velocity, anemia, recurrent pneumonia, apnea, or behavioral disturbance, including hyperactivity (Luzzani et al., 2003 Refs). Gastroesophageal reflux may worsen during puberty (Kline and Audette, 2002 Refs), may present at any age and symptoms may wax and wane. A high index of suspicion is essential. Stories of the dramatic improvement in behavior and development are common in successfully treated individuals.
Malformations of the gastrointestinal tract presenting shortly after birth include pyloric stenosis in approximately 1% of affected individuals and, very rarely, an annular pancreas causing duodenal obstruction. Uncommonly, abnormalities of mesenteric insertion and failure of normal rotation of the bowel during embryonic development can lead to malrotation and has resulted in life-threatening volvulus with ischemia and infarction of the bowel (Husain et al., 1994; Masumoto et al., 2001 Refs). Signs including severe abdominal pain, bilious vomiting and hard abdomen on palpation should be treated emergently. Cecal volvulus may also occur. Several cases of diaphragmatic hernia have been seen, with high mortality rates. Rumination and chronic constipation are reported with aging (Kline et al., 2007a Refs).
Congenital heart defects are present in up to 14% of individuals with Cornelia de Lange syndrome (Beck and Fenger, 1985; Jackson et al., 1993; Rao and Sissman, 1971; Tsukahara et al., 1998 Refs). The most common abnormality is ventricular septal defect, followed by atrial septal defect and stenosis of the pulmonary valve, either alone or in combination with a ventricular septal defect. A wide range of other cardiac defects has also been reported, including tetralogy of Fallot, coarctation of the aorta, hypoplastic left heart, single ventricle, and atrioventricular canal defect. Mild pulmonary branch stenosis is seen in 2% of more mildly affected individuals, but rarely requires treatment (Ireland, 1996 Refs). The most severe cardiac defects are often seen in infants with diaphragmatic hernia and limb reduction defects.
It should be noted that perioral blueness is very common in Cornelia de Lange syndrome and may not, in itself, require further investigation. The prognosis for those with Cornelia de Lange syndrome and congenital heart defects is related to the severity of the malformation and the degree to which surgical intervention can correct or palliate the hemodynamic status.
Ptosis, recurrent blepharitis and myopia are common in Cornelia de Lange syndrome (Levin et al., 1990; Wygnanski-Jaffe et al., 2005 Refs). Ptosis surgery may assist in motor development. The severity of ptosis has been correlated with specific mutations in NIPBL (Nallasamy et al., 2006 Refs). Baby shampoo eyelash scrubs may be helpful in relieving recurrent blepharitis and red eye discharge although some children may require nasolacrimal duct probing for obstruction. Nystagmus, mild microcornea, and/or strabismus can occur. Cataract and glaucoma have been reported rarely and may represent chance occurrences or the result of self-injury. Children with severe myopia may be at higher risk for retinal detachment. Optic nerve pallor is uncommon although a visually insignificant pigmented ring around the optic nerve is almost universal (Levin et al., 1990; Wygnanski-Jaffe et al., 2005 Refs).
Structural anomalies of the kidney and genitourinary tract have been detected in 41% of individuals (Selicorni et al., 2005 Refs). The most common abnormality of the renal tract seen in Cornelia de Lange syndrome is a horseshoe kidney (Wick et al., 1982 Refs) . Vesiculoureteric reflux has been noted in up to 12% of children (Jackson et al., 1993 Refs). Cryptorchidism is an extremely common finding in males with Cornelia de Lange syndrome and may occur in association with hypospadias, micropenis, and a hypoplastic scrotum (Van Allen et al., 1993 Refs).
During early childhood the umbilicus and nipples are hypoplastic. Puberty may be slightly delayed in both sexes and can be incomplete. Secondary sexual development is often normal although primary amenorrhoea is seen in up to 25% of females (Kline and Audette, 2002; Kline et al., 2007a; Van Allen et al., 1993 Refs). Most females have normal gynaecologic exams and pap smears. Individuals with milder forms of the syndrome should be presumed to be fertile (Russell et al., 2001 Refs).
Hypertonicity and hyperreflexia are common. Many caregivers report a high threshold for pain in affected individuals (Kline et al., 2001 Refs). Unusual hand posturing at eye level is very common. Seizures occur in 23%, and tend to be easily managed medically (Kline et al., 2007b Refs); they may be under-recognized, and non-convulsive seizure activity has been observed (Calderon-Gonzalez et al., 1966; Nechay et al., 2006 Refs). Sleep disturbance has been reported (Berney et al., 1999 Refs). Radiologic brain findings may include: enlarged ventricles, including enlargement of basal cisterns, thinning or atrophy of white matter particularly frontal lobes, with relative sparing of parietal lobes, brainstem hypoplasia, and cerebellar vermal hypoplasia or agenesis (Kline et al., 2007b Refs). Neuropathological examination has been reported in a few cases (Barr et al., 1971; Vuilleumier et al., 2002; Yamaguchi and Ishitobi, 1999 Refs)_. Commonly reported features are microcephaly with hypoplasia and poor myelination of the pyramidal tracts. Several reports suggest a neuronal migration defect may be present with mild abnormalities of the gyri.
Anemia is not uncommon in Cornelia de Lange syndrome and may be an indicator of chronic gastroesophageal reflux (Fryns and Vinken, 1994 Refs) reported two individuals with pancytopenia associated with severe, symptomatic thrombocytopenia.
Cutis marmorata and generalized hypertrichosis are very common features of Cornelia de Lange syndrome and do not merit further investigation (Vissian and Rovinski, 1978 Refs). Medical professionals should be aware that plucking or waxing of both synophrys and body hair is now commonly used by caregivers and affected individuals. Premature gray hair is frequently seen with aging (Kline et al., 2007a Refs). Cutis verticis gyrata has been reported in two older male patients.
We are grateful to the families and individuals with Cornelia de Lange syndrome whom we have encountered, and to the support organizations for their tireless and critical help. DRF would like to express particular thanks to Professor Chris Oliver, Dr Peter Gillett, Dr Penny Fallon, Professor Raoul Hennekam, Dr Angelo Selicorni and Professor Peter Hammond for very valuable advice, discussion and support and Alan Peaford for his flawless and tireless leadership of the Cornelia de Lange Syndrome Foundation of UK and Ireland. We are also grateful to Dr. Maggie Ireland who wrote the first edition of this chapter for her kind gift of a comprehensive literature collection related to Cornelia de Lange syndrome.
Abraham, J. M., and Russell, A. (1968). De lange syndrome. A study of nine examples. Acta Paediatr Scand 57, 339-353.
Aitken, D. A., Ireland, M., Berry, E., Crossley, J. A., Macri, J. N., Burn, J., and Connor, J. M. (1999). Second-trimester pregnancy associated plasma protein-A levels are reduced in Cornelia de Lange syndrome pregnancies. Prenat Diagn 19, 706-710.
Anneren, G., and Gustavson, K. H. (1984). Partial trisomy 3q (3q25----qter) syndrome in two siblings. Acta Paediatr Scand 73, 281-284.
Arron, K., Oliver, C., Hall, S., Sloneem, J., Forman, D., and McClintock, K. (2006). Effects of social context on social interaction and self-injurious behavior in Cornelia de Lange syndrome. Am J Ment Retard 111, 184-192.
Barisic, I., Tokic, V., Loane, M., Bianchi, F., Calzolari, E., Garne, E., Wellesley, D., and Dolk, H. (2008). Descriptive epidemiology of Cornelia de Lange syndrome in Europe. Am J Med Genet A 146A, 51-59.
Barr, A. N., Grabow, J. D., Matthews, C. G., Grosse, F. R., Motl, M. L., and Opitz, J. M. (1971). Neurologic and psychometric findings in the Brachmann-De Lange syndrome. Neuropadiatrie 3, 46-66.
Basile, E., Villa, L., Selicorni, A., and Molteni, M. (2007). The behavioural phenotype of Cornelia de Lange Syndrome: a study of 56 individuals. J Intellect Disabil Res 51, 671-681.
Beck, B. (1976). Epidemiology of Cornelia de Lange's syndrome. Acta Paediatr Scand 65, 631-638.
Beck, B., and Fenger, K. (1985). Mortality, pathological findings and causes of death in the de Lange syndrome. Acta Paediatr Scand 74, 765-769.
Berg, J. M., McCrear, y. B. D., Ridler, M. A. C., and Smith, G. F. (1970). The De Lange Syndrome (Oxford: Pergamon Press).
Berney, T. P., Ireland, M., and Burn, J. (1999). Behavioural phenotype of Cornelia de Lange syndrome. Arch Dis Child 81, 333-336.
Bhuiyan, Z. A., Klein, M., Hammond, P., van Haeringen, A., Mannens, M. M., Van Berckelaer-Onnes, I., and Hennekam, R. C. (2006). Genotype-phenotype correlations of 39 patients with Cornelia De Lange syndrome: the Dutch experience. J Med Genet 43, 568-575.
Borck, G., Zarhrate, M., Bonnefont, J. P., Munnich, A., Cormier-Daire, V., and Colleaux, L. (2007). Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations. Hum Mutat 28, 205-206.
Brachmann, W. (1916). Ein Fall von symmetrischer Monodaktylie durch Ulnadefekt, mit symmetrischer Flughautbildung in den Ellenbeugen, sowie anderen Abnormitaten (Zwerghaftigkeit, Halsrippen, Behaarung). Jahr Kinderheilkunde 84, 225-235.
Bull, M. J., Fitzgerald, J. F., Heifetz, S. A., and Brei, T. J. (1993). Gastrointestinal abnormalities: a significant cause of feeding difficulties and failure to thrive in Brachmann-de Lange syndrome. Am J Med Genet 47, 1029-1034.
Calderon-Gonzalez, R., Hopkins, I., and McLean, W. T. J. (1966). Tap seizures. A form of sensory precipitation epilepsy. JAMA 198, 521-523.
Cates, M., Billmire, D. F., Bull, M. J., and Grosfeld, J. L. (1989). Gastroesophageal dysfunction in Cornelia de Lange syndrome. J Pediatr Surg 24, 248-250.
Clarren, S. K., and Smith, D. W. (1978). The fetal alcohol syndrome. N Engl J Med 298, 1063-1067.
de Lange, C. (1933). Sur Un Type Nouveau de Degeneration (Typus Amstelodamensis). Archives de Medecine des Enfants 36, 713-719.
de Lange, C. (1938). Novelle observation du "Typus Amstelodamensis" et examin anatomo-pathologique de ce type. Archives de Medecine des Enfants 41, 193-203.
Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., and Krantz, I. D. (2007). Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet 80, 485-494.
DuVall, G. A., and Walden, D. T. (1996). Adenocarcinoma of the esophagus complicating Cornelia de Lange syndrome. J Clin Gastroenterol 22, 131-133.
Fear, C., and Briggs, A. (1979). Familial partial trisomy of the long arm of chromosome 3 (3q). Arch Dis Child 54, 135-138.
Filippi, G. (1989). The de Lange syndrome. Report of 15 cases. Clin Genet 35, 343-363.
Fineman, R. M., Hecht, F., Ablow, R. C., Howard, R. O., and Breg, W. R. (1978). Chromosome 3 duplication q/deletion p syndrome. Pediatrics 61, 611-618.
Fraser, W. I., and Campbell, B. M. (1978). A study of six cases of de Lange Amsterdam dwarf syndrome, with special attention to voice, speech and language characteristics. Dev Med Child Neurol 20, 189-198.
Fryns, J. P., Moerman, F., Goddeeris, P., Bossuyt, C., and Van den Berghe, H. (1979). A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum Genet 50, 65-70.
Fryns, J. P., and Vinken, L. (1994). Thrombocytopenia in the Brachmann-de Lange syndrome. Am J Med Genet 49, 360.
Gillis, L. A., McCallum, J., Kaur, M., DeScipio, C., Yaeger, D., Mariani, A., Kline, A. D., Li, H. H., Devoto, M., Jackson, L. G., and Krantz, I. D. (2004). NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet 75, 610-623.
Goodban, M. T. (1993). Survey of speech and language skills with prognostic indicators in 116 patients with Cornelia de Lange syndrome. Am J Med Genet 47, 1059-1063.
Grant, R. E., Schneider, J. A., Ferguson, E. J., and Cummings, P. B. (1997). Total hip reconstruction in a woman with Cornelia de Lange syndrome: a case report. J Natl Med Assoc 89, 530-532.
Halal, F., and Preus, M. (1979). The hand profile on de Lange syndrome: diagnostic criteria. Am J Med Genet 3, 317-323.
Harland, K., and Bowden, M. (1998). Speech and language development in mild Cornelia de Lange Syndrome. R Coll Speech Lang Therapists Bull 555, 12-13.
Husain, K., Fitzgerald, P., and Lau, G. (1994). Cecal volvulus in the Cornelia de Lange syndrome. J Pediatr Surg 29, 1245-1247.
Hyman, P., Oliver, C., and Hall, S. (2002). Self-injurious behavior, self-restraint, and compulsive behaviors in Cornelia de Lange syndrome. Am J Ment Retard 107, 146-154.
Ireland, M. (1996). Cornelia de Lange Syndrome: Clinical features, common complications and long-term prognosis. Curr Pediatr 6, 69-73.
Jackson, L., Kline, A. D., Barr, M. A., and Koch, S. (1993). de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet 47, 940-946.
Kliewer, M. A., Kahler, S. G., Hertzberg, B. S., and Bowie, J. D. (1993). Fetal biometry in the Brachmann-de Lange syndrome. Am J Med Genet 47, 1035-1041.
Kline, A. D., and Audette, L. (2002). Puberty and adolescence in CdLS: a survey of 67 patients. Am J Hum Genet 71, 672.
Kline, A. D., Barr, M., and Jackson, L. G. (1993). Growth manifestations in the Brachmann-de Lange syndrome. Am J Med Genet 47, 1042-1049.
Kline, A. D., Grados, M., Sponseller, P., Levy, H. P., Blagowidow, N., Schoedel, C., Rampolla, J., Clemens, D. K., Krantz, I., Kimball, A., Pichard, C., and Tuchman, D. (2007a). Natural history of aging in Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet 145C, 248-260.
Kline, A. D., Krantz, I. D., Sommer, A., Kliewer, M., Jackson, L. G., FitzPatrick, D. R., Levin, A. V., and Selicorni, A. (2007b). Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance. Am J Med Genet A 143A, 1287-1296.
Kline, A. D., Stanley, C., Belevich, J., Brodsky, K., Barr, M., and Jackson, L. G. (1993). Developmental data on individuals with the Brachmann-de Lange syndrome. Am J Med Genet 47, 1053-1058.
Kline, A. D., Krantz, I. D., Goldstein, A., Koo, B., and Jackson, L. G. (2001). Cornelia de Lange syndrome: Evidence for a sensorineuropathy. Am J Hum Genet 69, 280.
Kousseff, B. G., Thomson-Meares, J., Newkirk, P., and Root, A. W. (1993). Physical growth in Brachmann-de Lange syndrome. Am J Med Genet 47, 1050-1052.
Krantz, I. D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L. A., Yaeger, D., Jukofsky, L., Wasserman, N., Bottani, A., Morris, C. A., Nowaczyk, M. J., Toriello, H., Bamshad, M. J., Carey, J. C., Rappaport, E., Kawauchi, S., Lander, A. D., Calof, A. L., Li, H. H., Devoto, M., and Jackson, L. G. (2004). Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet 36, 631-635.
Levin, A. V., Seidman, D. J., Nelson, L. B., and Jackson, L. G. (1990). Ophthalmologic findings in the Cornelia de Lange syndrome. J Pediatr Ophthalmol Strabismus 27, 94-102.
Luzzani, S., Macchini, F., Valade, A., Milani, D., and Selicorni, A. (2003). Gastroesophageal reflux and Cornelia de Lange syndrome: typical and atypical symptoms. Am J Med Genet A 119A, 283-287.
Marchisio, P., Selicorni, A., Pignataro, L., Milani, D., Baggi, E., Lambertini, L., Dusi, E., Villa, L., Capaccio, P., Cerutti, M., Esposito, S., and Principi, N. (2008). Otitis media with effusion and hearing loss in children with Cornelia de Lange syndrome. Am J Med Genet A 146A, 426-432.
Masumoto, K., Izaki, T., and Arima, T. (2001). Cornelia de Lange syndrome associated with cecal volvulus: report of a case. Acta Paediatr 90, 701-703.
Misulovin, Z., Schwartz, Y. B., Li, X. Y., Kahn, T. G., Gause, M., MacArthur, S., Fay, J. C., Eisen, M. B., Pirrotta, V., Biggin, M. D., and Dorsett, D. (2008). Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome. Chromosoma 117, 89-102.
Moss, J., Oliver, C., Hall, S., Arron, K., Sloneem, J., and Petty, J. (2005). The association between environmental events and self-injurious behaviour in Cornelia de Lange syndrome. J Intellect Disabil Res 49, 269-277.
Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., and Larizza, L. (2006). X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet 38, 528-530.
Nallasamy, S., Kherani, F., Yaeger, D., McCallum, J., Kaur, M., Devoto, M., Jackson, L. G., Krantz, I. D., and Young, T. L. (2006). Ophthalmologic findings in Cornelia de Lange syndrome: a genotype-phenotype correlation study. Arch Ophthalmol 124, 552-557.
Nechay, A., Smulska, N., and Chepiga, L. (2006). Anoxic-epileptic seizures in Cornelia de Lange syndrome: case report of epileptic seizures induced by obstructive apnea. Eur J Paediatr Neurol 10, 142-144.
Oostra, R. J., Baljet, B., and Hennekam, R. C. (1994). Brachmann-de Lange syndrome "avant la lettre". Am J Med Genet 52, 267-268.
Opitz, J. M. (1985). The Brachmann-de Lange syndrome. Am J Med Genet 22, 89-102.
Peeters, F. L. (1975). Radiological manifestations of the Cornelia de Lange syndrome. Pediatr Radiol 3, 41-46.
Preus, M., and Rex, A. P. (1983). Definition and diagnosis of the Brachmann-De Lange syndrome. Am J Med Genet 16, 301-312.
Ptacek, L. J., Opitz, J. M., Smith, D. W., Gerritsen, T., And Waisman, H. A. (1963). The Cornelia de Lange Syndrome. J Pediatr 63, 1000-1020.
Rao, P. S., and Sissman, N. J. (1971). Congenital heart disease in the de Lange syndrome. J Pediatr 79, 674-677.
Roposch, A., Bhaskar, A. R., Lee, F., Adedapo, S., Mousny, M., and Alman, B. A. (2004). Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients. J Pediatr Orthop B 13, 118-122.
Rosenbach, Y., Zahavi, I., and Dinari, G. (1992). Gastroesophageal dysfunction in Brachmann-de Lange syndrome. Am J Med Genet 42, 379-380.
Russell, K. L., Ming, J. E., Patel, K., Jukofsky, L., Magnusson, M., and Krantz, I. D. (2001). Dominant paternal transmission of Cornelia de Lange syndrome: a new case and review of 25 previously reported familial recurrences. Am J Med Genet 104, 267-276.
Sakai, Y., Watanabe, T., and Kaga, K. (2002). Auditory brainstem responses and usefulness of hearing aids in hearing impaired children with Cornelia de Lange syndrome. Int J Pediatr Otorhinolaryngol 66, 63-69.
Sarimski, K. (2007). Infant attentional behaviours as prognostic indicators in Cornelia-de-Lange syndrome. J Intellect Disabil Res 51, 697-701.
Sataloff, R. T., Spiegel, J. R., Hawkshaw, M., Epstein, J. M., and Jackson, L. (1990). Cornelia de Lange syndrome. Otolaryngologic manifestations. Arch Otolaryngol Head Neck Surg 116, 1044-1046.
Selicorni, A., Russo, S., Gervasini, C., Castronovo, P., Milani, D., Cavalleri, F., Bentivegna, A., Masciadri, M., Domi, A., Divizia, M. T., Sforzini, C., Tarantino, E., Memo, L., Scarano, G., and Larizza, L. (2007). Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation. Clin Genet 72, 98-108.
Selicorni, A., Sforzini, C., Milani, D., Cagnoli, G., Fossali, E., and Bianchetti, M. G. (2005). Anomalies of the kidney and urinary tract are common in de Lange syndrome. Am J Med Genet A 132, 395-397.
Strachan, T. (2005). Cornelia de Lange Syndrome and the link between chromosomal function, DNA repair and developmental gene regulation. Curr Opin Genet Dev 15, 258-264.
Tonkin, E. T., Wang, T. J., Lisgo, S., Bamshad, M. J., and Strachan, T. (2004). NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet 36, 636-641.
Tranebjaerg, L., Baekmark, U. B., Dyhr-Nielsen, M., and Kreiborg, S. (1987). Partial trisomy 3q syndrome inherited from familial t(3;9)(q26.1; p23). Clin Genet 32, 137-143.
Tsukahara, M., Okamoto, N., Ohashi, H., Kuwajima, K., Kondo, I., Sugie, H., Nagai, T., Naritomi, K., Hasegawa, T., Fukushima, Y., Masuno, M., and Kuroki, Y. (1998). Brachmann-de Lange syndrome and congenital heart disease. Am J Med Genet 75, 441-442.
Van Allen, M. I., Filippi, G., Siegel-Bartelt, J., Yong, S. L., McGillivray, B., Zuker, R. M., Smith, C. R., Magee, J. F., Ritchie, S., Toi, A., and et, a. (1993). Clinical variability within Brachmann-de Lange syndrome: a proposed classification system. Am J Med Genet 47, 947-958.
Vissian, L., and Rovinski, J. (1978). [Hypertrichosis in the malformative syndrome of Cornelia de Lange]. Ann Dermatol Venereol 105, 427-430.
Westergaard, J. G., Chemnitz, J., Teisner, B., Poulsen, H. K., Ipsen, L., Beck, B., and Grudzinskas, J. G. (1983). Pregnancy-associated plasma protein A: a possible marker in the classification and prenatal diagnosis of Cornelia de Lange syndrome. Prenat Diagn 3, 225-232.
Wick, M. R., Simmons, P. S., Ludwig, J., and Kleinberg, F. (1982). Duodenal obstruction, annular pancreas, and horseshoe kidney in an infant with Cornelia de Lange syndrome. Minn Med 65, 539-541.
Wygnanski-Jaffe, T., Shin, J., Perruzza, E., Abdolell, M., Jackson, L. G., and Levin, A. V. (2005). Ophthalmologic findings in the Cornelia de Lange Syndrome. J AAPOS 9, 407-415.