Cornelia de Lange syndrome (CdLS)

is a syndrome of multiple congenital anomalies characterized by a distinctive facial appearance, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor delay, behavioral problems, and associated malformations that mainly involve the upper extremities. Cornelia de Lange first described it [1] as a distinct syndrome in 1933, although Brachmann had described a child with similar [2] features in 1916. Diagnosing classic cases of Cornelia de Lange syndrome is usually straightforward; however, diagnosing mild cases may be challenging, even for an experienced clinician. Pathophysiology More than 99% of cases are sporadic. Cornelia de Lange syndrome is occasionally transmitted in an autosomal dominant pattern, according to several instances in which a usually mildly affected parent had one or more affected offspring. Twins with concordance and discordance have been reported. Although possible autosomal recessive inheritance has been reported in some families, these instances were likely to be due to germline [3] mosaicism. The recurrence risk is 0.5-1.5% if parents are unaffected and 50% if a parent is affected. Heterozygous mutations in a gene named NIPBL, the human homolog of [4] theDrosophila melanogaster Nipped-B gene, have been identified in approximately 50% of individuals [5, 6, 7] with Cornelia de Lange syndrome. Although the exact function of the protein product of NIPBL in humans (delangin) remains unknown, its homologs in other species are known to play roles in developmental regulation and in cohesion of sister chromatids. Mutations in genes, coding for two other proteins involved in cohesion of sister chromatids, SMC1A and SMC3, have been reported in 5% and 1% [8] of patients with Cornelia de Lange syndrome, respectively. Thus, Cornelia de Lange syndrome is considered to be a cohesinopathy, along with Roberts syndrome/SC phocomelia. Inheritance is autosomal dominant in families with NIPBL and SMC3 mutations and is X-linked dominant in families with SMC1A mutations. All types of NIPBL mutations, including missense, splice-site, nonsense, and frameshift mutations, have been reported to result in the Cornelia de Lange syndrome phenotype. The most likely effect of these mutations is haploinsufficiency. The mutation-detection rate is approximately 50%. Genomic deletions [9, 10] and duplications of the NIPBL locus are rare. Reported mutations ofSMC1A include missense mutations and in-frame deletions. One reported SMC3mutation is an in-frame deletion. The correlation between genotype and phenotype suggested that individuals with an identifiable mutation in NIPBL have a phenotype more severe than the phenotype of those without mutations. Moreover,

missense mutations in NIPBLare associated with mild phenotypic features. Patients with mutations in SMC1Aand SMC3 consistently have a milder phenotype, with absence of severe limb defects and other structural anomalies. The phenotype in some patients is close to those with nonsyndromic mental retardation. A phenotype similar to that of Cornelia de Lange syndrome may be observed in patients with a [11] duplication of band q26-27 on chromosome 3. Molecular studies of genes mapped to this region of chromosome arm 3q have failed to reveal mutations in patients with Cornelia de Lange syndrome. Some autopsy data have indicated cerebral dysgenesis, with a decreased number of neurons, neuronal heterotopias, and focal gyral folding abnormalities as causes of psychomotor delay. Epidemiology Frequency The incidence is 1 case per 10,000-50,000 live births. No differences based on sex or race have been described. Mortality/Morbidity Gastrointestinal disease complications are one of the most common causes of death in this syndrome. They include diaphragmatic hernia in infancy and aspiration pneumonia and volvulus at an older age. A retrospective review of 295 propositi with Cornelia de Lange syndrome found that respiratory issues (eg, aspiration, reflux, pneumonia) were the most common causes of death (31%), followed by gastrointestinal disease, including obstruction/volvulus (19%), congenital anomalies (15%), neurological causes, (8%), accidents (8%), sepsis (4%), acquired cardiac disease (3%), cancer (2%), renal disease [12] (1.7%), and other causes (9%). History The history of patients with Cornelia de Lange syndrome (CdLS) may include the following: Intrauterine growth retardation (68%) Average birth weight is 2221 g (4 lb 12 oz) for boys and 2145 g (4 lb 10 oz) for girls. In most patients, growth occurs at rates lower than those on normal growth curves throughout life. Height velocity is equal to the reference range, but pubertal growth is slowed. Weight velocity is lower than the reference range until late adolescence. Average head circumferences remain less than the second percentile. Prematurity (31%) Low-pitched weak cry in infancy - Noted in classic cases and disappears as the child grows (74%) Initial hypertonicity (100%) Respiratory and feeding difficulties in the newborn period and infancy (71%) o Respiratory and feeding difficulties usually result in failure to thrive. o Associated findings may include gastroesophageal reflux (90%), which affects many children with irreversible esophageal scarring by the time intervention is attempted; pyloric stenosis (3%); malrotation or duplication of the bowel with obstruction (10%); and congenital diaphragmatic hernia. Developmental delay and mental retardation o Most initial developmental skills are moderately delayed. o Severe speech delay is typical. Approximately one half of patients aged 4 years or older combine 2 or more words into sentences, one third have no words or only 1-2 words, and only 4% have normal or low-normal language skills. Children who have severe speech impairment are likely to have intrauterine growth retardation, hearing impairment, upper-limb malformations, poor social interactions, and severe motor delays. o o o o o

Most affected individuals have mild-to-moderate mental retardation (intelligence quotient [IQ] of 3085, with an average of 53). Patients with IQs higher than this tend to have a relatively high birth weight and head circumference. o Visual-spatial memory and perceptual organization skills are strengths. Perceptual organization, which involves the use of fine motor skills and which incorporates visual-spatial memory, is also on a higher level than that of other facets. o In patients with mild Cornelia de Lange syndrome, psychomotor retardation is less severe and prenatal and postnatal growth deficiency is milder than in severe Cornelia de Lange syndrome. In addition, major malformations are absent or surgically correctable. Children with mild disease may have classic facial findings at birth but develop intellectual outcomes better than those expected in classic Cornelia de Lange syndrome. As an alternative, their typical facial changes may develop during the first 2-4 years of life. Although individuals with mild Cornelia de Lange syndrome function at the low-normal range and although they have certain characteristics of the syndrome, their disease is occasionally not diagnosed until they have a child with classic findings. Seizures (23%) with no specific EEG pattern Behavioral manifestations o Hyperactivity (40%), self-injury (44%), daily aggression (49%), and sleep disturbance (55%) occur. o Behavioral manifestations are correlated with the presence of an autisticlike syndrome and with the degree of mental retardation. o Children with Cornelia de Lange syndrome prefer a structured routine and have difficulty with changes in their daily routine. Activities that stimulate the vestibular system, such as swinging, bouncing, swimming, and horseback riding, are pleasurable to patients with Cornelia de Lange syndrome, o Forms of self-injurious behavior in some children with CdLS are associated with certain environmental events. However, the characteristics of setting events are extremely variable among individuals. o The main characteristics in severely affected children include a diminished ability to relate socially, repetitive and stereotypic behavior, infrequent facial expression of emotion, and severe language delays. o Even in mild cases, behavioral phenotype may be helpful for diagnosis. Physical Physical findings in patients with Cornelia de Lange syndrome may include the following: Short stature: In some patients, extreme short stature may be caused by growth hormone deficiency. Specific growth curves in Cornelia de Lange syndrome are available. Average adult weight is 30.5 kg in females and 47.6 kg in males; average height is 131 cm in females and 156 cm in males. Microcephaly (98%): Average adult head circumference is 49 cm in both sexes. Facial features o These are perhaps the most diagnostic of all the physical signs and combine to create a unique gestalt for the clinician. This combination of findings may be absent in postpubertal male patients. o The following are classic features: Confluent eyebrows (synophrys) (99%) Long curly eyelashes (99%) Low anterior and posterior hairline (92%) Underdeveloped orbital arches (100%) Neat, well-defined, and arched eyebrows (as though they had been penciled) Long philtrum Anteverted nares (88%) Down-turned angles of the mouth (94%) Thin lip (especially upper vermillion border) Low-set and posteriorly rotated ears Depressed nasal bridge (83%) High arched palate (86%) and overt or submucous cleft palate (20%) Late eruption of widely spaced teeth (86%) Micrognathia (84%)

Short neck (66%) Hirsutism (78%) o Generalized hirsutism is observed most easily in dark-haired individuals. o Many infants lose their obvious excessive body hair later in life. Cutis marmorata and perioral cyanosis (56%) Hypoplastic nipples and umbilicus (50%) Micromelia (93%) o Severe abnormalities, such as oligodactyly (missing digits) or other deficiencies of the arms, may be present (27%). They usually occur in severely affected patients. o Less-striking limb findings include single palmar flexion crease, clinodactyly of the fifth fingers, proximally placed thumbs, partial syndactyly of the second and third toes, and limitation of elbow extension. o Relative smallness of the hands or feet is almost universal. Congenital heart disease (25%), typically ventricular septal defect or atrial septal defect: Any lesion may be seen. Hip abnormalities, including dislocation or dysplasia (10%), scoliosis, tight Achilles tendons and the development of bunions Hypoplastic external male genitalia (57%), small labia majora Undescended testes (73%) Hypospadias (33%) Ophthalmologic manifestations (50%) o Myopia (58%), ptosis (44%), blepharitis (25%), epiphora (22%), microcornea (21%), strabismus (16%), nystagmus (14%) occur. Peripapillary pigment ring was noted in most patients. o Glasses are often poorly tolerated. o Astigmatism, optic atrophy, coloboma of the optic nerve, aniridia, and congenital glaucoma have been described. Causes Heterozygous mutations in the NIPBL and SMC3 and heterozygous (in females) or hemizygous (in males) mutations in SMC1A result in Cornelia de Lange syndrome. Most cases are sporadic due to de novo mutations (see Pathophysiology). Genetic diagnosis: Molecular genetic diagnosis of Cornelia de Lange syndrome (CdLS) with screening of mutations in the NIPBL and SMC1A genes is clinically available. Updated laboratory information can be obtained at Gene Tests. This testing can confirm the diagnosis, especially in mild or atypical cases, and the results can help in identifying the family-specific mutation for prenatal testing in future pregnancies. Recently, a fetus with Cornelia de Lange syndrome was diagnosed after termination of pregnancy at 21 [13] weeks' gestation. The diagnosis was confirmed by a truncating mutation in the NIPBL gene. CBC count: Thrombocytopenia has been reported. Imaging Studies Radiography may reveal the following: Retarded bone age (100%) Spurs in the anterior angle of the mandible (42%) and a prominent symphysis (66%) Digital abnormalities, which range from acheiria to oligodactyly Long-bone abnormalities, including ulnar aplasia and/or hypoplasia, aplasia and/or hypoplasia of the radial head, or fusion of the elbow: When a single forearm bone is present, fusion at the elbow and oligodactyly often occur; this condition makes it difficult to determine if the radius or ulna is absent. Hypoplastic first metacarpal (79%), hypoplastic fifth middle phalanx (93%), and clinodactyly (64%) Short sternum with precocious fusion (54%) Thirteen ribs (56%) Thin rib cortices with undulating appearance (33%) Hiatal hernia Aspiration pneumonia (50%)

Gastroesophageal reflux (90%) Intestinal obstruction, malrotation, volvulus (17%) Pelvic abnormalities (33%) Ultrasonography at diagnosis to assess for kidney and urinary tract abnormalities (40%) may reveal the following: Horseshoe kidney Altered corticomedullary differentiation Pelvic dilation Small kidneys Renal cysts Renal ectopia Voiding cystourethrography is indicated for evaluation of recurrent urinary tract infections or hydronephrosis. Echocardiography is indicated for evaluation of congenital heart disease. 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. Other Tests High-resolution chromosomal studies are indicated when the diagnosis is uncertain. Hearing evaluation is recommended. More than 90% of individuals with Cornelia de Lange syndrome [14] have sensorineural hearing loss when properly evaluated. A spectrum of endocrinopathies may be observed in addition to growth-hormone deficiency. These conditions include problems in gonadotropin and prolactin secretion and panhypopituitarism. Staging Diagnosis requires (1) positive mutation finding on Cornelia de Lange syndrome gene testing; (2) confirmed facial findings and confirmed criteria from any 2 of the growth, developmental, or behavioral categories; or (3) confirmed facial findings and confirmed criteria for 3 other categories, including one [15] from growth, developmental, or behavioral categories and 2 from the other categories. Facial characteristics must include synophrys and at least 3 of the following: Long eyelashes Short nose, anteverted nares Long, prominent philtrum Broad or depressed nasal bridge Small or square chin Thin lips, down-turned corners High palate Widely spaced or absent teeth Growth characteristics must include at least 2 of the following: o Weight below the fifth percentile for age o Height or length below the fifth percentile for age o Occipitofrontal circumference below the second percentile for age Developmental characteristics must include at least 1 of the following: o Developmental delays or mental retardation o Learning disabilities Behavioral characteristics must include at least 2 of the following: o Attention deficit disorder, hyperactivity o Obsessivecompulsive characteristics o Anxiety o Constant roaming o Aggression o Self-injurious behavior o Extreme shyness or withdrawal o o o o o o o o

Autisticlike features Musculoskeletal characteristics include reduction defects with absent forearms alone, small hands or feet (below the third percentile for age) or oligodactyly and at least two of the following, or none of these features and at least three of the following: o Clinodactyly of the fifth finger o Abnormal palmar crease o Radial head dislocation, abnormal elbow extension o Short first metacarpal, proximally placed thumb o Bunion o Partial syndactyly toes o Scoliosis o Pectus excavatum o Hip dislocation or dysplasia Neurosensory and skin characteristics must include at least 3 of the following: o Ptosis o Tear duct malformation or blepharitis o Myopia o Major eye malformation or peripapillary pigmentation o Deafness or hearing loss o Seizures o Cutis marmorata o Hirsutism, generalized o Small nipples and/or umbilicus Other major system characteristics must include at least 3 of following: o GI malformation/malrotation o Diaphragmatic hernia o Gastroesophageal reflux disease o Cleft palate or submucous cleft palate o Congenital heart defect o Micropenis o Hypospadias o Cryptorchidism o Renal or urinary tract malformation [15] Table. Scoring System for Severity of Cornelia de Lange Syndrome (Open Table in a new window) Parameter Birth weight Sitting alone Walking alone Saying first word Upper limb malformation Number of other major malformations Hearing loss 1 point Above 2,500 g < 9 mo < 18 mo < 24 mo No defect 0-1 Absent 2 point 2,0002,500 g 920 mo 1842 months 2448 mo Partial defect (>2 digits) 2-3 ... 3 point Below 2,000 g >20 mo >42 mo >48 mo Severe defect (< 2 digits) >3 ...

A score of less than 15 points indicates mild involvement, a score of 15-22 points indicates moderate involvement, and a score of more than 22 points indicates severe involvement.

Medical Care Early intervention in patients with Cornelia de Lange syndrome (CdLS) is necessary for feeding problems, hearing and visual impairment, congenital heart disease, and urinary system abnormalities. Early intervention for psychomotor delay is also indicated. Computer programs that emphasize visual memory are more beneficial than standard methods of verbal instruction. Perceptual organizational tasks should be emphasized. Tactile stimulation during indirection helps the children remember and perform maximally. Fine motor activities, when physical impairments do not limit them, should be stressed in education, especially activities related to activities of daily living. Surgical Care Surgery may be necessary for the following conditions: Cleft palate Nasal polyps Gastroesophageal reflux disease Pyloric stenosis Intestinal malrotation/volvulus Undescended testis Lacrimal duct stenosis Hip dislocations Consultations Consultation with the following specialists may be indicated: Geneticist Cardiologist Gastroenterologist and nutritionist Nephrologist (if recurrent urinary tract infections, impaired renal functions or congenital abnormalities are present) Ophthalmologist Hearing specialist Neurologist