DiagnosisClinical DiagnosisDiagnosis of Cornelia de Lange syndrome (CdLS) is made on a clinical basis. The most important clinical signs of CdLS are the following [Kline et al 2007a]: Craniofacial appearance (>95%)Classic CdLS. The craniofacial features are easily recognized and are some of the most useful in diagnosis: (Figure 1)Microbrachycephaly (mean occipital frontal circumference [OFC] <2nd centile) Synophrys, arched eyebrows in 98% [Jackson et al 1993] Long, thick eyelashes Low-set posteriorly rotated and/or hirsute ears with thickened helices Depressed or broad nasal bridge, upturned nasal tip with anteverted nares, and prominence of the lateral aspects Long smooth philtrum, thin vermillion border of the upper lip with a midline "drip" appearance (lowering of the apical part of the upper lip at the base of the philtrum below the arc of the upper lip), downturned corners of the mouth High and arched palate with clefts in 30% [Sataloff et al 1990] Small widely-spaced teeth Micrognathia in 80% [Jackson et al 1993]; mandibular spurs in 42% [Braddock et al 1993] Short neckMild CdLS. A milder phenotype that retains many of the characteristic facial features but with less severe cognitive and limb involvement has been consistently described and is more typical of individuals with mutations in SMC1A and SMC3 [Deardorff et al 2007, Selicorni et al 2007, Rohatgi et al 2010]. Diagnostic criteria for milder cases have been proposed [Ireland et al 1993, Jackson et al 1993, Selicorni et al 1993, Van Allen et al 1993, Allanson et al 1997]. (Figure 2)
Note: This milder phenotype, which is less striking clinically than the classic or severe form of CdLS, may represent the majority of individuals with CdLS [Greenberg & Robinson 1989, Jackson et al 1993, Moeschler & Graham 1993, Selicorni et al 1993, Van Allen et al 1993, Allanson et al 1997, Deardorff et al 2007, Rohatgi et al 2010].FigureFigure 1. Classic CdLS Craniofacial features FigureFigure 2. Patient with SMC1A mutation Growth failure (>95%). Growth failure occurs prenatally (although it may not be noted until the third trimester). Height and weight remain below the 5th centile throughout life [Bruner & Hsia 1990, Kliewer et al 1993, Kline et al 1993a, Kousseff et al 1993, Boog et al 1999]. CdLS-specific growth charts have been developed (www.cdlsusa.org). In addition, failure to thrive may be superimposed on the constitutional growth retardation secondary to gastroesophageal reflux and other issues with feeding. Intellectual disability (>95%)Classic CdLS. Severe-to-profound pervasive developmental delay Mild CdLS. Less affected individuals with higher functioning and higher IQs (some in the normal range) have been identified. The overall IQ in CdLS ranges from below 30 to 102, with an average IQ of 53 [Kline et al 1993b, Saal et al 1993]. Limb abnormalities (>95%). Upper extremities are primarily involved, with relative sparing of the lower extremities. Limb abnormalities may be symmetric or asymmetric.Classic CdLS. Upper extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) occur in approximately 30%. In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth finger clinodactyly occur in nearly all individuals. (Figure 3)
Radioulnar synostosis is common and may result in flexion contractures of the elbows.
The lower extremities are less involved than the upper extremities. The feet are often small and two-three syndactyly of the toes occurs in more than 80% of affected individuals [Jackson et al 1993].Mild CdLS. The radiographic finding of a short first metacarpal resulting in a proximally placed thumb can be useful in diagnosis.FigureFigure 3. Range of limb anomalies in CdLS Hirsutism (>80%). Thick scalp hair extends onto the temporal regions and at times involves the face, ears, back, and arms. Molecular Genetic TestingGene. NIPBL, SMC1A, and SMC3 are the only genes in which mutations are currently reported to be associated with CdLS [Krantz et al 2004, Tonkin et al 2004, Musio et al 2006, Deardorff et al 2007].Evidence for further locus heterogeneity. Lack of identified NIPBL mutations in 50% of individuals with CdLS suggested possible genetic heterogeneity [Borck et al 2004]. Note: Although earlier work based on chromosomal breakpoint analysis in individuals with CdLS-like disorders suggested 3q26 as a possible locus [Falek et al 1966, Ireland et al 1991, Ireland et al 1995], evidence in support of linkage to this region was not seen consistently in a study of ten familial cases of CdLS [Krantz et al 2001]. Further assessment of individuals with 3q26 duplications suggests that they have features that differ from typical CdLS. Table 1. Summary of Molecular Genetic Testing Used in Cornelia de Lange SyndromeView in own windowGene ^{1Proportion of CdLS Attributed to Mutations in This GeneTest MethodMutations Detected 2Test AvailabilityNIPBL~60% 3Sequence analysis / mutation scanningSequence variants 4Clinical Deletion / duplication analysis 5Partial or whole-gene deletions 6SMC1A~5% 7Sequence analysis / mutation scanningSequence variants 4Clinical Deletion / duplication analysis 5Exonic or whole-gene deletions / duplications 8 SMC3<1% 9Sequence analysis Sequence variants 4Clinical1. See Table A. Genes and Databases for chromosome locus and protein name.2. See Molecular Genetics for information on allelic variants. 3. In three studies of 179 individuals with CdLS, mutation scanning identified NIPBL frameshift, nonsense, splice-site, and missense mutations in approximately 60% of individuals [Borck et al 2004, Gillis et al 2004, Tonkin et al 2004, Bhuiyan et al 2006, Musio et al 2006, Yan et al 2006, Selicorni et al 2007]. 4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. About 1% of NIPBL-related CdLS [Bhuiyan et al 2007, unpublished observations].7. Sequence analysis identified a SMC1A mutation in approximately 5% of probands, particularly those with milder features [Musio et al 2006, Borck et al 2007, Deardorff et al 2007].8. None reported to date 9. Sequence analysis identified a SMC3 mutation in one proband with milder features [Deardorff et al 2007].Interpretation of test results Given the current 60% mutation detection rate of NIPBL mutations, failure to identify a mutation would not preclude the diagnosis of CdLS, particularly in a mild case, where mutation detection rates are closer to 30%. Testing StrategyTo confirm the diagnosis of CdLS in classic cases and to establish the diagnosis in an atypical case, molecular genetic testing of NIPBL:Perform sequence analysis or mutation scanning first. If no mutation is identified, perform deletion/duplication analysis. If no NIPBL mutation is identified and the patient has milder physical features of CdLS, consider SMC1A sequence analysis or mutation scanning.If no NIPBL or SMC1A mutation is identified and CdLS is highly suspected especially in a patient with milder features, consider SMC3 sequence analysis.When the diagnosis of CdLS is not clear or molecular genetic testing does not identify a mutation, consider cytogenetic testing or array-based testing (i.e., chromosome microarray analysis or array genomic hybridization) because a few individuals with deletions of 5p13 that include the NIPBL locus have been reported [Taylor & Josifek 1981, Hulinsky et al 2005, Hayashi et al 2007]. In addition, this testing may be helpful in evaluating for other possible etiologies, as the clinical findings in several chromosomal abnormalities overlap with those of CdLS [DeScipio et al 2005, Rohatgi et al 2010]. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in NIPBL, SMC1A, or SMC3.}

Natural HistoryAlthough CdLS was formally characterized over 70 years ago and well delineated clinically [Ptacek et al 1963, Motl & Opitz 1971, Jackson et al 1993], the natural history of CdLS has only been studied recently [Kline et al 2007a]. Life expectancy appears to be normal in affected individuals who do not have the complications described below. See Cause of death.The majority of familial cases suggest that expressivity is relatively consistent within a family.The medical issues faced by individuals with the mild and classic forms of CdLS are similar; however, the greater cognitive impairment in individuals with classic CdLS may make identification of medical complications more difficult. Classic Cornelia de Lange Syndrome Growth. Prenatal-onset growth failure occurs in most newborns with CdLS. Symmetric slow growth resulting in proportionate short stature becomes more significant by age six months. Mean height and weight are below the fifth centile throughout life [Bruner & Hsia 1990, Kliewer et al 1993, Kline et al 1993b, Kousseff et al 1993, Boog et al 1999]. Intellectual disability. Most individuals with classic CdLS have been reported to have severe-to-profound intellectual disability with IQs ranging from 30 to 86 (mean: 53). However, more recent reports of children with CdLS and adults with milder intellectual disability have suggested a broader range of intellectual abilities [Barr et al 1971, Kline et al 1993b, Moeschler & Graham 1993].Neuropsychiatric. Many individuals demonstrate autistic behavior, including self-destructive tendencies, and they may avoid or reject social interactions and physical contact. (See Autism Spectrum Disorders.)Behavior problems are often directly related to frustration from inability to communicate.Approximately 25% of children have had seizures. Some parents have described temperature intolerance and decreased pain sensation.Limb involvement. Severe abnormalities of the upper extremities are seen in 25% of individuals with CdLS.Gastrointestinal. Gastroesophageal reflux (GER) is almost universally a problem [Bull et al 1993, Sommer 1993, Kline et al 2007b]. Other complications of GER including esophagitis, aspiration, chemical pneumonitis, and irritability can be avoided by diagnosis and treatment of GER in the neonatal period (see Management). Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period and was identified in 4%.Other gastrointestinal abnormalities include intestinal malrotation (2%) and congenital diaphragmatic hernia (CDH) (1%). CDH has been diagnosed both pre- and postnatally [Fryns 1987, Cunniff et al 1993, Jelsema et al 1993, Pankau & Jänig 1993, Marino et al 2002], but may be underascertained, especially in infants who die in the perinatal period. Otolaryngologic. Sensorineural hearing loss is noted in 80% of children with CdLS, with 40% being profoundly affected [Sataloff et al 1990]. (See Deafness and Hereditary Hearing Loss Overview.)Ophthalmologic. As many as 50% of affected individuals demonstrate some degree of ptosis as well as other ocular problems including myopia (60%) and nystagmus (37%) [Levin et al 1990]. Other ophthalmologic abnormalities include glaucoma, nasolacrimal duct stenosis, microcornea, astigmatism, optic atrophy, coloboma of the optic nerve, strabismus, and proptosis [Nicholson & Goldberg 1966, Milot & Demay 1972, Folk et al 1981, Levin et al 1990].Genitourinary. Cryptorchidism occurs in 73% of males with CdLS and hypoplastic (small) genitalia occur in 57%. Renal abnormalities, primarily vesicoureteral reflux, have been reported in 12% [Jackson et al 1993]. Cardiovascular. Approximately 25% of individuals with CdLS have congenital heart disease [Jackson et al 1993, Mehta & Ambalavanan 1997, Tsukahara et al 1998]. The most common abnormalities include (in descending order): ventricular septal defects, atrial septal defects, pulmonic stenosis, tetralogy of Fallot, hypoplastic left heart syndrome, and bicuspid aortic valve.Other featuresA characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases [Jackson et al 1993]. Thrombocytopenia has been reported in a few children [Froster & Gortner 1993, Fryns & Vinken 1994], two of whom subsequently developed pancytopenia. Cutis marmorata is seen in 60%. Hypoplastic nipples and umbilicus are seen in 50%. Single palmar creases and abnormal dermatoglyphic patterns have been reported [Smith 1966, Opitz 1985]. Cause of death. Beck & Fenger [1985] looked at mortality in 48 individuals with CdLS born between 1917 and 1982 and found a modest increase in mortality over the general population when comparing cumulative survival rates; the increase is more significant among the younger age groups. They also reported two individuals who died at ages 54 and 61 years.Beck & Fenger [1985] and Jackson et al [1993] reported a total of 24 deaths from aspiration pneumonia (9), recurrent apnea (3), congenital heart disease (3), volvulus and intestinal obstruction (2), post-surgical complications (thrombocytopenia and intracranial bleeding) (1), and cerebral edema and herniation after spine surgery (1). Severe bronchopulmonary dysplasia, mediastinitis, uremia, bronchial asthma, coronary artery occlusion, and pulmonary embolus were other causes of death.

Genotype-Phenotype CorrelationsWhereas individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are likely to have a mutation in NIPBL, NIPBL mutations have been found in individuals with both mild and severe phenotypes. NIPBL mutations are evenly distributed throughout the coding sequence. Individuals with missense NIBPL mutations typically have milder disease. Individuals with a SMC1A or SMC3 mutation typically have fewer structural anomalies than those with NIPBL mutations; however, they have significant intellectual disability that can range from moderate to severe [Deardorff et al 2007]. Facial features include slightly flatter and broader eyebrows and a broader and longer nasal bridge than are seen in individuals with an NIPBL mutation [Rohatgi et al 2010].

Differential DiagnosisSeveral conditions demonstrate overlap of clinical features with CdLS:Partial duplication of 3q. Features in common with CdLS include developmental delay, failure to thrive, low anterior hairline, prominent eyelashes, depressed nasal bridge, anteverted nares, long prominent philtrum (retaining the central canal), micrognathia, rhizomelic shortening of the limbs, and genital hypoplasia. However, individuals with partial duplication of 3q usually have normal birth weight, bushy eyebrows, ocular hypertelorism, upward-slanting palpebral fissures, epicanthal folds, broad nose, and normal lips [Fineman et al 1978, Fear & Briggs 1979, Annerén & Gustavson 1984, Tranebjaerg et al 1987].Deletions of chromosome 2q31. Deletions in this region that encompass the HOXD cluster produce limb reduction defects similar to those seen in CdLS as well as genitourinary and developmental abnormalities [del Campo et al 1999]. Individuals with deletion of 2q31 do not have the characteristic facies of CdLS.Fryns syndrome is characterized by coarse facies, diaphragmatic hernia (85%), cleft palate (30%), and distal limb hypoplasia (75%) [Fryns et al 1979]. Hypertrichosis, narrow palpebral fissures, flat nasal bridge, upturned nose, micrognathia, and cardiac, renal, and genital abnormalities are common in both CdLS and Fryns syndrome. Individuals with Fryns syndrome have a short upper lip, macrostomia, prenatal polyhydramnios, premature birth, and normal birth weight. Inheritance of Fryns syndrome is autosomal recessive. See also Congenital Diaphragmatic Hernia Overview.Fetal alcohol syndrome (FAS). Features common to both FAS and CdLS include intrauterine growth retardation, failure to thrive, developmental abnormalities, microcephaly, facial hirsutism in the newborn, short palpebral fissures, short upturned nose, smooth underdeveloped philtrum, thin upper lip, and cardiac defects. However, the hands and feet in FAS are not small and speech is less affected than in CdLS. A history of alcohol use in the pregnancy is useful in discriminating FAS from CdLS. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required). Classic CdLSMild CdLS

ManagementEvaluations Following Initial DiagnosisThe following recommendations for evaluation of individuals diagnosed with Cornelia de Lange syndrome (CdLS) are based on recent guidelines [Kline et al 2007b (click for full text)] and the authors' experience:Gastrointestinal evaluation (including upper GI series, endoscopy, milk scan and/or pH probe) to evaluate for malrotation and gastrointestinal reflux which, if undiagnosed or undertreated, can lead to feeding intolerance, life-threatening recurrent aspiration, and volvulus Plotting growth parameters on CdLS-specific growth charts. See www.cdlsusa.org (girls; boys). Evaluation by a nutritionist if CdLS growth curves reveal failure to thrive Radiographs of the upper extremities to evaluate for radioulnar synostosis. Physical therapy must be performed with caution to avoid causing fractures if radioulnar synostosis is present. Multidisciplinary developmental evaluation to formulate education/therapeutic interventions with an emphasis on communication skills Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss Ophthalmologic evaluation, including assessment of visual acuity, dilated fundus examination, measurement of intraocular pressure, and evaluation of tear ducts for patency and function Echocardiogram to screen for cardiac defects. ASDs are common and may not be picked up by auscultation. Neurologic evaluation and EEG in all affected individuals Renal ultrasonography to evaluate for structural kidney anomalies; if indicated, a vesicoureterogram (VCUG) to evaluate for vesicoureteral refluxUrologic evaluation in males with hypospadias and/or cryptorchidism Complete blood count if signs of anemia, bruising, bleeding are presentComplete blood count and consideration of immunologic evaluation if recurrent infections are presentTreatment of ManifestationsThe following is appropriate:Aggressive management of gastroesophageal reflux with consideration of fundoplication if GER is severe Surgical correction of intestinal malrotation if present Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs if there is failure to thrive Surgical intervention of arms/hands if limb defects hinder utilization or mobility Ongoing physical, occupational, and speech therapies to optimize developmental outcomes; alternative communicative methods (e.g., sign language, picture exchange communication system [PECS]) to facilitate communication if verbal skills are inadequate to express wants and needs Standard treatment for hearing loss Aggressive treatment for nasolacrimal duct obstruction as massage therapy is often unsuccessful because of malformed ducts; standard treatment for refractive errors, strabismus, glaucoma, and ptosis Standard interventions for cardiac defects Appropriate treatment for seizures Antibiotic prophylaxis and follow-up for vesicoureteral reflux Orchiopexy if cryptorchidism is present Complete blood count if signs of anemia, bruising, bleeding are presentComplete blood count and consideration of immunologic evaluation if recurrent infections are presentPrevention of Secondary ComplicationsTo prevent secondary complications:Care during sedation and/or operative procedures in an institution with pediatric anesthesiologists experienced in the management of the small airways of children with CdLS During anesthesia, attention to the risk of malignant hyperthermia (see Malignant Hyperthermia Susceptibility), which has been reported in a few children with CdLS [Papadimos & Marco 2003] SurveillanceThe following are appropriate:Annual gastrointestinal evaluation including monitoring of growth Yearly evaluations by a developmental pediatrician to assess developmental progress and to target therapeutic interventions and educational modalities Regular follow-up of ophthalmologic and/or audiologic abnormalities Routine monitoring of existing cardiac or renal anomalies Agents/Circumstances to Avoid No known agents exacerbate the severity of CdLS; however, caution should be exercised to avoid exacerbation of existing comorbidities including gastroesophageal reflux, self-injurious behavior, pica, and less commonly, thrombocytopenia and immunologic features.Evaluation of Relatives at Risk See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Cornelia de Lange Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNIPBL5p13​.2Nipped-B-like proteinCatalogue of Somatic Mutations in Cancer (COSMIC)
NIPBL @ The Human Genetics Unit Edinburgh U.K.
NIPBL @ LOVDNIPBLSMC1AXp11​.22Structural maintenance of chromosomes protein 1ASMC1A @ The Human Genetics Unit Edinburgh U.K.
SMC1A @ LOVDSMC1ASMC310q25​.2Structural maintenance of chromosomes protein 3SMC3 @ LOVDSMC3RAD218q24​.11Double-strand-break repair protein rad21 homolog RAD21HDAC8Xq13​.1Histone deacetylase 8HDAC8 @ LOVDHDAC8Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Cornelia de Lange Syndrome (View All in OMIM) View in own window 122470CORNELIA DE LANGE SYNDROME 1; CDLS1 300040STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC1A 300269HISTONE DEACETYLASE 8; HDAC8 300590CORNELIA DE LANGE SYNDROME 2; CDLS2 300882CORNELIA DE LANGE SYNDROME 5; CDLS5 606062STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SMC3 606462RAD21, S. POMBE, HOMOLOG OF; RAD21 608667NIPPED-B-LIKE; NIPBL 610759CORNELIA DE LANGE SYNDROME 3; CDLS3 614701CORNELIA DE LANGE SYNDROME 4; CDLS4NIPBL Normal allelic variants. The NIPBL transcript spans approximately 9.5 kb and is composed of 47 exons (NM_133433.3). The gene was identified in 2004 by two independent groups [Tonkin et al 2004, Krantz et al 2004]. At least 43 allelic variants that do not appear to be pathogenic have been reported [Gillis et al 2004].Pathologic allelic variants. More than 80 causative mutations have been reported; they include missense (~20%), frameshift (~40%), nonsense (~20%), and splice-site mutations (~15%) [Borck et al 2004, Gillis et al 2004, Krantz et al 2004, Tonkin et al 2004, Bhuiyan et al 2006, Yan et al 2006, Selicorni et al 2007]. The majority of identified mutations have been private; however, mutations have been seen in several unrelated probands [Gillis et al 2004]. It has been suggested that milder forms of CdLS are more likely to be caused by missense mutations and more severe forms by truncating mutations [Gillis et al 2004]. (For more information, see Table A) Normal gene product. The NIPBL, or delangin or nipped-B-like, protein is composed of 2,804 amino acids and is a novel protein displaying homology to the Drosophila nipped-b and yeast sister chromatid cohesion protein 2 (scc2) [Krantz et al 2004, Tonkin et al 2004]. The normal functioning NIPBL protein appears to play a role in sister chromatid cohesion and in regulating long-range enhancer-promoter interactions, possibly through interactions with the cohesin complex reviewed in Dorsett [2004]. The reference sequence is NP_597677.2. Abnormal gene product. Mutations in NIPBL either lead to haploinsufficiency (frameshift, nonsense, and possibly splice-site mutations) or to altered proteins (missense mutations) whose function and viability is unknown at this time. Haploinsufficiency of the NIPBL protein results in CdLS as demonstrated by two reports of CdLS in infants with deletions of the entire gene [Taylor & Josifek 1981, Hulinsky et al 2005]. Alteration of NIPBL can have some effect on sister chromatid cohesion [Kaur et al 2005]; however, the manifestations of CdLS are more likely caused by disruption of long-range enhancer-promoter interactions with resultant dysregulation of multiple downstream genes. SMC1A Normal allelic variants. The SMC1A transcript spans approximately 9.7 kb and comprises 25 exons. Mutations in individuals with CdLS were identified in this gene in 2006 by Musio et al [2006]. A number of allelic variants have been reported in Deardorff et al [2007]. Pathologic allelic variants. To date, approximately 25 mutations in SMC1A have been reported (NM_006306.2). All of these mutations have resulted in the retention of an open reading frame; 23 were missense and two were in-frame deletions [Musio et al 2006, Borck et al 2007, Deardorff et al 2007, Liu et al 2009, Mannini et al 2010]. The phenotypes of the affected individuals reported in these studies indicate that mutations in SMC1A result in a milder form of CdLS, with no predominant structural anomalies of the limbs or viscera, but notable cognitive involvement of many of the patients. Normal gene product. The SMC1A protein is composed of 1233 amino acids and is the human homolog of the yeast Smc1 gene, a core component of the cohesin complex forming a heterodimer with Smc3. The cohesin complex plays a critical role in sister chromatid cohesion as well as a role in regulating gene expression by long-range enhancer-promoter interactions [Dorsett 2004]. SMC1A, although residing on chromosome Xp11.22, has been reported to escape X-chromosome inactivation [Brown et al 1995], which has important implications for phenotypic penetrance and genetic counseling. Abnormal gene product. The two mutations reported to date both result in an altered but presumably intact protein [Deardorff et al 2007, Revenkova et al 2009]. Since SMC1A is reported to escape X-chromosome inactivation [Brown et al 1995], it is presumed that the normal allele in females is somewhat protective. No mutations that completely disrupt the protein (e.g., nonsense, frameshift) have been reported, although complete lack of the SMC1A protein in males may be an embryonic lethal. However, data are insufficient to extrapolate any conclusions at this time. The phenotypic manifestations caused by mutations in SMC1A are likely the result of mechanisms similar to those seen with NIPBL: namely, alterations of gene expression [Dorsett et al 2005]. SMC3 Normal allelic variants. The SMC3 transcript spans approximately 4.1 kb and comprises 29 exons (NM_005445.3). Mutations resulting in CdLS were identified in this gene in 2007 by Deardorff et al [2007]. A number of allelic variants have been reported [Deardorff et al 2007].Pathologic allelic variants. To date, one mutation (a 3-bp deletion) has been reported in an individual with a mild variant form of CdLS. Findings included arched eyebrows, synophrys, and long eyelashes, thin lips, small hands and feet, proximally set thumbs, fifth finger clinodactyly, restriction of elbow movements, and hirsutism, in addition to high nasal bridge and high palate. He lacked brachycephaly, low anterior hairline, anteverted nostrils, long philtrum, downturned corners of the mouth, micrognathia, and hearing loss. He was employed in a supervised position. The authors noted that both SMC3 and SMC1A mutation-positive individuals exhibit very mild facial dysmorphism, no absence or reduction of limbs or digits, and no other major structural anomalies [Deardorff et al 2007].Normal gene product. The SMC3 protein comprises 1217 amino acids (NP_005436.1) and is the human homolog of the yeast Smc3 gene, a core component of the cohesin complex forming a heterodimer with Smc1.Abnormal gene product. The single report of a de novo 3-bp deletion in SMC3 in an affected individual was predicted to result in an altered, but presumably intact, protein that behaved similarly to the missense mutations noted in SMC1A [Deardorff et al 2007].