Portal de Periódicos da CAPES

Cornelia de Lange Syndrome

2015; Elsevier BV; Volume: 40; Issue: 12 Linguagem: Inglês

10.1016/j.jhsa.2015.07.023

1531-6564

Karen Cheung, Joseph Upton,

Cancer and Skin Lesions

Cornelia de Lange syndrome (Online Mendelian Inheritance in Man #122470) is characterized by ulnar dysplasia, facial hirsuitism with synophrys, and diminutive stature.1Kniffin C. Cornelia de Lange syndrome 1; CDLS1. OMIM. 2013. Available at: http://www.omim.org/entry/122470. Accessed May 11, 2015.Google Scholar Diagnosis can be made prenatally based on sonographic findings of growth retardation, limb defects, hirsuitism, and diaphragmatic hernia. Alternative terminology includes Brachmann-de Lange syndrome, de Lange syndrome, Amsterdam syndrome, Typus Degenerativus Amstelodamensis (new type of degeneration), and CDLS1. The syndrome's eponym is attributed to Cornelia de Lange, a pediatrician from Amsterdam who, in 1933, described 2 children with the condition. However, in 1916, Brachman first described a child at autopsy with similar but more severe features to this syndrome.2Rayan G.M. Upton III, J. Congenital Hand Anomalies and Associated Syndromes. Springer, Berlin2014: 155-158Google Scholar, 3Kline A.D. Krantz I.D. Sommer A. et al.Cornelia de Lange syndrome: Clinical review, diagnostic and scoring systems, and anticipatory guidance.Am J Med Genet A. 2007; 143A: 1287-1296Crossref PubMed Scopus (199) Google ScholarEtiologyIncidence of Cornelia de Lange syndrome has been estimated to range from 1 in 10,000 to 1 in 30,000 newborns. Most cases are sporadic, although some families demonstrate autosomal dominance. A heterozygous mutation in the NIPBL gene, which encodes for a component of the cohesion complex, on chromosome 5p13.1 is responsible in 50% to 60% of cases. Other identified gene mutations responsible for X-linked or milder variants of Cornelia de Lange syndrome include SMC1A, SMC3, RAD21, and HDAC8.1Kniffin C. Cornelia de Lange syndrome 1; CDLS1. OMIM. 2013. Available at: http://www.omim.org/entry/122470. Accessed May 11, 2015.Google ScholarClinical PhenotypesThis is a multisystem malformation syndrome, which has very broad phenotypic variation. The diagnosis of most children is usually obvious at birth, but owing to the wide clinical phenotypic variation, many milder forms of the syndromes often go unrecognized. The most characteristic features involve the hands and the curious face. Severely affected children fail to thrive and demonstrate significant mental compromise. Common early problems include feeding difficulty, seizures, irritability, a deep hoarse cry, and obvious limb abnormalities.Upper extremity anomaliesUlnar dysplasia is the most frequent upper extremity finding in Cornelia de Lange syndrome. Phenotypes vary from partial to complete absence of the ulna, radial dysplasia, and humeroradial synostosis.The most characteristic hand finding is hypoplasia on both ulnar and radial sides. The hand may contain as few as one digit or as many as five. Ectrodactyly is common with ulnar digits more often absent than radial digits. A biphalangeal thumb on the radial side of the hand is the most persistent single digit in a monodactylous hand. Many of the two-digit hands are unstable at the carpometacarpal level with similarities to a typical cleft hand with a very deep central cleft (Fig. 1). Many hands with two or three digits, referred to as oligodactyly in the pediatric and genetic literature, have soft tissue webbing connecting these digits. Many of the thumbs lack thenar musculature and a normal web space and in the pediatric literature are called "proximal implantation thumbs." Kirner deformity of the fifth digit and a palmar simian crease may also be observed2Rayan G.M. Upton III, J. Congenital Hand Anomalies and Associated Syndromes. Springer, Berlin2014: 155-158Google Scholar, 4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google Scholar, 5Jones K. Smith's Recognizable Patterns of Human Malformation.6th ed. Elsevier Saunders, Philadelphia2006: 82-87Google Scholar (Fig. 1) Clinodactyly of the fifth digit, when present, is present in 88% of these children. Skeletal maturation is delayed. Carpal coalition may involve both distal and proximal rows.6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar, 7Poznanski A.K. Pratt G.B. Manson G. Weiss L. Clinodactyly, camptodactyly, Kirner's deformity and other crooked fingers.Radiology. 1969; 93: 573-582Crossref PubMed Scopus (19) Google Scholar When a hand is present, there is a characteristic metacarpal profile in which the first digit is shorter than the others, and the second and fifth are shorter than the third and fourth. The middle phalanx of the index finger is always hypoplastic.8Halal F. Preus M. The hand profile on de Lange syndrome: diagnostic criteria.Am J Med Genet. 1979; 3: 317-323Crossref PubMed Scopus (21) Google ScholarPhocomelia and antecubital pterygium may be present, a condition distastefully referred to as "chicken wing–like appendices" (radial head dislocation with secondary elbow contracture).6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar In these children, upper limb posture typically involves an elbow stiff in extension and a wrist flexed with ulnar deviation. The flexion contracture of the elbow is typically unyielding. In addition, the glenohumeral joint motion is usually limited. These contractures are present at birth and persist without surgery (Fig. 1). The contralateral limb may be normal but is usually affected.Musculoskeletal anomaliesAdditional musculoskeletal anomalies in Cornelia de Lange syndrome include toe syndactyly of the second web space, toe hypoplasia, absence of the tibia, micromelia, and metatarsus adductus; talipes equinovarus, Legg-Perthes disease, and scoliosis have also been reported.4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google ScholarCraniofacialFacial features in Cornelia de Lange syndrome are distinct and diagnosis is usually made easily. Brachycephaly and synophrys are characteristics present in all of these children. Common features also include excess facial hair and generalized hirsutism, unusually long curly eyelashes of the upper and lower eyelids, and low anterior and posterior hairlines. Microcephaly, small widely spaced teeth with delayed eruption, thin upper lip, depressed corners of the mouth, and occasional high-arched palate or cleft palate may also be present. Patients have an upturned nose, depressed nasal bridge, long philtrum, low-set ears, and short neck (Fig. 1).Ophthalmological findings include ptosis, nystagmus, and myopia. Hearing loss is usually secondary to otitis media.VisceralPatients frequently have gastroesophageal reflux disease and pyloric stenosis. Congenital heart disease, including valvular pulmonary stenosis or left-to-right shunt, may be present. Urogenital anomalies include structural anomalies of the kidney and urinary tract, and hypoplasia of male genitalia with undescended testicles and hypospadias. Common neurological manifestations include mental retardation, language delay, and hypertonicity. Endocrinopathies related to dysfunction of gonadotropin and prolactin secretion may be observed. Cornelia de Lange syndrome (Online Mendelian Inheritance in Man #122470) is characterized by ulnar dysplasia, facial hirsuitism with synophrys, and diminutive stature.1Kniffin C. Cornelia de Lange syndrome 1; CDLS1. OMIM. 2013. Available at: http://www.omim.org/entry/122470. Accessed May 11, 2015.Google Scholar Diagnosis can be made prenatally based on sonographic findings of growth retardation, limb defects, hirsuitism, and diaphragmatic hernia. Alternative terminology includes Brachmann-de Lange syndrome, de Lange syndrome, Amsterdam syndrome, Typus Degenerativus Amstelodamensis (new type of degeneration), and CDLS1. The syndrome's eponym is attributed to Cornelia de Lange, a pediatrician from Amsterdam who, in 1933, described 2 children with the condition. However, in 1916, Brachman first described a child at autopsy with similar but more severe features to this syndrome.2Rayan G.M. Upton III, J. Congenital Hand Anomalies and Associated Syndromes. Springer, Berlin2014: 155-158Google Scholar, 3Kline A.D. Krantz I.D. Sommer A. et al.Cornelia de Lange syndrome: Clinical review, diagnostic and scoring systems, and anticipatory guidance.Am J Med Genet A. 2007; 143A: 1287-1296Crossref PubMed Scopus (199) Google Scholar EtiologyIncidence of Cornelia de Lange syndrome has been estimated to range from 1 in 10,000 to 1 in 30,000 newborns. Most cases are sporadic, although some families demonstrate autosomal dominance. A heterozygous mutation in the NIPBL gene, which encodes for a component of the cohesion complex, on chromosome 5p13.1 is responsible in 50% to 60% of cases. Other identified gene mutations responsible for X-linked or milder variants of Cornelia de Lange syndrome include SMC1A, SMC3, RAD21, and HDAC8.1Kniffin C. Cornelia de Lange syndrome 1; CDLS1. OMIM. 2013. Available at: http://www.omim.org/entry/122470. Accessed May 11, 2015.Google Scholar Incidence of Cornelia de Lange syndrome has been estimated to range from 1 in 10,000 to 1 in 30,000 newborns. Most cases are sporadic, although some families demonstrate autosomal dominance. A heterozygous mutation in the NIPBL gene, which encodes for a component of the cohesion complex, on chromosome 5p13.1 is responsible in 50% to 60% of cases. Other identified gene mutations responsible for X-linked or milder variants of Cornelia de Lange syndrome include SMC1A, SMC3, RAD21, and HDAC8.1Kniffin C. Cornelia de Lange syndrome 1; CDLS1. OMIM. 2013. Available at: http://www.omim.org/entry/122470. Accessed May 11, 2015.Google Scholar Clinical PhenotypesThis is a multisystem malformation syndrome, which has very broad phenotypic variation. The diagnosis of most children is usually obvious at birth, but owing to the wide clinical phenotypic variation, many milder forms of the syndromes often go unrecognized. The most characteristic features involve the hands and the curious face. Severely affected children fail to thrive and demonstrate significant mental compromise. Common early problems include feeding difficulty, seizures, irritability, a deep hoarse cry, and obvious limb abnormalities.Upper extremity anomaliesUlnar dysplasia is the most frequent upper extremity finding in Cornelia de Lange syndrome. Phenotypes vary from partial to complete absence of the ulna, radial dysplasia, and humeroradial synostosis.The most characteristic hand finding is hypoplasia on both ulnar and radial sides. The hand may contain as few as one digit or as many as five. Ectrodactyly is common with ulnar digits more often absent than radial digits. A biphalangeal thumb on the radial side of the hand is the most persistent single digit in a monodactylous hand. Many of the two-digit hands are unstable at the carpometacarpal level with similarities to a typical cleft hand with a very deep central cleft (Fig. 1). Many hands with two or three digits, referred to as oligodactyly in the pediatric and genetic literature, have soft tissue webbing connecting these digits. Many of the thumbs lack thenar musculature and a normal web space and in the pediatric literature are called "proximal implantation thumbs." Kirner deformity of the fifth digit and a palmar simian crease may also be observed2Rayan G.M. Upton III, J. Congenital Hand Anomalies and Associated Syndromes. Springer, Berlin2014: 155-158Google Scholar, 4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google Scholar, 5Jones K. Smith's Recognizable Patterns of Human Malformation.6th ed. Elsevier Saunders, Philadelphia2006: 82-87Google Scholar (Fig. 1) Clinodactyly of the fifth digit, when present, is present in 88% of these children. Skeletal maturation is delayed. Carpal coalition may involve both distal and proximal rows.6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar, 7Poznanski A.K. Pratt G.B. Manson G. Weiss L. Clinodactyly, camptodactyly, Kirner's deformity and other crooked fingers.Radiology. 1969; 93: 573-582Crossref PubMed Scopus (19) Google Scholar When a hand is present, there is a characteristic metacarpal profile in which the first digit is shorter than the others, and the second and fifth are shorter than the third and fourth. The middle phalanx of the index finger is always hypoplastic.8Halal F. Preus M. The hand profile on de Lange syndrome: diagnostic criteria.Am J Med Genet. 1979; 3: 317-323Crossref PubMed Scopus (21) Google ScholarPhocomelia and antecubital pterygium may be present, a condition distastefully referred to as "chicken wing–like appendices" (radial head dislocation with secondary elbow contracture).6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar In these children, upper limb posture typically involves an elbow stiff in extension and a wrist flexed with ulnar deviation. The flexion contracture of the elbow is typically unyielding. In addition, the glenohumeral joint motion is usually limited. These contractures are present at birth and persist without surgery (Fig. 1). The contralateral limb may be normal but is usually affected.Musculoskeletal anomaliesAdditional musculoskeletal anomalies in Cornelia de Lange syndrome include toe syndactyly of the second web space, toe hypoplasia, absence of the tibia, micromelia, and metatarsus adductus; talipes equinovarus, Legg-Perthes disease, and scoliosis have also been reported.4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google ScholarCraniofacialFacial features in Cornelia de Lange syndrome are distinct and diagnosis is usually made easily. Brachycephaly and synophrys are characteristics present in all of these children. Common features also include excess facial hair and generalized hirsutism, unusually long curly eyelashes of the upper and lower eyelids, and low anterior and posterior hairlines. Microcephaly, small widely spaced teeth with delayed eruption, thin upper lip, depressed corners of the mouth, and occasional high-arched palate or cleft palate may also be present. Patients have an upturned nose, depressed nasal bridge, long philtrum, low-set ears, and short neck (Fig. 1).Ophthalmological findings include ptosis, nystagmus, and myopia. Hearing loss is usually secondary to otitis media.VisceralPatients frequently have gastroesophageal reflux disease and pyloric stenosis. Congenital heart disease, including valvular pulmonary stenosis or left-to-right shunt, may be present. Urogenital anomalies include structural anomalies of the kidney and urinary tract, and hypoplasia of male genitalia with undescended testicles and hypospadias. Common neurological manifestations include mental retardation, language delay, and hypertonicity. Endocrinopathies related to dysfunction of gonadotropin and prolactin secretion may be observed. This is a multisystem malformation syndrome, which has very broad phenotypic variation. The diagnosis of most children is usually obvious at birth, but owing to the wide clinical phenotypic variation, many milder forms of the syndromes often go unrecognized. The most characteristic features involve the hands and the curious face. Severely affected children fail to thrive and demonstrate significant mental compromise. Common early problems include feeding difficulty, seizures, irritability, a deep hoarse cry, and obvious limb abnormalities. Upper extremity anomaliesUlnar dysplasia is the most frequent upper extremity finding in Cornelia de Lange syndrome. Phenotypes vary from partial to complete absence of the ulna, radial dysplasia, and humeroradial synostosis.The most characteristic hand finding is hypoplasia on both ulnar and radial sides. The hand may contain as few as one digit or as many as five. Ectrodactyly is common with ulnar digits more often absent than radial digits. A biphalangeal thumb on the radial side of the hand is the most persistent single digit in a monodactylous hand. Many of the two-digit hands are unstable at the carpometacarpal level with similarities to a typical cleft hand with a very deep central cleft (Fig. 1). Many hands with two or three digits, referred to as oligodactyly in the pediatric and genetic literature, have soft tissue webbing connecting these digits. Many of the thumbs lack thenar musculature and a normal web space and in the pediatric literature are called "proximal implantation thumbs." Kirner deformity of the fifth digit and a palmar simian crease may also be observed2Rayan G.M. Upton III, J. Congenital Hand Anomalies and Associated Syndromes. Springer, Berlin2014: 155-158Google Scholar, 4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google Scholar, 5Jones K. Smith's Recognizable Patterns of Human Malformation.6th ed. Elsevier Saunders, Philadelphia2006: 82-87Google Scholar (Fig. 1) Clinodactyly of the fifth digit, when present, is present in 88% of these children. Skeletal maturation is delayed. Carpal coalition may involve both distal and proximal rows.6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar, 7Poznanski A.K. Pratt G.B. Manson G. Weiss L. Clinodactyly, camptodactyly, Kirner's deformity and other crooked fingers.Radiology. 1969; 93: 573-582Crossref PubMed Scopus (19) Google Scholar When a hand is present, there is a characteristic metacarpal profile in which the first digit is shorter than the others, and the second and fifth are shorter than the third and fourth. The middle phalanx of the index finger is always hypoplastic.8Halal F. Preus M. The hand profile on de Lange syndrome: diagnostic criteria.Am J Med Genet. 1979; 3: 317-323Crossref PubMed Scopus (21) Google ScholarPhocomelia and antecubital pterygium may be present, a condition distastefully referred to as "chicken wing–like appendices" (radial head dislocation with secondary elbow contracture).6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar In these children, upper limb posture typically involves an elbow stiff in extension and a wrist flexed with ulnar deviation. The flexion contracture of the elbow is typically unyielding. In addition, the glenohumeral joint motion is usually limited. These contractures are present at birth and persist without surgery (Fig. 1). The contralateral limb may be normal but is usually affected. Ulnar dysplasia is the most frequent upper extremity finding in Cornelia de Lange syndrome. Phenotypes vary from partial to complete absence of the ulna, radial dysplasia, and humeroradial synostosis. The most characteristic hand finding is hypoplasia on both ulnar and radial sides. The hand may contain as few as one digit or as many as five. Ectrodactyly is common with ulnar digits more often absent than radial digits. A biphalangeal thumb on the radial side of the hand is the most persistent single digit in a monodactylous hand. Many of the two-digit hands are unstable at the carpometacarpal level with similarities to a typical cleft hand with a very deep central cleft (Fig. 1). Many hands with two or three digits, referred to as oligodactyly in the pediatric and genetic literature, have soft tissue webbing connecting these digits. Many of the thumbs lack thenar musculature and a normal web space and in the pediatric literature are called "proximal implantation thumbs." Kirner deformity of the fifth digit and a palmar simian crease may also be observed2Rayan G.M. Upton III, J. Congenital Hand Anomalies and Associated Syndromes. Springer, Berlin2014: 155-158Google Scholar, 4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google Scholar, 5Jones K. Smith's Recognizable Patterns of Human Malformation.6th ed. Elsevier Saunders, Philadelphia2006: 82-87Google Scholar (Fig. 1) Clinodactyly of the fifth digit, when present, is present in 88% of these children. Skeletal maturation is delayed. Carpal coalition may involve both distal and proximal rows.6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar, 7Poznanski A.K. Pratt G.B. Manson G. Weiss L. Clinodactyly, camptodactyly, Kirner's deformity and other crooked fingers.Radiology. 1969; 93: 573-582Crossref PubMed Scopus (19) Google Scholar When a hand is present, there is a characteristic metacarpal profile in which the first digit is shorter than the others, and the second and fifth are shorter than the third and fourth. The middle phalanx of the index finger is always hypoplastic.8Halal F. Preus M. The hand profile on de Lange syndrome: diagnostic criteria.Am J Med Genet. 1979; 3: 317-323Crossref PubMed Scopus (21) Google Scholar Phocomelia and antecubital pterygium may be present, a condition distastefully referred to as "chicken wing–like appendices" (radial head dislocation with secondary elbow contracture).6Temtamy S.A. McKusick V.A. The Genetics of Hand Malformations. Alan R Liss Inc., New York1978: 149-154Google Scholar In these children, upper limb posture typically involves an elbow stiff in extension and a wrist flexed with ulnar deviation. The flexion contracture of the elbow is typically unyielding. In addition, the glenohumeral joint motion is usually limited. These contractures are present at birth and persist without surgery (Fig. 1). The contralateral limb may be normal but is usually affected. Musculoskeletal anomaliesAdditional musculoskeletal anomalies in Cornelia de Lange syndrome include toe syndactyly of the second web space, toe hypoplasia, absence of the tibia, micromelia, and metatarsus adductus; talipes equinovarus, Legg-Perthes disease, and scoliosis have also been reported.4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google Scholar Additional musculoskeletal anomalies in Cornelia de Lange syndrome include toe syndactyly of the second web space, toe hypoplasia, absence of the tibia, micromelia, and metatarsus adductus; talipes equinovarus, Legg-Perthes disease, and scoliosis have also been reported.4Roposch A. Bhaskar A.R. Lee F. Adedapo S. Mousny M. Alman B.A. Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.J Pediatr Orthop B. 2004; 13: 118-122PubMed Google Scholar CraniofacialFacial features in Cornelia de Lange syndrome are distinct and diagnosis is usually made easily. Brachycephaly and synophrys are characteristics present in all of these children. Common features also include excess facial hair and generalized hirsutism, unusually long curly eyelashes of the upper and lower eyelids, and low anterior and posterior hairlines. Microcephaly, small widely spaced teeth with delayed eruption, thin upper lip, depressed corners of the mouth, and occasional high-arched palate or cleft palate may also be present. Patients have an upturned nose, depressed nasal bridge, long philtrum, low-set ears, and short neck (Fig. 1).Ophthalmological findings include ptosis, nystagmus, and myopia. Hearing loss is usually secondary to otitis media. Facial features in Cornelia de Lange syndrome are distinct and diagnosis is usually made easily. Brachycephaly and synophrys are characteristics present in all of these children. Common features also include excess facial hair and generalized hirsutism, unusually long curly eyelashes of the upper and lower eyelids, and low anterior and posterior hairlines. Microcephaly, small widely spaced teeth with delayed eruption, thin upper lip, depressed corners of the mouth, and occasional high-arched palate or cleft palate may also be present. Patients have an upturned nose, depressed nasal bridge, long philtrum, low-set ears, and short neck (Fig. 1). Ophthalmological findings include ptosis, nystagmus, and myopia. Hearing loss is usually secondary to otitis media. VisceralPatients frequently have gastroesophageal reflux disease and pyloric stenosis. Congenital heart disease, including valvular pulmonary stenosis or left-to-right shunt, may be present. Urogenital anomalies include structural anomalies of the kidney and urinary tract, and hypoplasia of male genitalia with undescended testicles and hypospadias. Common neurological manifestations include mental retardation, language delay, and hypertonicity. Endocrinopathies related to dysfunction of gonadotropin and prolactin secretion may be observed. Patients frequently have gastroesophageal reflux disease and pyloric stenosis. Congenital heart disease, including valvular pulmonary stenosis or left-to-right shunt, may be present. Urogenital anomalies include structural anomalies of the kidney and urinary tract, and hypoplasia of male genitalia with undescended testicles and hypospadias. Common neurological manifestations include mental retardation, language delay, and hypertonicity. Endocrinopathies related to dysfunction of gonadotropin and prolactin secretion may be observed.