Handbook of Genetic Counseling/Cornelia de Lange Syndrome

Cornelia de Lange Syndrome

Definition

 * Cornelia de Lange Syndrome is a rare developmental malformation syndrome characterized by mental retardation, short stature, limb abnormalities, and distinctive craniofacial features.
 * Within the phenotypic pattern, there is a wide range of severity (from mildly to severely affected). "Classical" refers to children who are severely growth retarded and "mild" refers to those with less severe growth problems and less developmental delay.

Historical significance

 * In 1933, a Dutch pediatrician, Dr. Cornelia de Lange, described 2 children with similar features. The syndrome is also referred to as Brachmann-de Lange Syndrome after Dr. W. Brachmann, who described a similar patient in 1916.

Diagnosis

 * Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in NIPBL, RAD21, or SMC3 or a hemizygous pathogenic variant in HDAC8 or SMC1A.
 * no diagnostic biochemical, cytogenetic, or molecular abnormalities
 * medical evaluation (history and physical exam showing distinctive craniofacial features)
 * family history
 * laboratory tests (chromosome analysis)
 * X-rays

Symptoms

 * low birthweight (under 5 lbs.) due to prenatal onset growth deficiency
 * delayed growth & short stature (failure to thrive) (>90%)
 * low-pitched, weak, growling cry in infancy
 * hypertonicity (abnormally increased muscle tone)
 * delayed bone age/skeletal abnormalities
 * microcephaly (with possible brachycephaly)
 * episodes of aspiration & apnea in infancy
 * synophrys (thick, arched eyebrows which meet at midline)
 * long, curly eyelashes
 * short, upturned nose with anteverted nares
 * long, smooth philtrum
 * thin, downturned lips
 * micrognathnia
 * late eruption of widely-spaced teeth
 * low-set, malformed ears
 * hirsutism (excessive body hair)
 * small hands & feet
 * syndactyly of the 2nd and 3rd toes
 * 5th finger clinodactyly
 * GI abnormalities (bowel obstruction)
 * gastroesophageal reflux
 * genitourinary malformations (horseshoe kidney, bicornate uterus)
 * hypoplasia of male genitalia with undescended testes or hypospadias
 * seizures (11-23%)
 * congenital heart defects (20-25%)
 * cleft palate or high arched palate (18-59%)
 * feeding difficulties (chewing & swallowing problems, regurgitation, projectile vomiting)
 * developmental delay/MR (moderate to severe, usually) - IQ range 30-86 (ave. 53)
 * significant speech/communication delay and psychomotor delay
 * behavioral problems (acting out)
 * limb abnormalities (reduction defects - missing forelimbs or portions thereof)
 * myopia (60%), ptosis (45%), nystagmus, astigmatism, or strabismus
 * hearing loss (>90%)
 * short neck with low posterior hairline
 * increased susceptibility to repeated respiratory infections

Incidence

 * congenital syndrome
 * 1:10,000 to 1:100,000 (most accurate study showed 1:50,000)
 * males & females affected equally

Life expectancy

 * Not known with certainty. Earlier, many children died of serious medical problems due to complications of their congenital anomalies. However, many are now expected to live into adulthood.

Genetics

 * exact cause is not known, possibly a gene located on chromosome 3 (3q26.3)
 * duplication of chromosome 3q26-27 yields a similar phenotype
 * sporadic; rare and random mutation
 * rare cases where mildly affected individuals had children with the syndrome (suggests autosomal dominant inheritance)
 * estimated 1% recurrence rate within affected families (due to possible germline mosaicism)

Management

 * Treatment is directed toward the specific symptoms & medical complications in each individual (symptomatic and supportive).
 * Involves a comprehensive team of specialists (pediatricians, surgeons, orthopedists, gastroenterologists, urologists, otolaryngologists, cardiologists, dentists, speech pathologists, audiologists, optometrists, PT's, OT's, geneticists).
 * Issues involve growth & feeding, development (speech and motor skills) & behavior, vision & hearing, limb abnormalities, gastrointestinal problems, congenital heart defects, craniofacial, genitourinary, and neurological.

Prenatal diagnosis
Available if familial mutation is known

Level II ultrasound to detect poor fetal growth, limb abnormalities, diaphragmatic hernia, cystic hygroma, heart abnormalities, or characteristic facial profile

Differential Diagnosis

 * Coffin-Siris Syndrome
 * Fetal Alcohol Syndrome
 * Ruvalcaba Syndrome
 * Scott Craniodigital Syndrome with MR
 * Chromosome 3, Trisomy 3q2
 * Fryns Syndrome

Resources

 * Cornelia de Lange Syndrome Foundation
 * Smith's Recognizable Patterns of Human Malformation
 * NORD
 * Management of Genetic Syndromes