276 In 1933, Cornelia de Lange reported two nonfamilial infant girls with severe mental retardation and multiple abnormalities of the skull, face, and extremities. Earlier in 1916, Brachmann had described a child with similar features. The syndrome is also called Brachmann-de Lange syndrome or Cornelia de Lange syndrome. The prevalence is estimated to be 1 in 10,000 births.
GENETICS/BASIC DEFECTS
1. A heterogeneous clinical entity
a. Sporadic in vast majority of cases (99%) b. Striking concordance in MZ twins c. Rare familial occurrences
i. Autosomal dominant inheritance
ii. Autosomal recessive inheritance: unlikely 2. Both missense and protein-truncating mutations in
NIPBL, the human homolog of the Drosophila melan- gaster Nipped-B gene, have recently been reported to cause de Lange syndrome
3. Inconsistent chromosome abnormalities occasionally associated with de Lange phenotype
CLINICAL FEATURES
1. Marked clinical variability 2. General history
a. Prenatal and/or postnatal growth deficiency b. Prematurity
c. Diminished sucking and swallowing ability
d. Low pitched cry (74%) in the newborn period and in the early infancy but may disappear in the late infancy e. Global developmental delay
f. Initial hypertonicity
g. Recurrent respiratory tract infections h. Gastroesophageal reflux
i. Failure to thrive 3. Growth
a. Prenatal onset growth retardation b. Short stature
4. Skin
a. Hypertrichosis (hirsutism) (78%): often with hairy whorls over the shoulders, lower back, and extremities b. Cutis marmorata (60%)
c. Periorbital “cyanosis”
5. Characteristic craniofacial appearance a. Microcephaly (98%)
b. Brachycephaly
c. Hairy (low hairline) forehead
d. Mask like (grim, devoid of expression) facies e. Hypertelorism
f. Antimongoloid slant of palpebral fissures
g. Synophrys (prominent bushy, confluent eyebrows joining at the nose) (99%)
h. Long and curly eyelashes (99%)
i. Depressed nasal bridge (83%) j. Small nose
k. Anteverted nares (88%) l. Micrognathia (84%)
m. Long bulging, prominent philtrum (94%) n. Thin upper lip (94%)
o. Central depression below lower lip p. Down turned corners of the mouth (94%) q. Late eruption of teeth
r. Widely spaced teeth (86%) s. High arched palate (86%)
t. Low set, malformed, and hairy ears (70%) u. Low posterior hairline (92%)
v. Short neck (66%) 6. Eye abnormalities (57%)
a. Strabismus b. Nystagmus (37%) c. Myopia (60%) d. Ptosis (45%) e. Microcornea f. Astigmatism g. Optic atrophy
h. Coloboma of the optic nerve i. Eccentric pupils
j. Microphthalmia k. Blue sclerae 7. Limb abnormalities
a. Upper extremities
i. Micromelia (shortened limbs) (93%) ii. Ectrodactyly/oligodactyly/phocomelia (27%) iii. Clinodactyly of the 5th fingers (74%)
iv. Small hands
v. Proximally placed thumbs vi. Camptodactyly
vii. Webbings of fingers viii. Brachydactyly
ix. Flexion contractures of the elbows common (64%)
x. Restriction of supination and pronations xi. Subluxation or dislocation of the radial head b. Lower extremities
i. Small feet
ii. Cutaneous syndactyly of the second and third toes (86%)
iii. Tight Achilles tendon (equines deformity) iv. Pes planus
v. Valgus heel
vi. Flexion contractures of the knees 8. CNS anomalies
a. Variable mental retardation to near-normal intellect b. Seizures (23%)
c. Abnormal speech development d. Hearing deficits (60–100%)
e. Hypoplasia of the vermis f. Hypertonia/hypotonia 9. Behavior disorder
a. Sleep disturbance (55%) b. Aggression (49%)
c. Self-destructive tendencies (44%) d. Hyperactivity (40%)
e. Low-pitched growling sound rather than cry f. Infrequent facial expressions of emotion g. Severe language delay
h. Autistic-like behavior
i. Repetitive stereotypic movement
j. Eliciting pleasurable responses by vestibular stimula- tion or vigorous movement
10. Other anomalies
a. Small hypoplastic nipples (55%) b. Small hypoplastic umbilicus (53%) c. Cardiovascular anomalies (15–20%)
i. Ventricular septal defect ii. Atrial septal defect iii. Patent ductus arteriosus
iv. Aortic valve anomaly v. Hypoplasia of the aorta
vi. Persistent left superior vena cava vii. Pulmonary stenosis
viii. Endocardial cushion defect ix. Tetralogy of Fallot
d. Gastrointestinal anomalies i. Inguinal hernia ii. Hiatus hernia
iii. Congenital diaphragmatic hernia iv. Gut duplication
v. Malrotation of colon vi. Pyloric stenosis e. Genitourinary anomalies
i. Hypoplastic, dysplastic, or cystic kidneys ii. Hypoplastic external genitalia, cryptorchidism
or hypospadias in males
iii. Small labia majora, bicornuate or septate uterus in females
f. Abnormal dermatoglyphics
i. Transverse palmar creases (51%) ii. Increased atd angle
iii. Hypoplastic finger ridge patterns
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Skull
i. Microcephaly: frequent ii. Brachycephaly: frequent
iii. Trigonocephaly with orbital hypotelorism iv. Parietal foramina
v. Micrognathia vi. High-arched palate vii. Cleft palate b. Spine
i. Kyphoscoliosis ii. Platyspondyly iii. Scheuermann disease
iv. Spina bifida v. Square vertebrae vi. Coxa valga c. Chest
i. Aspiration pneumonia: frequent ii. Thin ribs
iii. Short clavicles
iv. Short hypoplastic sternum with reduced number of ossification centers
v. Abnormal sternal angle vi. Cervical ribs
vii. Hypoplasia of the first rib viii. Chronic pneumonia
ix. Bronchiolitis d. Congenital heart diseases e. Gastrointestinal tract
i. Swallowing dysfunction: frequent
ii. Bowel rotation anomalies with bands: frequent iii. Hiatal hernia
iv. Hypertrophic pyloric stenosis v. Duodenal stenosis
vi. Colon duplication vii. Inguinal hernia viii. Umbilical hernia f. Genitourinary tract
i. Incomplete rotation of the kidneys ii. Renal duplication
iii. Polycystic kidneys iv. Chronic pyelonephritis
v. Abnormal renal function with poor visualization on excretory urography
vi. Vesicoureteral reflux
vii. Divided uterine canal with septate vagina g. Limbs
i. Micromelia: frequent
ii. Short humerus and/or forearm bones: frequent iii. Elongated humeral neck (similar to femoral
neck): frequent
iv. Subluxation or dislocation of malformed radius and/or ulna at elbow with fixation in flexion v. Absent or hypoplastic ulna: frequent
vi. Retarded bone maturation with abnormal sequence of appearance of ossification centers:
frequent
vii. Absent carpals, metacarpals, and fingers (ectro- dactyly/oligodactyly): frequent
viii. Short, broad metacarpals, particularly 1 and 5:
frequent
ix. Hypoplastic phalanges particularly middle 5th (curved) and middle second fingers: frequent x. Cutaneous syndactyly of second and third toes or
other toes and fingers: frequent xi. Cutis valgus
xii. Absent or hypoplastic radius xiii. Lunate and triquetral fusion
xiv. Aplastic or hypoplastic ulnar styloid
xv. Double distal phalanges of thumbs and/or great toes
xvi. Congenital dislocated hips xvii. Aseptic necrosis of femoral head
xviii. Broad ischial bones xix. Large obturator foramina
xx. Short broad femoral necks xxi. Absent tibia with deformed fibula xxii. Fusion of phalanges of fifth toe xxiii. Rocker-bottom foot
xxiv. Metatarsus adductus xxv. Planovalgoid foot xxvi. Talipes equinovarus
xxvii. Shortening of femur and/or leg bones xxviii. Wide gap between first and second toes
xxix. Osteoporosis
2. Endocrinologic studies in patients with severe growth retardation
3. Echocardiography for evaluation of congenital heart defects
4. Abdominal ultrasonography for GU anomalies 5. EEG for seizures
6. High resolution chromosome analysis for associated chromosome anomaly
7. DNA mutation analysis of NIPBL (positive in 47%)
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: an empiric risk of about 1–4%
b. Patient’s offspring: 50% in case of an autosomal dom- inant inheritance
2. Prenatal diagnosis by ultrasonography a. Intrauterine growth retardation b. Characteristic facies
i. A small bulging nose ii. Long bulging philtrum
iii. Protruding and overhanging upper lip iv. Micrognathia
c. Limb defects i. Micromelia ii. Monodactyly iii. Ulnar agenesis d. Diaphragmatic hernia 3. Management
a. Adequate caloric intake
b. Treat gastroesophageal reflux with thickened feeds in an upright position and pharmacotherapy
c. Fitting of hearing aids and early consistent training for hearing impaired children
d. Early intervention and special education programs for psychomotor delay
e. Behavioral modification
f. Correction of refractory errors with glasses g. Anticonvulsants for seizures
h. Surgical repairs
i. Fundoplication and gastrostomy feedings necessary in patients with severe esophagitis and progressive failure to thrive despite conservative intervention ii. Diaphragmatic hernia
iii. Cardiac defect
iv. Severe skeletal deformities v. Renal malformations
vi. Ptosis obstructing the visual axis vii. Orchiplexy
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Fig. 1. A neonate and a child with de Lange syndrome showing char- acteristic facies, oligodactyly, and severe hirsutism.
Fig 2. Four patients with classic De Lange syndrome of different ages showing typical facial appearance (synophrys, coarse eyebrows, long curly eyelashes, depressed nasal bridge with anteverted nares, long thin upper lip, down-turned angles of the mouth, and widely spaced teeth) and ectrodactyly/oligodactyly in the first two cases.
Fig 3. A 46,XX male with de Lange phenotype.
Fig 4. Two adults with de Lange syndrome showing hirsutism and mental retardation.
