AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

de Lange syndrome is a relatively common multiple congenital anomaly/mental retardation (MCA/MR) disorder of unknown cause. It is entry 122470 in the Online Mendelian Inheritance in Man (OMIM) database.

The essential features of this multisystem developmental disorder include prenatal and postnatal growth retardation, distinctive facial appearance, various structural upper limb abnormalities, neurodevelopmental delay, and behavioral problems. In 1916, Brachmann reported the first case in the literature, describing a child at autopsy with severe growth retardation, hirsutism, and an additional finding of upper limb deficiencies. In 1933, Cornelia de Lange described 2 unrelated infant girls with mental retardation and similar dysmorphic features under the designation typus degenerativus amstelodamensis. de Lange suggested that these manifestations comprised a new malformation syndrome.

Because of their contribution, both Brachmann's and de Lange's names have been attached to the syndrome, Brachmann-de Lange syndrome (BDLS). Several hundred cases have been reported. Consensus among clinical geneticists on the phenotypic dichotomy with classic and mild cases was reached at the 12th Annual D.W. Smith Workshop on Malformations and Morphogenesis in 1991.

Pathophysiology

In 2004, 2 groups independently found that NIPBL gene mutations are responsible for BDLS in a proportion of patients. NIPBL is the human homolog of the Drosophila nipped-B gene. The gene is located on band 5p13.1, consists of 47 exons, and encodes for the protein delangin. Although the exact function of vertebrate delangin is unknown, it may play a role in the sister chromatid cohesion process, as has been reported for its homologs in Drosophila and yeast, probably as part of oligomeric complexes required to load cohexin subunits onto chromatin.

The pathogenesis of BDLS arises from a loss or altered function of a single NIPBL gene allele, which is consistent with a dominant pattern of inheritance. To date, NIPBL mutations have been identified in 20-50% of individuals in different studies, both with the severe and mild BDLS phenotypes. A trend toward a milder phenotype is observed in persons with missense mutations compared with those with truncating mutations. Both locus heterogeneity (possibly another gene or other genes) and limitations of the screening methods are considered causes of the relatively low mutation detection rate.

Most cases are sporadic, but a familial occurrence and parental consanguinity have been recorded. Autosomal dominant transmission, both maternal and paternal, has been documented. In some families, the autosomal recessive inheritance was suggested to most likely be due to germline mosaicism. Paternal mosaicism of the NIPBL mutation was documented in analyzed sperm.

Recently, mutations in the SMC1L1 gene, encoding a different subunit of the cohexin complexes, were found to be responsible for the BDLS phenotype in 3 affected male siblings and in 1 sporadic case, suggesting that X-linked BDLS might represent a clinical subset.

A number of patients with BDLS were found to have one or another type of chromosomal aberration. A phenotypic overlap between BDLS and partial trisomy on band 3q26-27 was found, and it was proposed that the gene for BDLS may be located at band 3q26.3 (CDL1 locus). Recently, research has shown that the 3q26.3 breakpoint locus contains a giant gene, NAALADL2, which has not yet been characterized. However, mutation screening of the gene in a series of BDLS individuals failed to detect patient-specific mutations.

Frequency

International

BDLS is a relatively common disorder, with an estimated birth prevalence of 1 case in 10,000-50,000 population.

Mortality/Morbidity

• Patients with BDLS have a slightly elevated mortality rate. The most frequent direct causes of death are pneumonia, cardiac malformations, and GI malformations. Most recorded deaths (approximately two thirds) occur during the first year of life or in the following 2 years, and most deaths occur in patients with severe disease.

Race

• No racial predilection is reported. One of the largest clinical surveys in the United States, by Jackson et al in 1993, included 310 patients, of which black, white, Hispanic, Asian groups were represented.

Sex

• No sex predilection is observed.

Age

• Approximately one third of children with BDLS are delivered prematurely. The characteristic facial gestalt of classic BDLS is present at birth and changes little throughout life.
• In mild BDLS, the typical facial appearance may become obvious only after 2-3 years. In addition, the patient's face loses the characteristic appearance by adulthood, with normalization of the dimensions.
• During the neonatal period, respiratory and feeding difficulties (failure to thrive) predominate.
• The low-pitched cry frequently noted in the newborn period or in early infancy may disappear in late infancy.
• Self-injury is common in patients older than 12 years.
• Pubertal development and fertility are normal in BDLS individuals. The control of fertility of young adult women should be considered.
• Some patients with BDLS survive to adulthood; 61 years and 54 years of survival in a woman and a man, respectively, have been recorded.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The patient history may reveal clues to the diagnosis, such as the following:

• The course of pregnancy and delivery offer clues. Preterm delivery is noted in approximately 30% cases.
• Retardation of growth is often profound and of prenatal onset.
• The difficulties in weight and height gain persist in the postnatal period as a result of feeding difficulties
• Sucking and swallowing problems and an inability to take an appropriate amount of food for age in the first months of life result in failure to thrive.
• Recurrent respiratory tract infections, hyperactivity, nocturnal agitation, and behavioral problems may be atypical manifestations of gastroesophageal reflux (GER).
• A diminished responsiveness to pain has been reported and was found to be associated both with mental retardation and with autism; it might contribute to self-injury behaviors.
• Psychomotor development and behavior findings are as follows:
• • Most affected individuals with the classic phenotype have moderate-to-profound mental retardation.
  • Borderline-to-mild deficiency is usually observed in patients who are mildly affected; near-normal intelligence has occasionally been recorded.
  • The cognitive profile is characterized by delayed verbal communication with specific deficits in expressive language; receptive language and verbal comprehension are less affected. Visuospatial memory and perceptual organization are usually normal.
  • The behavioral manifestations include a wide spectrum of symptoms, such as sleep disturbances, daily aggression and hyperactivity, poor relationship abilities, stereotyped behavior, autism, and self-injury.

Physical

BDLS is a highly variable MCA/MR syndrome, ranging from perinatal lethality with multiple malformations, including severe upper limb deficiency, to a degree of mildness compatible with reproduction and near-normal intellect. Diagnosis is based on the characteristic phenotype, in particular a striking facial gestalt, prenatal and postnatal growth retardation, various skeletal abnormalities, hypertrichosis, and developmental delay.

The phenotypic dichotomy, classic and mild cases, is now well established. The prognosis for patients with the mild phenotype is much better than that of patients with the classic form.

• A classification system based on the clinical variability in BDLS has been proposed.
• • Patients with BDLS type I (classic) have the characteristic facial and skeletal changes, a prenatal growth deficiency that is progressive postnatally, moderate-to-profound psychomotor retardation, and major malformations resulting in severe disability or death.
  • Patients with BDLS type II (mild) have facial and minor skeletal abnormalities similar to those seen in type I; however, they are distinguished by less severe psychomotor retardation and milder growth deficiency. The prognosis is more optimistic, but, paradoxically, behavior dysfunction may be more evident.
• The following craniofacial characteristics are unique and of great diagnostic value:
• • Microbrachycephaly: The average head circumference remains less than the second percentile throughout life.
  • Low frontal hairline
  • Well-defined, arched "pencilled" eyebrows
  • Synophrys
  • Long, curly eyelashes
  • Short nose with anteverted nares
  • Triangular nasal tip
  • Long philtrum
  • Crescent-shaped mouth
  • Thin lips
  • Widely spaced (late-erupting) teeth
  • Micrognathia
  • Low-set and posteriorly rotated ears
• Retardation of growth, often of prenatal onset, is one diagnostic criterion for BDLS that can also help to discriminate classic cases from mild cases.
• • Profound prenatal growth deficiency (<2.5 standard deviations below the mean for gestation) becomes more severe postnatally ( <3.5 standard deviations below the mean) and is characteristic for classic (type I) BDLS.
  • Birth weight greater than 2500 g and less marked postnatal growth deficiency may help to classify a patient as having mild (type II) BDLS.
  • Growth persists below the normal curves in most of the patients throughout life.
  • Height velocity is equal to the reference range, and weight velocity is below the reference range throughout life until adolescence.
• Skeletal abnormalities characteristic for classic BDLS include major longitudinal reduction abnormalities of the upper limbs, including hypoplastic or absent ulnas and/or oligodactyly (which, if bilateral, can be asymmetric). This abnormality is not observed in persons with mild BDLS.
• • Severe malformations of the lower limbs are less common than upper limb anomalies.
  • Most patients have relatively small hands, feet, or both.
  • Limitation of extension at the elbows with accompanying radiological characteristics may help with the diagnosis because they are not frequently observed.
  • Other minor variable anomalies, such as clinodactyly, single palmar crease, proximal placement of the thumb(s), and syndactyly of toes 2 and 3 are frequently observed in many other syndromes or in healthy individuals; therefore, they are of limited diagnostic aid.
• Common cutaneous manifestations include hypertrichosis in form of synophrys, long eyelashes, and hirsutism on the back.
• • Cutis marmorata is noted in BDLS patients.
  • Hypoplastic nipples and umbilicus are observed most commonly in persons with the classic type and are observed less frequently in those with the mild phenotype.
  • Multiple capillary or cavernous hemangiomas are occasionally reported; these hemangiomas may cause the observed thrombocytopenia that is reported, most likely occurring as a result of a slow, consumptive coagulopathy.
  • Patients also reported have multiple pigmented nevi.
  • Ulerythema ophryogenes was reported in a 17-year-old girl with BDLS.
• GI problems occur with high frequency, and they contribute to feeding difficulties and failure to thrive.
• • Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period.
  • GER and its sequelae are thought to be the most underappreciated medical problems in persons with BDLS. Approximately two thirds of children are first seen with clinical signs that might be referred to this area.
  • Pathological GER was found in 65% individuals. Silent GER can cause esophageal damage and symptoms of pulmonary congestion and irritation due to chemical pneumonitis.
  • The most severe complications of GER include Barrett esophagus and the Sandifer complex, which is characterized by torticollis, opisthotonus, and paroxysmal dystonic posture.
  • Two other GI-related problems are intestinal malrotation with volvulus and congenital diaphragmatic hernia. The latter anomaly might be more common than initially realized.
  • Omphalocele was reported in one patient.
• Cardiovascular problems in the form of congenital heart malformations are diagnosed in approximately 14% of children. Most common are ventricular and atrial septal defects, pulmonic stenosis, and tetralogy of Fallot; various other anomalies occasionally occur.
• Most respiratory problems are probably initiated and/or complicated by undetected GER:
• • Upper respiratory tract infections and pneumonias are reported in 25% of individuals.
  • Severe complications due to bronchopulmonary dysplasia have also been described.
  • Choanal atresia was diagnosed at birth in 3 children.
• Hearing problems occur frequently:
• • Hearing deficits from mild to severe may be present in 60-100% of all BDLS patients.
  • Stenosis of the external auditory canals is found in 80% of examined children.
• Ophthalmologic problems occur in a high proportion of children with BDLS.
• • Myopia was reported in 60% of patients, ptosis in 45%, nystagmus in 37%, microcornea in 21%, and nasolacrimal duct obstruction in 16%.
  • Chronic blepharitis is a frequent complication.
  • Glasses are poorly tolerated.
• Other problems are variable and include the following:
  • Urinary tract anomalies are common and include hydronephrosis, urethral reflux, subcortical renal cysts, and renal dysplasia or hypoplasia.
  • Male hypogonadism and cryptorchidism are present in more than half the boys.
  • Seizures are reported in 23% of individuals.
  • Heat intolerance and absence of pain sensation have been observed in several patients.

Causes

Single-allele mutations at the NIPBL locus account for approximately 50% of affected individuals. The low mutation rate could be because some mutations might have escaped detection if standard analysis was used or because of the presence of locus heterogeneity. For details, see Pathophysiology.

• Most cases are sporadic, but a familial occurrence and parental consanguinity have been recorded. Strong evidence indicates autosomal dominant inheritance in most multicase families; germinal mosaicism can be an explanation for unaffected parents having more than one affected child.
• When parents are affected, the risk of recurrence has been estimated at 0.8-1.5%.
• Numerous chromosomal rearrangements have been reported in patients with BDLS or a BDLS-like phenotype. Some of these rearrangements may be causative of a disease phenotype.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Partial trisomy on chromosome arm 3q, ie, dup(3q) syndrome
Coffin-Siris syndrome
Holt-Oram syndrome
Fetal alcohol syndrome
Fryns syndrome (prenatal diagnosis)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The diagnosis is based on a characteristic phenotype. The following genetic tests for the standard karyotype are recommended at diagnosis:
• • Molecular analysis of the NIPBL gene allows confirmation of a disease-causing mutation in a proportion of cases, and it provides the basis for prenatal diagnosis in families with parental transmission or proven paternal gonadal mosaicism. To find a genetics or prenatal diagnosis clinic, see the Laboratory Directory at GeneTests.
  • High-resolution chromosome studies (specific fluorescence in situ hybridization assay and/or genome-wide array comparative genomic hybridization) on cultured lymphocytes are worthwhile if molecular test results are negative.
• Endocrinologic studies are warranted in patients with severe growth retardation.
• Periodical evaluations, including routine blood cell counts, iron metabolism testing, liver and renal function tests, urinalysis, and a search for stool blood, are recommended, especially in first years of life.
• • Anemia (normochromic or hypochromic) may occur as a consequence of GI problems such as malnutrition or recurrent episodes of pneumonia.
  • Thrombocytopenia, most probably related to cavernous or capillary hemangiomas, has occasionally been reported.

Imaging Studies

• Skeletal radiography may help increase diagnostic precision. A high incidence of microcephaly, various distal limb defects, a dislocated and/or hypoplastic radial head, and delayed ossification are stressed. Chest anomalies often involve a short sternum with premature fusion and the occurrence of 13 pairs of ribs. Pattern profiles commonly show shortness of the first metacarpal and fifth distal phalanx.
• Barium esophagography under fluoroscopic control may allow demonstration of hiatal hernia, GER, and esophageal dysmotility.
• Gastric scintigrams can also be used to document GER.
• Echocardiography can be used for imaging structural heart abnormalities.
• Assessment of the genitourinary system may require abdominal ultrasonography or radiologic examination, such as urography or cystography.

Other Tests

• Ear examination and hearing assessment are strongly recommended for all children as soon as possible. Hearing deficits frequently occur in patients with BDLS and are related to the significant developmental and speech delays that are experienced in many of the children. Specific testing appropriate for individuals with mental retardation is required; such testing includes brain evoked response audiometry.
• Ophthalmologic examination is important in early care of the child. Myopia is common, but glasses are often poorly tolerated.
• EEG is recommended in patients with seizures.
• Esophagoscopy with biopsy is a superior diagnostic technique for evaluation of GER, and it may reveal the presence of Barrett esophagitis. The severity and frequency of reflux can be documented by using continuous pH monitoring in the distal esophagus or by using apnea evaluations with the thermistor oxygenation pneumocardiogram.
• Assessment of the growth rate with serial anthropometric measurements of height, weight, and occipitofrontal circumference is recommended.

Histologic Findings

Postmortem examination has revealed various congenital malformations of the internal organs, including cardiac defects, pulmonary hypoplasia, diaphragmatic hernias, GI anomalies, and genitourinary anomalies. Microscopy of the internal organs has shown no consistent abnormalities. Microcytic changes of the kidney have been observed in some individuals. Histological examination of the brain has demonstrated neuronal heterotopias in the cerebellum and ectopic neurons in the cerebral white matter in one newborn. A detailed neuropathologic analysis of a 35-year-old patient has revealed abnormal convolution patterns of the cerebral gyri and frontal lobe hypoplasia.

TREATMENT

Section 6 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The results of medical therapy are better in infants than in older children.

• Patients with symptoms of GER require intensive medical therapy. Frequent use of antacids, histamine-2 blockers, and metoclopramide can be helpful. Feeding by a nasogastric tube and by having the patient sit upright may be beneficial.
• Application of appropriate hearing aids is recommended in children with hearing deficits.
• Antiepileptic treatment may be required in a proportion of patients.

Surgical Care

• Operative procedures, including Nissen fundoplication and gastrostomy tube (G-tube) placement for feeding, may be necessary in patients with severe esophagitis and in those with worsening failure to thrive despite conservative intervention.
• Surgical repair may also be indispensable in patients with diaphragmatic hernia, cardiac defects, or severe skeletal deformities.

Consultations

• Patients may require various specialist consultations, depending on the clinical manifestations and the physical examination findings. Specialists may include the following:
• • Gastroenterologist
  • Cardiologist
  • Pulmonologist
  • Laryngologist/audiologist
  • Ophthalmologist
  • Neurologist
  • Nephrologist/urologist
  • Endocrinologist
• Genetic counseling provides families with information on the nature of the disease and the low risk of recurrence. Careful clinical examination of the parents for minor signs is recommended because autosomal dominant inheritance has been implicated in some families (see Deterrence/Prevention).

Activity

• In general, children with BDLS have difficulty accepting sudden changes in their daily routine and environment.
• Activities that stimulate the vestibular system, including swinging, bouncing, swimming, and horseback riding, are pleasurable to the patient.
• The use of sign language can help the patient to overcome frustration caused by expressive speech delay.

FOLLOW-UP

Section 7 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Further inpatient care is needed as indicated by associated abnormalities or complications that may require surgical correction and/or intensive medical therapy.

Further Outpatient Care

• Associated developmental abnormalities and disabilities determine further outpatient care.
• A systematic auxology evaluation of growth rate using the specific growth chart is recommended. Specifically, this should include standard growth curves for weight, height, and head circumference from birth through adulthood based on serial measurements of patients with clinically confirmed diagnoses of BDLS.

Deterrence/Prevention

• Genetic counseling and prenatal diagnosis may be offered:
• • In families with parental transmission of the disease, prenatal diagnosis based on a fetal DNA analysis is possible, if the mutation is precisely identified.
  • Ultrasound screening for evidence of manifestations of the syndrome (ie, intrauterine growth retardation, limb defects, diaphragmatic hernia, nuchal translucency) may be helpful.
  • A second trimester maternal serum pregnancy-associated plasma protein-A measurement may have predictive value as an addition to ultrasonography.
  • Detection of a mild form of BDLS using 3-dimensional ultrasonography combined with 3-dimensional computed tomography has been reported.

Complications

• Complications may arise from the associated anomalies.

Prognosis

• The prognosis for patients with the mild form is much better than that of patients with the classic form.
• Life expectancy is generally normal; patient survival to adult age is recorded.
• Most recorded deaths occur in infancy, and they mostly happen in severely affected individuals.
• Aspiratory pneumonia or apnea, cardiac defects, and/or GI anomalies are reported as the most frequent direct causes of death.

Patient Education

• The patient's education level depends on the intellectual potential. Incidental attendance of children with BDLS to normal schools is reported, but, in general, children need special education and care.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• This relatively common MCA/MR disorder requires recognition to facilitate correct patient management.

Special Concerns

• For information about the Cornelia de Lange Syndrome Foundation please visit the CdLS-USA Foundation Outreach Web site or contact the foundation at the address or phone numbers below.
  The Cornelia de Lange Syndrome Foundation, Inc
  302 West Main Street #100
  Avon, CT 06001
  800-223-8355 (Voice - Toll-free)
  800-753-2357 (Voice - Toll-free)
  860-676-8166 (Voice)
  860-676-8337 (FAX)

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Case study 1 of classic de Lange phenotype is shown (same patient as in Images 2-6). Facial characteristics of a 10-month-old girl are pictured. Note well-defined eyebrows with synophrys, depressed nasal bridge, and long smooth philtrum.
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Media file 2:  Case study 1 (same patient as in Images 1 and 3-6). Lateral facial profile is pictured. The eyebrows are neat, arched, and well defined. The nasal bridge is depressed, and the nares are upturned.
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Media file 3:  Case study 1 (same patient as in Images 1-2 and 4-6). The patient, aged 5 years, is shown; note microbrachycephaly, well-defined eyebrows, anteverted nares, long and thin upper lip, down-turned angles of mouth, and widely spaced teeth.
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Media file 4:  Case study 1 (same patient as in Images 1-3 and 5-6). Upper limb reduction anomalies are pictured with only 2 fingers present.
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Media file 5:  Case study 1 (same patient as in Images 1-4 and 6). Note short hypoplastic fifth finger.
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Media file 6:  Case study 1 (same patient as in Images 1-5). Small feet with short hypoplastic toes and syndactyly of the second and third toes is pictured.
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Media file 7:  Case study 2 of mild de Lange syndrome is shown (same patient as in Images 8-10). The face of a 1.5-year-old girl is pictured. Note neat eyebrows with delicate synophrys, long eyelashes, depressed nasal bridge, upturned nares, long philtrum, thin upper lip, and small chin.
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Media file 8:  Case study 2 (same patient as in Images 7 and 9-10). Lateral facial profile shows depressed nasal bridge, thin upper lip, and small mandible.
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Media file 9:  Case study 2 (same patient as in Images 7-8 and 10). The patient, aged 8 years, is shown; note delicate synophrys of the eyebrows, upturned nares, long philtrum, and thin upper lip.
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Media file 10:  Case study 2 (same patient as in Images 7-9). Lateral facial profile of the patient, aged 8 years, is shown.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Mar 8, 2007