Cornelia de Lange syndrome is a genetically mediated multisystem disease involving multiple developmental abnormalities and oligophrenia. The phenotypic signs of the syndrome are represented by microbrachycephaly, an understated hairline, thin fused eyebrows, a wide sunken bridge of the nose, microgenia, etc. Characterized by stunting, congenital malformations are possible (CHD, genitourinary abnormalities, pylorostenosis, diaphragmatic hernia). The diagnosis takes into account clinical criteria and the results of genetic testing. Children with this pathology need symptomatic therapy, defectological assistance.
Q87.1 Syndromes of congenital anomalies, manifested mainly by dwarfism
The syndrome, characterized by a complex of dysembriogenesis stigmas, malformations and mental disability, was described in 1916 by V. Brahman, Doctor of Medicine. However, the disease received its official name in honor of a pediatrician from Amsterdam, Cornelia de Lange, who described in detail two clinical observations at once in 1933. In the literature, along with the generally accepted – Cornelia de Lange syndrome – there are names “Brahman de Lange syndrome”, “Amsterdam dwarfism / nanism”. Pathology is registered with a frequency of 1:10000-1:30000, the prevalence has no geographical, racial and gender differences.
The syndrome is characterized by genetic heterogeneity, at the moment three genes responsible for this pathology are known. About 50% of the described cases are associated with defects in the NIPBL gene encoding the delangin protein (5p13.2), about 5% – with mutations of the SMC1A cohesin complex gene (Xp11.22). One known case is associated with a violation of another cohesin subunit encoded by SMC3 (10q25). In about 40% of cases, Cornelia de Lange syndrome is caused by unknown mutations that have yet to be calculated.
Most of the NIPBL mutations are newly emerged, so more often sick children are born from genetically healthy parents. However, there are known observations of family cases with autosomal dominant inheritance. The SMC1A gene is located on the sexual X chromosome – with its defects, inheritance is linked to gender (men are ill, women are heterozygous carriers).
Spontaneous pathological changes in genetic material can be caused by the following factors:
- intoxications and infections of a pregnant woman suffered in the first trimester;
- endocrinopathies of a pregnant woman;
- medicinal (including cytostatic), radiation effects on the fetus;
- closely related marriage;
- late childbirth (in women over 35 years old).
In the absence of gene mutations in parents, the risk of re-birth of a child with Brahman de Lange syndrome in one family is 2-5%.
The molecular basis of pathology is a violation of the functioning of proteins of the cohesin complex. Cohesins play an important role in the process of cell division. They are located inside the chromosome, interlocking and holding together two sister chromatids. Other equally important functions of cohesin are DNA repair and regulation of gene expression.
Apparently, exposure to various mutagenic factors during critical periods leads to incorrect cell division and organ laying. Pathoanatomic examination reveals significant changes in the brain: aplasia of the opercular cortex, underdevelopment of the Roland sulcus, delayed myelination and myelodegeneration. Malformations of the kidneys, adrenal glands, gonads, heart, hypoplasia of the thymus are also found.
According to the severity of phenotypic manifestations, there are 2 variants of Cornelia de Lange syndrome. They differ both in the manifestation of external symptoms and vital prognosis:
classic: significant delay in fetal development, gross malformations and severe mental disability;
benign: facial and skeletal anomalies without gross defects of internal organs, borderline ZPR. Defects in the SMC3 and SMC1A genes correlate with the benign course of the syndrome.
Infants with Cornelia de Lange syndrome are born with low height and weight indicators: the average weight is 2100-2300 g. They are not very active, rarely express their needs by shouting. From the first days, sluggish breast sucking, frequent regurgitation, dyspeptic disorders are noted. Such problems are often forced to feed the child through a nasogastric tube or gastrostomy. Children often suffer from recurrent respiratory infections. Physical and psychomotor development lags behind the age norm.
The appearance of the child is very peculiar. The listed craniofacial dysmorphia are among the main criteria for the diagnosis of pathology:
- anomalies of the skull and facial skeleton: micro- and brachycephaly, Gothic palate, palatine cleft, micrognathia;
- facial features: thin fused eyebrows, long eyelashes, wide nose bridge with saddle-shaped deformity and wide nostrils, low-set ears, thin lips with downturned corners;
- anomalies of the skin and its appendages: on the head ‒ thick hair with a low growth line, on the body – hypertrichosis, marble skin.
Patients have a funnel-shaped chest, a short neck. In the area of the vertebral column, defects such as Spina bifida, lumbalization or sacralization of the vertebrae can be detected. There is hypoplasia of the hands and feet, defects in the development of fingers (clinodactyly, syndactyly, oligodactyly), joint contractures, dysplasia and congenital dislocation of the hip. The growth lag persists in adulthood: men with Amsterdam nanism have a height of about 156 cm, women ‒ 131 cm.
Neurological and psychopathological problems
Patients with the classic form of Cornelia de Lange syndrome have intellectual disabilities in the degree of imbecility or profound debility. With a mild form, the intellectual defect is not clearly expressed – patients are diagnosed with ZPR. A quarter of patients occasionally have convulsive syndrome.
Behavioral features are represented by hyperactivity syndrome, anxiety, signs of OCD. Aggression towards others, autoaggression and self-harming behavior, stereotypical actions are noted. Speech disorders are systemic in nature, verbal communication suffers, and rhinolalia occurs with palatine clefts.
Common problems on the part of the visual system are myopia, ptosis of the eyelid, blepharitis. Strabismus, microcornea are less often diagnosed, cataract and glaucoma were detected in isolated cases. With a severe variant of Cornelia de Lange syndrome, the risk of retinal detachment and optic nerve atrophy is high.
Defects of internal organs
In almost half of cases, the syndrome is accompanied by congenital cardiac defects: defects of the septa of the heart (aortopulmonary, interventricular, atrial), coarctation of the aorta, tetrad of Fallot. Gastrointestinal anomalies are most often represented by gastroesophageal reflux (90%), diaphragmatic hernia (2%), pylorostenosis (4%), incomplete bowel rotation (10%) can be detected. Frequent pathologies of the genitourinary system are polycystic or horseshoe kidney, hydronephrosis, two-horned uterus, undescended testicles, hypospadias. A delay in sexual development is characteristic.
Severe variants of the syndrome are associated with developmental defects incompatible with life and the death of newborns shortly after birth. With a milder course, recurrent sinusitis, otitis media with the subsequent development of conductive hearing loss can inhibit the development of the child. Against the background of gastroesophageal reflux, anemia, aspiration pneumonia, esophageal stenosis, sometimes Barrett’s esophagus, adenocarcinoma often occurs. In everyday terms, patients with Cornelia de Lange syndrome need care, comprehensive assistance. They require special training and defectological support.
At birth, a diagnostic hypothesis about the presence of Cornelia de Lange syndrome in a child can be put forward on the basis of visually detectable defects. The newborn should be examined by a neonatologist, pediatric cardiologist, surgeon, neurologist. Consultations of a maxillofacial surgeon, an endocrinologist, an orthopedist, and a speech therapist are carried out as planned. Diagnostic tactics include:
- Anthropometry. At birth and throughout early childhood, regular measurements of length (height), body weight, and head circumference are carried out. All anthropometric indicators are below the age norms (<5 percentiles).
- Examination of the cardiovascular system. The presence of heart defects can be detected by EchOG, ECG. If necessary, invasive examinations may be required: cardiac catheterization, ventriculography, etc.
- Examination of the gastrointestinal tract. To detect GERD and morphological changes in the esophagus, EGDS is indicated under anesthesia. In order to exclude possible intestinal abnormalities, radiography with barium is necessary.
- Psychoneurological diagnostics. During the initial examination, reflexes, muscle tone, and the level of psychomotor development are determined. In the future, NSG, EEG are examined, X-ray of the skull bones, MRI of the brain are performed.
- Other surveys. In order to identify anomalies of the organs, ultrasound of the abdominal cavity, kidneys, genitals is performed. It is mandatory to check the function of vision (refractometry, ophthalmoscopy, biomicroscopy), hearing (otoscopy, audiogram, auditory VP). Skeletal abnormalities are detected with the help of X-rays of bones and spine.
- Molecular testing. Genodiagnostics of the syndrome involves consulting a family geneticist with karyotyping of a sick child, searching for mutations in the NIPBL, SMC1A genes.
Detection of the syndrome is possible at the prenatal stage within the framework of prenatal ultrasound screening and fetometry of the fetus. Echographic markers of pathology are the sound, features of the skull, anomalies of the limbs. With the help of ultrasound, CHD, diaphragmatic hernia and other anomalies of fetal organs can be detected.
During the examination, it is necessary to exclude other diseases that have similar phenotypic features:
- fetal alcohol syndrome;
- trisomy 3q;
- Frins syndrome;
- Noonan syndrome;
- Prader-Willi syndrome;
- Rubinstein-Tabey syndrome.
Tactics depend on the complex of identified defects, the degree of their influence on the quality of life of the child, his socialization. First of all, the treatment of those pathologies that can lead to destabilization of the condition is carried out:
- Gastrointestinal reflux: development of a diet, taking antacids and H2-histamine blockers, according to indications – fundoplication.
- Heart defects: suturing/plasty of septum defects, dilation or resection of aortic coarctation, correction of the tetrad of Fallot.
- Neurological disorders: taking anticonvulsants, anxiolytics, SSRIs, environmental treatment.
- Anomalies of the genitourinary system: orchipexia, correction of hypospadias, plasty of hydronephrosis, correction of vesicoureteral reflux.
- Cleft palate: uranoplasty, velopharyngoplasty.
- Skeletal abnormalities: physical therapy, massage, physiotherapy to prevent joint contractures.
Correction of hearing loss is carried out with the help of hearing aids, visual anomalies – with the use of glasses, hardware techniques. The program of pedagogical support of the child necessarily includes classes with a defectologist, psychologist, speech therapist. Growth hormone therapy is ineffective.
Prognosis and prevention
Due to the large number of developmental anomalies, the average life expectancy of people with Cornelia de Lange syndrome is lower than in the population. However, with a favorable option, patients can live up to 50-60 years. Patients need social and psychological support, labor rehabilitation, self-care assistance. Due to the existing immunodeficiency, the prevention of infections is critically important.
Prevention of genetic syndrome requires the exclusion of consanguineous marriages and responsible pregnancy planning. Pregnant women must undergo laboratory and ultrasound screening, and, if necessary, invasive prenatal diagnostics.