Carpenter syndrome (acrocephalopolysyndactyly type 2) is an extremely rare hereditary disease caused by a mutation of the RAB23 gene. Pathology is transmitted by autosomal recessive type. The disease has a characteristic triad of symptoms: early overgrowth of cranial sutures (craniosynostosis) with congenital dysmorphia of the facial skeleton, multiple malformations of the limbs, obesity. Diagnosis includes radiography or CT of the skeleton, echocardiography, molecular genetic diagnostics to identify a specific mutation. The basis of treatment is surgical correction of craniosynostosis, which creates conditions for the development of the brain.
ICD 10
Q87.0 Syndromes of congenital anomalies affecting mainly the appearance of the face
General information
The disease was first described by the English pediatrician George Alfred Carpenter, who in 1909 noticed a characteristic set of symptoms in 3 children from the same family. The genetic prerequisites for the appearance of pathology were established in 2000. The disease is extremely rare, only 40 cases are described in the literature, which is why there are no statistical indicators of morbidity. Despite the rarity of the syndrome, it does not lose its relevance in modern genetics, since it requires early detection, carrying out a complex of surgical measures in infancy.
Causes
The syndrome occurs due to the RAB23 gene defect encoding the protein of the same name. The gene is located on the short arm of chromosome 6 and consists of 237 amino acid residues. For the development of the disease, it is necessary that the child receives one copy of the mutant gene from each parent. At the same time, the probability of Carpenter syndrome is 25%, regardless of the sex of the newborn.
Pathogenesis
According to the biochemical structure, RAB23 is a guanosine triphosphatase of the Ras superfamily. The main function of the protein is to participate in the intracellular transport of proteins, which is necessary in the process of laying and differentiation of tissues. It is located in cell membranes, cell cytoplasm, vesicles and endosomes. In addition, RAB23 controls the activity of the SHH gene responsible for cell development during ontogenesis.
With protein deficiency due to Carpenter syndrome, the processes of differentiation of bone tissue primarily suffer. As a result, early fusion of the cranial sutures occurs, which forms a closed head space without the possibility of increasing it accordingly to the growth of the brain. RAB23 pathology also causes disturbances of signaling cascades during the formation of the central nervous system.
Taking into account the peculiarities of suture overgrowth, 2 types of craniosynostosis are formed — sagittal (a long narrow skull with a protruding forehead and a large occiput) and bicoronal (a wide short skull with deformed forehead and eye sockets). The type of craniosynostosis has the greatest influence on the features of the formation of neurological disorders.
Symptoms
Bone anomalies in Carpenter disease are formed in the prenatal period, so they are determined immediately after birth. Parents pay attention to the elongated tower-like shape of the head (acrocephaly). Over time, the skull is deformed due to the early closure of sutures (craniosynostosis), which limit the growth of bones and do not allow the head to increase in volume. There are also multiple congenital anomalies of the facial skeleton.
Craniosynostosis is manifested by various symptoms. With bicoronal deformation of the skull, pathologies of the visual apparatus are noted: strabismus, lacrimation, exophthalmos (bulging of the eyeballs). A delay in psychomotor development is characteristic: the child begins to hold his head late, sits and stands poorly, hardly learns to walk. Also of great importance is a cosmetic defect that causes psychological trauma in the patient in the absence of correction.
Another typical sign of Carpenter syndrome is abnormalities in the development of fingers and toes. Skin syndactyly often occurs — fusion of soft tissues of neighboring fingers, the absence of middle phalanges, deformation of the thumb is also possible. Some patients have six fingers, and there is more often an additional little finger on their hands, and any finger from I to IV on their feet. As the patient grows older, short-fingered, stunted growth becomes noticeable.
Dysembriogenesis of internal organs, as a rule, is manifested by congenital cardiac abnormalities, which are detected in a third of patients. Gradually, children develop obesity, first mild, and then moderate, with a predominant distribution of fat on the face, body, and proximal parts of the limbs. Boys may have cryptorchidism. The intellectual level of approximately 75% of patients corresponds to mild mental retardation.
Complications
The most serious problem with craniosynostosis is intracranial hypertension, which is manifested by regurgitation, repeated vomiting, anxiety due to severe headache. Convulsions, meningeal syndrome may develop, and coma occurs in severe cases. The danger is represented by heart defects, fraught with critical circulatory disorders.
Diagnostics
The examination of the patient is carried out by a neonatologist / pediatrician, according to the indications, a maxillofacial surgeon and a neurosurgeon, a geneticist, a pediatric cardiologist are connected to the diagnosis. Carpenter syndrome can be suspected by its characteristic phenotypic features, however, laboratory and instrumental studies are carried out to confirm the diagnosis:
- CT of the skull. To clarify the degree of bone deformities, the condition of cranial sutures, spiral computed tomography is used, which gives the most detailed image of all structures, helps in choosing the tactics of surgical treatment.
- Ultrasound of the heart. Given the high probability of cardiac defects, echocardiography is indicated for all patients with suspected Carpenter disease. If anomalies are detected, an ECG, MRI of the heart, and cardiac catheterization are additionally performed.
- Genetic testing. Genome sequencing in order to diagnose the mutant RAB23 gene is the only possible way to 100% confirm the diagnosis. After the disease is established, it is advisable to conduct a genetic study for parents, closest blood relatives.
- Prenatal diagnosis. If the heredity is burdened or suspicious signs are detected during ultrasound screening, a chorion biopsy is performed in the 2nd trimester of pregnancy. The resulting material is used for molecular genetic testing.
Treatment
Conservative therapy
Etiopathogenetic treatment of the disease has not been developed. In order to correct excess body weight, patients are recommended to follow a lifelong diet with reduced calories. To reduce the severity of possible concomitant disorders are shown:
- Special teaching methods. Children with mental retardation need to study according to special programs compiled by oligophrenopedagogues. Also, the development of household self-service skills plays an important role.
- Correction of emotional disorders. In the presence of signs of neurotic or depressive disorders, psychotherapy methods are used, soothing herbal remedies, mild antidepressants are selected.
- Ophthalmological care. With a decrease in visual acuity, strabismus, lacrimation and other visual disturbances typical of bicoronal craniosynostosis, the patient may need appropriate correction.
Surgical treatment
In Carpenter syndrome, the main task becomes the correction of craniosynostosis, performed only surgically. The optimal age for surgery is 3-9 months. Early removal of the skull deformity creates favorable conditions for the physical and intellectual development of the patient. Neurosurgeons perform endoscopic or open cranioplasty, use biodegradable and articulated titanium implants.
Patients with syndactyly are recommended surgery to separate the fingers. With the terminal type of fusion, surgical intervention is indicated in the second half of the baby’s life, in other cases, the operation is performed at the age of 4-5 years. When six-fingered, the method of amputation of an additional finger is used. In the case of congenital heart defects, the consultation of cardiac surgeons is required for the individual selection of a way to eliminate defects.
Prognosis and prevention
With timely detection of Carpenter syndrome and surgical correction of craniosynostosis, it is possible to completely neutralize the signs of the disease. The prognosis is favorable in the absence of mental retardation and severe heart defects. Prevention of pathology involves medical and genetic counseling of parents who already have a sick child or a family history is burdened.