Pfeiffer syndrome is a genetic disease with an autosomal dominant mechanism of inheritance, characterized by a violation of the formation of the bones of the skull and limbs. Symptoms are deformities of the skull (as a result of craniosynostosis), bones of the fingers and toes. Some forms of the disease are characterized by deafness, impaired intellectual development, dental pathologies. Diagnosis of Pfeiffer syndrome is based on the data of the patient’s current status, X-ray studies, molecular genetic analyses. There is no specific treatment, palliative measures are used to prevent severe complications (including surgical ones) and symptomatic therapy.
Pfeiffer syndrome is a congenital genetically determined disorder of the formation of the skull and limbs, which is characterized by craniosynostosis, facial deformity, expansion and shortening of fingers, frequent syndactyly. For the first time this disease was described in 1964 by the German pediatrician Rudolf Pfeiffer, later several clinical forms of pathology were identified.
According to modern genetics, Pfeiffer syndrome is an autosomal dominant condition with complete penetrance, the sexual distribution of patients has no peculiarities – both boys and girls suffer with the same frequency. The occurrence is not precisely determined, according to some data it is approximately 1:100,000 newborns. There were also no national or racial characteristics in the distribution of this disease. With regard to Pfeiffer syndrome, early diagnosis is extremely important, since the prognosis of the disease and the quality of the patient’s future life largely depend on the time of the start of palliative treatment.
Despite the fact that Pfeiffer syndrome is a hereditary disease with an autosomal dominant transmission mechanism, most cases of this pathology are the result of spontaneous germinative mutations in the germ cells of parents. At the same time, defects of two genes are responsible for the development of the condition, the proteins encoded by them have similar functions.
- The first gene, FGFR1, is located on the 8th chromosome and encodes the sequence of the protein receptor for fibroblast growth factor-1. The most common type of genetic defect in this case becomes the missense mutation 252Pro-Arg in exon 7a.
- Another gene whose mutations lead to the development of Pfeiffer syndrome is FGFR2, located on the 10th chromosome – the product of its expression is also a receptor for fibroblast growth factor (RFRF-2). More than 26 different variants of mutations have been identified in this gene that can lead to various forms of Pfeiffer syndrome.
Due to the fact that the above proteins have very similar functions, the pathogenesis of Pfeiffer syndrome with FGFR1 and FGFR2 gene defects is also very similar. As a result of missense mutations, the structure of the expressed protein changes, due to which the resulting receptor becomes unable to fully bind to a stimulant substance (fibroblast growth factor) and transmit information inside the cell. Since fibroblasts are actively involved in the processes of osteogenesis in the embryonic period and in the first years of a child’s life, such a change in receptors leads to a variety of bone pathologies.
The proof of this is the fact that FGFR1 gene defects, in addition to Pfeiffer syndrome, lead to type 1 trigonocephaly and a number of other disorders, and FGFR2 – to nonspecific craniosynostosis, Crouzon syndrome and other similar pathologies. With Pfeiffer syndrome, premature fusion of the skull bones occurs, which causes deformation of the head and face, increased intracranial pressure – this, in turn, can cause a number of secondary disorders from sensorineural disorders to profound mental retardation.
Classification and symptoms
To date, there are at least three clinical forms of Pfeiffer syndrome, which differ in the severity of disorders, the course and prognosis of the disease. The reason for this difference lies in the molecular genetic mechanisms of pathology development – type 1 is caused by a single mutation of the FGFR1 gene (252Pro–Arg) and some disorders of the FGFR2 structure, whereas types 2 and 3 are caused by different variants of defects of the FGFR2 gene alone.
More subtle features of the pathogenesis of each form of the disease are currently under study. Due to the characteristic clinical picture, specialists can determine the type of Pfeiffer syndrome based only on the symptoms of pathology. Molecular genetic analysis in many cases is necessary only for the final confirmation of the diagnosis.
Type 1 is the most common and prognostically favorable variant of the disease. In this condition, from the very birth of the child, anomalies of facial development are noted – hypertelorism, underdevelopment of the maxillary bones, expanded flat bridge of the nose and the back of the nose. Sometimes there may be cleavage of the hard palate and exophthalmos. In this form of Pfeiffer syndrome, the characteristic changes in the shape of the skull are reduced to an increase in its height and length, asymmetry is very rarely noted. In the future, anomalies of the teeth may occur – curvature of the dentition, hypoplasia, a tendency to caries. Deformities of the bones of the extremities are reduced to the expansion of the phalanges of the first fingers and toes, partial syndactyly may be noted.
Type 2 is a more severe form of the disease, manifested by a significant degree of fusion of the skull bones with each other and a number of other anomalies. The head, due to craniosynostosis, acquires the characteristic shape of a “shamrock” or “clover leaf”, there is significant hypoplasia of the middle third of the face. Due to a gross violation of the formation of the skull, this type of Pfeiffer syndrome is characterized by severe mental retardation and a number of neurological disorders. Malformations of the limbs are reduced to the expansion of the first fingers, syndactyly, ankylosis of the elbow joints. In addition, type 2 Pfeiffer syndrome is often accompanied by various malformations of internal organs. All of the above violations can cause death at an early age.
Type 3 is largely similar in its manifestations to the previous variant of the disease, but craniosynostosis does not lead to the formation of a deformity of the skull in the form of a “leaf clover”. Patients have an increase in head height, malformations of the extremities (syndactyly, ankylosis of the joints), exophthalmos, neurological disorders. This variant of Pfeiffer syndrome is characterized by early development of teeth, often babies are already born with them (natal teeth). Defects of internal organs and early death due to a combination of disorders are also possible.
Such a difference in the clinical picture and prognosis of various variants of Pfeiffer syndrome leaves its mark on the inheritance of this disease. Since type 1, especially in the case of timely detection and proper treatment, is characterized by maintaining a normal level of intelligence, fertility and survival of patients, autosomal dominant transmission of pathology to offspring is possible. More severe types 2 and 3 most often lead to early death or profound disability of patients, these variants of Pfeiffer syndrome arise only as a result of spontaneous mutations.
Timely diagnosis of Pfeiffer syndrome is extremely important, as it allows you to draw up a palliative treatment scheme in time, thereby avoiding complications and significantly improving the quality of life of the patient. But this is true only with respect to type 1 of the disease, since with other variants of pathology, the complex of malformations is so severe that it practically leaves no chance of preserving intelligence, and in the future – the lives of patients.
Ultrasound techniques (including prenatal diagnostics), radiography, molecular genetic analyses are used to detect Pfeiffer syndrome. On preventive ultrasound during pregnancy, in the presence of this disease in a child in the 2-3 trimester, it is possible to detect a violation of the formation of the skull, syndactyly, malformations of internal organs.
X–ray methods are rarely used in the early diagnosis of Pfeiffer syndrome in children – basically, a study of the skull is performed, which detects the presence of craniosynostosis of varying severity, hypoplasia of the maxillary bones, a change in the shape of the eye sockets. Also, an X-ray can determine the change in the shape of the bones of the thumbs and toes.
Molecular genetic diagnostics is performed by a geneticist – in this case, if Pfeiffer syndrome type 1 is suspected, a point mutation 252Pro-Arg is searched for by direct sequencing of exon 7a of the FGFR1 gene. In other cases, the 7th and 9th exons of the FGFR2 gene are sequenced – this is where most of the defects that lead to the development of Pfeiffer syndrome occur. Medical imaging techniques aimed at determining abnormalities in the development of internal organs can play an auxiliary role in the diagnosis of the disease.
Treatment of Pfeiffer syndrome is only symptomatic and palliative – specialists try to eliminate increased intracranial pressure, ensure the normal development of the nervous system, and reduce the severity of disorders from the internal organs. For this purpose, surgical techniques are widely used – finger separation, skull plastic surgery and a number of others. Also prescribe drugs aimed at improving the nutrition of nervous tissue – nootropic drugs, vitamins. With timely treatment of Pfeiffer syndrome type 1, the survival rate of patients increases significantly. Unfortunately, the volume of medical care is often insufficient for the full treatment of patients with Pfeiffer syndrome of the 2nd and 3rd types.
Prognosis and prevention
The prognosis of Pfeiffer syndrome is determined by a variant of this disease. The first type is characterized by a relatively favorable prognosis, which depends on the timely detection of pathology and the correctness of the selected treatment. In favorable conditions, patients retain normal intelligence, live to an advanced age and are able to have offspring – while the risk of transmitting the disease to children is at least 50%.
However, Pfeiffer syndrome of the 2nd and 3rd types has an extremely unfavorable prognosis – a combination of neurological and other disorders often causes death in early childhood. Even when performing palliative measures, patients have pronounced oligophrenia and deep disability. Prevention of Pfeiffer syndrome, taking into account the often spontaneous mechanism of development of this disease, is possible only within the framework of prenatal diagnosis by ultrasound or genetic methods.