Mandibuloacral dysplasia is a congenital malformation syndrome associated with abnormalities of the skeleton that is inherited in an autosomal recessive manner. Two different types of the disease are known, caused by mutations in two different genes. A causative therapy does not yet exist.
What is mandibuloacral dysplasia?
In medicine, dysplasias are congenital malformations in human anatomy that correspond to changes in cells, whole tissues, or organs and result, for example, from abnormal growth processes or lack of differentiation during embryonic development. Dysplasias can be further subdivided. One subgroup is that of manibuloacral dysplasias, of which two different manifestations exist. The manifestation MADA mainly affects the extremities. In the form MADB, the disease manifests on the whole body. Both forms are included under the malformation syndromes with congenital changes of the skeleton. The prevalence for manibuloaxial dysplasia is extremely low, with a frequency of one in 1000000 people. Synonyms for the congenital disorder are restrictive dermopathy and craniomandibular dermatodysostosis. In 1971, the disease group was first documented by L. W. Young and colleagues. Four years later, O. Welsh delineated the symptomatology as a distinct clinical picture. The main features of the disease, in addition to the late closure of the fontanel and patchy skin pigmentation, are considered to be the facial abnormalities, mandibular hypoplasia, and underdeveloped clavicles of the patients.
Causes
The two distinct forms of mandibuloacral dysplasia do not occur sporadically. Familial clusters have been observed in the cases documented to date. Inheritance seems most likely to be in the autosomal dominant mode. A mutation appears to underlie the symptom complex of both forms as the genetic cause. MADA and MADB differed in the type of mutation. MADA with A lipodystrophy is associated with homozygous missense mutations affecting Arg527His and Ala529Val of the LMNA gene at locus 1q21.2. This gene encodes lamin A/C, which are nuclear structural proteins. The LMNA gene is associated with numerous, other disorders, most notably partial lipatrophies, Emery-Dreifuss muscular dystrophy, limb-girdle dystrophy, and some non-obstructive cardiomyopathies. In addition, related syndromes include Charcot-Marie-Tooth disease and Hutchinson-Gilford syndrome. The MADB manifestation of mandibuloacral dysplasia corresponds to B-lipodystrophy and is caused by mutations in the ZMPSTE24 gene. The gene is located in DNA at locus 1p34 and encodes zinc endoprotease, which is necessary for the synthesis of lamin A/C protein.
Symptoms, complaints, and signs
Patients of mandibuloacral dysplasia suffer from various clinical symptoms. The most important criteria of the disease include delayed closure of the fontanel and insulin resistance. Symptomatically, these symptoms are associated with facial abnormalities, most notably wide cranial sutures, so-called switching bones, and a prominently protruding cephalic vein. In addition, patients may exhibit baldness, a bird’s head face, or pseudoexophthalmos. The dental alignment of affected individuals is often abnormal. Growth retardation usually presents after the age of six. Dermal manifestations of the disease include sclerosis of the skin and patchy hyperpigmentation of the neck. The mandible and clavicles of the patients are underdeveloped. The thorax is deformed like a bell. In addition, acroosteolysis of the hands and feet often presents in infancy. The finger and toe nails of affected individuals often exhibit dystrophies. The interphalangeal joints are often prominent. The clinical picture is rounded out by signs of progeria and diffusely altered connective tissue or abnormalities of the vascular walls.
Diagnosis and disease progression
The physician has a first suspicion of mandibuloacral dysplasia already after the visual diagnosis. The clinical abnormalities are characteristic. Nevertheless, a differential diagnosis must be made to differentiate it from conditions such as Werner syndrome, Hutchinson-Gilford syndrome, kleidocranial dysplasia, and acrogeria. The clinically similar clinical pictures of Crane-Heise syndrome and Yunis-Varon syndrome must also be excluded.The exclusion of these diseases and the confirmation of the diagnosis is done by molecular genetic analysis if mandibuloacral dysplasia is suspected. For this purpose, coding exons of the LMNA gene or ZMPSTE24 gene are analyzed from the genomic DNA. MLPA is used to check the gene for duplications or deletions. Detection of any mutations at the characteristic site is considered diagnostic.
Complications
This disease usually results in various malformations or deformities that appear on the patient’s face. It is not uncommon for those affected to feel ashamed of their symptoms in the process, and they also continue to suffer from inferiority complexes or significantly lowered self-esteem. For this reason, the patients are not infrequently also dependent on psychological treatment. Furthermore, those affected suffer from hair loss and thus baldness. In children, this can lead to teasing or even bullying. In addition, it is not uncommon for children to suffer from growth disorders, which can lead to subsequent damage and possible complications in adulthood. The pigmentation of those affected is also usually disturbed. However, mental development is not disturbed or otherwise affected by this disease. The disease can usually be treated well. Complications do not occur and most of the symptoms can be treated. Some deformities and malpositions cannot be removed. The life expectancy of the patient is also not reduced by this disease in most cases. Treatments usually need to be performed at an early age to avoid complications in adulthood.
When should you see a doctor?
If an unusual gap in the skull is noticed when the baby is born, action is needed. Since in most cases the expectant mother is in an inpatient stay with the child at the time of delivery, the necessary steps are taken independently by the medical team. In the case of a home birth or a birth in a birth center, the midwife usually takes over the first examinations of the newborn and takes care of comprehensive medical care of the infant. If a spontaneous birth occurs without the presence of nurses, obstetricians or physicians, an emergency medical service should be alerted immediately so that emergency medical care can be initiated. If a child’s lack of hair growth becomes apparent during the further course of development, this is a sign of an existing health impairment and must be clarified by a doctor. Delayed growth is also a cause for concern. If the growing child shows a strong reduction in growth in direct comparison to children of the same age, the observations should be discussed with a doctor. Changes and abnormalities in the appearance of the skin should also be examined by a specialist. Spots on the skin or discoloration should be presented to a physician. Deformities of the body are indications of a present disease. If deformities of the upper body or limbs occur, a visit to the doctor is necessary.
Treatment and therapy
Mandibuloacral dysplasias are considered incurable to date. A cure would only be conceivable by causative therapy on the mutated genes. Gene therapy is a major subject of medical research but has not yet reached the clinical stage. For this reason, mutation-related diseases such as mandibuloacral dysplasia have so far been treated purely symptomatically. In particular, the insulin resistance of affected individuals is treated as part of this treatment. Therapeutic options to combat insulin resistance include increasing the supply of insulin by means of an intravenous drug pump. Dietary measures are also an option in connection with insulin resistance. However, the effect of this measure is still controversial. To date, the most common agents used to reduce resistance are acarbose, metformin, and insulin sensitizers such as pioglitazone. Depending on the patient’s other symptoms, additional administration of leptin, for example, may be required to treat any lipatrophies. The abnormal tooth positions usually require orthodontic intervention. The deformity of the thorax requires surgical treatment. The hypoplasias of the clavicles can be reconstructed surgically.If there is a desire to continue having children, parents of affected children will receive genetic counseling to inform them of the risk of recurrence and any other links to inheritance.
Outlook and prognosis
Mandibuloacral dysplasia has an unfavorable prognosis. To date, there is no therapy directed at treating the cause. The dysplasia is based on a genetic defect in the patient. Therefore, the first impairments show up immediately after birth. Since it is not legally allowed to change the genetics of the human being, doctors have to focus on treating the symptoms. The severity of the disorder must be evaluated individually in each patient with mandibuloacral dysplasia. What they all have in common is that lifelong medical care is necessary. Otherwise, unfavorable changes in the course of the disease may occur or irreversible secondary disorders may set in. In order to improve the overall situation, the earliest possible medical care is necessary. Often the first steps are taken immediately after birth. Malformations in the area of the face or the cranial suture are corrected by various medical procedures. This leads to the necessity of surgical interventions already in the first years of life. This has a negative impact on the psychological stability of many of those affected. Often there is a need for psychotherapeutic treatment. Otherwise, there is a risk of secondary disorders, which contribute to a further deterioration of the prognosis. Although freedom from symptoms is not achieved despite all efforts, significant improvements and alleviation of symptoms have been achieved in recent years.
Prevention
Mandibuloacral dysplasia is a genetic hereditary disease. Therefore, to date, it can only be prevented by deciding not to have one’s own children if there is a family predisposition.
Follow-up
As a rule, the options for aftercare in the case of a malformation syndrome are extremely limited. Since no complete cure is possible, follow-up care can only focus on purely symptomatic treatment and not causal treatment. If there is a desire for children in the affected person, genetic counseling may be advisable to exclude the inheritance of the syndrome to the descendants. Self-cure may not occur. Whether the life expectancy of the affected person is reduced by the malformation syndrome can also not be universally predicted. In most cases, the affected persons are dependent on intensive care and permanent support from their parents and family. Above all, loving and intensive care has a positive effect on the course of the disease and can prevent complications. Furthermore, regular examinations by doctors are also necessary in order to detect and treat damage to the body and internal organs at an early stage. In the case of psychological upsets or depression, discussions with friends or family are also very helpful in alleviating the symptoms. Contact with other sufferers of the syndrome can also be useful.
This is what you can do yourself
Patients with mandibuloacral dysplasia are usually not limited in their mental development and therefore suffer mainly from the physical deformities associated with the disease. In particular, the abnormalities in the face of affected individuals sometimes result in inferiority complexes or even depression. In such cases, patients seek the help of a psychotherapist to improve their individual quality of life. Since patients sometimes suffer from sparse hair growth or even baldness, wigs can conceal the cosmetic blemish if the desire to do so exists. To better deal with the physical anomalies, physiotherapeutic care makes sense, with the patient performing appropriate exercises at home. Nevertheless, surgical interventions to correct certain deformities are often essential, so the patient temporarily undergoes inpatient treatment. In addition, the affected person is dependent on various medications, especially regarding the drug therapy of the existing insulin resistance. Attending a special school is useful for the patients in order to facilitate social contacts and integration. Basically, mandibuloacral dysplasia does not affect the life expectancy of the patients, so that a comparatively high quality of life can be achieved.The prerequisite for this is the support of the social environment and adequate medical care for the patients.
