Mandibuloacral Dysplasia

Mandibuloacral dysplasia is a congenital malformation syndrome associated with skeletal anomalies and is inherited in an autosomal recessive manner. Two different types of the disease are known, caused by mutations in two different genes. A causal therapy does not yet exist.

Mandibuloacral Dysplasia

What is mandibuloacral dysplasia?

According to Sportingology, dysplasia is the medical term for congenital malformations in the human anatomy, which correspond to changes in cells, entire tissues or organs and are caused, for example, by abnormal growth processes or a lack of differentiation in embryonic development. Dysplasia can be further subdivided.

A subgroup is that of manibuloacral dysplasia, of which two distinct manifestations exist. The expression MADA mainly affects the extremities. In the MADB form, the disease manifests itself all over the body. Both forms are grouped under malformation syndromes with congenital changes in the skeleton.

The prevalence of manibuloactral dysplasia is extremely low, occurring in one in 1,000,000 people. The terms restrictive dermopathy and craniomandibular dermatodysostosis are synonyms for the congenital disease. In 1971, the group of diseases was first documented by LW Young and colleagues.

Four years later, O. Welsh defined the symptoms as an independent clinical picture. In addition to the late closure of the fontanel and patchy skin pigmentation, the main features of the disease are facial abnormalities, mandibular hypoplasia and underdeveloped collarbones of the patients.


The two different forms of mandibuloacral dysplasia do not occur sporadically. Familial accumulations have been observed in the previously documented cases. Inheritance appears to be most likely to be autosomal dominant. The symptom complex of both forms is apparently based on a mutation as a 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 codes for lamin A/C, which are part of the core 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.

Related syndromes are 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 the DNA at locus 1p34 and codes for the zinc endoprotease, which is necessary for the synthesis of the lamin A/C protein.

Symptoms, Ailments & Signs

Patients with mandibuloacral dysplasia suffer from various clinical symptoms. The most important criteria of the disease include the delayed closure of the fontanel and insulin resistance. Symptomatically, these symptoms are associated with facial abnormalities, especially with wide cranial sutures, so-called interlocking bones and a prominent head vein.

In addition, patients may be bald, have a bird’s-head face, or have pseudoexophthalmos. The tooth position of those affected is often abnormal. Growth retardation usually occurs from the age of six. Dermally, the disease manifests itself in the form of sclerosis of the skin and patchy hyperpigmentation in the neck area.

The mandible and the clavicles of the patients are underdeveloped. The chest is deformed like a bell. In addition, acroosteolysis of the hands and feet often occurs in infancy. The fingernails and toenails of those affected often show dystrophies. The interphalangeal joints are often prominent. The clinical picture is rounded off by signs of progeria and diffusely altered connective tissue or anomalies in the vessel walls.

Diagnosis & course of disease

The doctor harbors a first suspicion of mandibuloacral dysplasia after the visual diagnosis. The clinical abnormalities are characteristic. Nevertheless, a differential diagnosis must be made to distinguish it from diseases such as Werner syndrome, Hutchinson-Gilford syndrome, clodocranial dysplasia and acrogery. The clinically similar symptoms of Crane-Heise syndrome and Yunis-Varon syndrome must also be excluded.

If mandibuloacral dysplasia is suspected, molecular genetic analysis is used to rule out these diseases and confirm the diagnosis. For this purpose, coding exons from the LMNA gene or ZMPSTE24 gene are analyzed from the genomic DNA. With the help of MLPA, the gene is checked for duplications or deletions. Evidence of any mutations at the characteristic site is regarded as conclusive for the diagnosis.


This condition usually leads to various deformities or deformities appearing on the patient’s face. It is not uncommon for those affected to feel ashamed of the symptoms and continue to suffer from inferiority complexes or a significantly reduced sense of self-esteem. For this reason, patients are often dependent on psychological treatment.

Furthermore, those affected suffer from hair loss and thus from a bald head. This can lead to teasing or even bullying in children. In addition, children often suffer from growth disorders, so that there can be consequential damage and possible complications in adulthood. The pigmentation of those affected is usually disturbed. However, mental development is not disturbed or otherwise affected by this disease.

The disease can usually be treated well. There are no complications and most complaints can be treated. Some malpositions and deformations cannot be removed with it. In most cases, the life expectancy of the patient is not reduced by this disease. The treatments usually have to be carried out at an early age to avoid complications in adulthood.

When should you go to the doctor?

If an unusual gap is found in the skull when the child is born, there is a need for action. Since the mother-to-be is in most cases in hospital when giving birth with the child, the necessary steps are taken independently by the medical team. In the case of a home birth or childbirth in a birth center, the midwife usually carries out the initial examinations of the newborn and takes care of comprehensive medical care for the infant.

If a spontaneous birth occurs without the presence of nurses, obstetricians or doctors, an emergency service must be alerted immediately so that emergency medical care can be initiated. If the child shows a lack of hair growth in the further course of development, this is a sign of an existing health impairment and must be clarified by a doctor. Delays in growth are also a concern. If the growing child shows severe short stature in direct comparison to children of the same age, the observations should be discussed with a doctor.

Changes and abnormalities in the complexion should also be examined by a specialist. Stains on the skin or discoloration should be presented to a doctor. Deformations of the body are indications of an existing disease. If there are malformations of the upper body or limbs, a doctor’s visit is necessary.

Treatment & Therapy

Mandibuloacral dysplasia has so far been considered incurable. A cure would only be conceivable through causal 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.

Above all, the insulin resistance of those affected is treated as part of this treatment. Therapy options against insulin resistance are, for example, increasing insulin delivery through an intravenous drug pump. Dietary measures can also be considered in connection with insulin resistance. However, the effect of this measure is still the subject of controversy.

The most commonly used drugs to reduce resistance are acarbose, metformin and insulin sensitizers such as pioglitazone. Depending on the other symptoms of the patient, the administration of leptin, for example, may also be necessary to treat any lipatrophies. The abnormal tooth positions usually require orthodontic intervention.

The deformity of the chest must be treated surgically. The hypoplasia of the clavicles can be repaired surgically. If there is a desire to have more children, the parents of affected children receive genetic counseling, which informs them of the risk of recurrence and all other aspects of inheritance.

Outlook & Forecast

Mandibuloacral dysplasia has an unfavorable prognosis. So far, there is no therapy that is aimed at treating the cause. The dysplasia is based on a genetic defect in the patient. Therefore, the first impairments become apparent immediately after birth. Because it’s not legal to change people’s genetics, doctors must focus on treating the symptoms. The extent of the disorder must be assessed individually for each patient with mandibuloacral dysplasia. What they all have in common is that lifelong medical care is necessary.

Otherwise, there may be unfavorable changes in the course of the disease or irreversible sequelae. In order to improve the entire situation, medical care must be provided as soon as possible. The first steps are often taken immediately after birth. Malformations in the area of ​​the face or the cranial suture are corrected by various medical procedures. As a result, surgical interventions are already necessary in the first years of life. This has a negative impact on the psychological stability of many of those affected.

Psychotherapeutic treatment is often necessary. Otherwise there is a risk of subsequent disorders that contribute to a further deterioration in the prognosis. Although no freedom from symptoms is achieved despite all efforts, significant improvements and alleviations of the symptoms have been achieved in recent years.


Mandibuloacral dysplasia is an inherited genetic disorder. So far, it can only be prevented if the decision is made against one’s own children in the case of family disposition.


As a rule, the options for aftercare in the case of a malformation syndrome are extremely limited. Since complete healing is not possible, aftercare can only focus on purely symptomatic and not causal treatment. If the affected person wishes to have children, genetic counseling may be advisable in order to rule out passing the syndrome on to the descendants.

Self-healing cannot occur. Whether the life expectancy of the affected person is reduced by the malformation syndrome cannot be universally predicted either. In most cases, those affected 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 and can prevent complications.

Regular examinations by doctors are also necessary in order to detect and treat damage to the body and internal organs at an early stage. Talking to friends or family is also very helpful in relieving the symptoms of mental upsets or depression. Contact with other people affected by the syndrome can also be useful.

You can do that yourself

Patients with mandibuloacral dysplasia are usually intellectually unrestricted and suffer primarily from the physical deformities associated with the disease. In particular, the abnormalities on the face of those affected sometimes result in inferiority complexes or even depression. In such cases, patients seek the help of a psychotherapist in order to increase the individual quality of life. Since the patients sometimes suffer from sparse hair growth or even a bald head, wigs can conceal the cosmetic flaws if there is a desire to do so.

To deal better with the physical abnormalities, physiotherapeutic care makes sense, with the patient doing suitable exercises at home. Nevertheless, surgical interventions to correct certain malformations are often essential, so that the patient is temporarily admitted to inpatient treatment. In addition, those affected are dependent on various medications, in particular the drug therapy of the existing insulin resistance.

Attending a special school makes sense for the patients to facilitate social contacts and integration. In principle, mandibuloacral dysplasia does not affect the life expectancy of the patient, 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 of the patients.