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Mandibuloacral Dysplasia


Last updated: January 28, 2013
Years published: 2013


NORD gratefully acknowledges Guiseppe Novelli, MD, Department of Biopathology and Diagnostic Imaging, University of Rome, Italy and Maria Rosaria D’Apice, MD, Laboratory of Medical Genetics, University of Rome, Italy, for assistance in the preparation of this report.

Disease Overview


Mandibuloacral dysplasia (MAD) is an extremely rare genetic disorder characterized by underdevelopment (hypoplasia) of the lower jaw (mandible) and the collarbone (clavicle), bone loss at the ends of the fingers and toes (acro-osteolysis), skin degeneration (cutaneous atrophy), and partial lipodystrophy, a condition marked by selective loss of body fat (adipose tissue) from various areas of the body. Cutaneous atrophy and lipodystrophy may contribute to affected children having a prematurely-aged appearance (progeroid features). Lipodystrophy may be associated with clinical features of metabolic syndrome including insulin resistance, impaired glucose tolerance, and diabetes mellitus. Additional symptoms can occur as well. Two types of mandibuloacral dysplasia have been identified, type A and type B. Both types are inherited as autosomal recessive conditions. Mandibuloacral dysplasia type A (MADA) is caused by mutations of the lamin A/C (LMNA) gene; mandibuloacral dysplasia type B (MADB) is caused by mutations of the zinc metalloproteinase (ZMPSTE24) gene.


Mandibuloacral dysplasia may be classified as a form of lipodystrophy or progeria because of its overlapping symptoms. Mandibuloacral dysplasia type A may also be classified as a laminopathy, a general term for the group of disorders associated with a mutation of the LMNA gene. The ZMPSTE24 mutation that causes mandibuloacral dysplasia type B can also cause restrictive dermopathy syndrome.

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  • MAD type A (MADA)
  • MAD type B (MADB)
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Signs & Symptoms

The signs and symptoms of mandibuloacral dysplasia can vary from one person to another. The age of onset of certain symptoms can vary as well. Children with mandibuloacral dysplasia type A often develop normally for the first 4 to 5 years of life. Children with mandibuloacral dysplasia type B can develop noticeable symptoms of the disorder by the age of 2. Mandibuloacral dysplasia type B has only been described in a handful of children. Common symptoms associated with both forms of the disorder have been characterized, but, because of the low number of identified cases, it is difficult to get an accurate picture of associated symptoms and prognosis.

Affected individuals often develop skeletal abnormalities including underdevelopment of the jaw bone giving the appearance of a receding chin. The collarbone may be underdeveloped or malformed (dysplastic) giving the appearance of sloping shoulders. Delayed closure of the fibrous joints of the skull (cranial sutures) in affected infants is common. Bone loss may occur at the ends of the finger and toes, giving them a rounded (bulbous) or stubby appearance.

Affected individuals may have “progeroid” features that give them a prematurely aged appearance. Such features include a distinctive facial appearance, a mottled skin color (pigmentation), thin, sparse hair with patchy areas of hair loss (alopecia), loss of eyebrows, malformation of the fingernails and toenails, and degeneration of the skin, especially the skin of the hands and feet. The distinctive facial features associated with this disorder may include prominent eyes, pointed (pinched) nose, small mouth, and a receding chin (due to mandibular hypoplasia). Affected individuals may also have a high-pitched voice. Some individuals may experience delayed sexual maturation. The progeroid appearance may be more pronounced in individuals with mandibuloacral dysplasia type B.

Individuals with mandibuloacral dysplasia may develop lipodystrophy, a condition characterized by the loss of body (subcutaneous) fat. Two different patterns of partial lipodystrophy have been identified. In one form, fat loss occurs primarily on the arms and legs and sometimes the trunk. Fat may be normal or slightly excess in the neck, the back of the head (occiput) and upper back causing a hump, and trunk areas. In the other form, fat loss occurs in a more widespread (generalized) form affecting the face, trunk and arms and legs. Many individuals with mandibuloacral dysplasia type A have developed lipodystrophy around puberty, but earlier development has been reported. Individuals with mandibuloacral dysplasia type B have developed the generalized form of lipodystrophy, but onset may not be until later during childhood.

Lipodystrophy may be associated with the clinical features of metabolic syndrome. Metabolic complications have generally been mild in individuals with mandibuloacral dysplasia. Insulin resistance may occur and can be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Acanthosis nigricans has not been reported in individuals with mandibuloacral dysplasia type B. Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes.

Additional symptoms have been reported including dental abnormalities such as premature loss of teeth and overcrowding, stiff and/or rigid joints, and growth retardation ultimately resulting in adult height that is below normal (short stature).

Some individuals with mandibuloacral dysplasia type B have developed muscle disease (myopathy). Later in life, they are at risk of developing calcified skin nodules, cardiovascular disease such as high blood pressure or hardening of the arteries (atherosclerosis), and a kidney disease known as focal segmental glomerulosclerosis (FSGS). This kidney disorder occurs when clusters of capillaries known as renal glomeruli, which normally filter the blood that passes through the kidneys, are replaced by scar tissue. This condition can cause foamy urine due to the presence of excess protein, swelling due to abnormal fluid accumulation (edema), high blood pressure, and weight gain. FSGS can potentially progress to cause severe complications such as nephrotic syndrome and, ultimately, kidney failure.

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Mandibuloacral dysplasia type A is caused by mutations of the LMNA gene; type B is caused by mutations of the ZMPSTE24 gene. Some individuals with mandibuloacral dysplasia do not have mutations of either gene suggesting that additional, as-yet-unidentified genes may also cause the disorder.

The identified mutations that cause mandibuloacral dysplasia are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

The LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22). It contains instructions for creating (encoding) the proteins lamin A and lamin C. These proteins are active in the nuclear lamina, a structure found within many types of cells. The exact functions of lamins A and C and their exact roles in causing the symptoms of mandibuloacral dysplasia are not fully understood. However, researchers believe that the lamin A protein serves as the scaffolding that holds the nucleus of a cell together. Defective lamin A most likely causes the nucleus to become unstable and ultimately leads to the premature aging symptoms seen in mandibuloacral dysplasia. Researchers also suspect that mutations in the LMNA gene ultimately result in the impairment of fat cells (adipocytes) differentiation causing lipodystrophy and of bone cells (osteoclasts) differentiation causing altered bone turnover.

Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of familial partial lipodystrophy (Dunnigan variety), a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and some cases of Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. Some individuals with mutations of the LMNA gene are at a greater risk than the general population of developing cardiovascular disease; it is not known whether individuals with mandibuloacral dysplasia type A are affected by this risk. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

The ZMPSTE24 gene is located on the short arm (p) of chromosome 1 (1p34.2). It contains instructions for creating (encoding) an enzyme whose exact roles in the body is not fully understood, but that is involved in the maturation of lamin A. Researcher believe that this enzyme is required for prelamin A to be processed into mature lamin A. Mutations of the ZMPSTE24 gene ultimately result in an accumulation of prelamin A in various tissues of the body.

Mutations of the ZMPSTE24 gene have also been shown to cause restrictive dermopathy syndrome, a rare, severe disorder characterized by intrauterine growth retardation, malformed collarbones, joint contractures, a fixed facial expression and tight, rigid skin that is easily eroded. In restrictive dermopathy syndrome, there are almost no detectable levels of the enzyme encoded by the ZMPSTE24 gene and the disorder is often fatal during the newborn period. Consequently, some researchers believe that mutations of this gene result in a spectrum of disease, with restrictive dermopathy syndrome representing the severe end of the syndrome and mandibuloacral dysplasia type B representing a less severe form. Researchers believe that the amount of residual enzyme activity among individuals with a ZMPSTE24 gene mutation correlates directly with the severity of the disorder.

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Affected populations

Approximately 40 cases of mandibuloacral dysplasia have been reported in the medical literature. Fewer than 10 cases of mandibuloacral dysplasia type B have been reported in the medical literature. Many cases of the disorder most likely go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of mandibuloacral dysplasia in the general population.

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A diagnosis of mandibuloacral dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.

Molecular genetic testing can confirm a diagnosis of mandibuloacral dysplasia in some cases. Molecular genetic testing can detect mutations in the specific genes that cause the disorder, but the test is only available on a clinical basis.

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Standard Therapies


The treatment of mandibuloacral dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, endocrinologists, dermatologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

Individuals with mandibuloacral dysplasia and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.

Additional therapies to treat individuals with mandibuloacral dysplasia are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin may be recommended to treat hyperglycemia. Insulin or insulin analogues can also be used to treat affected individuals. There have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with mandibuloacral dysplasia.

Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.

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Clinical Trials and Studies

Research is underway to study the use of leptin for the treatment of individuals with lipodystrophy. Leptin is a hormone found in fat cells (adipocytes). Severe lipodystrophy is associated with leptin deficiency. Initial studies have shown that leptin-replacement therapy (metreleptin) has been effective in improving some of the in individuals with certain forms of lipodystrophy with low leptin levels. However, metreleptin has not been studied as a treatment for mandibuloacral dysplasia. Currently, the availability of leptin is restricted to clinical trials and has not yet been approved by the Food and Drug Administration (FDA).

Some researchers have speculated that treatment with a drug known as a farnesyltransferase inhibitor (FTI), used alone or in combination with other drugs including statins and bisphosphonates, may be an effective treatment for mandibuloacral dysplasia. An FTI drug known as lonafarnib has been studied for individuals with Hutchinson-Gilford progeria syndrome for a minimum of 2 years. Nine patients experienced a =50% increase, six experienced a =50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status. A protocol has been designed for treatment of four MADA patients using a combination of pravastatin (statin) and zoledronic acid (nitrogen bisphosphonate), two drugs capable of blocking farnesyl group production. The first results showed good safety and tolerability profile of the treatment, associated to an improvement of MADA phenotype. However, more research is necessary to determine the long-term safety and effectiveness of this potential therapy.

Information on current clinical trials for HGPS patients is posted on the Internet at www.clinicaltrials.gov.

All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. The MADA protocol has been approved by AIFA, the Italian competent authority for drugs.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:


For information about MADA clinical trials being conducted at the Policlinico Tor Vergata, Rome, Italy, contact Prof. Giuseppe Novelli Tel. +39/06/20900664/665, fax +39/06/20900669 or Prof. Paolo Sbraccia Tel. +39/06/72596888, fax +39/06/72596890.

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Cunningham VJ, D’Apice MR, Licata N, et al. Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24. Bone. 2010;47:591-597.

http://www.ncbi.nlm.nih.gov/pubmed/20550970Garavelli L, D’Apice MR, Rivieri F, et al. Mandibuloacral dysplasia type A in childhood. Am J Med Genet A. 2009;149A:2258-2264. http://www.ncbi.nlm.nih.gov/pubmed/19764019

Garg A, Subramanyam L, Agarwal AK, et al. Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab. 2009;94:4971-4983. http://www.ncbi.nlm.nih.gov/pubmed/19875478

Agarwal AK, Kazachkova I, Ten S, Garg A. Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation. J Clin Endocrinol Metab. 2008;93:4617-4623. http://www.ncbi.nlm.nih.gov/pubmed/18796515

Agarwal AK, Zhou XJ, Hall RK, et al. Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med. 2006;54:208-213. http://www.ncbi.nlm.nih.gov/pubmed/17152860

Shackleton S, Smallwood DT, Clayton P, et al. Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype. J Med Genet. 2005;42:e36. http://www.ncbi.nlm.nih.gov/pubmed/15937076

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