MDP syndrome

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MDP syndrome
Other namesMandibular hypoplasia-deafness-progeroid syndrome
Autosomal dominant - en.svg
This condition is inherited in an autosomal dominant manner

MDP syndrome, also known as mandibular dysplasia with deafness and progeroid features, is an extremely rare metabolic disorder that prevents fatty tissue from being stored underneath the skin. It is only known to affect a very small number of people worldwide (less than 12 cases have been diagnosed as of December 2014). Recent research has suggested that it may be caused by an abnormality of the POLD1 gene on chromosome 19, which causes an enzyme crucial to DNA replication to be defective.

Contents

Presentation

Genetics

Initially all people that have been identified with this syndrome have an identical genetic change, an inframe single codon deletion in POLD1 resulting in a loss of serine at position 605. [1] The POLD1 gene is expressed in all cells and the particular change seen in most patients results in loss of DNA polymerase activity but only mildly impairs the proof reading exonuclease activity. In 2014 a second genetic change was reported in an Italian patient, a novel heterozygous mutation in exon 13 (R507C). [2]

Most cases identified to date[ when? ] have been caused by a spontaneous genetic change (so the parents of the individual are unaffected).[ citation needed ]

Diagnosis

The diagnosis of MDP syndrome is suggested by the clinical features. [3] It can be confirmed by finding a mutation in the POLD1 gene, a service offered by the molecular genetics team at the Royal Devon and Exeter NHS Foundation Trust / Exeter University who originally discovered the genetic cause.[ citation needed ]

Management

General appearance

Appearance at birth and during the early years is normal but features become more prominent during later childhood prior to puberty. The main issues appear to be lipodystrophy (see below) and slow growth of cartilage and ligaments. The slow growth of cartilage and ligaments results in a small nose, small mandible (jaw), small ears and tightening of ligaments in the limbs. A small larynx (due to the reduced growth of cartilage) can mean the voice is likely to remain high pitched (even in boys after puberty).[ citation needed ]

Lipodystrophy

A major feature is lipodystrophy (a reduction in fat under the skin). The characteristic changes in facial appearance occur from the loss of fat from the cheeks, and around the eyes. Dry eyes and the failure to close eyes during sleep can be a feature due to the loss of fat around the eyes (rather than any excessive prominence of the eyeballs). Limbs appear very thin due to lack of fat storage and also reduced muscle mass. There is a large amount of fat within the abdominal cavity which, can be particularly marked in the liver (but not always) and surrounds the other organs. A major result of the lipodystrophy in some people is severe insulin resistance so insulin does not work very well leading to diabetes and high triglyceride levels in the blood. The effect of insulin resistance can be variable and may relate to progression of the lipodystrophy or may reflect variation between individuals.[ citation needed ]

The skin has a lack of fat and fibrosis. These in turn result in the tight skin on the face and limbs. One direct feature of the lipodystrophy is that the skin is fragile and there is not the protection normally provided by fat under the skin.[ citation needed ]

Management of lipodystrophy

As fat cannot be stored under the skin it is important to have a healthy diet without excess fat. Often due to failure to thrive or lack of subcutaneous fat there may have been encouragement to add supplements or fat to the diet however this will not result in any increase in fat under the skin and can easily result in it going into tissues such as the liver or kidney where it is not desired. In people with moderate / severe lipodystrophy a low fat diet would be recommended but in those where the lipodystrophy has not progressed (for example in younger children) a healthy relatively low fat diet may be sufficient. The fat and muscle reduction is not the result of dietary insufficiency and cannot be treated with dietary measures. Apart from diet the other thing that is important is exercise which should be encouraged and will make insulin work more effectively.[ citation needed ]

In those who have not developed diabetes it is recommended fasting insulin, triglycerides, glucose and HbA1c should be measured annually to monitor insulin resistance and blood glucose.[ citation needed ]

In those with diabetes it is suggested using metformin in doses of at least 2g/day as it decreases insulin resistance and improves insulin sensitivity, following appropriate clinical consultation.[ citation needed ]

The thin skin means if there is trauma there should be rapid attention to any wounds to avoid infection and help primary healing as there can be problems with skin ulcers.[ citation needed ]

Low testosterone/hypogonadism in males

Some males have had undescended testes but in all cases, whether or not this was corrected, they have hypogonadism (reduced function of the testes) and many may be infertile due to inadequate testicular development. In females normal periods have been observed. Low testosterone will require testosterone replacement. In peri-pubertal males, adequate testosterone replacement is required for its anabolic affects such as growth and also the induction of puberty with high doses. This needs to be coordinated with growth hormone replacement (if given) to avoid early closure of the epitheses (ends of the bones) which would reduce height.[ citation needed ]

Growth

Although in the original clinical description short stature was included in the characteristics of MDP syndrome, looking at the data closely it showed that many patients were well within the normal range. If growth is of concern growth hormone therapy could be considered and coordinated with testosterone replacement where appropriate.[ citation needed ]

Deafness

Deafness is a feature of MDP syndrome as a result of the nerves not working well and people often have difficulty getting hearing aids because of the small size of their ears. Digital hearing aids can be helpful and audiometry follow up will be needed.[ citation needed ]

Feet/contractures

There may be different problems associated with MDP syndrome in the feet. The lack of subcutaneous fat means that there is direct pressure on the skin resulting in callus (hard skin) on the heels and also the weight-bearing parts of the forefoot. This is best managed by trying to find insoles to support the foot but it's difficult to avoid completely. There is no approach that will increase the subcutaneous fat. The second feature is clawed toes as a result of contraction of the long extender tendons. The contractured constrictions can get worse over time. It is worth considering a physiotherapy referral with an aim to establish exercises to try to keep the tendons stretched if possible.[ citation needed ]

Dental

The failure of growth of the mandible (lower jaw) can rapidly result in dental overcrowding. In this case it is best to remove teeth early rather than hoping that there will be mandibular (lower jaw) growth. Overcrowding can result in the teeth being severely displaced and again it is best to act early because later correction orthodontically can be extremely difficult.[ citation needed ]

Development

Many people with MDP syndrome are high achievers intellectually following careers in law, medicine and computing. A crucial point is that they do not have progeria and there is no evidence of accelerated intellectual decline with age in these patients. Equally life expectancy has not been shown to be reduced. Patients of 65 have been described in the literature and none of the patients are known to have malignancy. Therefore, there are many crucial differences with progeria and the name of progeroid in the title is confusing as this really refers to the lack of fat in the face and taut skin and not any intellectual or other age associated features.[ citation needed ]

General

It is helpful to co-ordinate clinical care as much as possible, this may be managed best by a consultant endocrinologist as the most active management is going to relate to the management of lipodystrophy, insulin resistance, diabetes and testosterone replacement therapy and growth hormone replacement if required. Other local specialists could provide care when this is needed.[ citation needed ]

Research

The condition was diagnosed by researchers at the University of Exeter Medical School and Molecular Genetics Department at the Royal Devon and Exeter Hospital.

Society and culture

British para-cyclist Tom Staniford is reported to have this condition. [4] [5] [6] [7]

Related Research Articles

Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy, is used when describing the loss of fat from one area. This condition is also characterized by a lack of circulating leptin which may lead to osteosclerosis. The absence of fat tissue is associated with insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome.

<span class="mw-page-title-main">Wolfram syndrome</span> Human disease

Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration.

<span class="mw-page-title-main">SHORT syndrome</span> Medical condition

SHORT syndrome is an uncommon autosomal-dominant condition marked by ocular depression, Rieger anomaly, teething delay, small height, hyperextensibility of joints, and/or hernias. It was characterized in 1975.

<span class="mw-page-title-main">Alström syndrome</span> Rare genetic disorder involving childhood obesity and multiple organ dysfunction

Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early-onset type 2 diabetes, cone-rod dystrophy resulting in blindness, sensorineural hearing loss and dilated cardiomyopathy. Endocrine disorders typically also occur, such as hypergonadotrophic hypogonadism and hypothyroidism, as well as acanthosis nigricans resulting from hyperinsulinemia. Developmental delay is seen in almost half of people with Alström syndrome.

<span class="mw-page-title-main">Micrognathism</span> Condition in which the jaw is small

Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can hamper feeding. It can also, both in adults and children, make intubation difficult, either during anesthesia or in emergency situations.

Macrodontia is a type of localized gigantism in which teeth are larger than normal. Macrodontia seen in permanent teeth is thought to affect around 0.03 to 1.9 percent of the worldwide population. Generally, patients with macrodontia have one or two teeth in their mouth that is abnormally large; however, single tooth growth is seen in a number of cases as well.

Rabson–Mendenhall syndrome is a rare autosomal recessive disorder characterized by severe insulin resistance. The disorder is caused by mutations in the insulin receptor gene. Symptoms include growth abnormalities of the head, face and nails, along with the development of acanthosis nigricans. Treatment involves controlling blood glucose levels by using insulin and incorporating a strategically planned, controlled diet. Also, direct actions against other symptoms may be taken This syndrome usually affects children and has a prognosis of 1–2 years.

Barraquer–Simons syndrome is a rare form of lipodystrophy, which usually first affects the head, and then spreads to the thorax. It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician. Some evidence links it to LMNB2.

<span class="mw-page-title-main">Gerodermia osteodysplastica</span> Medical condition

Gerodermia osteodysplastica (GO) is a rare autosomal recessive connective tissue disorder included in the spectrum of cutis laxa syndromes.

Congenital generalized lipodystrophy is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystrophy disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

Acquired generalized lipodystrophy (AGL), also known as Lawrence syndrome and Lawrence–Seip syndrome, is a rare skin condition that appears during childhood or adolescence, characterized by fat loss affecting large areas of the body, particularly the face, arms, and legs. There are four types of lipodystrophy based on its onset and areas affected: acquired or inherited, and generalized or partial. Both acquired or inherited lipodystrophy present as loss of adipose tissues, in the absence of nutritional deprivation. The near-total loss of subcutaneous adipose tissue is termed generalized lipodystrophy while the selective loss of adipose tissues is denoted as partial lipodystrophy. Thus, as the name suggests, AGL is a near-total deficiency of adipose tissues in the body that is developed later in life. It is an extremely rare disease with only about 100 cases reported worldwide. There are three main etiologies of AGL suspected: autoimmune, panniculitis-associated, or idiopathic. After its onset, the disease progresses over a few days, weeks, months, or even in years. Clinical presentations of AGL are similar to other lipodystrophies, including metabolic complications and hypoleptinemia. Treatments are also similar and mainly supportive for symptomatic alleviation. Although HIV- or drug-induced lipodystrophy are types of acquired lipodystrophy, their origins are very specific and distinct and hence are usually not discussed with AGL.

Familial partial lipodystrophy, also known as Köbberling–Dunnigan syndrome, is a rare genetic metabolic condition characterized by the loss of subcutaneous fat.

<span class="mw-page-title-main">Wolcott–Rallison syndrome</span> Medical condition

Wolcott–Rallison syndrome,WRS, is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the eukaryotic translation initiation factor 2-alpha kinase 3. Other disease names include multiple epiphyseal dysplasia and early-onset diabetes mellitus. Most patients with this disease do not survive to adulthood. The majority of WRS patients die from fulminant hepatitis during childhood. There are few reported cases for this disease. Of the 54 families worldwide with reported WRS cases, 22.2% of them are from the Kingdom of Saudi Arabia. Of the 23 WRS patients in Saudi Arabia, all but one is the result of consanguineous marriages. Another country where WRS cases have been found is Kosovo. Here, the Albanian population is also known for consanguineous marriages, but there were some cases involving patients from non-consanguineous parents that were carriers for the same mutant allele.

<span class="mw-page-title-main">Johanson–Blizzard syndrome</span> Medical condition

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<span class="mw-page-title-main">Donohue syndrome</span> Medical condition

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Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term progeroid syndrome does not necessarily imply progeria, which is a specific type of progeroid syndrome.

<span class="mw-page-title-main">Wiedemann–Rautenstrauch syndrome</span> Medical condition

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<span class="mw-page-title-main">Marfanoid–progeroid–lipodystrophy syndrome</span> Medical condition

Marfanoid–progeroid–lipodystrophy syndrome (MPL), also known as Marfan lipodystrophy syndrome (MFLS) or progeroid fibrillinopathy, is an extremely rare medical condition which manifests as a variety of symptoms including those usually associated with Marfan syndrome, an appearance resembling that seen in neonatal progeroid syndrome, and severe partial lipodystrophy. It is a genetic condition that is caused by mutations in the FBN1 gene, which encodes profibrillin, and affects the cleavage products of profibrillin, fibrillin-1, a fibrous structural protein, and asprosin, a glucogenic protein hormone. As of 2016, fewer than 10 cases of the condition have been reported. Lizzie Velásquez and Abby Solomon have become known publicly through the media for having the condition.

References

  1. ↑ Weedon, Michael N; Ellard, Sian; Prindle, Marc J; Caswell, Richard; Allen, Hana Lango; Oram, Richard; Godbole, Koumudi; Yajnik, Chittaranjan S; Sbraccia, Paolo; Novelli, Giuseppe; Turnpenny, Peter; McCann, Emma; Goh, Kim Jee; Wang, Yukai; Fulford, Jonathan; McCulloch, Laura J; Savage, David B; O'Rahilly, Stephen; Kos, Katarina; Loeb, Lawrence A; Semple, Robert K; Hattersley, Andrew T (2013). "An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy". Nature Genetics. 45 (8): 947–950. doi:10.1038/ng.2670. ISSN   1061-4036. PMC   3785143 . PMID   23770608.
  2. ↑ Pelosini C, Martinelli S, Ceccarini G, Magno S, Barone I, Basolo A, et al. (2014). "Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome". Metabolism. 63 (11): 1385–9. doi:10.1016/j.metabol.2014.07.010. PMID   25131834.
  3. ↑ Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, et al. (2010). "A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism". J Clin Endocrinol Metab. 95 (10): E192–7. doi:10.1210/jc.2010-0419. PMC   3050107 . PMID   20631028.
  4. ↑ Philippa Roxby (16 June 2013). "Gene mutation means paracyclist has no fat under skin". BBC News.
  5. ↑ "Riddle of athlete's illness is solved by scientists". Herald Scotland. 17 July 2013.
  6. ↑ "Advances in genetic sequencing diagnose Paralympic hopeful's rare condition". University of Exeter. 14 February 2014.
  7. ↑ Heather Saul (17 June 2013). "Scientists track down genetic mutation that stops former paracyling champion Tom Staniford storing fat". The Independent.
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