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Enfermedad de Machado-Joseph

Table of Contents (click to jump to sections)

What is Machado-Joseph Disease?
What are the different types of Machado-Joseph Disease?
What causes Machado-Joseph Disease?
How is Machado-Joseph Disease diagnosed?
How is Machado-Joseph Disease treated?
What research is being done?
Where can I get more information?

What is Machado-Joseph Disease?

Machado-Joseph disease (MJD)-also called spinocerebellar ataxia type 3-is a rare hereditary ataxia. (Ataxia is a general term meaning lack of muscle control.) The disease is characterized by clumsiness and weakness in the arms and legs, spasticity, a staggering lurching gait easily mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements, double vision, and frequent urination. Some patients have dystonia (sustained muscle contractions that cause twisting of the body and limbs, repetitive movements, abnormal postures, and/or rigidity) or symptoms similar to those of Parkinson’s disease. Others have twitching of the face or tongue, or peculiar bulging eyes.

The severity of the disease is related to the age of onset, with earlier onset associated with a more severe form of the disease. Symptoms can begin any time between early adolescence and about 70 years of age. MJD is also a progressive disease, meaning that symptoms get worse with time. Life expectancy ranges from the mid-thirties for those with severe forms of MJD to a normal life expectancy for those with mild forms. For those who die early from the disease, the cause of death is often aspiration pneumonia.

The name, Machado-Joseph, comes from two families of Portuguese/Azorean descent who were among the first families described with the unique symptoms of the disease in the 1970s. The prevalence of the disease is still highest among people of Portuguese/Azorean descent. For immigrants of Portuguese ancestry in New England, the prevalence is around one in 4,000. The highest prevalence in the world, about one in 140, occurs on the small Azorean island of Flores. Recently, researchers have identified MJD in several family groups not of obvious Portuguese descent, including an African-American family from North Carolina, an Italian-American family, and several Japanese families. On a worldwide basis, MJD is the most prevalent autosomal dominant inherited form of ataxia, based on DNA studies.


What are the different types of Machado-Joseph Disease?

The types of MJD are distinguished by the age of onset and range of symptoms. Type I is characterized by onset between 10 and 30 years of age, fast progression, and severe dystonia and rigidity. Type II MJD generally begins between the ages of 20 and 50 years, has an intermediate progression, and causes symptoms that include spasticity (continuous, uncontrollable muscle contractions), spastic gait, and exaggerated reflex responses. Type III MJD patients have an onset between 40 and 70 years of age, a relatively slow progression, and some muscle twitching, muscle atrophy, and unpleasant sensations such as numbness, tingling, cramps, and pain in the hands, feet, and limbs. Almost all MJD patients experience vision problems, including double vision (diplopia) or blurred vision, loss of ability to distinguish color and/or contrast, and inability to control eye movements. Some MJD patients also experience Parkinson’s-like symptoms, such as slowness of movement, rigidity or stiffness of the limbs and trunk, tremor or trembling in the hands, and impaired balance and coordination.


What causes Machado-Joseph Disease?

MJD is classified as a disorder of movement, specifically a spinocerebellar ataxia. In these disorders, degeneration of cells in an area of the brain called the hindbrain leads to deficits in movement. The hindbrain includes the cerebellum (a bundle of tissue about the size of an apricot located at the back of the head), the brainstem, and the upper part of the spinal cord. MJD is an inherited, autosomal dominant disease, meaning that if a child inherits one copy of the defective gene from either parent, the child will develop symptoms of the disease. People with a defective gene have a 50 percent chance of passing the mutation on to their children.

MJD belongs to a class of genetic disorders called triplet repeat diseases. The genetic mutation in triplet repeat diseases involves the extensive abnormal repetition of three letters of the DNA genetic code. In the case of MJD the code “CAG” is repeated within a gene located on chromosome 14q. The MJD gene produces a mutated protein called ataxin-3. This protein accumulates in affected cells and forms intranuclear inclusion bodies, which are insoluble spheres located in the nucleus of the cell. These spheres interfere with the normal operation of the nucleus and cause the cell to degenerate and die.

One trait of MJD and other triplet repeat diseases is a phenomenon called anticipation, in which the children of affected parents tend to develop symptoms of the disease much earlier in life, have a faster progression of the disease, and experience more severe symptoms. This is due to the tendency of the triplet repeat mutation to expand with the passing of genetic material to offspring. A longer expansion is associated with an earlier age of onset and a more severe form of the disease. It is impossible to predict precisely the course of the disease for an individual based solely on the repeat length.


How is Machado-Joseph Disease diagnosed?

Physicians diagnose MJD by recognizing the symptoms of the disease and by taking a family history. They ask detailed questions about family members who show, or showed, symptoms of the disease, the kinds of symptoms these relatives had, the ages of disease onset, and the progression and severity of symptoms. A definitive diagnosis of MJD can only be made with a genetic test. Unfortunately, many legal and ethical considerations, such as loss of health insurance and employment discrimination, may discourage some individuals with symptoms from getting tested. For the same reasons, many physicians recommend against genetic testing for those individuals who have a family history of the disease but do not show symptoms. For more information on genetic testing and counseling, please consult the organizations listed in the section titled “Where can I get more information?


How is Machado-Joseph Disease treated?

MJD is incurable, but some symptoms of the disease can be treated. For those patients who show parkinsonian features, levodopa therapy can help for many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also treat severe spasticity as well as some symptoms of dystonia. However, botulinum toxin should be used as a last resort due to the possibility of side effects, such as swallowing problems (dysphagia). Speech problems (dysarthria) and dysphagia can be treated with medication and speech therapy. Wearing prism glasses can reduce blurred or double vision, but eye surgery has only short-term benefits due to the progressive degeneration of eye muscles. Physiotherapy can help patients cope with disability associated with gait problems, and physical aids, such as walkers and wheelchairs, can assist the patient with everyday activities. Other problems, such as sleep disturbances, cramps, and urinary dysfunction, can be treated with medications and medical care.


What research is being done?

The National Institute of Neurological Disorders and Stroke (NINDS) supports research on MJD and other neurodegenerative diseases in an effort to learn how to better treat, prevent, and even cure these diseases. Ongoing research includes efforts to better understand the genetic, molecular, and cellular mechanisms that underlie triplet repeat diseases. Other research areas include the development of novel therapies to treat the symptoms of MJD, efforts to identify diagnostic markers and to improve current diagnostic procedures for the disease, and population studies to identify affected families.

Where can I get more information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:

P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424


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Progressive non-infectious anterior vertebral fusion, split cord malformation and situs inversus visceralis

Ali Al Kaissi1,2 email, Farid Ben Chehida3 email, Maher Ben Ghachem2 email, Franz Grill4 email and Klaus Klaushofer1 email

1Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 4th Medical Department, Hanusch Hospital. Heinrich Collins Str. 30 A-1140, Vienna, Austria

2Department of Paediatric Orthopaedic Surgery-Children Hospital of Tunis, Jabari, 1007, Tunisia

3Center of Radiology-Department of Imaging Studies-Ibn Zohr Institute, Tunis, City Khadra 1003, Tunisia

4Orthopaedic Hospital of Speising, Paediatric Department, Speisinger Str. 109, Vienna-1130, Austria

author email corresponding author email

BMC Musculoskeletal Disorders 2006, 7:94doi:10.1186/1471-2474-7-94

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2474/7/94

Received: 24 July 2006
Accepted: 5 December 2006
Published: 5 December 2006

© 2006 Al Kaissi et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Progressive non-infectious anterior vertebral fusion is a unique spinal disorder with distinctive radiological features. Early radiographic findings consist of narrowing of the anterior aspect of the intervertebral disk with adjacent end plate erosions. There is a specific pattern of progression. The management needs a multi-disciplinary approach with major input from the orthopaedic surgeon.

Case report

We report a 12-year-old-female with progressive anterior vertebral fusion. This occurred at three vertebral levels. In the cervical spine there was progressive fusion of the lateral masses of the Axis with C3. Secondly, at the cervico-thoracic level, a severe, progressive, anterior thoracic vertebral fusion (C7-T5) and (T6-T7) resulted in the development of a thick anterior bony ridge and massive sclerosis and thirdly; progressive anterior fusion at L5-S1. Whereas at the level of the upper lumbar spines (L1) a split cord malformation was encountered. Situs inversus visceralis was an additional malformation. The role of the CT scan in detecting the details of the vertebral malformations was important. To our knowledge, neither this malformation complex and nor the role of the CT scan in evaluating these patients, have previously been described.


The constellations of the skeletal abnormalities in our patient do not resemble any previously reported conditions with progressive anterior vertebral fusion. We also emphasise the important role of computerized tomography in the investigation of these patients in order to improve our understanding of the underlying pathology, and to comprehend the various stages of the progressive fusion process. 3D-CT scan was performed to improve assessment of the spinal changes and to further evaluate the catastrophic complications if fracture of the ankylosed vertebrae does occur. We believe that prompt management cannot be accomplished, unless the nature of these bony malformations is clarified.


Progressive non-infectious anterior vertebral fusion is a unique spinal disorder with distinctive radiological features. Early radiographic findings consist of narrowing of the anterior aspect of the intervertebral disk with adjacent end plate erosions. There is a specific pattern of progression. The management needs a multi-disciplinary approach with major input from the orthopaedic surgeon.

Case presentation

The child was referred to our department at the age of 12 years because of progressive thoraco-lumbar kyphoscoliosis and progressive limitations of neck movement (fig 1). She was born at full term, the product of an uneventful gestation. At birth her length, weight, and OFC were around the 10th percentile. The mother was a 27-year-old-healthy woman, gravida 1 abortus 0, married to a 32-year-old unrelated man.

thumbnailFigure 1. Lateral radiogram showed the severe kyphosis.

At birth the parents observed a patch of hair over the lumbar region, and the child was investigated for this. A split cord malformation was identified, but the parents refused further interventions. At the age of 9 years the parents observed marked worsening of the spinal tilting and problems in bending over. Her head movements became difficult, particularly flexion, and this was accompanied by pain, more marked in the occipital and suboccipital regions. Walking a distance was difficult.

Her subsequent course of development has been described as within the normal limits, except for a moderate delay in motor development. There was no history of serious illnesses. Physical examination at the age of 12 years revealed; short stature. Her height was 121 cm (-3SD) and her head circumference was 53 cm (+2SD). She was of normal intelligence, and neurological examination, apart from a neuropathic bladder was unremarkable. Hearing and vision were normal. Stiffness of the neck was noted, with limitation of neck movement, particularly in flexion. Musculo-skeletal examination showed relative ligamentous hyperlaxity in the limbs, normal hands and feet, and the skeletal survey did not reveal limb abnormalities. The spinal column showed; severe, rigid, thoraco-lumbar kyphoscoliosis (fig 2, 3, 4, 5, 6).

thumbnailFigure 2. Early stage of progressive vertebral fusion in which C4-C6, showed progressive anterior disc narrowing and end plate irregularities (arrows; a-b), whereas (arrow c) showed the development of a thick anterior and posterior bony ridge.

thumbnailFigure 3. End stage of the progressive anterior vertebral fusion and the multi-level anterior fusion with disc space obliteration (T1-T5). There is a massive bony ridge extending anteriorly and in some vertebrae, posteriorly as well. However, (arrow b) note the sparing of the disc space posteriorly, whereas the anterior end plate is totally obliterated (arrow a). Absence of the normal concavity of the anterior body surface. There is a proliferation of sclerotic bone.

thumbnailFigure 4. 3 d reconstruction CT scan showed the massive anterior fusion of (C7-T5) and (T6-T7), and the apparent anterior thick bony ridge (arrow), the latter developed secondary to progressive ossification of the anterior longitudinal ligament. from T7-T12; note the narrowing of the anterior part of the disc space, accompanied by erosion and irregularity of the anterior end plates.

thumbnailFigure 5. Note sparing of the lumbar spines and progressive anterior fusion of L5-S1, and the exaggerated lumbar lordosis secondary to massive fusions of the thoracic vertebrae.

thumbnailFigure 6. sagittal MRI imaging showed a split cord malformation, atthe level of L1, with a bony bar at the L1 level. It also revealed situs inversus visceralis. MRI imaging of the brain did not show any abnormality, and sagittal MRI of the cervical region did not reveal any Arnold-Chiari malformation. Other imaging studies such, as echo-cardio-Doppler was normal. The pelvic ultrasound showed normal ovaries, uterus and vagina, and renal ultrasound showed a normal genito-urinary system.

Laboratory tests included hematological indices, urine screening for metabolic abnormalities, karyotype (for the child and her parents) and rhematological screening. These were all normal and the HLA B-27 was negative.

Family history was unremarkable. Parents were reluctant to give any relevant information.

Progressive, non-infectious anterior vertebral fusion is a rare disorder; which is often referred to as the Copenhagen syndrome [1]. In the classical form, there may be a characteristic anterior defect in the affected vertebrae from shortly after birth, associated with narrowing of the anterior part of the disc space. This is accompanied by erosion and irregularity of the anterior end plates, and when the process of narrowing progresses with age, there is eventual disc space obliteration and bony ankylosis anteriorly, via a thick bony ridge [2].

It is important, to differentiate progressive non-infectious anterior vertebral fusion from the congenital form of block vertebrae, firstly by its clinical history and secondly, by using CT scanning (fig 3, 4, 5)

Scoliosis and kyphoscoliosis in children can occur either in isolation or as a part of a number of syndromes. Spinal malsegmenatation occurs in many of these syndromes, and this includes spondylocarpotarsal synostosis, spondylothoracic dysplasia, and other rare conditions [3,4]. All of these disorders have characteristic patterns of vertebral malformation, such as a posterior unsegmented spinal bar, congenital block vertebra, carpal and tarsal malformations [5].

Knutsson et al., [6] and others [1,2,7] reported children with progressive anterior vertebral fusion as the only malformation, and in none was this part of a syndrome.

Hughes et al., [8] reported three children with progressive fusion, and other congenital and developmental abnormalities. However, there were no distinctive clinical or radiological features signifying a syndromic association, apart from one child, who presented with spinal dysraphism, but neither cervical vertebral fusion nor situs inversus visceralis were described. Philip et al. [9] described involvement of both the upper thoracic (T2-T5) and lower thoracic (T10-S1) vertebrae, associated with radio-ulnar synostosis, exostosis, short and broad clavicles, and a balanced t(10;20)(p11;p13) translocation. There was no cervical vertebral fusion, spilt cord malformation or situs inversus visceralis.

Farrior et al., [10] described a male child with progressive vertebral fusion of the cervical, thoracic, and lumbar vertebrae, with additional manifestations, such as absence of one cervical vertebra, clefting of the vertebral bodies, and other few minor non-spinous abnormalities. The overall features were different from these found in our patient.

Fryns et al., [11], described a child who presented with progressive anterior vertebral body fusion, and other abnormalities such as a generalised overgrowth, especially of the hands and feet, and unusually thick skin and subcutaneous tissue of upper and lower limbs. There was facial dysmorphism. These features were not seen in our patient.

Tubbs et al., [12,13] reported split cord malformation in association with Klippel-Feil syndrome, and another child presented with split cord malformation and situs inversus totalis and scoliosis. They focused on the possibility that defects of the midline and laterality defects (situs inversus) are etiologically related. However, the reported patient manifested congenital blocked vertebrae and not the progressive condition as described here (fig 3, 4, 5, 6).

McRae and Barnum [14] reviewed 25 patients who presented with atlanto-occipital fusion. They found a bony continuity between the anterior arch of the atlas and the anterior lip of the foramen magnum. However, it is uncertain given the absence of sophisticated imaging techniques whether the bony continuity was because of progressive fusion, or was congenital. Situs inversus was not documented.

Kalifa et al., [15] described the nature of progressive non-infectious vertebral fusion, in which the lesions involved mainly the anterior end plates and sparing the posterior parts, whereas in congenital vertebral blocking (failure of segmentation) it usually involves the posterior part of the disk.


The constellations of the skeletal abnormalities in our patient do not resemble any previously reported conditions with progressive anterior vertebral fusion. We also emphasise the important role of computerized tomography in the investigation of these patients in order to improve our understanding of the underlying pathology, and to comprehend the various stages of the progressive fusion process. 3D-CT scan was performed to improve assessment of the spinal changes and to further evaluate the catastrophic complications if fracture of the ankylosed vertebrae does occur. We believe that prompt management cannot be accomplished, unless the nature of these bony malformations is clarified.

Competing interests

The author(s) declare that they have no competing interests.

Authors’ contributions

All authors contributed to this work and all read and approved the final manuscript.

A A: Was responsible for, writing the manuscript, Conception and design and data analysis.

F B C, and M B G: Data analysis.

F G and K K: Conception and design.


We wish to thank Dr. Michael Baraitser (Institute of Child Health-Clinical and Molecular Genetics-University College London) for his unlimited help. And we thank Dr. Marwa Hilmi, West Hertfordshire Hospitals, Watford Herts, UK, for her technical help.

We also thank the patient’s family for their cooperation and a written consent was obtained from the patient’s family for publication of study


  1. Andersen J, Rostgaard-Christensen E: Progressive non-infectious anterior vertebral fusion.

    J Bone Joint Surg [Br] 1991, 73:859-62. PubMed Abstract | Publisher Full Text OpenURL

    totext()Return to text

  2. Smith JRG, Martin IR, Shaw DG, Robinson RO: Progressive non-infectious anterior vertebral fusion.

    Skelet Radiol 1986, 15:599-604. OpenURL

    totext()Return to text

  3. Maroteaux P, Le Merrer M: Maladies osseuses de l’ enfant. 4th edition. Medicine-Science, Flammarion, Paris; 2002:266-268. OpenURL

    totext()Return to text

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Henoch-Schonlein purpura


Henoch-Schonlein purpura is a disease that involves purple spots on the skin, joint pain, gastrointestinal problems, and glomerulonephritis (a type of kidney disorder).

Alternative Names

Anaphylactoid purpura; Vascular purpura


Henoch-Schonlein is a type of hypersensitivity vasculitis and inflammatory response within the blood vessel. It is caused by an abnormal response of the immune system. It is unclear why this occurs.

The syndrome is usually seen in children, but it may affect people of any age. It is more common in boys than in girls. Many people with Henoch-Schonlein purpura had an upper respiratory illness in the previous weeks.


Exams and Tests

The doctor will examine your body and look at your skin. The physical exam will reveal skin lesions and joint tenderness.

A urinalysis shows microscopic blood in the urine. A skin biopsy shows vasculitis.


There is no specific treatment. Most cases go away on their own without treatment. If symptoms persist, your doctor may recommend therapy with corticosteroids such as prednisone.

Outlook (Prognosis)

The disease usually resolves spontaneously without treatment.

Possible Complications

  • Symptoms return
  • Kidney problems (may occur in rare cases)

When to Contact a Medical Professional

Call for an appointment with your health care provider if:

  • Symptoms of Henoch-Scholnlein purpura develop, particularly if they last for more than a few days
  • If low urine output develops after an episode of Henoch-Schonlein purpura


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The purpose of this study was to describe the phenotypic characteristics of an inherited myxomatous valvular dystrophy mapped to Xq28.


Myxomatous valve dystrophies are a frequent cause of valvular diseases, the most common being idiopathic mitral valve prolapse. They form a group of heterogeneous diseases difficult to subclassify. The first mapping of the gene for a myxoid valvular dystrophy to Xq28 allowed investigation of the phenotype of affected members in a large family and characterization of the disease.


Among the 318 members in the pedigree, 89 agreed to participate in this study. Phenotypic characteristics were investigated using clinical examination, transthoracic echocardiography and biological analysis (F.VIII activity). Genetic status was based on haplotype analysis.


Among 46 males, 9 were hemizygous to the mutant allele and had an obvious mitral and/or aortic myxomatous valve defect, and 4 had undergone valvular surgery. All had typical mitral valve prolapse associated in six cases with moderate to severe aortic regurgitation. The valve defect cosegregated with mild hemophilia A (F.VIII activity = 0.32 ± 0.05). The 37 remaining males had normal valves and normal F.VIII activity. Heterozygous women were identified on the basis of their haplotypes. Among the 17 women heterozygous to the mutant allele, moderate mitral regurgitation was present in 8, associated with mild mitral valve prolapse in 1 and aortic regurgitation in 3, whereas 2 women had isolated mild aortic regurgitant murmur. In heterozygotes, the penetrance value was 0.60 but increased with age.


X-linked myxomatous valvular disease is characterized by mitral valve dystrophy frequently associated with degeneration of the aortic valves affecting males and, to a lower severity, females. The first localization of a gene for myxomatous valvular diseases is the first step for the subclassification of these diseases.

Abbreviations and Acronyms
AML = anterior mitral leaflet
F.VIII = antihemophilic factor VIII
LAA = left atrial area
LVOTD = left ventricular outflow tract diameter
MVD = myxomatous valve dystrophies
PML = posterior mitral leaflet
RJA = regurgitating jet area

Valvular disease with myxomatous degeneration forms a complex group of disorders. Common histological features and a clinical continuum from isolated nonsyndromic valvular defects (e.g., idiopathic mitral valve prolapse) to multivalvular diseases and syndromic disorders (e.g., Marfan syndrome) make it difficult to subclassify these heterogeneous and complex pathologies. Defects in fibrillin (1) and collagen genes (2) have already been identified in syndromic valvular disease. In other valvular dystrophies with myxomatous degeneration, identification of genetic defects would appear to be an essential step in their subclassification.

In nonsyndromic valvular dystrophies with myxomatous degeneration, idiopathic mitral valve prolapse is by far the most common defect, occurring in 2% to 4% of the population (3) and displaying a broad clinical spectrum from mild valve defects without clinical repercussions to severe valvular disease (4). The valve anomaly is the main defect, but some studies are in favor of a more diffuse disease affecting other cardiac structures (5). Although the exact prevalence of inherited cases is still uncertain, most familial forms appear to be inherited in an autosomal dominant manner with incomplete penetrance (6). There is also clinical evidence of genetic heterogeneity (7). Despite autosomal transmission, the disease is twice as frequent in females as in males (8), but more severe in the latter (9). A second type of inherited nonsyndromic valvular dystrophy was identified three decades ago by Monteleone and Fagan (10). This apparently rare disease, known as sex-linked valvular dysplasia, is supposedly transmitted as an X-linked recessive trait and may involve one or several valves in affected males. Both forms display classical histological abnormalities of myxomatous valve degeneration, with fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycan.

Because of the presence of valvular anomalies in type IV Ehlers-Danlos syndrome, it has been suggested that genes coding for collagen isoforms could be implicated in nonsyndromic valvular diseases. However, genetic studies have failed to find a link between collagen genes and familial mitral valve prolapse (11,12). We recently identified a large French family with myxoid valvular dystrophy. Its cosegregation with mild hemophilia A enabled us to map the disease gene on Xq28 and characterize the genetic status of each patient (13).

The purpose of this study is to describe the clinical characteristics of inherited X-linked valvular dystrophy. It shows that heterozygous women, in addition to obviously affected hemizygous men, can be mildly affected by the disease. The fact that penetrance is complete in men and incomplete in heterozygous women (for whom it increases with age) provides new insight into the clinical characteristics of myxomatous valvular diseases and should improve genetic analysis of inherited valvular diseases in general.


In our familial study, the proband was a 16-year-old boy with severe aortic regurgitation as a result of valvular dystrophy. During his hospitalization for clinical evaluation before valvular surgery, mild asymptomatic hemophilia A was detected. Subsequent inquiry revealed that a cousin had mitral valve regurgitation due to valvular dystrophy and led to the identification of a very large five-generation family.

The study was conducted according to French guidelines for genetic research. Informed written consent was obtained from each family member. Baseline measurement included a review of medical history, a physical examination with particular attention to the cardiovascular system and any connective tissues diseases, a 12-lead electrocardiogram, a two-dimensional echocardiography with color-coded Doppler analysis, blood samples for genetic studies and quantification of antihemophilic factor VIII. Ophthalmologic examination was performed in two affected members and was normal.

Echocardiography. The phenotypic assignment of family members was based on echocardiographic examination.

Transthoracic M-mode and two-dimensional echocardiograms were recorded according to the criteria of the American Society of Echocardiography (14) using a Sonos 2000 (Hewlett-Packard Inc., Andover, Massachusetts) with a 3.5-MHz probe, or a Sequoia C256 (Acuson Inc., Mountain View, California) equipped with a multifrequency probe (3.5 to 2.0 MHz). Examinations were recorded on SVHS videotapes for further analysis. All recordings were analyzed in a blinded manner by two experienced physicians. Measurements of mitral valves were performed on parasternal long-axis two-dimensional images (15). The length of each leaflet was determined just before valve closure. The thickness of the free edge of the mitral leaflets was measured on a selected diastolic frame that clearly separated the mitral leaflets and chordae. Valves were considered dystrophic when the thickness was superior to 4 mm. Mitral annular diameter was calculated by measuring the length of the line between the anterior and the posterior leaflet hinge points at end-diastole, just before the onset of the QRS complex, and at end-systole, before valve opening. Mitral valve prolapse was considered to exist when two-dimensional recordings in the parasternal long-axis view showed protrusion of mitral leaflets into the left atrium, crossing the line between the annular hinge points, and when the coaptation point of the leaflets remained at or above the mitral annular plane during systole (16). Mitral regurgitation was estimated quantitatively by transthoracic color Doppler flow mapping in three spatial planes. Doppler color gain was optimized by first turning down the setting completely and then increasing the scale gradually until static background noise appeared (17). The severity of mitral regurgitation was assessed by calculating the maximum regurgitating jet area (RJA) expressed as a percentage of left atrial area (RJA/LAA). Regurgitant flow signals localized in the vicinity of valve closure were considered as physiological regurgitation, and these patients were classified as unaffected (18). Mitral regurgitation was rated as mild when RJA/LAA was <20%, moderate when ≥20% to <40%, and severe when ≥40% (19).

Measurements of left ventricular outflow tract diameter (LVOTD) were obtained from parasternal long-axis two-dimensional images at the level of aortic cusp insertion, and aortic root dimensions were calculated from M-mode tracings. Aortic regurgitation was considered to exist if an abnormal diastolic flow originating from aortic cusps was identified in the left ventricular outflow tract. The diameter of the regurgitated jet (AJD) was measured at its origin in the left outflow tract. The AJD/LVOTD ratio was calculated for quantification of aortic regurgitation (20), which was rated as mild when <25%, moderate when ≥25% and <40% and severe when ≥40%. Tricuspid valve images were recorded in four-chamber apical views, and the pulmonary valve was analyzed in high left parasternal short-axis view.

Patients were defined as affected when echocardiographic examination showed mitral valve dystrophy associated or not with mitral valve prolapse, aortic valve dystrophy or mild to severe aortic regurgitation.

Biological analysis. Antihemophilic factor VIII (F.VIII) activity was estimated by a one-stage clotting assay based on activated partial thromboplastin time, using F.VIII-deficient plasma (Diagnostica Stago, Gennevilliers, France) on an STA analyzer (Diagnostica Stago). The Second International Reference Preparation for Factor VIII-related activity (National Institute for Biological Standards and Control, London, United Kingdom) was used as a standard.

Genetic study. A detailed linkage study of this family has been reported elsewhere (13).

Only male phenotypes were used to calculate the lod score because the number of affected males was sufficient to produce a highly significant score. Moreover, penetrance in obligate female carriers (Fig. 1), unlike that in males, was not complete and could have been misleading. Two-point linkage analysis found a maximal lod score of 5.91 at {theta} = 0 for markers INT-13 and DXS1108. Based on the results of the linkage study, patients who had valvular defect and who inherited the complete haplotype were affected. Females heterozygous to this haplotype were defined as carriers.

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Figure 1 Pedigree of the family. Black symbols denote males simultaneously affected by severe X-linked myxoid valvular dysplasia and hemophilia A, and hatched symbols indicate women showing abnormalities in echocardiography. Markers are not shown in order to simply the figure. Black bars represent the markers inherited from the ancestor who transmitted the disease. Marker order was as follows (top to bottom): DXS998, DXS8091, DXS8011, DXS8061, INT-13 and DXS1108. Blackened arrows indicate recombinations of parental alleles. A recombination event in male III-5 with a normal phenotype allowed us to delineate the linked area between marker DXS8011 and Xqter.

Statistical methods. Statistical analysis was performed using Student’s t test and the Mann-Whitney U test. A p value of less than 0.05 was considered significant. Results are expressed as the mean ± SD.


The proband, a 16-year-old boy (Patient V-11), had class II dyspnea according to the New York Heart Association classification. He was of normal size and morphology, and a physical examination found no connective tissue or joint abnormalities. Cardiac auscultation revealed aortic regurgitant murmur, and echocardiography showed severe aortic regurgitation. Aortic root dimensions were normal as confirmed by a nuclear magnetic resonance study of the thoracic aorta. The left ventricle was enlarged (end-diastolic diameter 34 mm/m2), with normal systolic function. Mild hemophilia A was diagnosed at the time of aortic valve replacement.

Histological examination of the excised valve showed typical features of myxomatous valvular disease, with marked thickening of the free edge of the valve. Light microscopy using blue-alcyan, hemalun-eosin-safran and Weigert stains was performed, showing extensive accumulation of proteoglycan and fragmentation of the collagenous bundle. Aortic root analysis was strictly normal.

The same hematologic disease was identified in his cousin (Patient V-9) when he underwent valvuloplasty for severe mitral regurgitation due to mitral valve dystrophy. This second case led to the identification of a very large family.

Among the 318 members of the pedigree, 302 are still alive and 89 accepted to participate in the study (Fig. 1): 43 females (36 ± 17 years) and 46 males (22 ± 15 years). A valve defect was found in 22 (9 males and 13 females) of these subjects. None of the subjects was the result of a consanguineous mating. No family member showed clinical evidence of syndromic disorders such as Marfan or Elhers-Danlos disease.

Clinical characteristics of males. Among the 46 males (Table 1), 9 had obvious aortic and/or mitral valve defect and were classified as affected, including 4 who underwent valvular surgery. Subsequent to surgery, one patient was asymptomatic and three had dyspnea (two class II, one class I). Seven of the nine affected males had mitral regurgitant murmur. No differences were found between affected and unaffected patients concerning age and body surface area.

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Table 1 Echocardiographic Characteristics of Men

Mitral valve defect
All affected men had mitral valvular dystrophy (Fig. 2), and one had undergone mitral valvuloplasty when he was 18 years old (Patient V-9). Mitral valves were characterized by thicker anterior (AML) and posterior (PML) leaflets, longer AML and PML, and larger mitral annular diameters at end-diastole and end-systole. Mitral valve dystrophy was associated with moderate billowing in all but one (Patient V-10) of the affected males (mean anterior leaflet prolapse: 3.1 ± 1.5 mm). Mitral regurgitation was moderate in four patients (IV-48, V-10, V-11, V-13; RJA/LAA = 0.37 ± 0.02) and severe in five (III-12, III-6, III-16, IV-50, V-9; RJA/LAA = 0.46 ± 0.07).

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Figure 2 Parasternal long-axis two-dimensional view, at end diastole (A) and end systole (B), performed in an affected male (Patient IV-48), showing the structural abnormalities of the mitral valve with thickening of mitral valve leaflets (A) and a mild prolapse (B).

Aortic valve defect
As aortic valve dystrophy is difficult to assess by transthoracic echocardiography, we chose to quantify aortic regurgitation, which was associated with mitral valve dystrophy in six affected men. In three of these patients (III-6, III-16 and V-11), the severity of aortic regurgitation led to valve replacement at 42, 24 and 16 years of age, respectively. Histological examination of the aortic valves found abnormalities similar to those described in the proband. In the other three men (III-12, IV-50, and V-10), aortic regurgitation was quantified as mild or moderate, with an AJD/LVOTD of 0.1, 0.24 and 0.26, respectively. Aortic root diameters and the left ventricular outflows tract were normal and did not differ significantly in affected and unaffected men. The three remaining affected men had no detectable aortic valve defect.

Affected males had larger left ventricular diastolic diameters, whereas left atrial diameters did not differ significantly. Ejection fractions were similar in the two groups.

Finally, the phenotypic status of men could easily be characterized because affected patients had obvious valvular dystrophy clearly differentiating them from the normal phenotype.

Hematologic defect
Because of low F.VIII biological activity in the proband and his cousin (0.31 and 0.29, respectively), hemophilia A was suspected in cosegregation with the valve defect. Von Willebrand disease was excluded, and mild hemophilia A was detected in all men affected by valvular disease, whereas all unaffected men had normal F.VIII activity (0.32 ± 0.05 vs. 0.91 ± 0.29, p < 0.0001) (Fig. 3).

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Figure 3 Comparison of F.VIII activity of males affected by the valvular disease (A, 32 ± 9%), heterozygous women (B, 75 ± 26%) and nonaffected members (C, 105 ± 35%). Affected males have a significantly lower F.VIII activity (p < 0.0001) than heterozygous and normal subjects. Heterozygous women have significantly lower F.VIII activity (p < 0.02) than normal subjects.

Clinical characteristics of women. The linkage study was the key factor for detailed clinical analysis of X-linked valvular dystrophy, allowing identification of female carriers on the basis of their haplotypes and analysis of the expression of the diseased gene in heterozygous women (Fig. 1). Among the 43 females in the pedigree, 17 who inherited the entire haplotype were heterozygous to the disease-associated gene. Four other women (III-34, IV-41, V-1 and V-12) had inherited part of the haplotype, with recombination events within the candidate region, so that their genetic status is unknown.

Characteristics of the 17 heterozygous women. All women were asymptomatic, but echocardiography identified 10 (mean age 40 ± 15 years) with mitral and/or aortic valve abnormalities. Eight had holosystolic murmur (III-3, III-8, III-24, III-30, IV-18, IV-25 and IV-49) and moderate mitral regurgitation (mean RJA/LAA = 0.31 = 0.04), with mitral valve prolapse in one and mild aortic regurgitation in three. Two women had isolated mild aortic regurgitation.

None of these women had obvious valvular dystrophy, and echocardiographic parameters such as leaflet thickness and mitral annulus, aortic root, left ventricular outflow tract and the left ventricle diastolic diameters did not differ in heterozygous and unaffected women (Table 2).

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Table 2 Echocardiographic Characteristics of Women

In two heterozygous women, the valvular defect could have been due to another cause. Patient II-3, the 83-year-old mother of two affected males, had isolated moderate mitral regurgitation without valvular dystrophy or mitral valve prolapse and a history of systemic hypertension. Patient IV-26, the 19-year-old daughter of an affected male, had an atypical valve defect with moderate pulmonary regurgitation without left valve defect.

According to echocardiographic data for genetically affected women, the penetrance of the disease in heterozygous was estimated as between 0.59 and 0.71, depending on the phenotypic status of the last two cases. The penetrance of the disease-associated gene in heterozygous women was age dependent, but valve defects were seen in 5 out of 7 women over 40 years of age and in only 5 out of 10 under 40.

Characteristics of women with undetermined genetic status. Echocardiographic examinations were normal in the four women (III-34, IV-41, V-1 and V-12) with recombination events in the candidate area. The genetic status of Patient III-34 was considered normal, as her son, who inherited the same haplotype, was unaffected.

Characteristics of women with normal genetic status. If it is assumed that Patient III-34 did not inherit the “diseased” haplotype, 23 women can be considered to have normal genetic status, including 3 (III-20, IV-1, IV-4) with a valve defect and 20 with normal echocardiography.

Patient III-20, a 64-year-old woman with isolated mild mitral regurgitation (RJA/LAA = 0.12) without valvular dystrophy or mitral valve prolapse, had received thoracic radiotherapy for breast cancer 10 years before. Patient IV-1, with severe mitral regurgitation (RJA/LAA = 0.49), had experienced an episode of prolonged fever, treated by antibiotics, shortly after delivery 10 years before. A diagnosis of endocarditis was considered but never confirmed, despite the occurrence of mitral regurgitation. In these two cases, the valve defect could have been secondary to radiotherapy or endocarditis. Patient IV-4, a 33-year-old woman with mild mitral regurgitation (RJA/LAA = 0.20) associated with moderate aortic regurgitation (AJD/LVOTD = 0.27), had no clinical history indicative of acquired valvular disease. When these cases were taken into consideration, a risk of phenocopy of 0.12 was found for heterozygous women.


Valvular dystrophy with myxomatous degeneration is a frequent cause of valve defects. It has been well described in mitral valve prolapse (21) and also occurs in aortic regurgitation (22,23). Although most affected patients are asymptomatic, they risk complications such as endocarditis, spontaneous cordal rupture and sudden death. Moreover, progressive worsening of valvular regurgitation can lead to heart failure. Within the last decade, this disease has become an increasing cause of valvular surgery (representing almost 20% of such patients in our institution [unpublished data]).

The clinical spectrum of myxomatous valvular disorders, ranging from isolated mild defects to severe multivalvular lesions, is in favor of a heterogeneous disease that is in fact difficult to subclassify because of the absence of specific features, even at the histological level. To date, only genes for syndromic diseases have been mapped or cloned (1–3), but the identification of genetic defects would appear to be the key factor for determining subclassifications.

Isolated mitral dystrophy associated with billowing is the most common form of myxomatous valvular disease. It is easy to diagnose an obviously affected patient but the continuum from normal to severely affected valves, and from isolated to multivalvular defects, can complicate the identification of affected patients (5).

In our study, men were either clearly normal or affected; the latter all had an obvious mitral valve dystrophy with thicker and longer leaflets and a mild prolapse similar to abnormalities described in floppy mitral valve (21), associated with aortic regurgitation in two-thirds of cases. Valvular degeneration was not associated with other detectable cardiovascular or morphological defects. Clinical examinations of affected patients indicated a nonsyndromic disease because no features of a connective tissue disease such as Marfan or Elher-Danlos syndrome were detected, nor were any signs of osteogenesis imperfecta. Moreover, the thoracic aorta, particularly the aortic root, was echocardiographically and histologically normal, and skin histology performed in one affected patient was normal.

An X-linked disease with anticipation. Several factors indicated that the inherited valvular disease was X-linked. There was no male-to-male transmission, the severity of myxomatous valvular disease was far greater in males and all affected men had mild hemophilia, whereas those with normal valves showed normal F.VIII activity. This also suggested that both valvular dysplasia and hemophilia A were cosegregated in the family and that the gene responsible for the valvular dysplasia was closely linked to the factor VIII gene.

One of the most striking features of this disease is a tendency toward earlier severity from generation to generation. Reconstruction of the haplotype of ancestors indicated that the male in generation I was probably genetically affected and responsible for the transmission of the disease. Although no clinical cardiac analysis exists for this man, it is unlikely that he had severe valvular disease because he died at 65 years of age from peritonitis without any indication of cardiovascular symptoms. In generation III, three males were affected. The disease was identified when they were in their 40s, and two of them underwent valvular surgery, at ages 51 and 49 years. In generation IV, two men were affected. The diagnosis of valvular disease was made during their 20s, and at ages 30 and 24 years, they are still asymptomatic with moderate mitral regurgitation. Finally, four males of generation V are affected by the disease. Two underwent valvular surgery at the age of 17 years because of severe mitral (V-11) or aortic (V-9) valvular regurgitation, and two others (16 and 12 years old) are severely affected. This apparent tendency toward earlier severity could actually be due to improvement of echocardiographic techniques. However, similar tendencies were noted in two previous descriptions of this disease. In the family reported by Monteleone and Fagan (10), a fourth-generation patient died of cardiac failure due to valvular disease when he was eight months old, whereas several men from the previous generation were still alive, although clinically affected. In the family described by Newbury-Ecob et al (24), a fourth-generation baby died from valve defect and cardiac failure 24 h after birth, whereas his grandfather in the second generation was asymptomatic until the age of 25 years and underwent valve replacement at the age of 41 years. This tendency toward earlier severity, called anticipation, needs to be confirmed in other families.

An X-linked disease with mildly affected female carriers. Our clinical observations differ from those previously described for X-linked valvular dysplasia, even though the same genetic disease is probably involved. An important result not previously described is the identification of an intermediate phenotype in heterozygous women. With the mapping of the gene in monozygous males, it has become possible to identify female carriers on the basis of their haplotypes and to analyze the expression of the disease gene. As has been demonstrated for idiopathic mitral valve prolapse, there was no clear delineation between normal and abnormal valves, and there is a continuum from normal to abnormal valves because some heterozygous women in our study had normal echocardiography, whereas others had mitral or aortic regurgitation, giving a penetrance value of 59% to 71%, which increased with age. Furthermore, valve defects were less severe than in men, as shown by the absence of differences in mitral valve thickness, length and diameter between affected heterozygous and normal women and by a better outcome (no valvular surgery). This could have been due to the low accuracy of transthoracic echocardiography in identifying small valve defects.

Implications for genetics of myxomatous valve dystrophies. The clinical phenotype of patients with mitral valve prolapse constitutes a continuum from Marfan syndrome to isolated mitral valve prolapse. To emphasize the involvement of mitral valve prolapse, aorta, skeleton and skin, patients with connective tissue disorder have been described using the acronym MASS phenotype (25). Isolated mitral valve prolapse is by far the most frequent syndrome (4), and one study has identified at least two different phenotypes with a strong family pattern (7). Both forms appear to be inherited in an autosomal dominant manner (6). This mode of inheritance was also identified in other studies that have reported family cases (26–28). However, epidemiological studies have shown striking results that can hardly be explained by this mode of inheritance. The mitral valve prolapse is twice as frequent in females as in males (8), it is more severe in men than in women (9), as confirmed by several surgical series of mitral valve prolapse as well as myxoid aortic valve regurgitation in which the patients were largely male (22,23), and no clear delineation exists between normal and affected patients, especially women. Although these results could have been due to hormonal as well as environmental factors, they are still surprising for an autosomal dominant disease.

Contrary to idiopathic mitral valve prolapse, X-linked valvular dystrophy seems to be a rare disease, described only twice (10,24). This could have been due to the rarity of the disease or to misinterpretation in the mode of inheritance of the valvular defect. Indeed, the presence of affected heterozygous women, particularly in small pedigree, the tendency toward earlier severity (the anticipation of the disease), the risk of phenocopies and the low sensitivity of echocardiography could be clinically misleading. Owing to the presence of these confusing factors, it is possible that some patients with myxomatous valve defects may have been affected by an unidentified X-linked valvular disease. In this respect, only male-to-male transmission can rule out an X-linked disease.

Conclusions. It is quite likely that myxomatous valvular diseases are heterogeneous and that myxoid degeneration is the final pathway for several protein defects that will not be identified with conventional clinical tools. The first localization of a gene for nonsyndromic myxomatous valvular diseases should facilitate the subclassification of this complex group of diseases. Ultimately, the cloning of the gene will give a new insight into the pathophysiology of these diseases.


This study was supported in part by INSERM and the DRRC of Nantes.


  1. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337–339[CrossRef][Medline]
  2. Superti-Furga A, Gugler E, Gitzelmann R, Steinmann B. Ehlers-Danlos syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen. J Biol Chem. 1988;263:6226–6232[Abstract/Free Full Text]
  3. Savage D, Garrison RJ, Devereux RB, et al. Mitral valve prolapse in the general population. I. Epidemiologic features: the Framingham study. Am Heart J. 1983;106:571–576[CrossRef][Medline]

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A case is reported of a 30-year-old male patient, who presented a purulent area in his scalp, which was initially diagnosed as Celsus kerion. The microbiologic examinations were negative for fungi and isolated only Staphylococcus aureus. The lesion was controlled with systemic antibiotics, which enabled the visualization of tufted hairs inside a cicatricial alopecia. There were two recurrences that were again controlled with systemic antibiotics. Surgical excision was indicated.

Keywords: Folliculitis; Staphylococcus aureus


Folliculitis decalvans constitutes a subgroup of cicatricial alopecia, in which a bacterial component plays an important role in the follicular destruction, thereby differing from pseudopelade of Brocq, discoid lupus and pilar lichen planes, in which the alopecia occurs without infection.

The classic clinical picture of folliculitis decalvans, as described by Quinquaud in 1888,1 is characterized by follicular pustules associated to central cicatricial areas withoat hair2 secondary to the bacterial aggression and/or inflammation. Clinical pictures with intense suppuration and formation of intercommunicating abcessos constitute another variant denominated dissecting follicerlitis of the scalp.2

In 1978, another clinical picture was described bv Smith and Sanderson, in which the follicles present in tufts,3 as a result of a particular cicatritiation after the inf annnatorv process. There are approximately 30 cases published, though none in the Latin-American literature.


Male patient, 30 years old, presented with a lesion in the scalp that had appeared ttivo months previously.

At der matological exam, plaque was observed with fes­tering crusts measuring five centimeters in diameter located in the vertex. With diagnostic hyotheses of Infectious folliculitis and Celsus kerion, bacteriological exams were requested, which isolated Staphylococcus aureus. Mycological exams were also performed and the result was negative.

The patient was treated with oral cephalosporin and four consecutive doses of I50mg fluconazole every five days, in view of the possibility that the milcological exam was false-negative, a significant improvement was observed. Following the falling off the crust and decrease in the suppuration it was possible to observe areas of alopecia, follicular pustules and presence of tufted hair (Figure 1).

Four weeks later there was a recurrence and further microbiological exams requested, with identical results to the first. The lesions were controlled with oral lymecycline. After nvo months there was a third recurrence, again con­trolled with oral lymecycline and surgical exeresis of the affected area was indicated.

Between recurrences several topical antibiotics were maintained, such as neomycin, erythromycin, clindamycin, nurpirocin and rifarnpicin, without a satisfactory response.


Tufted folliculitis decalvans (TFD) is considered a variant of the classical folliculitis decalvans4 and both have in common areas of cicatricial alopecia and follicular- pustules, the important difference being the tufts of remaining hair.

Normally only one area is affected, with few reports of multiple lesions.4 The ratio of male and female patients is 3:1 and in general it involves individuals in their third or fourth decade of life.

Pathogenically it is an accepted fact that the process triggered by the infection provokes a fibrosis of the superior third of the perifollicular dermis, leading to a confluence of the remaining follicles,4,5 which has been confirmed histologically by several authors, since the inflammatom infiltrate is limited to the papillary and media dermis, non affecting the reticular dermis and hypodermis.6 In the classic folliculi­tis decalvans a destruction of the follicles occurs with fibrosis of the entire dermis.5

Pili multigemini appear not to precede thelesions of TFD, as the patients refer normal scalp before onset of the picture. Furthermore, histologically in TFD there is a convergence of the follicles and not a true coalition, as in pili multigemini.6 In that the former presents an external radicular sheath in common, while only the internal one is individualized.7 It has been reported that a patient initially presented only follicular pustules and after three years tufts were observed,8 thereby demonstrating their appearance subsequent to the bacterial process.

It is interesting that there are nvo reports of TFD in patients with pernhigus vulgaris,9,10 and it has been sugges­ted that the erosions provoked by the pemphigus facilitated an infection by S. aureus.

Another two reports refer to the presence of tufts in folliculitis keloidalis of the neck11,12 In this situation an important fibrosis also occurs, characteristic of the keloids, leading to the formation of the tufts. Both these entities can be easily differentiated clinically by the presence of keloids.1

The bacteriological exam almost always isolates S. aureus,1,4,6,8,13 and on rare occasions an association with other bacteria, such as Klebsiella or Providencia;14 there have been no reports of the isolated detection of a bacteriron other than Staphylococcus.

Treatment should be initiated with systemic antibio­tics and based on an antibiograin, which enables some cases to be controlled. However recinrence or resistance have been described by several authors,1,4,6,11 causing the disease to become chronic as ire the current case report, in such situations exegesis of the area is indicated.1,6 Techniques using laser depilation can offer an alternative in resistant cases, thereby avoiding a surgical management.


  • 1. Trüb RM, Pericin M, Hafner J, Burg G. Bündelhaar – Follikulitis. Der Hautarzt 1997; 48: 266-269.
  • 2. Sampaio SAP, Rivitti EA. Dermatologia. Editora 1999, pp306.
  • 3. Smith NP, Sanderson KV. Tufted folliculitis of the scalp. J R Soc Med 1978; 71:606-8.
  • 4. Annessi G. Tufted folliculitis of the scalp: A distintive clinicohistological variant of folliculitis decalvans. British J Dermatol 1998; 138: 799-805.

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Study links diabetes, advanced breast cancer

An international study has established a link between type 2 diabetes and advanced breast cancer.

An international study has established a link between type 2 diabetes and advanced breast cancer. (ABC TV)

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An international study has established a link between type 2 diabetes and advanced breast cancer.

It has been known for a while that being overweight puts post-menopausal women at greater risk of breast cancer.

But now it has been found that women who are resistant to insulin, or who are overweight, are 50 per cent more likely to be diagnosed with the cancer, and only when it is in its advanced stages.

The finding comes after an international research team followed more than 60,000 Swedish women over 20 years.

Dr Anne Cust from the University of Melbourne is a collaborator in the study and will present the findings at a medical conference in Brisbane today.

Dr Cust told AM the study looked at the stage of breast cancer and the diagnosis.

“We found that women who were overweight or with insulin resistance were more likely to be diagnosed with an advanced stage of breast cancer,” she said.

“We don’t know the exact reasons why that might be. It might be that the cancer is growing more quickly or that it wasn’t diagnosed early but we need to do more research to find out exactly why that might be.”

She says there are a number of hypotheses as to why overweight or diabetic women aren’t diagnosed earlier with breast cancer.

“It may be that the hormones that are involved, that are linked with being overweight or having insulin resistance, might be making the tumour grow more quickly but we need to do more research to find out exactly why that might be the case,” she said.

But Dr Cust says that does not necessarily mean that women who are at risk of type 2 diabetes should be screened for breast cancer more often.

“The question of screening is something that would need to be looked at separately but I think it is just providing another indication that being overweight is linked to lots of different health problems and this is another reason to get off the couch and try to stay active and maintain a healthy weight,” she said.

“And also, the link with insulin resistance may provide a new avenue of research for looking at the causes of breast cancer and possibly new treatments.”

Based on an interview by Simon Lauder for AM

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