AUTHOR AND EDITOR INFORMATION

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Differentials
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Background

Acquired partial lipodystrophy, also known as Barraquer-Simons syndrome or cephalothoracic lipodystrophy, is one of the rare forms of lipodystrophy. Mitchell initially reported this variety in 1885¹. Barraquer and Simons further characterized the syndrome at the beginning of the 20th century. Since then, approximately 250 cases have been reported in English literature.

Acquired partial lipodystrophy usually begins in childhood, at a median age of 7 years². It predominantly affects females and often follows an acute febrile illness. Fat loss is usually limited to the face, trunk, and upper extremities. Simultaneously, fat hypertrophy occurs in the lower extremities. These patients may develop nephropathies. Activation of alternate complement pathway has been demonstrated in most patients.

Compared to other types of lipodystrophy, acquired partial lipodystrophy is seldom associated with insulin resistance and its related metabolic derangements. This may be related to the fact that in this syndrome, patients have limited fat loss.

Disorders associated with acquired partial lipodystrophy include the following:

• Membranoproliferative glomerulonephritis has been reported in about 20% of cases and proteinuria in 45% of cases. However, contribution of other concomitant diseases to rates of proteinuria is possible, such as urinary tract infection, diabetes, etc². Patients with membranoproliferative glomerulonephritis are more likely to have low C3 levels and presence of C3 nephritic factor (C3NeF).



• Autoimmune diseases, with systemic lupus erythematosus being the most common; other reported autoimmune diseases include the following, among others:
  
  
  • Dermatomyositis
  
  
  
  • Pernicious anemia
  
  
  
  • Celiac disease
  
  
  
  • Dermatitis herpetiformis
  
  
  
  • Rheumatoid arthritis
  
  
  
  • Temporal arteritis
  
  
  
  • Leukocytoclastic vasculitis
     
• Propensity to bacterial infections



• Other: POEMS syndrome³ (polyneuropathy, organomegaly, endocrinopathy, monoclonal component, skin changes), mental retardation, retinal disease among others



• Diabetes and impaired glucose tolerance are rare, in contrast to most other lipodystrophies, and are reported in 6.7% and 8.9% of patients².

Pathophysiology

The precise pathophysiology of fat loss is unclear. Activation of an alternate complement pathway, C3 hypocomplementemia with C3-nephritic factor–induced lysis of adipocytes has been implicated. C3 hypocomplementemia likely contributes to association of this syndrome with autoimmune diseases and propensity to bacterial infections². Other proposed mechanisms include an autoimmune process and genetic associations⁴.

Frequency

United States

Approximately 250 cases have been reported since the recognition of this syndrome. It is a rare syndrome with no known prevalence, although it is more common than the generalized form of acquired lipodystrophy (Lawrence syndrome)².

International

Several case reports have been described in different parts of the world. However, the international incidence and prevalence of this disease are not known.

Mortality/Morbidity

Estimating the mortality rate based on the available literature is difficult. Several case reports reveal an association between acquired partial lipodystrophy and other diseases (see Disorders associated with acquired partial lipodystrophy).

• Nephropathy, in the form of membranoproliferative glomerulonephritis, occurs in approximately 20% of the patients².
• Usually, patients do not have clinically evident renal disease or abnormalities in renal function until they have had the disease for 8 or more years.
  
  
  • Membranoproliferative glomerulonephritis usually presents with asymptomatic proteinuria or hematuria.
  • The disease may gradually progress. About 40-50% of patients develop end-stage renal disease over 10 years. It is responsible for most of the recurrent hospital admissions².
  • Rapid progression of renal disease in a pregnant patient was reported⁵. 
• Associated autoimmune diseases (eg, systemic lupus erythematosus, thyroiditis) contribute significantly to increased morbidity in these patients compared to the general population.
• Although uncommon, insulin resistance increases cardiovascular risk.
• Susceptibility to bacterial infections, likely resulting from C3 deficiency (due to complement activation and consumption of C3). Low C3 levels may impair complement-mediated phagocytosis and bacterial killing.

Race

No clear relationship exists between incidence and race in this syndrome; however, most reported patients were of the European descent.

Sex

Women are affected approximately 4 times more often than men².

Age

The median age of onset of lipodystrophy has been reported to be around 7 years; however, onset as late as in the 4th to 5th decades of life has also been reported².

The median age at presentation was around 25 years, and women were older than men (age 28 y versus 18 y).

CLINICAL

Section 3 of 11  

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History

• The problem usually begins in childhood. In most reports, disease onset occurs when patients are younger than 16 years.



• The onset usually follows an acute febrile viral illness, most commonly measles. Minor surgical procedures and psychological stress have also been reported before the onset of fat loss.



• Lipodystrophy progresses slowly and occurs over a period of few months to 2 years. Seventy five percent of patients had significant fat loss when younger than 13 years.



• Acquired partial lipodystrophy is characterized by the loss of fat spreading in the cephalocaudal distribution from the face, neck, shoulders, arms, and forearms and extending to involve the thoracic region and upper abdomen. Occasionally, fat loss may involve the groin or thighs. Hips and legs are usually spared (see Image 1). After puberty, women have the tendency to accumulate fat (lipohypertrophy) disproportionately in the hips and legs⁶.



• The process does not affect the growth of the patients, and children usually experience developmental milestones with no difficulties. No pain is associated, but patients may occasionally complain of muscle weakness.



• Patients with acquired partial lipodystrophy do not usually experience the metabolic abnormalities observed in persons with other forms of lipodystrophy. However, inquiring about a history of menstrual irregularities, hirsutism, diabetes mellitus, and dyslipidemia is important because metabolic abnormalities have been reported in these patients and therapeutic interventions are available for these diseases. Further, looking for evidence of renal disease, which occurs in approximately 20% of the patients, is essential. Most of the patients are asymptomatic until the development of advanced renal impairment or acute decompensation².



• Hepatomegaly has been reported in above 60% of patients. However, this finding might be due to associated autoimmune diseases.



• Patients with acquired partial lipodystrophy may present with a history suggestive of autoimmune or rheumatologic diseases.

Physical

Patients usually have normal growth and secondary sexual characteristics. No specific bony abnormalities are present. 

• General inspection may reveal features of one of the associated autoimmune diseases (see Disorders associated with acquired partial lipodystrophy). Hepatomegaly might be present. Acanthosis nigricans and increased skin tags are very rare and indicate the presence of insulin resistance.



• Exposing the patient properly for examination is very important; otherwise, the diagnosis can be easily missed. The best exposure during examination is achieved when the patient wears a gown exposing the extremities and trunk.



• These patients usually have characteristic body changes. These include both loss of fat and deposition of fat.
  
  
  • Loss of fat occurs in the face (around the cheeks and temples, eg, sunken cheeks), neck, shoulders and upper extremities, and upper abdomen. Breasts may lose fat and consist of firm glandular tissue only. Prominent veins in the arms with a muscular appearance (not associated with heavy exercise or muscle-building routines) are very characteristic of this syndrome.
  
  
  
  • Fat deposits can occur in the hips, lower extremities, the breasts (in both men and women), or other scattered areas around the body. These patients do not have cushingoid features.

 Diagnostic criteria

• Gradual loss of subcutaneous fat in face, neck, trunk, and upper extremities occurring during childhood or adolescence (essential)



• Normal or excess subcutaneous fat in the hips and lower extremities



• Proteinuria or biopsy-proven membranoproliferative glomerulonephritis



• Low C3 level, reported in about 70% of patients (C3 level might be normal with an elevated C3 degradation product, C3d)



• Presence of C3NeF, a polyclonal immunoglobulin G (IgG), able to breakdown C3 in normal human serum (It is reported to be present in about 80% of patients.)



• Absence of other metabolic derangement



• Characteristic fat distribution as measured by skinfold thickness or  images from  MRI studies



• Presence of autoimmune disease

Causes

Proposed mechanisms include activation of an alternate complement pathway, autoimmune diseases, genetic associations, and idiopathic disease.

DIFFERENTIALS

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Other Problems to be Considered

Because of the variable patterns of lipodystrophy in these patients, several other syndromes should be considered in the differential diagnoses of acquired partial lipodystrophy, including the following:

• Idiopathic localized lipodystrophy



• Familial partial lipodystrophy



• Drug-induced lipodystrophy



• HIV-1–related lipodystrophy



• Acute panniculitis



• SHORT syndrome (short stature, hyperextensibility of joints, ocular depression, Reiger [ocular and dental] anomaly, and teething delay)



• Werner syndrome



• Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome)



• Leprechaunism (Donohue syndrome)



• Mandibuloacral dysplasia

WORKUP

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Lab Studies

The diagnosis of the disease is mainly clinical (see Diagnostic criteria). The laboratory workup is needed mainly to investigate for the presence of associated disorders, which are metabolic, autoimmune, and renal diseases.

• Every patient should have a fasting blood glucose and lipid profile, creatinine evaluation, and urinalysis for protein content at the first visit and then regularly thereafter.



• Although uncommon, lipid abnormalities can occur in the form of raised triglyceride levels and low high-density lipoprotein (HDL) cholesterol levels. 



• Patients usually have decreased serum C3 levels, normal levels of C1 and C4, and high levels of C3 nephritic factor (autoantibody), which may indicate the presence of renal involvement.



• Antinuclear antibodies (ANA) and anti–double-stranded DNA antibodies have reportedly been observed in some patients with acquired partial lipodystrophy.



• A genetic workup should be performed if the familial form of lipodystrophy is suggested.

Laboratory work for associated diseases includes the following:

• Metabolic disease - Fasting glucose, glucose tolerance test, lipid profile, and fasting insulin to characterize the insulin resistance state; free testosterone (in women) to look for polycystic ovary syndrome



• Autoimmune disease - ANA, anti–double-stranded DNA, rheumatoid factor, thyroid antibodies, C3, and C3 nephritic factor

Imaging Studies

As a confirmatory test, whole-body MRI usually clearly demonstrates the extent of lipodystrophy. MRI is not recommended on a routine basis.

Procedures

Renal biopsy is the test of choice to help diagnose the type of renal impairment in these patients. It is a transcutaneous procedure performed under ultrasound guidance to obtain renal tissue using a fine needle. Nephrologists should direct this procedure.

Histologic Findings

Under light microscopy, biopsy specimens of affected areas show loss of subcutaneous fat; relative adipocyte volume is reduced to 65% of baseline. Lipocytes are usually atrophic or reduced in number. No infiltrates with lymphocytes have been reported.

TREATMENT

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Medical Care

• In general, treatment of acquired partial lipodystrophy is limited to cosmetic, dietary, or medical options.



• Currently, no effective treatment exists to halt the progression of lipodystrophy.
  


• Thiazolidinediones have been used in management of various types of lipodystrophies. They bind to peroxisome proliferator-activator receptor–gamma, which stimulates the transcription of genes responsible for growth and differentiation of adipocytes. A single report has suggested beneficial effect of treatment with rosiglitazone on fat distribution in acquired partial lipodystrophy; however preferential fat gain was in the lower body.
  


• The US Food and Drug Administration issued an alert on May 21, 2007 to patients and health care professionals of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity. The drug is highly selective and a potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
   
  For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled Effect of "Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (the heart.org from WebMD) including the following articles: 1) Rosiglitazone increases MI and CV death in meta-analysis, 2) The rosiglitazone aftermath: Legitimate concerns or hype? and 3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers.
  


• Direct drug therapy according to the associated condition.
  
  

  • Membranoproliferative glomerulonephritis and presence of renal dysfunction largely determine prognosis of acquired partial lipodystrophy. Standard guidelines for management of renal disease should be followed.

  • The course of membranoproliferative glomerulonephritis in acquired partial lipodystrophy has not been significantly altered by treatment with corticosteroids or cytotoxic medications.

  • Recurrent bacterial infections, if severe, might be managed with prophylactic antibiotics.

Surgical Care

• The purpose of surgery is mainly cosmetic. According to the American Academy of Dermatology guidelines, lipodystrophy is one of the indications for fat transplant.
• Surgical intervention cannot restore adipose tissue distribution in the affected areas except the face. Several facial reconstruction techniques have been used to restore facial contour, with variable success.
• The literature is controversial regarding these procedures. The best approach is to individualize the treatment options based on the patient's condition and requirements. These procedures are not recommended for prepubertal children.
• Procedures may include transposition of facial muscles, adipose tissue transplantation (liposuction), and silicone or other implants.

Consultations

Early consultation with a nephrologist or an endocrinologist is very important if any of the renal or metabolic complications are suggested.

Diet

No evidence in the literature favors any specific diets in this group of patients. A low-fat, high-carbohydrate diet can be detrimental with regard to triglyceride levels, and weight gain should be avoided to reduce the risk of worsening metabolic status. However, children with this syndrome should have normal food intake to allow for normal growth.

Activity

Regular exercise should be encouraged to help improve metabolic status.

MEDICATION

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Pharmacological intervention is limited in this syndrome. Biguanides and thiazolidinediones have been used in the treatment of the insulin-resistant state (which includes type 2 diabetes and polycystic ovary disease) and in HIV-related glucose intolerance. Although not studied in this group of patients, these drugs should be the first line of treatment if diabetes occurs. Fibrates are the drug of choice for the treatment of hypertriglyceridemia and low HDL cholesterol syndrome.

Drug Category: Hypoglycemic agents

These medications would be started if the patient develops diabetes not controlled with diet. Insulin sensitizers (biguanides and thiazolidinediones) can be used in women with polycystic ovarian syndrome and with irregular periods to reduce insulin levels.

Drug Name	Pioglitazone (Actos)
Description	Improves target cell response to insulin without increasing insulin secretion from pancreas. Decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and possibly liver and adipose tissue.
Adult Dose	15 or 30 mg PO qd; may increase, not to exceed 45 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active liver disease; ketoacidosis; type 1 diabetes
Interactions	May reduce plasma concentrations of contraceptives containing ethinyl estradiol and norethindrone; lab studies suggest ketoconazole may inhibit metabolism (monitor blood glucose levels closely); in combination with insulin or oral hypoglycemics (eg, sulfonylureas), may increase risk for hypoglycemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor transaminases; discontinue if ALT rises >3 times upper limit of normal; caution in edema and congestive heart failure; may decrease hemoglobin, hematocrit, and white blood cell counts

FOLLOW-UP

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Complications

The most significant complications are disfigurement in severe facial involvement, renal disease, and, rarely, insulin resistance state.

Prognosis

Patients with acquired partial lipodystrophy have a slowly progressive disease. In the absence of associated renal impairment or insulin resistance, the prognosis is excellent.

Patient Education

• Educating patients about the disease and associated complications is very important.



• Parents should be notified about the possible facial changes and the importance of balancing dietary intake to avoid metabolic complications and to ensure healthy development.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

Failure to educate patients about the disease and associated complications

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Fat distribution in acquired partial lipodystrophy.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

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1. Mitchell SW. Singular case of absence of adipose matter in the upper half of the body. Am J Med Sci. 1885;90:105-6.
2. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). Jan 2004;83(1):18-34.
3. Caramaschi P, Biasi D, Lestani M, Chilosi M. A case of acquired partial lipodystrophy associated with POEMS syndrome. Rheumatology (Oxford). Mar 2003;42(3):488-90.
4. Hegele RA, Cao H, Liu DM, Costain GA, Charlton-Menys V, Rodger NW. Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am J Hum Genet. Aug 2006;79(2):383-9.
5. Demetriou K, Kallikas I, Zouvani I, Kyriacou K, Pierides A. The pregnant patient with partial lipodystrophy developing acute renal failure--onset of de novo membranoproliferative glomerulonephritis. Nephrol Dial Transplant. Aug 1998;13(8):2121-4.
6. Garg A. Lipodystrophies. Am J Med. Feb 2000;108(2):143-52. [Medline].
7. Cronin CC, Higgins TJ, Molloy M. Lupus, C3 nephritic factor and partial lipodystrophy. QJM. Apr 1995;88(4):298-9. [Medline].
8. Poley JR, Stickler GB. Progressive Lipodystrophy. A clinical study of 50 patients. Am J Dis Child. Oct 1963;106:356-63.
9. Sissons JG, West RJ, Fallows J, et al. The complement abnormalities of lipodystrophy. N Engl J Med. Feb 26 1976;294(9):461-5. [Medline].
10. Walker UA, Kirschfink M, Peter HH. Improvement of acquired partial lipodystrophy with rosiglitazone despite ongoing complement activation. Rheumatology (Oxford). Feb 2003;42(2):393-4.
11. Walport MJ, Davies KA, Botto M, et al. C3 nephritic factor and SLE: report of four cases and review of the literature. QJM. Oct 1994;87(10):609-15. [Medline].
12. Winhoven SM, Hafejee A, Coulson IH. An unusual case of an acquired acral partial lipodystrophy (Barraquer-Simons syndrome) in a patient with extrinsic allergic alveolitis. Clin Exp Dermatol. Jul 2006;31(4):594-6.

Article Last Updated: Jun 19, 2007