Progressive Lipodystrophy 

Updated: Apr 09, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD 

Overview

Background

Lipodystrophy syndromes represent a group of rare, heterogeneous disorders characterized by progressive loss of fat tissue, mainly from the subcutaneous compartment and occasionally from visceral fat.[1] Subcutaneous loss of fat can occur as generalized or partial lipodystrophy; the latter is more common. Progressive lipodystrophy is the most common type of partial lipodystrophy.

The other types, such as the Kobberling-Dunnigan variety or the familial mandibuloacral dysplasia syndrome, may be familial and tend to be associated with metabolic anomalies such as glucose intolerance and hypertriglyceridemia. Nakajo-Nishimura syndrome is an inherited inflammatory disease that usually begins in early infancy with a perniolike rash, periodic high fever, and nodular erythemalike eruptions, with gradually progressive partial lipoatrophy of the upper body, mainly the face and the upper extremities.[2, 3] Acquired partial lipodystrophy is a rare condition of unknown etiology characterized by progressive loss of fat of the face, neck, trunk, and upper extremities beginning during childhood and is more common in girls.[4]

Progressive lipodystrophy is a rare condition that typically affects children and young adults. The first case was described by Mitchell in 1886,[5] and later cases were described by Barraquer in 1907 and Simons in 1911. The onset is usually insidious with the slow, progressive disappearance of subcutaneous fat involving the upper half of the body. The predictive progression of the disease from the face to the neck, upper extremities, and trunk (sparing the buttocks and lower limbs) is characteristic. Evidence of ongoing complement activation on adipose tissue was documented in a child with this syndrome.[6] Associated hypocomplementemia, glomerulonephritis, and autoimmune disorders are frequently present in some patients. However, some forms of partial lipodystrophy in children do not seem to fit the diagnostic criteria for any of the established lipodystrophy subset.[7]

Pathophysiology

The etiology of this condition is obscure. Lipodystrophy is often associated with glomerulonephritis, low C3 serum complement levels, and the presence of a C3 nephritic factor. C3 nephritic factor is a serum immunoglobulin G that interacts with the C3bBb alternative pathway convertase to activate C3.

C3 nephritic factor induces the lysis of adipocytes that secrete adipsin, a product identical to complement factor D. The distribution of the lipoatrophy is postulated to be dictated by the variable amounts of adipsin secreted by the adipocytes at different locations.

Human PTRF mutations may cause secondary deficiency of caveolins, resulting in generalized lipodystrophy in association with in muscular dystrophy.[8]

Dunnigan-type familial partial lipodystrophy was linked with heterozygous R482W mutation in the LMNA gene in an analysis of 3 women from one family.[9, 10]

Berardinelli-Seip congenital lipodystrophy type 2, the severest form of human lipodystrophy with an almost complete loss of adipose tissue, is due to loss-of-function mutations in the BSCL2/SEIPIN gene.[11] It is characterized by near-total fat atrophy linked with the progressive development of metabolic complications. It is a result of mutations in AGPAT2.[12]

Nakajo-Nishimura syndrome is an autoinflammatory disorder due to a mutation of the PSMB8 gene.[13]

A family with dilated cardiomyopathy associated with lipodystrophy and neurological manifestations and overlapping phenotype from lamin A/C mutation was delineated in detail with a follow-up of 22 years.[14]

See the model below.

Model of the adipocyte destruction in acquired par Model of the adipocyte destruction in acquired partial lipodystrophy showing complement activation at the adipocyte surface resulting in adipocyte lysis. Adipocytes synthesize C3, factor B, and factor D (adipsin), which allows C3bBb to be formed locally, but which usually does not result in the activation of the terminal lytic part of the complement pathway (C5-9).The IgG antibody, C3Nef, prevents the alternative complement C3-convertase C3Bb from dissociative inactivation, resulting in adipocyte lysis. Adipocytes synthesize factor D, the limiting component of the alternative complement pathway, which cleaves C3-bound factor B to its active enzymatic form. Factor D is expressed to a higher extent in the fat cells of the upper half of the body compared with the lower half, and it is possibly this regional difference that accounts for the restriction of fat loss to the head, arms, and trunk. C3Nef is also associated with type II, dense-deposit membranoproliferative glomerulonephritis in which subendothelial deposits of immunoglobulin and C3 are probably due to a deregulated alternative complement pathway.

Etiology

No specific cause or risk factor has been elucidated for progressive lipodystrophy. Some reports have shown a correlation of progressive lipodystrophy with prior acute viral or bacterial infection. Acquired partial lipodystrophy (Barraquer-Simons syndrome) usually follows acute febrile illness; it can rarely be seen in association with varicella.[15]

Epidemiology

Frequency

Progressive lipodystrophy is rare, with fewer than 200 cases reported in the world literature since the first case was reported in 1885.[16]

Race

No racial predilection is reported for progressive lipodystrophy.

Sex

Progressive lipodystrophy is 4-5 times more common in women than in men. Of patients with progressive lipodystrophy, 80% are females. The accumulation of fat in the buttocks and lower limbs occurs almost exclusively in females. Males who are affected usually have lipoatrophy without lower body hypertrophy.

Age

Progressive lipodystrophy typically starts in individuals aged 0-20 years, with most cases starting before individuals are aged 15 years. Progressive lipodystrophy tends to develop earlier in most male patients compared with female patients.

Prognosis

The prognosis for progressive lipodystrophy is correlated with the renal complications and the onset of renal failure. Acquired progressive lipodystrophy is a nonfatal condition, but it is frequently associated with mesangiocapillary glomerulonephritis, which can lead to renal insufficiency. In pregnancy, more severe renal disease is associated with a risk of intrauterine growth retardation, prematurity, and fetal death.[17] Associated autoimmune disorders are also present in some patients, including systemic lupus erythematosus and dermatomyositis.

 

Presentation

History

Patients with progressive lipodystrophy are born healthy with a normal appearance and fat distribution. In individuals aged 0-20 years, progressive loss of fat, which first involves the face, spreads distally to the neck, arms, and trunk; the lower part of the body is usually spared.

Physical Examination

Because of the insidious onset and slow progression of progressive lipodystrophy, most patients present when the disease is in an advanced stage. Advanced cases have a characteristic physical appearance.

The face appears cachectic. Buccal fat pads are absent, resulting in a prominent zygoma and chin. The temples and cheeks are hollowed, causing a cadaverous appearance. The eyes are deeply sunken due to the loss of periorbital fat. The face is heavily lined, creating numerous wrinkles lying over the cheeks, which causes the appearance of premature senility. The scalp, hair, and other facial areas are generally unaffected. However, centrifugal lipodystrophy has been described in a child with progressive arch–form alopecia. The alopecia continuously extended for a decade, after which expansion ceased, leaving a linear nonhairy patch.[18]

Frequently, the breasts are underdeveloped, with a firm, nodular feel. The arms and shoulders have a clear, well-demarcated outline of muscles below the skin, which gives the false impression of increased muscularity.

The area of fat loss is sharply demarcated at a level above the thighs; the lower extremities are spared. The uninvolved lower part of the body appears obese when contrasted with the upper, thin area. In female patients, excessive fat may develop on the legs and buttocks after puberty. A form of familial partial lipodystrophy with a highly selective partial fat loss pattern and proteinuria has been described.[19]

The overlying skin itself is normal in color, elasticity, and texture. No muscular hypertrophy is noted.

A patient with acquired partial lipodystrophy (Barraquer-Simons syndrome) was described with localized scleroderma.[20]

Complications

Renal disease

Mesangioproliferative glomerulonephritis occurs in 50% of patients with lipodystrophy and a low C3 complement level. Mesangioproliferative glomerulonephritis often follows an aggressive course and may lead to renal insufficiency.

Immune disorders

Systemic lupus may develop in a few patients. Other autoimmune diseases include dermatomyositis,[21]  rheumatoid arthritis, leukocytoclastic vasculitis, hypothyroidism, and pernicious anemia.

 

DDx

Diagnostic Considerations

Genetic testing may identify patients whose phenotypes may be inapparent, but who may still be affected by severe metabolic complications.[22]

Also consider the following:

  • Generalized lipodystrophies such as Berardinelli-Seip syndrome (associated with acanthosis nigricans) [23]
  • Other types of partial lipodystrophy
  • Centrifugal lipodystrophy [24]
  • Facial hemiatrophy
  • Short, hyperextensibility or hernia, ocular depression, Rieger anomaly, and teething (SHORT) syndrome
  • Anterior hypothalamus tumor

Progressive generalized lipodystrophy may be a sign of autoimmune polyglandular syndrome type 1.[25]

Lipodystrophy may be stigmatizing, implying use of highly active antiretroviral therapy (HAART) for HIV disease.[26]

Differential Diagnoses

 

Workup

Laboratory Studies

Urinalysis may be helpful in progressive lipodystrophy. Approximately one third of patients with this condition have some degree of glomerulonephritis, and, if hypocomplementemia is present, the risk is higher. Manifestations of glomerulonephritis range from asymptomatic proteinuria to a nephrotic syndrome and renal insufficiency.

Baseline creatinine and blood urea nitrogen studies, as well as urine studies, should be performed to detect proteinuria and hematuria.

A CBC count should be obtained. Normochromic normocytic anemia is often present.

Immune studies can be ordered. Immune studies may be needed to identify patients with associated immune disorders, particularly if the diagnosis of partial lipodystrophy is made at a younger age. The presence of serum antinuclear antibodies and anti–double-stranded DNA antibodies has been reported in some patients.

Complement levels may be determined. The most common laboratory abnormality in patients with progressive lipodystrophy is a low complement level. Hypocomplementemia is characterized by a low C3 complement level, a normal C4 level, and the presence of C3 nephritic factor.

Lipid studies may be performed. Hypertriglyceridemia secondary to nephrotic syndrome may be present in some patients.

Genetic testing may identify patients whose phenotypes may be inapparent, but who may still be affected by severe metabolic complications.[22]

Imaging Studies

Head MRIs show evidence of fat loss in progressive lipodystrophy patients.

Other Tests

Immunofluorescence studies in progressive lipodystrophy patients show deposits of C3 in a granular pattern in the basement membranes.

Procedures

Skin biopsy findings confirm the progressive lipodystrophy diagnosis. Kidney biopsy is required if a glomerulonephritis is associated with the progressive lipodystrophy.

Histologic Findings

Cutaneous biopsy in progressive lipodystrophy reveals a reduction or absence of subcutaneous fat in affected areas. Subcutaneous fat cells are decreased in number.

Traces of adipose tissue may be found around hair follicles and sebaceous glands. The dermis and epidermis are normal.

Renal biopsy findings are characterized by a membranoproliferative glomerulonephritis with a proliferation of mesangial cells and matrix, as well as thickening of the basement membranes by amorphous electron-dense deposits.

Immunofluorescence studies show deposits of C3 in a granular pattern in the basement membranes.

 

Treatment

Medical Care

No specific treatment for progressive lipodystrophy is effective. Symptomatic therapy should be prescribed as necessary for the treatment of renal complications and associated autoimmune disorders in progressive lipodystrophy patients.

Renal and immunologic disturbances may warrant inpatient care at times.

During pregnancy, the health status of the fetus should be ascertained with modalities such as an electronic fetal monitor. Fetal health assessment is particularly important during the third trimester to reduce the risk of intrauterine fetal death associated with progressive lipodystrophy.

Surgical Care

Various surgical techniques have been adopted through the years in an effort to improve progressive lipodystrophy patients’ facial appearance.[27, 28] Dermal-fat grafts from the gluteal region, temporal muscle flaps, silicone-filling material, and subcutaneous injections of fat from unaffected areas have been used with variable results. A novel surgical technique consists of a 1-stage transfer of 2 paddles of thoracodorsal artery perforator flap with 1 pair of vascular anastomoses for simultaneous restoration of bilateral facial atrophy.[4] It may be useful in selected patients for the reconstruction of bilateral facial atrophy.

Consultations

Referral to a nephrologist or an internist may be warranted for progressive lipodystrophy patients with severe nephropathy and those with associated autoimmune diseases.

Diet

Hyperalimentation can result in the excessive accumulation of fat in an unaffected area with no improvement on dystrophic areas.

Long-Term Monitoring

Note the following:

  • Renal status: Patients should be monitored regularly for evidence of glomerulonephritis. Glomerulonephritis can develop more than 10 years after the onset of progressive lipodystrophy.

  • Autoimmune disorders: Patients should be monitored for the development of systemic lupus erythematosus because it was reported in a few patients 2-28 years after the onset of progressive lipodystrophy.[29] Other autoimmune disorders have also been associated with this disease.

 

Medication

Medication Summary

No medical treatment for progressive partial lipodystrophy has proven effective. However, leptin replacement in lipodystrophy patients may lead to significant and sustained improvements in glycemic control and dyslipidemia and thus be effective in the various forms of lipodystrophy.[30]

Symptomatic therapy may be indicated in progressive lipodystrophy patients with severe nephropathy or associated immune disorders.