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Adipose Tissue Distribution Pattern in Patients with Familial Partial Lipodystrophy (Dunnigan Variety)¹

Departments of Internal Medicine (A.G., R.M.P.), Radiology (J.L.F., R.M.P.), and the Center for Human Nutrition (A.G.), The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235

Address all correspondence and requests for reprints to: Abhimanyu Garg, M.B.B.S., M.D., University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9052. E-mail: agarg{at}mednet.swmed.edu

	Abstract

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Familial partial lipodystrophy, Dunnigan type (FPLD), is a rare autosomal dominant genetic disorder characterized by gradual loss of sc fat from the extremities, commencing at the time of puberty. Excess fat deposition may occur in the face and neck area. Limited information is available about adipose tissue distribution in patients with FPLD. To investigate whether there is a unique pattern of fat distribution in both affected men and women with FPLD, we performed whole-body magnetic resonance imaging in one male and three female patients from two pedigrees. Magnetic resonance imaging studies confirmed the clinical findings of near-total absence of sc fat from all extremities. Reduction in sc adipose tissue from the truncal area was more prominent anteriorly than posteriorly. Increased fat stores were observed in the neck and face. Intermuscular adipose tissue in the extremities and pelvic area were subjectively increased. Intraabdominal and intrathoracic adipose tissue was not reduced. Bone marrow fat, as well as mechanical adipose tissue, was present in normal amounts. The pattern of fat distribution in the male and females was similar. We conclude that FPLD results in a characteristic absence of sc fat from the extremities, with preservation of intermuscular fat stores.

	Introduction

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OZER AND co-workers (1) in 1973 described a 52-yr-old woman with a new variety of lipodystrophy. Several members of her family were found to have a so-called fat neck syndrome, characterized by excessive accumulation of fat on the face, neck, shoulder girdle, axillae, back, and genitalia. In contrast, the limbs were devoid of fat and had prominent musculature. All affected subjects had type IV hyperlipoproteinemia, two had diabetes mellitus, and four had abnormal glucose tolerance. Subsequently, Dunnigan et al. (2) provided full descriptions of two families with a similar type of lipodystrophy, which is now known as familial partial lipodystrophy, Dunnigan variety (FPLD).

FPLD is a rare genetic disorder characterized by gradual atrophy of sc adipose tissue in the extremities and trunk during early puberty and adolescence, with either normal or excessive adipose tissue on the face and neck (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). The phenotypic expression is conspicuous in affected women. However, prepubertal children do not show any features of FPLD. Furthermore, because even normal men may be quite muscular, distinction between affected and unaffected men can be difficult. Such difficulties probably led early investigators to assign an X-linked dominant inheritance pattern for FPLD (4). However, subsequent pedigrees (8, 12), including those reported by us (15), clearly show autosomal dominant inheritance.

Besides clinical description, there is only limited information about adipose tissue distribution in patients with FPLD (12). Furthermore, it is not clear whether the pattern of adipose tissue distribution is similar in affected men and women. The purpose of this investigation, therefore, was to study, in detail, the distribution of adipose tissue in four patients with FPLD, by using whole-body magnetic resonance imaging (MRI) similar to our previous study in a different type of genetic lipodystrophy, i.e. congenital generalized lipodystrophy (CGL) (16). We also aimed to identify characteristic features of adipose tissue distribution that could differentiate FPLD from other familial forms of lipodystrophies.

	Subjects and Methods

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Subjects

Three women (F200.11, F200.17, and F300.7) and one man (F300.3), with FPLD belonging to two pedigrees, were studied (15). They all had near-complete absence of sc fat, prominent veins, and increased muscularity in all extremities but had increased fat in the neck and face areas. All women had a characteristic double chin, excess of supraclavicular fat, and prominent labia majora. The male patient had a double chin only. All three women, but not the male patient, had hypertriglyceridemia and a history of eruptive xanthomas. None of the patients had acanthosis nigricans or acromegaloid features; and women had no hirsutism, virilization, or clitoromegaly. All patients had diabetes mellitus, which required insulin therapy. Other features of each subject are described separately and in Table 1. The protocol for this study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas, and each patient gave informed consent.

F200.17. This 33-yr-old non-Hispanic white woman had a normal appearance as a child. She noted gradual loss of adipose tissue from the gluteal area and became aware of double chin and cushingoid appearance at age 13. Her maximum weight was 68 kg at age 19, but then she lost weight (to 55 kg) by diet and exercise. Diabetes mellitus was diagnosed at age 26 and required sulfonylurea therapy. She was switched to insulin therapy during pregnancy. She had cholecystectomy at age 30 for gallstones. She had been on gemfibrozil therapy for hypertriglyceridemia but discontinued it 1 month before presentation. Physical examination revealed palpable liver, 2 cm below the costal margin.

F300.7. This 30-yr-old non-Hispanic white woman first presented with severe hypertriglyceridemia during her third pregnancy. She had a normal fat pattern during childhood. With onset of menstruation at age 12, she noted accumulation of adipose tissue around the neck and face and noted increased muscularity, with disappearance of fat from legs, arms, and hips. Gestational diabetes was diagnosed at age 18. At age 20, she underwent reconstructive surgery to remove excess fat around face and neck and liposuction to remove fat from shoulders and the posterior part of the neck. She lactated normally after each pregnancy; however, after weaning, her breasts seemed flat and atrophic. Hypertriglyceridemia during pregnancy was treated with fish oil and, afterwards, with gemfibrozil. She continued to require insulin therapy after delivery. On physical examination, liver and spleen were palpable, 8 and 4 cm below the costal margins, respectively. She had lipemia retinalis and eruptive xanthomas.

F300.3.This 42-yr-old non-Hispanic white male was first evaluated at age 38, as a part of family screening. He was asymptomatic, with an unremarkable past medical history. At this visit, physical examination revealed double chin and muscular habitus, with prominent superficial veins in arms and legs. He had never engaged in body building or weight training. During his next visit, at age 40, he reported polyuria, polydipsia, loss of weight from 70.5 to 64 kg, and was diagnosed with diabetes mellitus.

Healthy controls. Two healthy women (19- and 21-yr-old) volunteered as controls for the MRI studies. Their heights were 1.65 and 1.66 m, and body weights were 50 and 61.4 kg, respectively.

Anthropometric measurements

Height and weight were measured by standard procedures. Body volume was measured underwater by a Whitmore Volumeter. Residual lung volume was measured by body plethysmography. Proportion of body fat was estimated by Siri’s equation (17).

MRI technique

MRI was performed using a 0.35 Tesla imaging device (Toshiba America MRI, Inc., South San Francisco, CA). The entire body was surveyed employing contiguous, axial, 10-mm slices and a T1-weighted spin echo sequence [500/30, TR (repetition time)/TE (echo time)], a quadrature body coil, 128 x 256 matrix, 1.7 x 1.7 x 10 mm voxel, and 1 excitation. Cardiac gating was employed in the thorax, with TR set to every other heart beat, without changing other imaging parameters. Fat was easily identified on MRI because of its short T1 relaxation time and its relatively high signal intensity on images, compared with other tissues, such as muscle (17).

	Results

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Whole-body MRI studies revealed a similar pattern of adipose tissue distribution in each of the three women and the male patient with FPLD. The most striking finding was an extreme lack of sc adipose tissue from all the extremities, as well as the gluteal area (Fig. 1). No sc fat was visualized in the legs, but scant sc adipose tissue could be seen in the medial and posterior aspects of the proximal thighs. In the forearms, as well, some sc fat could be visualized medially. The sc truncal adipose tissue, both from the thoracic and abdominal areas, was less conspicuously reduced (Figs. 2 and 3). The loss of sc truncal fat was more marked in the anterior region than in the posterior region. The sc adipose tissue overlying the breasts was markedly reduced, although the mammary tissue in the two premenopausal women seemed to be preserved. Fat was present, deep to the pectoralis major, contiguous with the axilla. An excess of sc fat, however, was noted in the posterior cervical area extending to the suprascapular region. MRI studies further revealed excess adipose tissue in the face, neck, chin, and labia majora of the affected women (Figs. 4 and 5).

View larger version (149K): [in this window] [in a new window]   Figure 1. Axial MRI, at the level of thigh (A) and calf (B) in an affected woman with FPLD, showing near-complete absence of sc fat but preservation of intermuscular and bone marrow adipose tissue. Scant sc adipose tissue can be seen in the medial and posterior aspects of the thigh. Similar images, at the level of thigh (C) and calf (D), from a normal healthy female, showing normal amounts of sc, intermuscular, and bone marrow fat.

View larger version (131K): [in this window] [in a new window]   Figure 2. A, Axial MRI, at the level of the heart in an affected woman with FPLD, showing reduction in sc fat in the thoracic region. The loss of sc truncal fat is more prominent in the anterior than in the posterior region. Intrathoracic fat seems to be normal. Fat is present in the periarticular region around the shoulder joint and in the axillae. The sc tissue overlying the mammary glands has negligible amounts of fat. B, Similar image, in a normal healthy female, showing sc and epicardial fat. Fat is present in the axillae, and in the sc area overlying the mammary glands.

View larger version (144K): [in this window] [in a new window]   Figure 3. A, Axial MRI, at the level of kidneys in a patient with FPLD, showing reduction in sc abdominal fat, particularly anteriorly, but a normal amount of intraabdominal fat; B, similar image, from a normal healthy woman, showing normal amounts of intraabdominal and sc fat.

View larger version (124K): [in this window] [in a new window]   Figure 4. A, Axial MRI of the cervical region, in an affected woman with FPLD, showing an excess of submental, supraclavicular, and posterior cervical fat; B, similar image, from a healthy female, showing a normal amount of sc fat.

View larger version (138K): [in this window] [in a new window]   Figure 5. A, Axial MRI, at the level of pelvis in an affected woman with FPLD, showing marked reduction in sc fat. sc fat, underlying the labia majora and in the intermuscular fasciae, seems to be in excess. B, similar image, from a normal healthy woman, showing normal amounts of sc and intermuscular fat.

Axial MRI sections through both the upper and lower extremities, as well as through the gluteal region, revealed an apparent excess of adipose tissue in between the muscular fasciae (Fig. 1). Intermuscular fat was particularly prominent in the pelvic area (Fig. 5). Bone marrow fat was normal in appearance, as evident by normal medullary signal intensity. Normal amounts of fat were also noted in anatomic sites where mechanical adipose tissue is present, such as orbits, palm, sole, scalp, and periarticular regions.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data reveal a consistent pattern of distribution of adipose tissue in all four affected subjects belonging to two pedigrees, which suggests a peculiar, characteristic fat distribution pattern in FPLD. The pattern of fat distribution in the male patient was similar to that seen in women with FPLD. The characteristic or diagnostic features of adipose tissue distribution pertain to the anatomic sites from which atrophy of sc fat occurs. The other remaining anatomic sites may have either normal or excess fat stores.

The MRI images revealed that sc fat from the extremities was nearly absent; however, sc fat from the thoracic and abdominal region was clearly visualized, although it seemed to be reduced. The lack of adipose tissue was particularly noticeable in the anterior truncal region. In fact, sc fat in the suprascapular area seemed to be increased. MRI studies also confirmed clinical findings of excess of adipose tissue in the face, neck, chin, axillae, and labia majora. Although Jackson et al. (12) had concluded, in their study of two patients with FPLD, that there was a total lack of sc fat in all areas except the cheeks, palms and soles; their published magnetic resonance images of head, thorax, and abdomen showed that sc fat was present in these areas. Hence, fat distribution in their patients is similar to that seen in our patients.

The amount of intraabdominal fat varied with total body fat, which ranged from 6–40% (suggesting that some affected subjects could be lean, whereas others may, in fact, be obese). Similar observations were made by Robbins et al. (8), using computerized axial tomography of the abdomen in two affected women, one of whom had greatly increased amounts of adipose tissue in the perinephric, omental, and periintestinal depots; whereas the other woman seemed to have a normal amount of intraabdominal fat. Our MRI data reveal no excess of intrathoracic (mediastinal or epicardial) fat. The intermuscular adipose tissue excess is quite interesting and suggests that its development differs from that of sc adipose tissue in the extremities. Furthermore, adipose tissue distribution pattern in the extremities of the patients with FPLD (i.e. lack of sc fat, but preservation of bone marrow fat and excess of intermuscular fat) is unique and diagnostic.

Patients with FPLD did have normal amounts of adipose tissue in sc areas of scalp, temporal, buccal, palm, and sole, and in retroorbital, periarticular, and perineal regions. All these anatomic sites have mechanical adipose tissue. We previously reported similar sparing of the mechanical adipose tissue in CGL or Berardinelli-Seip syndrome (16, 18). However, other features differentiate fat distribution in the two types of lipodystrophies. Patients with CGL have total absence of metabolically active adipose tissue that is present in all sc sites other than those of mechanical adipose tissue, and in intraabdominal and intrathoracic regions, and in bone marrow (17, 18). Thus, patients with CGL lack sc fat from the face, neck, and trunk (unlike patients with FPLD). Intermuscular adipose tissue is also totally lacking in the patients with CGL, whereas its excess is observed in the patients with FPLD.

Patients with FPLD also need to be distinguished from the less common Kobberling variety of FPL (3, 4, 6). The Kobberling variety has been reported in only two small pedigrees and four sporadic cases (3, 4, 6, 19). The age of onset of lipodystrophy and the mode of inheritance are not clear. On the basis of clinical findings, the loss of adipose tissue in the Kobberling variety is said to be restricted to extremities only (3, 4, 6). Patients have normal amounts of fat in the face area and may have normal, or even excess, sc fat in the truncal area. Until computed tomography or MRI studies are performed in patients with the Kobberling variety of FPL, the distinguishing features between the two varieties will remain unclear.

Several patients with FPLD have a clinical appearance resembling that of patients with Cushing’s syndrome. Although excess of adipose tissue in the face and neck and increased visceral-to-sc abdominal fat ratio are present in both of the disorders (20), our study reveals some differentiating features. For example, excess adipose tissue may be present in the dorsal cervical region (buffalo hump) and in mediastinal, epicardial, presternal, and orbital regions in patients with Cushing’s syndrome (21, 22, 23, 24); but it was not observed in patients with FPLD. Furthermore, near-total absence of sc fat from all the extremities and reduction in the anterior sc truncal fat are not features of Cushing’s syndrome.

We conclude that the loss of adipose tissue that occurs at the time of puberty in patients with FPLD results in a characteristic absence of sc fat from the extremities, with preservation of intermuscular and bone marrow fat stores. On the basis of the similarities in adipose tissue distribution to that seen in Cushing’s syndrome, and the onset of lipodystrophy at puberty, it can be speculated that the genetic defect interferes with normal steroid-dependent pubertal growth and differentiation of adipose tissue. The precise genetic basis of FPLD is not known. Recent studies from our group have localized the gene for FPLD to the chromosome 1q21–22 region (15). Identification of the FPLD gene will further our understanding of the pubertal growth and differentiation of adipose tissue and how the gene defect results in the characteristic adipose tissue distribution.

	Acknowledgments

 
We are grateful to James Stray-Gundersen, M.D., for anthropometric measurements; David M. Feinstein, M.D., for referring patient F200.17 to us; and to Dorothy Gutekunst, Virginia Reed Vaughn, Alison Russell, Jerri Payne, Cindy Miller, Christi Ward, Travis Petricek, and the nursing and dietetic services of the General Clinical Research Center of the Parkland Memorial Hospital for excellent technical support.

	Footnotes

 
¹ This work was supported, in part, by grants from the National Institutes of Health (M01-RR-00633) and Toshiba America MRI, Inc.

Received June 12, 1998.

Revised September 30, 1998.

Accepted September 9, 1998.

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