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Familial Partial Lipodystrophy

FPLD

Familial partial lipodystrophy is a rare genetic disorder in which progressive loss of subcutaneous fat starts around puberty. Depending on the subtype, loss of fat in the extremities and trunk, with the accumulation of adipose tissue in the head and neck region may be seen. Laboratory tests and imaging studies are used for the diagnosis. Symptomatic treatment is the mainstay of care.


Presentation

There are two main types of FPLD [2]:

  • Type I - Loss of fat in the extremities and normal or increased distribution of adipose tissue on the head and neck area, as well as the trunk.
  • Type II - Seen only in a few cases, this type is distinguished by loss of fat from both the trunk and the extremities, with marked accumulation in the head and neck region.

Metabolic impairments, primarily in the form of diabetes mellitus, but also hirsutism and dysmenorrhea in women, typically starts during early years of life [3].

Turkish
  • The phenotype of this distinctive FPLD subtype was studied in three Turkish female siblings. Mutation testing was negative for the genes associated with lipodystrophy syndromes.[ncbi.nlm.nih.gov]
Euthyroid
  • Thyroid investigations showed a euthyroid multinodular goiter. In addition, the patient exhibited a juvenile akineto-hypertonic syndrome.[ncbi.nlm.nih.gov]
Hirsutism
  • She also had hirsutism. Anthropometry and whole body magnetic resonance imaging revealed marked loss of sc fat particularly from the extremities but sc truncal fat was slightly increased.[ncbi.nlm.nih.gov]
  • Some females may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. Patients are typically predisposed to early cardiovascular diseases.[orpha.net]
Absence of Subcutaneous Fat
  • Absence of subcutaneous fat from the upper and lower extremities during childhood or puberty. The trunk, arms and legs are affected by fat loss while the neck and face have more than normal fat deposits.[manbironline.com]
  • Thin wrinkles of skin under the buttocks confirm the absence of subcutaneous fat. Extremities often appear muscular with visible veins ( Fig. 1 C ) or thin without obvious veins.[care.diabetesjournals.org]
Xanthoma
  • Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome.[ncbi.nlm.nih.gov]
  • Xanthoma and nail changes may occur. Type 3 is due to mutations in the PPARG gene. It is rare with approximately 30 cases reported to date. It is similar to type 2 but tends to be milder. Type 4 is due to mutations in the PLIN1 gene.[en.wikipedia.org]
  • Eruptive xanthoma (0.6%), diabetic foot (0.2%), diabetic bulla (0.4%), diabetic dermopathy (0.2%), generalized granuloma annulare (0.2%), and insulin reactions (6.2%) and lipodystrophy (14%) were also seen.[e-ijd.org]
Facial Lipoatrophy
  • There are limited reports regarding the role of reconstructive procedures to address the physical defects imposed by the various lipodystrophy syndromes, and much of the work to date has focused around facial lipoatrophy in patients with HIV-1 protease[ncbi.nlm.nih.gov]
Labial Hypertrophy
  • In type 2 familial lipodystrophy, the trunk is also affected with the exception of the vulva, giving an appearance of labial hypertrophy.[ncbi.nlm.nih.gov]
Dysmenorrhea
  • Metabolic impairments, primarily in the form of diabetes mellitus, but also hirsutism and dysmenorrhea in women, typically starts during early years of life.[symptoma.com]
Labial Hypertrophy
  • In type 2 familial lipodystrophy, the trunk is also affected with the exception of the vulva, giving an appearance of labial hypertrophy.[ncbi.nlm.nih.gov]

Workup

The diagnostic workup must comprise a thorough patient history that might reveal a familial presence of symptoms and a thorough physical examination that will identify the distribution of adipose tissue. Laboratory workup reveals hypertriglyceridemia and insulin resistance [3], but because clinical features of this rare genetic syndrome strongly point to an endocrine disease, the diagnosis can be easily missed [2]. For this reason, the role of history taking in these patients is of vital importance.

Hypertriglyceridemia
  • Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance.[ncbi.nlm.nih.gov]
  • Complications include hypertension, insulin resistance and hypertriglyceridemia. The gene causing this condition is not yet known. This form was first described in 1975.[en.wikipedia.org]
  • In fact, the hypertriglyceridemia was so severe that 64% of FPLD1 subjects with hypertriglyceridemia had a history of pancreatitis due to chylomicronemia syndrome ( 23 ).[care.diabetesjournals.org]

Treatment

Management of diabetes mellitus and hyperlipidemia is the mainstay of therapy, whereas leptin replacement therapy is currently under review for use in treating patients with various forms of lipodystrophies [3].

Prognosis

In rare cases, marked hypertriglyceridemia can induce acute pancreatitis and hepatic steatosis, whereas myopathy and cardiomyopathy have been documented as well [3] [5].

Etiology

Mutations in genes that code for intermediate filaments proteins that serve as constituents of nuclear membranes, known as lamins, are the underlying cause of FPLD [1]. Lamin A and C mutations are transferred by an autosomal dominant pattern of inheritance and the condition is exclusively found in more than one family member [3]. Most recent studies have discovered that mutations in one of the nuclear receptors, the peroxisome proliferator-activated receptor gamma (PPARG), are also associated with the onset of FPLD [4].

Epidemiology

FPLD is a very rare condition and only isolated case reports or case series are the sources of data regarding this condition [1] [2] [3] [4] [5]. Neither gender nor ethnic predilection has been established, whereas risk factors are yet to be determined.

Sex distribution
Age distribution

Pathophysiology

Lamins are recognized as essential nuclear membrane proteins and they are coded by Lamin A and C genes [2]. In the setting of mutations, their structure is disrupted and through still unknown mechanisms, individuals suffer from adipose tissue loss and develop a clinical presentation of metabolic syndrome [2] [3].

Prevention

At this point, prevention strategies against FPLD do not exist.

Summary

Familial partial lipodystrophy (FPLD, also known as Köbberling–Dunnigan syndrome), is a rare autosomal dominant genetic disorder that belongs to the group of laminopathies, disorders that are associated with mutations in the lamin A/C gene (LMNA and LMNC, respectively) [1]. The pathogenesis model remains unclear but is thought that mutations in these intermediate filament proteins lead to fat loss and development of insulin resistance [2]. There are two main clinical types: type I, in which fat loss predominantly occurs on the extremities, with normal or slightly increased distribution of adipose tissue in the thorax and the head and neck area; and type II, characterized by loss of fat from both the limbs and the trunk and its accumulation in the neck region [2]. To make the diagnosis, it is necessary to obtain a thorough patient history, perform a detailed physical examination and evaluate serum lipid and glucose levels, as diabetes mellitus and dyslipidemia are frequent findings in these patients [3]. Treatment focuses on managing symptoms, mainly through lipid-lowering drugs and insulin [3].

Patient Information

Familial partial lipodystrophy (FPLD) is a rare genetic disease characterized by loss of fat tissue due to mutations of proteins that serve as building blocks of cell membranes. FPL is transferred by an autosomal dominant pattern of inheritance, meaning that parents will almost certainly transfer the mutated gene to their children and the majority of reported cases involve more than one family member. The disease most frequently presents with loss of fat in the extremities and a normal or somewhat increased amount of fat in the chest and the head and neck area and metabolic diseases such as diabetes mellitus are commonly encountered. Symptoms start in early childhood and the diagnosis can be made by obtaining a detailed patient history that reveals the presence of symptoms in other family members, while blood tests show elevations of triglycerides and glucose. Treatment is currently aimed at controlling diabetes and high lipid levels.

References

Article

  1. Drac H, Madej-Pilarczyk A, Gospodarczyk-Szot K, Gaweł M, Kwieciński H, Hausmanowa-Petrusewicz I. Familial partial lipodystrophy associated with the heterozygous LMNA mutation 1445G>A (Arg482Gln) in a Polish family. Neurol Neurochir Pol. 2010;44(3):291-296.
  2. Herbst KL, Tannock LR, Deeb SS, Purnell JQ, Brunzell JD, Chait A. Köbberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care. 2003 Jun;26(6):1819-1824.
  3. Handelsman Y, Oral EA, Bloomgarden ZT, et al. The clinical approach to the detection of lipodystrophyy - An AACE concensus statement. Endocr Pract 2013;19(1):107-116.
  4. Demir T, Onay H, Savage DB, Temeloglu E, Uzum AK, Kadioglu P, et al. Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -γ (PPARG) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations. Diabet Med. 2016;33(10):1445-1450.
  5. Jackson SNJ, Howlett TA, McNally PG, O’Rahilly S, Trembath RC. Dunnigan-Kobberling syndrome: an autosomal dominant form of partial lipodystrophy. QJM. 1997;90(1):27-36.

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Last updated: 2019-07-11 20:11