GL And PL - the different forms

Both forms, generalised and partial lipodystrophy, can be familial or acquired1; prevalence is less than 1 (generalised forms) and less than 3 (partial forms) per million respectively.  There are also further subtypes with partially defined genetic characteristics and different manifestations. The cause of the acquired forms has not yet been clarified sufficiently. Autoimmune and/or infectious causes are being discussed.3,4,5

Subtypes and characteristics of generalised lipodystrophy 3,4,5,6,7,8

 

Congenital generalised lipodystrophy
(Berardinelli-Seip Syndrome)

Acquired generalised lipodystrophy
(Lawrence Syndrome)


            Little girl with generalised lipodystrophy and typical lack of subcutaneous fat

Raeya, congenital lipodysthrophy GL

Appearance


            Illustration of disturbed fat distribution which shows the total lack of subcutaneous body fat

Lack
of fat

Variable fat
accumulation


            Illustration of disturbed fat distribution which shows the loss of subcutaneous body fat

Loss
of fat

Variable fat
accumulation

Mean age of onset

0.3 years (range 0.0-12.0 years)

5 years (range 0.0-15.0 years)

Gender distribution
(male : female)

1:1-2

1:3

Typical presenting
appearance

  • Muscular appearance with prominent veins and umbilical prominence
  • Enlarged liver
  • Hyperphagia, accelerated linear growth, advanced bone age or acromegaloid features
  • Precocious puberty and rarely, premature pubarche and menarche
  • More common in ethnic groups with instances of parental consanguinity
  • Progression of fat loss takes weeks or years
  • Hyperphagia
  • Hyperkeratosis, and generalised or localised pigmentation
  • Enlarged liver

Signs and symptoms

  • Comorbidities are common and severe
  • Hepato- and splenomegaly
  • Diabetes mellitus and acanthosis nigricans
  • Irregular menstrual periods, hirsutism, hyperandrogenism, polycystic ovaries, and/or infertility in females
  • Presence of autoimmune diseases or panniculitis
  • Hepato- and splenomegaly
  • Diabetes mellitus
  • Hirsutism, hypogonadism and acanthosis nigricans

Subtypes seen
(Causes and effects)

  • CGL1: AGPAT2 mutations- Patients lack metabolically active fat
  • CGL2: BSCL2 mutations - Most severe form, patients lack mechanical and metabolically active fat; they may also suffer from mental retardation
  • CGL3: Caveolin 1 (CAV1) mutations - Associated with short stature and vitamin D resistance, only one patient known
  • CGL4: Polymerase I and transcript release factor (PTRF) mutations - Extreme lack of body fat, associated with pyloric stenosis
  • Cause of lipodystrophy not fully known

Subtypes and characteristics of partial lipodystrophy1,3,4,5,7,9,10

 

Familial partial lipodystrophy
(Dunnigan or Köbberling type)

Acquired partial lipodystrophy
(Barraquer-Simons Syndrome)


            Woman with congenital partial lipodystrophy and typical lack of subcutaneous fat combined with fat accumulation around the neck

Linda, familial lipodystrophy PL

Appearance


            Illustration of disturbed fat distribution which shows the partial lack of subcutaneous body fat

Loss
of fat

Variable fat
accumulation


            Illustration of disturbed fat distribution which shows the partial lack of subcutaneous body fat

Loss
of fat

Variable fat
accumulation

Mean age of onset

9.9 years (range 0.0-16.0 years)

8.2 years (range 0.5-16.0 years)

Gender distribution
(male : female)

1:1-2

1:4

Typical presenting
appearance

  • Appearance may be Cushingoid or resembling obesity
  • Fat accumulation around the neck in some subtypes
  • Hyperphagia
  • Fat loss occurs in cephalocaudal fashion
  • Progression of fat loss may take months or years
  • Fat accumulation around the hips or legs

Signs and symptoms

  • Metabolic abnormalities develop during adulthood
  • Diabetes and acanthosis nigricans
  • Hirsutism and hyperandrogenism in females
  • Hepatomegaly
  • Metabolic complications are less common
  • Main cause of morbidity is renal disease due to autoimmunity which may lead to kidney failure

Subtypes seen
(Causes and effects if described)

  • FPL1: Unknown cause - Loss of gluteal and limb fat, but leptin levels often unaffected
  • FPL2: Lamin A/C mutations – Fat accumulation around neck and reduced leptin levels
  • FPL3: Peroxisome proliferator activated receptor gamma (PPARG) mutations
  • FPL4: Perilipin 1 (PLIN1) mutations
  • FPL5: Cell-death-inducing DNA, fragmentation factor alphalike effector C (CIDEC) mutations
  • FPL6: Adrenoceptor alpha 2A (ADRA2A) mutations - Fat accumulation around neck
  • FPL7: Hormone-sensitive lipase (LIPE) mutations

Causes of lipodystrophy not fully known (autoimmune or genetic)

With familial PL in particular, subcutaneous loss of fat may not directly be perceived as a main symptom. Attention should be paid to any loss of subcutaneous fatty tissue on the arms or legs. By contrast, there can be fat accumulations in the area of the face and neck (buffalo’s or bull’s neck), particularly in women. The ectopic, intra-abdominal fat deposits with a corresponding increase in abdominal girth can lead to a Cushingoid or obese appearance.5

In the acquired form of PL, loss of fat is mostly slow, starting from the head to the upper abdomen. There can, however, be fat accumulation in the area of the buttocks, hips and lower extremities.5 The typical “saddlebags” appearance develops.

Pay attention to patients with unusual fat distribution and a Cushingoid appearance: they could have PL!
 

1 Brown et al., The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab. 2016; 101: 4500 – 4511.

2 Chiquette E, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2017:10 375-383.

3 Gupta et al., Clinical Features and Management of non-HIV related Lipodystrophy in Children: A Systematic Review. J Clin Endocrinol Metab. 2017; 102: 363 - 374“

4 Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J Hum Genet 2014;5:16-23.

5 Handelsman Y, Oral EA, Bloomgarden ZT, et al. The clinical approach to the detection of lipodystrophy – An AACE Consensus Statement. Endocr Pract 2013;19:107–116.

6 Garg A, Misra A. Hepatic steatosis, insulin resistance, and adipose tissue disorders. J Clin Endocrinol Metab 2002;87:3019-22.

7 Agarwal AK, Simha V, Oral EA, et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystro¬phy. J Clin Endocrinol Metab 2003;88:4840-47.

8 Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore) 2003;82:129-46.

9 Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 2000;85:1776-82.

10 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) 2004;83:8318-34.