GL or PL - A rare disease with many faces

GL and PL are heterogenous in appearance, very rare, and characterised by a partial or complete loss of subcutaneous fatty tissue. The disease is subdivided according to four primary categories: generalised, partial, familial and acquired.1

Subtypes and characteristics of the generalised lipodystrophy2,7,8,9,18,19

 

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 total lack 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)

Subtypes and characteristics of the partial lipodystrophy1,2,7,9,18,20,21

 

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)

The key symptoms and the appearance of GL and PL can lead to a suspected diagnosis. The essential clinical abnormalities are summarised in an international practice guideline that was developed in cooperation with various international medical associations.1

Main symptom

Generalised or partial absence of subcutaneous fat

Further physical characteristics

Prominent muscles and veins

Pronounced acanthosis nigricans, eruptive xanthomas

Cushingoid, acromegaloid or progeroid appearance

Failure to thrive in infants and children

Clinical characteristics

Diabetes with high insulin dose requirement
-    ≥200 U/day, ≥2 U/kg/day  
-    Use of U-500 insulin

Severe hypertriglyceridaemia
-    ≥500 mg/dL (≥ 5.65mmol/L)
-    ≥250 mg/dL (≥ 2.83 mmol/L) despite treatment and diet
-    History of pancreatitis associated with hypertriglyceridaemia

Non-alcoholic steatohepatitis in non-overweight patients

Early cardiomyopathy

Polycystic ovary syndrome
Amenorrhea
Secondary hypogonadism

Pronounced hyperphagia

Comorbidities

Hyperphagia caused by leptin deficiency can lead to an increased intake of calories, which further exacerbates the disease.1 In children, the prevalence of diabetes varies, depending on the subtype, between 48% and 70%.3 Hepatomegaly caused by the hepatic steatosis is frequently found. This can develop into steatohepatitis, liver cirrhosis or even liver failure.2,4 55% of patients with generalised lipodystrophy have cardiomyopathy.5 Reduced leptin levels lead to an increased rate of infections on account of an influence on the immune system.6 Patients with lipodystrophy may die prematurely. Major causes include: heart disease5 (cardiomyopathy, heart failure, myocardial infarction, arrhythmia), liver disease,7,8 (liver failure, gastrointestinal haemorrhage, hepatocellular carcinoma), kidney failure,8 acute pancreatitis, and sepsis.1

Do you have a patient who has developed Type 2 diabetes early despite having a low BMI? A young patient who eats too much and is still very thin?
A young patient with a fatty liver with no recognisable cause?

It may be GL or PL!

Pertinent symptoms are diabetes that is hard to treat and has a high insulin requirement, severe hypertriglyceridaemia, early development of a fatty
liver, steatohepatitis, early cardiomyopathy, pronounced hyperphagia, abnormal development and polycystic ovary syndrome.

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 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

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

5 Lupsa BC, Sachdev V, Lungu AO, et al. Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment. Medicine (Baltimore) 2010;89:245–50.

6 Fernández-Riejos P, González-Yanes C, Najib S, et al. Role of Leptin in the Immune System. Current Immunology Reviews 2008; 4:230-234.

7 Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011;301:E567–84.

8 Seip M. Generalized lipodystrophy. In: Frick P vHG, Miller AF, Prader A, Schoen R, WolfHP(eds), ed. Ergeb InnMedKinderheilkd: Springer Berlin;1971:59–95.

9 Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism 2015;64:146-56.

10 Van Maldergem L, Magre J, Khallouf TE, et al. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 2002;39:722–33.