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)	Raeya, congenital lipodysthrophy GL
Appearance	Lack of fat Variable fat accumulation	Loss of fat Variable fat accumulation	Raeya, congenital lipodysthrophy GL
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 lipodystrophy^{1,3,4,5,7,9,10}

	Familial partial lipodystrophy (Dunnigan or Köbberling type)	Acquired partial lipodystrophy (Barraquer-Simons Syndrome)	Linda, familial lipodystrophy PL
Appearance	Loss of fat Variable fat accumulation	Loss of fat Variable fat accumulation	Linda, familial lipodystrophy PL
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.