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1
Genetic Disorders of Adipose Tissue
George W. M. Millington
Dermatology Department, Norfolk and Norwich University Hospital, Norwich, UK
Congenital (familial) lipodystrophies, 1
Monogenic obesity without cutaneous
features, 3
Hereditary panniculitis, 9
Congenital generalized lipodystrophies, 1
Monogenic obesity with cutaneous features, 4
Familial partial lipodystrophies, 1
Genetic associations with lipoma, 6
Hereditary obesity, 3
Introduction
Subcutaneous fat consists of two main groups of cells, white adipose tissue (WAT) and brown adipose tissue, as well as capillaries,
which facilitate its metabolic functions [1]. In adults, it comprises
almost entirely WAT, where its functions include insulation, energy
storage and a recently recognized complex endocrine role [1–4].
Excess energy is stored in WAT, which leads to obesity [1–4]. Brown
fat is most detectable in the neonate and its function appears to be
quite different from that of WAT, particularly being involved in
thermogenesis [5]. Its role in the older child and adult is less clear
[5]. Disorders of adipose tissue can be divided principally into disorders of distribution of fat, the lipodystrophies [6], lipoedema [7]
and fibroadipose hyperplasia [8], disorders of excessive generalized
accumulation of fat, in other words obesity [9], tumours [10], and
finally inflammation, such as panniculitis [11,12]. There is increasing evidence of a hereditary component in the pathogenesis of all of
these conditions.
Congenital (familial) lipodystrophies
The congenital lipodystrophies are generally characterized by
selective loss of adipose tissue from various anatomical sites [13].
There are several different types and the degree of fat loss may
vary from very small depressed areas to near complete absence of
adipose tissue . Some patients may have only cosmetic problems,
while others may additionally have severe metabolic complications, as well as multisystem illness [13].
Acquired lipodystrophies, which are much more common than
familial lipodystrophies, are not currently thought to have a predominant genetic basis to their aetiology. They may be triggered
by various environmental factors, such as viral infections [13].
CLOVES syndrome, 6
Familial lipoedema, 10
References, 10
The clinical features common to all types of lipodystrophy
include insulin-resistance, hyperlipidaemia, liver disease and an
increased metabolic rate.
Lipodystrophy, congenital generalized
The congenital generalized lipodystrophies (CGLs; Berardinelli–
Seip syndrome) are very rare autosomal recessive conditions [13].
The earliest sign in the neonate is a virtual absence of fatty tissues,
followed by the development of a distinctive overall muscular
appearance. The linear growth of an affected child is then usually
significantly increased, associated with advanced bone age and
marked hyperphagia. Insulin resistance and hypertryglyceridaemia sometimes presents early in childhood as well [13,14]. Severe
hypertryglyceridaemia leading to acute pancreatitis can occur at this
age. Acanthosis nigricans in the typical flexural sites develops next,
together with fatty infiltration of the liver, which can lead to cirrhosis
[13,14]. At this stage, there can be palpable hepatosplenomegaly, with
umbilical herniation. A pseudoacromegalic appearance can appear,
with minor enlargement of the mandible, hands and feet [14]. With
adolescence, girls can develop features similar to polycystic ovarian syndrome (PCOS), together with clitoromegaly and subfertility.
Males have normal fertility [13,14]. Both genders will then usually
progress to type 2 diabetes [13]. Molecular techniques have helped
identify six clinico-genetic subtypes of CGL (Table 1), although some
patients do not have any of these defined mutations or exact clinical
phenotypes and there may be an overlap with other conditions such
as progeria [15,16], for example in the mandibuloacral dysplasia
(MAD) subtypes (see Syndromes with Premature Ageing) [15,17,18].
Part 6: GENETICS
Introduction, 1
Lipodystrophy, familial partial
The familial partial lipodystrophies (FPLs) are characterized
by the development of an atypical distribution of subcutaneous
Rook’s Textbook of Dermatology © 2016 John Wiley & Sons, Ltd.
This article is © 2016 John Wiley & Sons, Ltd.
This article was published in Rook’s Textbook of Dermatology in 2016 by John Wiley & Sons, Ltd.
DOI: 10.1002/9781118441213.rtd0075
1
2
Genetic Disorders of Adipose Tissue
Part 6: GENETICS
Table 1 Features of the congenital generalized lipodystrophies.
Clinical subtype
Mode of inheritance
Gene
Gene function
Clinical summary
MIM
CGL1
Autosomal recessive
AGPAT2
Enzyme that catalyzes the synthesis of
phospholipids and triacylglycerol in
adipocytes
Generalized lipodystrophy, insulin resistance, acanthosis
nigricans, muscular hypertrophy, hepatomegaly,
diabetes, hypertriglyceridaemia
608594
CGL2
Autosomal recessive
BSCL2
Encodes seipin with a function in lipid droplet As above but more severe plus mild learning difficulties,
formation in preadipocytes and neurons
sensorimotor neuropathy, secondary mitochondrial
dysfunction, cardiomyopathy
269700
CGL3
Autosomal recessive
CAV1
Adipocyte membrane protein. May facilitate
transmembrane insulin signalling
As for CGL1 plus prominent veins, hirsutism, short
stature, vitamin D resistance, hypocalcaemia
612526
CGL4
Autosomal recessive
PTRF
Encodes cavin factor in the biogenesis of
caveolae, which are involved in signal
transduction and membrane and lipid
trafficking
As for CGL1 plus congenital myopathy, cervical spine
instabilty, cardiac arrhythmias and myopathy, pyloric
stenosis
613327
MAD type A
Autosomal recessive
LMNA
Both lamin A and C (alternate splicing) are
two-nuclear laminin proteins. Disruption of
either leads to accelerated cell ageing
Lipodystrophy. Milder metabolic phenotype. Mandibular 248370
and clavicular hypoplasia and acro-osteolysis.
Occasional progeroid features, leukomelanodermic
papules, cardiomyopathy
MAD type B
Autosomal recessive
ZMPSTE24
Zinc metalloproteinase involved in the
processing and maturation of lamin A Generalized lipodystrophy. Milder metabolic phenotype.
Bone changes as for type A. Skin atrophy, prominent
superficial vessels, mottled hyperpigmentation, thin
beaked nose, alopecia, delayed dentition, crowded
teeth, late closure of cranial sutures, joint stiffness
(progeroid, glomerulosclerosis
BANF1
Mediates non-specific DNA binding and has a Generalized lipodystrophy, scoliosis, pulmonary
role in mitosis
hypertension, progeroid features
Nestor–Guillermo
Autosomal recessive
progeria syndrome
608612
614008
CGL, congenital generalized lipodystrophy; MAD, mandibuloacral dysplasia.
adipose tissue, which begins in late childhood or early adult life
[13,14]. In contrast to CGL, there is a normal distribution of body
fat throughout infancy and early childhood. There is a gradual loss
of adipose tissue from both the upper and lower limbs, as well
as from the buttocks and trunk (Figure 1) [13]. In some people,
(a)
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
(b)
fat accumulates paradoxically on the face and neck, which may
cause confusion with Cushing syndrome [13]. Associated features
develop in adulthood, including type 2 diabetes with acanthosis
nigricans, which is usually minimal, and hypertriglyceridaemia.
Hirsutism and menstrual abnormalities, which can mimic PCOS,
Figure 1 (a) Generalized lipoatrophy of
the upper and lower limbs. (b) Severe
lipoatrophy of the buttocks. (From
Martinez et al. 2000 [19]. Reproduced
with permission of John Wiley & Sons.)
Hereditary obesity
3
Table 2 Features of the familial partial lipodystrophies.
Mode of inheritance Gene
Gene function
Clinical summary
MIM
FPL1 (Kobberling type)
Autosomal dominant
?
?
Loss of subcutaneous adipose tissue from the extremities
608600
FPL2 (Dunnigan type)
Autosomal dominant
LMNA
Lamin A and C nuclear proteins (alternate
From puberty there is a loss of subcutaneous adipose
splicing)
tissue from the extremities and trunk (but not the face
Disruption of either leads to accelerated cell
and neck)
ageing and death of the adipocyte
151660
FPL3
Autosomal dominant
PPARG PPAR-γ is involved in adipocyte
differentiation
Loss of limb and gluteal fat with normal subcutaneous
604367
abdominal/visceral fat. Normal or mildly reduced facial fat
FPL4
Autosomal dominant
AKT2
AKT2 is involved in insulin signalling and
adipocyte differentiation
Loss of subcutaneous adipose tissue from the limbs
FPL5
Autosomal dominant
PLIN1
Perilipin is a phosphoprotein that surrounds Severe hyper-tryglyceridaemia
the lipid storage droplet in fat cells
615238
Hutchinson–Gilford
progeria syndrome
(see Syndromes with
Premature Ageing)
Autosomal recessive
LMNA
Specific splice mutations lead to the
accumulation of abnormal truncated
prelaminin A
Short stature, low body weight, partial or generalized
lipodystrophy, generalized alopecia, scleroderma,
decreased joint mobility, osteolysis, ageing of facial
features, insulin resistance
176670
Atypical progeroid
syndrome (see
Syndromes with
Premature Ageing)
Autosomal recessive
LMNA
As above
Progeroid features (as above) with variable loss of
subcutaneous fat, insulin resistance
–
SHORT syndrome
Autosomal dominant
PIK3R1 ?
Short stature, partial lipodystrophy, delayed dentition,
ocular depression, iris hypoplasia, ocular hypertelorism,
deafness, inguinal hernia, hyperextensibility
clinodactyly, developmental delay
269880
613877
FPL, familial partial lipodystrophy; SHORT, short stature, hyperextensibility of joints and/or inguinal herna, ocular depression, rieger anomaly and teething delay.
may develop in about one-quarter of affected women [13,14]. Mild
to moderate myopathy, cardiomyopathy and cardiac arrhythmias
are sometimes associated with FPL. As for CGL, the clinico-molecular subtypes of FPL overlap with CGL both at the clinical and
genetic level, including with progeria (Table 2). Also, there are
many individuals with an FPL phenotype who do not have established gene mutations [13].
Hereditary obesity
Obesity is considered a serious public health concern [20]. Excess
body weight contributes to psychological problems, cancers, metabolic disease, cardiovascular problems, musculoskeletal disorders
and dermatological conditions [20,21]. Simple obesity results from
a complex combination of multiple genetic factors, environmental
factors or gene–environment interactions [20–22]. However, there
is growing acknowledgement of the role of inherited traits in the
causation of obesity, especially where the onset is in childhood
[22]. Although in the vast majority of cases these influences are
polygenic, some obese children suffer from single-gene disorders,
which may present with obesity alone [22]. However, more often
than not, they display other clinical features [22]. Some of these
­syndromes have a clear dermatological phenotype [22].
Obesity, monogenic without cutaneous features
Certain rare monogenic human obesity syndromes exist that do
not have primary cutaneous features (Table 3) [23–25]. As these
conditions all produce severe obesity [20–22], affected individuals
Table 3 Monogenic obesity syndromes without cutaneous features.
Syndrome
Mode of inheritance
Gene(s) or chromosome
Other clinical features
Leptin receptor deficiency
Autosomal recessive
LEPR
Hypogonadism, hyperleptinaemia
Melanocortin-4 receptor
deficiency
Autosomal dominant
MC4R
Accelerated growth, tall stature
BDNF deficiency
Autosomal dominant
BDNF, p13p15.3 inv
Developmental delay, hyperactivity, memory problems, reduced pain sensation
TrkB deficiency
Autosomal dominant
NTRK2
Developmental delay, hyperactivity, memory problems, reduced pain sensation
SIM1 deficiency
Autosomal recessive
SIM1, 1p22.16q16.2 transl
Developmental delay (severe)
Bardet-Biedel syndrome
Autosomal recessive
BBS1-16, ARL6, MKKS,
MKS1, CEP290
Developmental delay, polydactyly, retinopathy, renal anomalies
Carpenter syndrome
Autosomal recessive
RAB23, 6p11
Craniosynostosis, polysyndactyly, cardiac defects
(Continued )
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
Part 6: GENETICS
Clinical subtype
4
Genetic Disorders of Adipose Tissue
Table 3 Monogenic obesity syndromes without cutaneous features. (Continued)
Syndrome
Mode of inheritance
Gene(s) or chromosome
Other clinical features
Börjeson-ForssmanLehman syndrome
X-linked recessive
PHF6, Xq27.3
Developmental delay, epilepsy, hypogonadism, facial swelling, narrow palpebral
fissures, large ears
SH2B deficiency
Copy number variation
SH2B, 16p11.2
Insulin resistance, hyperinsulinaemia
MOMO syndrome
?Autosomal recessive
?
Macrosomia, macrocephaly, retinal coloboma and nystagmus, downward slant of
the palpebral fissures, mental retardation and delayed bone maturation, short
stature
Cohen syndrome
?
VPS13B
Developmental delay, down-sloping palpebral fissures, maxillary hypoplasia,
micrognathia, high-arched palate, dental anomalies, short stature, delayed
puberty, insulin resistance, retinopathy, neutropenia
MORM syndrome
Autosomal recessive
INPP5E, 9q34
Mental retardation, truncal obesity, retinal dystrophy and micropenis
BDNF, brain derived neurotrophic factor; SH2B1, SH2B adaptor protein 1; SIM1, a human analogue of a fly gene and so is known as ‘SIM1’; TrkB, tyrosine receptor kinase B.
are all likely to develop the secondary consequences of obesity,
including skin problems (Box 1) [22].
Part 6: GENETICS
Obesity, monogenic with cutaneous features
There are a number of very rare diseases where obesity is inherited
with dermatological signs as part of a syndrome [22]. Deficiency
in the pro-opiomelanocortin (POMC) pathway (including prohormone convertase 1 (PC1) deficiency) and Prader–Willi syndrome
(PWS) are discussed below as specific examples and the remainder
are summarized in Table 4.
Pro-opiomelanocortin and prohormone
convertase 1 deficiency
Severe obesity, very fair skin and red hair are all features of autosomal recessive mutations in the POMC and PSK1 genes, respectively
(Figure 4). These are examples of where the pathology of both the
obesity and skin phenotype are well understood [27,28].
POMC and PC1 are involved in the same biochemical p
­ athway
[27,28]. POMC is a propeptide that produces active peptides via
several sequential enzymatic steps (including PC1 activity), in a
tissue-specific manner, yielding the melanocyte-stimulating hor-
Box 1 Secondary skin complications of primary
obesity
•Striae
•Poor wound healing
•Cutaneous infection
•Lymphovascular disorders and ulceration
•Hyperandrogenism and hirsutism
•Psoriasis
•Atopic eczema
•Keratosis pilaris
•Irritant contact dermatitis
•Skin cancer
•Hidradenitis suppurativa
•Scleredema
•Livedo reticularis
•Pilonidal sinus
•Skin changes associated with diabetes
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
mones (MSHs), corticotrophin (ACTH) and β-endorphin (Figure
4) [27,28]. The MSHs and ACTH bind to the extracellular melanocortin receptors (MCRs) [27–29]. α-MSH and ACTH bind to the
MC1R to increase pigmentation [27]. Homozygous and heterozygous mutations in MC1R lead to fair skin and red hair in humans
(but not necessarily obesity), which is also seen with inactivating
human POMC mutations [27]. MC1R mutations are associated
with an increased risk of skin cancer, but POMC single-nucleotide polymorphisms in European populations are not [30]. In
the central nervous system, MSH released from POMC neurons
binds to the MC4R in discrete feeding centres, decreasing feeding
[28,30]. Heterozygous mutations in the MC4R gene are associated with severe obesity and tall stature in humans (see Table
3), as with human POMC deficiency, but usually lacking the fair
skin and red hair phenotype [27,28]. ACTH binds to the MC2R
in the adrenal gland, causing a release of glucocorticoids [29].
Both MC2R deficiency and POMC deficiency are associated with
glucocorticoid deficiency. There is no hyperpigmentation with
POMC deficiency, although there is with MC2R deficiency, due
to the elevated levels of ACTH, which bind to the MC1R causing
excess pigmentation [27,29].
Humans with PC1 (PCSK1) deficiency are morbidly obese,
with associated glucocorticoid deficiency, hypogonadotrophic
hypogonadism and postprandial hypoglycaemia [31]. In addition, affected individuals develop severe malabsorption in neonatal life, perhaps as a result of impaired propeptide processing
due to the lack of PC1 within the intestinal hormone-secreting
cells [31]. In humans, PCSK1 mutations do not necessarily alter
pigmentation [31], whereas POMC mutations usually do (Figure 5) [27,32].
Prader–Willi syndrome
Imprinting is the process by which genetic alleles responsible
for a phenotype are inherited from one parent only. It is an epigenetic phenomenon resulting from altered DNA methylation,
the modification of protruding histones, or the effect of noncoding microRNAs on transcription [33,34]. PWS, Albright
hereditary osteodystrophy and McCune–Albright syndrome
are all inherited in an autosomal dominant fashion and feature
imprinting [33].
Hereditary obesity
5
Syndrome with
skin signs
Mode of
inheritance
Gene(s) or
chromosome
Cutaneous features
Other clinical features
Pro-opiomelanocortin
deficiency
Autosomal
recessive
POMC
Red hair, fair (type 1) skin
Tall stature, hypoadrenalism
Prohormone convertase
1 deficiency
Autosomal
recessive
PC1
Red hair, fair (type 1) skin
Postprandial hypoglycaemia, hypogonadism, elevated proinsulin and
32–33 split proinsulin
Prader–Willi syndrome
Imprinted
15q11-q13, SNRPN,
Necdin
Generalized hypopigmentation,
acanthosis nigricans
Developmental delay, hypotonia, short stature, small hands and feet,
hypogonadotrophic hypogonadism
McCune–Albright
syndromea
Imprinted
GNAS1
Atypical café-au-lait patches, linear
epidermal naevi, pigmentation of
the nape of the neck
Polyostotic fibrous dysplasia, thyrotoxicosis,b precocious puberty,
Cushing syndrome,b gigantism,b acromegalyb
Albright hereditary
osteodystrophy
(pseudo-hypoparathyroidism)
Imprinted
GNAS1
Subcutaneous ossification, dimpling
over the metacarpophalangeal
joints
Short stature, skeletal defects and brachydactyly, round facies,
multiple hormone resistance (including PTH) (Figures 2 and 3)
Carney complexa
Autosomal
recessive
PRKAR1A
Lentigines, oral and mucosal
pigmentation, multiple blue
naevi, schwannomata, café-au-lait
macules, breast ductal adenoma,
cutaneous and mucosal myxomas,
skin tags, lipomas, pilonidal sinus
Cardiac myxoma, cardiomyopathy, precocious puberty, Cushing
syndrome,b gigantism,b acromegalyb, thyroid nodules and
carcinoma, prolactinoma, osteochondromyxoma
Fragile X syndrome
X-linked
recessive
Xq26.3
Expansion of CGG
repeats on X
chromosome,
leading to failure to
express FMR1 gene
Regional hyperpigmentation
Developmental delay, prominent mandible, macro-orchidism, large
ears, elongated face, hypermobility, muscle hypotonia initially
accelerated growth but adult short stature, mitral valve prolapse
MOMES syndrome
Autosomal
recessive
4q35.1 del, 5p14.3
dup
Atopic eczema
Developmental delay, ocular abnormalities, macrocephaly, maxillary
hypoplasia, prognathism
Ulnar–mammary
syndrome
Autosomal
dominant
TBX3
Hypohidrosis, nipple hypoplasia to
absent breasts, absent axillary
hair, nail duplication
Malformed digits, hypogonadism, delayed growth, cardiac
conduction abnormalities, dental abnormalities
Majewski
osteodysplastic
primordial dwarfism
type II
Autosomal
recessive
PCNT
Generalized hyperpigmentation,
freckling, regional hypopigmentation, café-au-lait macules, xerosis,
fine sparse hair, poikiloderma,
sacral dimples
Delayed growth, bony dysplasia, scoliosis, microcephaly, prominent
nose and ears, hypoplastic dentition, developmental delay, CNS
aneurysms, risk of haemorrhagic stroke
Coffin–Lowry syndrome
X-linked
recessive
CLS
Enlarged lips, lax skin
Developmental delay, growth retardation, delayed puberty, kyphosis
and scoliosis, cervical ribs, pectus carinatum and excavatum,
prominent forehead, hypertelorism, down-slanting palpebral
fissures, prominent and low-set ears, deafness, seizures, ‘drop’
attacks, cardiac problems
Diploid/triploid
mosaicism
Chromosomal
defect
Diploid/triploid
mosaicism
Transverse palmar crease, irregular
skin pigmentation
Developmental delay, growth retardation, asymmetrical growth,
prominent forehead, micrognathia, low-set ears, hypotonia,
precocious puberty, micropenis, cryptorchidism, clinodactyly,
syndactyly, narrow and small hands
Prolidase deficiency
Autosomal
recessive
PEPD
Leg ulcers, papular, erythematous
and necrotic lesions,
telangiectasias, pruritus,
impetigo-like and eczema-like
lesions, photosensitivity, hirsutism
Developmental delay, recurrent respiratory infections, hypertelorism,
exophthalmos, micrognathia, saddle nose
Rubinstein–Taybi
syndrome
Autosomal
dominant
CREBBP, 16p13.3 and
EP300, 22q13.2
Keloids
Short stature, developmental delay, broad thumbs and great toes,
ocular, cardiac, renal and dental problems
Alström syndrome
Autosomal
recessive
ALMS1, 2p13
Acanthosis nigricans
Photophobia and visual disturbance, deafness and nystagmus,
dilated cardiomyopathy, severe insulin resistance, pulmonary,
hepatic and urological dysfunction
Leptin deficiency
Autosomal
recessive
LEP
Hair loss?
Hypogonadism, frequent infections, hypoleptinaemia
CNS, central nervous system; MORM, mental retardation, truncal obesity, retinal dystrophy and micropenis; PTH, parathyroid hormone.
obese if Cushing syndrome present.
bSecondary skin changes.
aOnly
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
Part 6: GENETICS
Table 4 Monogenic obesity syndromes with cutaneous features.
6
Genetic Disorders of Adipose Tissue
(b)
(d)
Part 6: GENETICS
(a)
(c)
Figure 2 Clinical features of Albright hereditary
osteodystrophy: (a) obesity; (b) round facies; (c) hypoplastic
skin lesion; and (d) detailed view of a skin lesion. (From
Klaasens et al. 2009 [26]. Reproduced with permission of
John Wiley & Sons.)
PWS is due to inactivation or deletion of a paternally (not maternally) inherited chromosome region, 15q11-q13, leading to severe
obesity [33]. Many people with PWS are hypopigmented, but most
lack the typical ocular features of albinism [33]. Other characteristics
of PWS include acanthosis nigricans and decreased pain sensitivity,
leading to chronic sores and scars [33]. One group has detected functional PC2 deficiency, along with 7B2 deficiency, in the hypothalamus of PWS patients at autopsy [35]. 7B2 is a chaperone interacting
with PC2 in the regulated secretory pathway [35]. Its gene is located
near the PWS locus on chromosome 15 [35]. As PC2, like PCSK1, is
involved in processing POMC to MSHs and ACTH in both the central nervous system and the skin, it is tempting to speculate that this
may explain the obese and/or fair skin phenotype in PWS [33,35,37].
Genetic associations with lipoma
Lipomas, benign tumours of adipocytes, are discussed in detail
in Soft-tissue Tumours and Tumour-like Conditions. Table 5
gives a summary of the genetic associations with lipoma [38–42].
CLOVES syndrome
Figure 3 X-ray showing brachydactyly in Albright hereditary osteodystrophy [26].
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
CLOVES (congenital lipomatous overgrowth, vascular
malformations, epidermal naevi and skeletal/spinal) syndrome
is a congenital overgrowth syndrome with progressive segmental
proliferation of the fibrous tissues, adipocytes and bony
tissues [43,44,45]. Mutations in the PIK3CA gene were recently
described in numerous cases of this condition [43,44,45]. More
recently, mutations in the same gene have been associated with
more restricted phenotypes, including macrodactyly and facial
lipomatosis [46,47].
CLOVES syndrome
Exon 2
Exon1
Exon 3
5′
3′
PC1/2
PC1/2
POMC
RK
KR
RR KR KR KKRR
KK
KK
KR
NH2
COOH
Figure 5 A pro-opiomelanocortin (POMC) deficient
patient and his unaffected sister showing a lack of red
hair. The arrows show a C202T mutation leading to a
premature stop within the protein just upstream of the
γ-melanocyte-stimulating hormone peptide. (From Cirillo
et al. 2012 [32]. Reproduced with permission of John
Wiley & Sons.)
α-MSH
KK
KR
β-LPH
KK
ACTH
RR
γ3-MSH
KK
KKRR
RR
β end
γ-LPH
CLIP
Part 6: GENETICS
RK
Figure 4 Gene structure and post-translational processing of
pro-opiomelanocortin (POMC). POMC in mammals consists
of three exons, of which exons 2 and 3 are translated.
Prohormone convertases 1 and 2 (PC1/2) break the parent
POMC peptide into successively smaller peptides by cleavage at
paired dibasic amino acid residues consisting lysine (K) and/or
arginine (R). ACTH, corticotrophin; β end, β-endorphin; MSH,
melanocyte-stimulating hormone. (From Millington 2006 [27].
Reproduced with permission of John Wiley & Sons.)
7
β-MSH
γ2-MSH
G A C G A G TA G C C T C T G
D66 E67 X68 +
+
GACGAGCAGCCTCTG
D66 E67 Q68 P69 L70
Patient
Sister
C202T(Q68X)
β-Lipotropin
ACTH
5′
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
Non-coding
Signal
peptide
γ-MSH
α-MSH
CLIP
β-MSH
γ -Lipotropin
β-Endorphin
3′
8
Genetic Disorders of Adipose Tissue
Part 6: GENETICS
Table 5 Hereditary lipomatoses.
Syndrome
Mode of inheritance
Gene or chromosome
Gene function
Clinical summary
MIM
Multiple lipomatosis
(Figure 6) (familial
multiple lipomatosis)
Autosomal dominant
Chromosomal
rearrangements
(12q13 or 12q14)
Unknown
Encapsulated non-painful lipomas on the trunk and
extremities. Late onset. No other syndromic features
151900
Multiple symmetrical
lipomatosis (Madelung
disease)
Unknown
A minority of
cases carry the
MERFF syndrome
(mitochondrial
m.A8344G
mutation)
Unknown
Uncapsulated lipomas in the neck area (‘collar of
fat’). Associated with high alcohol intake and
polyneuropathy. In cases associated with MERFF, there
are variable neurological symptoms
151800
Adiposis dolorosa (Dercum
disease)
Usually sporadic;
autosomal
dominant in some
families
Unknown
Unknown
Painful lipomas on the trunk and limbs. Late onset.
Female : male ratio of 5 : 1. Obesity, purpura, sleep
disturbances, impaired memory, depression, anxiety,
rapid heartbeat, shortness of breath, diabetes,
bloating, constipation, fatigue, weakness, joint pains
Neurofibromatosis type 1
(see Hamartoneoplastic
Syndromes)
Autosomal dominant
NF1 (neurofibromin)
Negative regulator
of the RAS-MAPK
pathway
CALMs, axillary freckling, neurofibromas, Lisch nodules,
lipomas, macrocephaly, optic gliomas, predisposition
to solid cancers and CNS tumours
Legius syndrome (see
Hamartoneoplastic
Syndromes)
Autosomal dominant
SPRED1
Negative regulator
of the RAS-MAPK
pathway
CALMs, axillary freckling, macrocephaly, lipomas,
predisposition to solid cancers (note no neurofibromas)
Cowden syndrome
Autosomal dominant
PTEN
Cell cycle, tumour
suppressor
Benign and malignant tumours of the thyroid, breast
and endometrium, macrocephaly, trichilemmomas,
papillomatous papules, lipomas
Bannayan–Riley–Ruvalcaba
(BRR) syndromea
Autosomal dominant
PTEN
Cell cycle, tumour
suppressor
Macrocephaly, intestinal hamartomatous polyposis,
lipomas, pigmented macules of the glans penis
Proteus syndromea (see
Congenital Naevi and
Other Developmental
Abnormalities Affecting
the Skin and Disorders
of the Lymphatic Vessels)
Mosaic disorder
AKT1
Oncogene, protein
kinase
Asymmetrical overgrowth, usually of a limb, hypertrophy
of skin of soles, epidermal naevi, cerebriform
connective tissue naevus, lymphangiomas,
haemangiomas, lipomas, vascular malformations
Multiple endocrine
neoplasia type 1
Autosomal dominant
MEN1 (MENIN)
Tumour suppressor
Parathyroid, gastrointestinal endocrine and pituitary
tumours, lipomas, facial angiofibromas and
collagenomas, CALMs, hypopigmentation, gingival
papules, meningioma, ependymoma
Naso-palpebral lipoma–
coloboma syndrome
Autosomal dominant
Unknown
Unknown
Upper eyelid and naso-palpebral lipomas, colobomas of
the upper and lower eyelids, telecanthus, aplasia or
malposition of lacrimal puncta, maxillary hypoplasia
Overgrowth and lipomas
One sporadic case
Pericentric inversion
of chromosome
12 – truncation of
HMGA2
Adipogenesis,
osteogenesis,
control of growth
Somatic overgrowth, advanced endochondral bone
and dental ages with epiphyseal dysplasia, multiple
lipomas, thrombocytopenia, arthritis, brachydactyly,
cerebellar tumour, facial dysmorphic features
Familial frontonasal
dysplasia type 1
Autosomal recessive
ALX3
Homeodomaincontaining protein
Frontonasal dysostosis, hypertelorism, anterior cranium
bifidum occultum, lipoma
Familial adenomatous
polyposis 1 (Gardner
syndrome)
Autosomal dominant
APC
Tumour suppressor
Multiple gastrointestinal adenomatous polyps, abnormal
dentition, osteomas, epidermoid cysts, lipomas,
hyperpigmentation, keloids, colo-rectal and other cancers
Aicardi syndrome
X-linked dominant
Unknown
Unknown
Infantile spasms, chorioretinal lacunae, agenesis of the
corpus callosum, may have cavernous haemangioma,
angiosarcoma, lipomas
Lipomeningomyelocele
Unknown
Unknown
Unknown
Cutaneous and intraspinal lipomas (linked anatomically)
Encephalocraniocutaneous
lipomatosis
Unknown
Unknown
Unknown
Eye anomalies, non-scarring alopecia, naevus psiloliparus,
cutaneous, intracranial and intraspinal lipomas, skin
tags, cutis aplasia, meningeal abnormalities, focal
vascular defects, mild learning difficulties coarctation
of the aorta, bone cysts, jaw tumours
a
136760
304050
613001
BRR and Proteus syndrome are now increasingly considered to be the same condition, with a spectrum of presentation.
CALMs, cafe-au-lait macules; CNS, central nervous system; MERFF, myoclonic epilepsy associated with ragged-red fibres; RAS-MAPK, rat sarcoma–mitogen-activated protein
kinase.
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
Panniculitis, Hereditary
9
(a)
Part 6: GENETICS
Figure 7 Hereditary panniculitis caused by homozygous ZZ α1-antitrypsin deficiency.
(From Chowdhury et al. 2002 [51]. Reproduced with permission of John Wiley &
Sons.)
(b)
Figure 6 Multiple lipomas in association with Proteus syndrome. (From Smithson and
Winter 2004 [42]. Reproduced with permission of John Wiley & Sons.)
Panniculitis, hereditary
Panniculitis, inflammation of adipose tissue, is discussed in detail
elsewhere in Panniculitis. Table 6 gives a summary of the genetic
associations with panniculitis [48–50].
Figure 8 Alpha-1-antitrypsin-deficiency panniculitis (phenotype PiZZ). (From Yesudian
et al. 2004 [52]. Reproduced with permission of John Wiley & Sons Ltd.)
Table 6 Hereditary panniculitis.
Syndrome
Mode of inheritance
Gene(s)
Gene function
Clinical summary
Alpha-1-antitrypsin deficiency
(Figures 7 and 8)
Autosomal recessive
SERPINA1
α1-antitrypsin is a serum protease
inhibitor, whose main role is in
inhibiting tissue elastase
Emphysema, liver disease, panniculitis,
glomerulonephritis, arthritis, vasculitis, uveitis
Chronic atypical neutrophilic
dermatosis with lipodystrophy
and elevated temperature
(CANDLE) syndrome (Nakajo–
Nishimura syndrome)
Autosomal recessive
PSMB8
Encodes a catalytic subunit of the
immunoproteasome, which
influences the antigenic repertoire
presented on MHC class I molecules
Failure to thrive, joint contractures, muscular atrophy,
panniculitis-induced lipodystrophy, loss of facial
fat, acral annular erythematous plaques, elevated
temperature, inflammatory markers, microcytic
anaemia
Autoimmune lymphoproliferative
syndrome (Canale–Smith
syndrome)
Autosomal dominant
TNFSF6,TNFRSF6
Apoptosis in cells of haematological
and immunological lineage
Lymphadenopathy, hepatosplenomegaly, autoimmune
anaemia and thrombocytopenia, urticaria, vasculitis,
panniculitis, increased risk of malignant lymphoma
MHC, major histocompatibility complex.
Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.
10
Genetic Disorders of Adipose Tissue
Congenital (familial) lipodystrophies
13 Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 2011;96:3313–25.
14 Semple RK, Savage DB, Cochran EK, et al. Genetic syndromes of severe insulin
resistance. Endocr Rev 2011;32:498–514.
15 Osorio FG, Ugalde AP, Mariño G, et al. Cell autonomous and systemic factors in
progeria development. Biochem Soc Trans 2011;39:1710–14.
16 Caux F, Dubosclard E, Lascols O, et al. A new clinical condition linked to a novel
mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab 2003;88:1006–13.
17 Cabanillas R, Cadiñanos J, Villameytide JA, et al. Néstor–Guillermo progeria
syndrome: a novel premature aging condition with early onset and chronic
development caused by BANF1 mutations. Am J Med Genet A 2011;155A:2617–25.
18 Puente XS, Quesada V, Osorio FG, et al. Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome.
Am J Hum Genet 2011;88:650–6.
19 Martinez A, Malone M, Hoeger P, et al. Lipoatrophic panniculitis and chromosome 10 abnormality. Br J Dermatol 2000;142:1034–9.
Part 6: GENETICS
Figure 9 Lipoedema. (From Langendoen et al. 2009 [54]. Reproduced with
permission of John Wiley & Sons.)
Lipoedema, familial
Lipoedema, which is the persistent accumulation of fat in the lower
limbs (Figure 9), is discussed in detail elsewhere in the book. There
is one family described with short stature and lipoedema affecting
four generations. This was associated with a mutation in the PIT1
gene across two generations and with growth hormone deficiency,
secondary hypothyroidism and hypoprolactinemia in the proband
[53].
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Hereditary obesity
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Prader–Willi syndrome
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behaviour. Nutr Metab 2007;4:18.
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39 Hansson E, Svensson H, Brorson H. Review of Dercum's disease and proposal of
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40 Al Fares A, Millington GWM, Tischkowitz M. Dermatological features of inherited cancer syndromes in adults. Clin Exp Dermatol 2010;35:462–7.
41 Karalis A, Tischkowitz M, Millington GWM. Dermatological manifestations of
inherited cancer syndromes in children. Br J Dermatol 2011;164:245–56.
42 Smithson SF, Winter RM. Diagnosis in dysmorphology: clues from the skin. Br J
Dermatol 2004;151:953–60.
47 Maclellan RA, Luks VL, Vivero MP, et al. PIK3CA activating mutations in facial
infiltrating lipomatosis. Plast Reconstr Surg 2014;133:12e–9e.
Hereditary panniculitis
48 Lomas DA. Twenty years of polymers: a personal perspective on alpha-1 antitrypsin deficiency. COPD 2013;10(S1):17–25.
49Kanazawa N. Nakajo-Nishimura syndrome: an autoinflammatory disorder
showing pernio-like rashes and progressive partial lipodystrophy. Allergol Int
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50 Lev A, Simon AJ, Amariglio N, et al. Thymic functions and gene expression profile distinct double-negative cells from single positive cells in the autoimmune
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51 Chowdhury MM, Williams EJ, Morris JS, et al. Severe panniculitis caused by
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52Yesudian PD, Dobson CM, Wilson NJ. a1-Antitrypsin deficiency panniculitis
(phenotype PiZZ) precipitated postpartum and successfully treated with dapsone. Br J Dermatol 2004;150:1222–3.
Familial lipoedema
53 Bano G, Mansour S, Brice G, et al. Pit-1 mutation and lipoedema in a family. Exp
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54 Langendoen SI, Habbema L, Nijsten TEC, Neumann HAM. Lipoedema:
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Part 6: GENETICS
CLOVES syndrome
43 Lindhurst MJ, Parker VE, Payne F, et al. Mosaic overgrowth with fibroadipose
hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet
2012;44:928–33.
44 Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating mutations in
PIK3CA cause CLOVES syndrome. Am J Hum Genet 2012;90:1108–15.
45 Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components
of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet
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46 Rios JJ, Paria N, Burns DK, et al. Somatic gain-of-function mutations in PIK3CA
in patients with macrodactyly. Hum Mol Genet 2013;22:444–51.
11
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