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 . 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 . Its role in the older child and adult is less clear . Disorders of adipose tissue can be divided principally into disorders of distribution of fat, the lipodystrophies , lipoedema  and fibroadipose hyperplasia , disorders of excessive generalized accumulation of fat, in other words obesity , tumours , 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 . 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 . 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 . 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 . 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 . 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 . 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) . 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 . 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 . 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 . Hereditary obesity Obesity is considered a serious public health concern . 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 . 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 . However, more often than not, they display other clinical features . Some of these syndromes have a clear dermatological phenotype . 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) . 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 . 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 . 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 . MC1R mutations are associated with an increased risk of skin cancer, but POMC single-nucleotide polymorphisms in European populations are not . 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 . 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 . 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 . In humans, PCSK1 mutations do not necessarily alter pigmentation , 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 . 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 . 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 . Many people with PWS are hypopigmented, but most lack the typical ocular features of albinism . Other characteristics of PWS include acanthosis nigricans and decreased pain sensitivity, leading to chronic sores and scars . One group has detected functional PC2 deficiency, along with 7B2 deficiency, in the hypothalamus of PWS patients at autopsy . 7B2 is a chaperone interacting with PC2 in the regulated secretory pathway . Its gene is located near the PWS locus on chromosome 15 . 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 . 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 . 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 . 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 . Reproduced with permission of John Wiley & Sons.) (b) Figure 6 Multiple lipomas in association with Proteus syndrome. (From Smithson and Winter 2004 . 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 . 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 . 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 . References Introduction 1 Szasz T, Bomfim GF, Webb RC. 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Attenuation of the polypeptide 7B2, prohormone convertase PC2, and vasopressin in the hypothalamus of some Prader–Willi patients: indications for a processing defect. J Clin Endocrinol Metab 1998;83:591–9. 36 Millington GWM. Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol 2006;31:407–12. 37 Millington GWM. The role of proopiomelanocortin (POMC) neurones in feeding behaviour. Nutr Metab 2007;4:18. References Genetic associations with lipoma 38 Gologorsky Y, Gologorsky D, Yarygina AS, et al. Familial multiple lipomatosis: report of a new family. Cutis 2007;79:227–32. 39 Hansson E, Svensson H, Brorson H. Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management. Orphanet J Rare Dis 2012;7:23. 40 Al Fares A, Millington GWM, Tischkowitz M. Dermatological features of inherited cancer syndromes in adults. 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Autoimmun Rev 2012;11:723–30. 51 Chowdhury MM, Williams EJ, Morris JS, et al. Severe panniculitis caused by homozygous ZZ alpha1-antitrypsin deficiency treated successfully with human purified enzyme (Prolastin). Br J Dermatol 2002;147:1258–61. 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 Clin Endocrinol Diabetes 2010;118:377–80. 54 Langendoen SI, Habbema L, Nijsten TEC, Neumann HAM. Lipoedema: from clinical presentation to therapy. A review of the literature. Br J Dermatol 2009;161:980–6. 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 2012;44:941–5. 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 Copyright © 2016 by John Wiley & Sons, Ltd. All rights reserved.