Berardinelli-Seip Congenital Lipodystrophy

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2021-01-18

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Genes

BSCL2, AGPAT2, CAV1, CAVIN1, PPARG, FOS, LMNA, ZMPSTE24, HNRNPUL2-BSCL2, LEP, KCNJ6, POLR3A, GZMH, FBN1, INSR, GARS1, AGPAT1, ADIPOQ, LPIN1, LPIN2, BEST1, SNAP23, AIFM1, ANGPTL3, SOST, SETD2, SETX, NOX1, SLC2A2, ACAT1, PLIN1, GCG, AGL, APRT, CAV3, DMD, EMD, ETFA, GART, GH1, PDE3B, GZMB, HIF1A, HNF4A, MAT1A, ADRB3, MUC1, PCYT1A, MFAP1

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Summary

Clinical characteristics.

Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.

Diagnosis/testing.

The diagnosis of BSCL is established in a proband with three major criteria or two major criteria plus two or more minor criteria and/or by the identification of biallelic pathogenic variants in AGPAT2 or BSCL2.

Management.

Treatment of manifestations: Restriction of total fat intake between 20% and 30% of total dietary energy maintains normal triglyceride serum concentration. Leptin therapy for treatment of hypertriglyceridemia and diabetes may be considered. Diabetes mellitus is managed as in childhood-onset diabetes mellitus.

Surveillance: Regular screening for glycosuria as a manifestation of diabetes mellitus, which usually starts in the teens (average age 12 years) but has also been described in infancy; monitoring for potential retinal, peripheral nerve, and renal complications of diabetes mellitus; yearly echocardiogram; yearly or biennial liver ultrasound examination to detect fatty infiltration.

Agents/circumstances to avoid: Excessive dietary fat intake.

Genetic counseling.

BSCL is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Berardinelli-Seip congenital lipodystrophy (BSCL) should be suspected in individuals with one or more of the following major and/or minor findings.

Major Criteria

Lipoatrophy affecting the trunk, limbs, and face. Generalized lipodystrophy is apparent at birth. In some individuals, the face may be normal at birth with lipoatrophy becoming apparent during the first months of life. Lipoatrophy gives an athletic appearance, especially because skeletal muscle hypertrophy is also present.

Acromegaloid features include gigantism, muscular hypertrophy, advanced bone age, prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, and enlarged external genitalia in males.

Hepatomegaly. Liver enlargement is secondary to fatty liver early on and to cirrhosis late in the disease course.

Elevated serum concentration of triglycerides. Serum concentration of triglycerides can be elevated up to 80 g/L, and is sometimes associated with hypercholesterolemia.

Insulin resistance. Elevated serum concentrations of insulin and C-peptide may occur starting in the first years of life. Its early clinical expression is acanthosis nigricans of the groin, neck, and axillae, which may have, in some cases, a verrucous appearance.

Minor Criteria

Hypertrophic cardiomyopathy may be present in infancy or develop later in life.

Psychomotor retardation or mild (IQ 50-70) to moderate (IQ 35-50) intellectual impairment. See Phenotype Correlations by Gene.

Hirsutism manifests with low frontal and posterior hairline; hypertrichosis is apparently independent of hormonal stimulation.

Precocious puberty in females. In a series of 75 individuals with BSCL, three females underwent puberty before age seven years [Van Maldergem et al 2002].

Bone cysts occur in 8%-20% of affected individuals and have a polycystic appearance on x-ray. Located in the epiphyseal and metaphyseal regions of the long bones, bone cysts are often diagnosed during the second decade and are mostly observed in individuals with biallelic pathogenic variants in AGPAT2.

Phlebomegaly. Prominence of the veins of the lower and upper limbs is observed, in part because of the lack of subcutaneous fat.

Establishing the Diagnosis

The diagnosis of BSCL is established in a proband with three major criteria or two major criteria plus two or more minor criteria and/or by the identification of biallelic pathogenic variants in one of the genes listed in Table 1.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing

In individuals with intellectual disability or cardiomyopathy, sequencing of BSCL2 should be considered first.
The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see Table 1, footnotes 5, 6, 8 and 9).

A multigene panel that includes AGPAT2 and BSCL2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes AGPAT2 and BSCL2) fails to confirm a diagnosis in an individual with features of BSCL. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Berardinelli-Seip Congenital Lipodystrophy

Gene ¹	Proportion of BSCL Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ² Detectable by Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
AGPAT2	See footnote 5.	See footnote 6.	Unknown
BSCL2	See footnote 8.	See footnote 9.	See footnote 10.
Unknown ¹¹		NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: AGPAT2 pathogenic variants accounted for the majority of affected individuals (26/45) in a study from the US [Agarwal et al 2003]. Individuals with biallelic pathogenic variants in AGPAT2 have been described worldwide, with clusters in sub-Saharan Africa, Brazil, Maghreb (Morocco, Algeria, and Tunisia) and occasionally Middle Eastern countries (e.g., Turkey) and northern Europe [Van Maldergem et al 2002].
6.: Nearly all individuals of African origin with BSCL have the AGPAT2 c.589-2A>G pathogenic variant. Other pathogenic variants have now been described worldwide in diverse populations.
7.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
8.: Pathogenic variants in BSCL2 account for the majority of cases in the Berardinelli-Seip study group [Van Maldergem et al 2002, Magré et al 2003] in which affected individuals originated mostly from Europe, the Middle East, and sub-Saharan Africa; studies from Brazil draw similar conclusions (18/26) [Fu et al 2004, Miranda et al 2009]; likewise, in a small sample from Japan, three of four affected individuals were homozygous for a BSCL2 pathogenic variant [Ebihara et al 2004].
9.: BSCL2 frameshift variant c.317_321delATCGT is identified in the Lebanese population [Magré et al 2001]. Other pathogenic variants are identified in individuals of European, Middle Eastern, Asian, or Portuguese ancestry.
10.: One large deletion and one large indel have been reported [Magré et al 2001].
11.: Magré et al [2003] found that 92/94 affected individuals harbor pathogenic variants that are either in BSCL2 or AGPAT2 or appear to be linked to their loci; Agarwal et al [2004] found this to be the case in 44/47 affected persons. Other reports provide evidence for at least two additional loci associated with congenital generalized lipodystrophy and other findings, resulting from biallelic pathogenic variants in CAV1 or CAVIN1 (formerly PTRF) respectively (see Differential Diagnosis) [Kim et al 2008, Simha et al 2008, Hayashi et al 2009, Shastry et al 2010].

Clinical Characteristics

Clinical Description

Berardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Severe forms of BSCL may have prenatal onset with intrauterine growth retardation. Presentation in the first months of life includes failure to thrive (or conversely gigantism), hepatomegaly, lipoatrophy, facial dysmorphia, enlarged tongue, or developmental delay. All children with the neonatal or infantile presentation demonstrate lipoatrophy in the first year of life.

Affected adults may first be seen in the plastic surgery clinic seeking cosmetic improvement of facial lipoatrophy or in the cardiology clinic or gastroenterology clinic for manifestations such as hypertrophic cardiomyopathy or hepatomegaly.

Endocrinologic findings

Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus, most commonly between the ages 15 and 20 years. Diabetes mellitus:
- Can be difficult to control;
- Manifests by weight loss, polydipsia, polyuria, or asthenia and is frequently the presenting finding in the second decade;
- Presents on occasion in early adulthood.
Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.

Hypertrophic cardiomyopathy is reported in 20%-25% of individuals and is a significant cause of morbidity from cardiac failure and early mortality around age 30 years.

Three children of Pakistani, Chinese, and Turkish ancestry, respectively, came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [Friguls et al 2009, Jeninga et al 2012, Debray et al 2013].
Affected individuals have died as early as age 19 months of complications of cardiomyopathy.

Hepatic findings. Because of the absence of functional adipocytes, lipid is stored in other tissues including liver. Hepatomegaly secondary to hepatic steatosis occurs in virtually all individuals with BSCL.

Intellectual impairment is common; intrafamilial variability, including variability in intellectual impairment, exists.

Skeletal muscle hypertrophy occurs in all affected individuals as a result of lipid storage in skeletal muscle.

Phenotype Correlations by Gene

BSCL2. Approximately 80% of individuals with biallelic pathogenic variants in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with biallelic pathogenic variants in AGPAT2 have intellectual impairment.

Genotype-Phenotype Correlations

AGPAT2. No relationship appears to exist between the site and type of AGPAT2 pathogenic variants and severity of lipodystrophy or metabolic complications.

BSCL2. With one exception (see following), no correlation between the site and type of a BSCL2 pathogenic variant and phenotype (including intellectual impairment) has been observed [Van Maldergem et al 2002]. Furthermore, related and unrelated individuals with the same pathogenic variant may be discordant for intellectual impairment.

A severe form of BSCL characterized by lipodystrophy followed after a couple of months by neurologic regression and death has been described in five infants in Spain [Guillén-Navarro et al 2013]. Affected infants were either homozygous for the BSCL2 pathogenic c.793C>T variant or had this pathogenic variant in combination with another pathogenic variant on the other allele. The pathogenic c.793C>T variant causes exon 7 skipping.

Nomenclature

Berardinelli-Seip syndrome is named after W Berardinelli, who reported the first affected individuals from Brazil in 1954. The syndrome was confirmed in 1959 in Norway by Martin Seip, whose affected population originated from the county of Rogaland. In the European literature, the terms "Seip syndrome," "generalized lipodystrophy," "congenital generalized lipodystrophy," or "total lipodystrophy" have been used.

Brunzell syndrome is the association of bone cysts and lipoatrophic diabetes mellitus described in five affected African Americans from the same sibship. Originally Brunzell syndrome was thought to be a separate entity, but it is now generally recognized that bone cysts represent a rare complication of Berardinelli-Seip congenital lipodystrophy. Furthermore, Fu et al [2004] identified biallelic pathogenic variants in AGPAT2 in three sibs with Brunzell syndrome.

After onset of diabetes mellitus, some have termed individuals with BSCL as having "lipoatrophic diabetes."

Lawrence syndrome is synonymous with acquired generalized lipodystrophy [Garg 2011].

Prevalence

More than three hundred cases of BSCL have been reported in the medical literature. Prevalence estimates:

USA: 1:10,000,000 [Agarwal & Garg 2006]
Norway: 1:1,000,000
Lebanon: 1:200,000
Portugal: 1:500,000
Sultanate of Oman: 1:25,000 [Rajab et al 2005]

Differential Diagnosis

Congenital generalized lipodystrophy 3 (CGL3) (OMIM 612526). Individuals with this condition typically have serum creatine kinase concentrations between 2.5 and ten times the upper limit of normal in addition to features resembling classic BSCL [Kim et al 2008]. Two sibs of Hispanic ancestry with a homozygous CAV1 pathogenic missense variant and hypotonia, elevated serum creatine kinase, atlas-axis instability, and generalized lipodystrophy have been described [Simha et al 2008].

Congenital generalized lipodystrophy 4 (CGL4) (OMIM 613327). Generalized lipodystrophy, distal myopathy, muscular hypertrophy, hypertriglyceridemia, insulin resistance, elevated serum creatine kinase concentration, and normal intelligence were described in five Japanese individuals with pathogenic variants in CAVIN1 (formerly PTRF), encoding polymerase I and transcript release factor [Hayashi et al 2009]. A series of affected individuals with cardiac arrhythmia originating from Oman and the UK were reported by Rajab et al [2010]. The polymerase I and transcript release factor protein is thought to play an essential role in the formation of caveolae (invaginations of the plasma membrane involved in many cellular processes, including clathrin-independent endocytosis, cholesterol transport, and signal transduction) and the stabilization of caveolins, proteins present in the caveolae. These data confirm caveolin deficiency as a cause of the lipodystrophic process.

Further diagnoses to consider include the following:

In infancy

SHORT syndrome
Neonatal progeroid syndrome (OMIM 264090)
Marfan syndrome, progeroid subtype, caused by pathogenic variants at the C-terminus of FBN1 [Graul-Neumann et al 2010]
Neurometabolic lysosomal storage disorders: Gaucher disease type 2, Krabbe disease
Russell diencephalic syndrome
Leprechaunism: Donohue syndrome (see INSR-Related Severe Syndromic Insulin Resistance)

In childhood

Familial partial Dunnigan-Koëberling lipodystrophy (OMIM 151660)
Rabson-Mendenhall syndrome (see INSR-Related Severe Syndromic Insulin Resistance)
Insulin-dependent diabetes mellitus
Acquired generalized lipodystrophy (Lawrence syndrome) [Misra & Garg 2003]. Three subtypes exist.
Mandibuloacral dysplasia (MAD) caused by LMNA/C and ZMPSTE24 pathogenic variants (see Mandibuloacral dysplasia with lipodystrophy: OMIM Phenotypic Series)
Hutchinson-Gilford progeria syndrome

In adulthood

Acquired partial lipodystrophy (Barraquer-Simons syndrome) (OMIM 608709)
Lipodystrophy associated with human immunodeficiency virus infection
Partial lipodystrophy with C3 nephritic factor (OMIM 613913)
Acquired generalized lipodystrophy (Lawrence syndrome)

See Lipodystrophy, congenital generalized: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:

Complete blood count
Serum concentration of electrolytes, AST, alanine transaminase, urea, creatinine, insulin, C-peptide, triglycerides, and cholesterol
Oral glucose tolerance test; when appropriate, clamp glucose homeostasis study
Ultrasound of the liver to evaluate liver size and fatty content
Echocardiogram to evaluate for cardiac hypertrophy
Renal ultrasound examination to evaluate for kidney size
Physical examination for orthopedic complications including reduced hip mobility and genu valgum
Skeletal survey, especially of the long bones, to evaluate for bone cysts
Bone age and assessment of sexual maturity rating/pubertal status
Complete ophthalmologic examination, including slit lamp examination, to evaluate for ophthalmologic complications due to hyperlipemia and/or diabetes mellitus
Assessment of cognitive ability with age-appropriate scales
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Restriction of total fat intake between 20% and 30% of total dietary energy is often sufficient to maintain normal triglyceride serum concentration.

Fibric acid derivatives and n-3 polyunsaturated fatty acids derived from fish oils can be tried for the treatment of extreme hypertriglyceridemia.

Leptin treatment has proven successful in controlling both hypertriglyceridemia and diabetes mellitus [Garg et al 1999, Beltrand et al 2007, Ebihara et al 2007]. Despite the absence of well-controlled randomized studies that could provide a more thorough assessment of the possible adverse effects of leptin therapy, the United States Food and Drug Administration granted approval of leptin administration [Tsoukas et al 2015].

Management of diabetes mellitus does not differ from that of childhood-onset diabetes mellitus.

Special education is required for individuals with psychomotor retardation or intellectual disability.

Prevention of Primary Manifestations

Dietary restriction of total fat intake may prevent hypertriglyceridemia (see Treatment of Manifestations).

Surveillance

The following are appropriate:

Periodic screening for glycosuria as a manifestation of diabetes mellitus
For individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications
Yearly cardiac ultrasound and EKG
Yearly or biennial liver ultrasound examination to detect fatty infiltration
Ultrasound surveillance is a noninvasive procedure that can, along with serum lipid concentrations and liver enzymes, provide information on the degree of lipid control and compliance with the fat-restricted diet.

Agents/Circumstances to Avoid

Excessive dietary fat intake should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected pregnant women should be followed in a high-risk pregnancy care unit by a multidisciplinary team including a specialist in fetal medicine and an expert in diabetic management. Pregnancy may increase the risk of diabetic decompensation. Babies born to women with diabetes are at an increased risk for fetal anomalies and postnatal complications compared to babies born to women without diabetes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Other drugs, including fenfluramine, have no proven efficacy and should be avoided.