Marfanoid–Progeroid–Lipodystrophy Syndrome (C-Terminal FBN1)

Autosomal dominant fibrillinopathy, almost always de novo, caused by truncating or splicing variants at the 3′ end of FBN1 that escape nonsense-mediated decay; it combines congenital lipodystrophy, a neonatal progeroid appearance and incomplete features of Marfan syndrome, with asprosin deficiency.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition

Marfanoid–progeroid–lipodystrophy syndrome (MPL) is a rare systemic disorder defined by the combination of three components present from birth or early infancy: a congenital, generalised and extreme absence of subcutaneous adipose tissue that spares the breast and iliac regions; a neonatal progeroid appearance without other manifestations of premature ageing; and incomplete features of Marfan syndrome, above all severe myopia, joint hyperextensibility and arachnodactyly, without associated metabolic disturbances [2]. The OMIM definition adds the growth pattern — preterm birth followed by accelerated linear growth disproportionate to weight gain — and the facies with proptosis, downslanting palpebral fissures and retrognathia, with normal psychomotor development [1]. The cause is a heterozygous variant in FBN1, almost always de novo, located at the 3′ end of the gene, in the penultimate exon or in the intron separating it from the last one, which produces a truncated profibrillin-1 able to escape nonsense-mediated mRNA decay (NMD) and which prevents the normal release of the C-terminal fragment known as asprosin [7, 12, 13].

MPL occupies a distinct place within the type 1 fibrillinopathies, the set of allelic FBN1 disorders that includes Marfan syndrome (#154700), familial ectopia lentis (#129600), the MASS phenotype, Weill–Marchesani syndrome type 2 (#608328), acromicric dysplasia (#102370), geleophysic dysplasia type 2 (#614185) and stiff skin syndrome (#184900) [13, 14, 22]. Marfan syndrome, including aortic management, and the genetic lipodystrophies, with the group of progeroid syndromes with lipodystrophy, provide the framework. Smith's Recognizable Patterns of Human Malformation includes “FBN1 lipodystrophy” among the allelic phenotypes that do not correspond to Marfan syndrome and stresses that, faced with a novel FBN1 variant, it is often difficult to predict whether it will cause Marfan syndrome or another phenotype, which complicates estimation of aortic risk [23].

1.2. Historical overview

The first record of the phenotype is an abstract by Verloes and colleagues presented in 1998, which described a Belgian female infant with severe intrauterine growth restriction, long narrow hands and feet, mild arthrogryposis of the large joints, extreme laxity of the small joints, relative macrocephaly with a wide anterior fontanelle, hypoplasia of the facial bones and entropion of the upper eyelids, and asked whether this was a variant of Wiedemann–Rautenstrauch syndrome or a new syndrome (“congenital marfanoid-progeroid syndrome”) [1, 4]. In 2007, O'Neill, Garg and colleagues, in Dallas, studied body fat distribution in two girls aged 17 and 10 years then diagnosed with “neonatal progeroid syndrome”, taken as a synonym of Wiedemann–Rautenstrauch syndrome; they showed loss of fat in the face and distal extremities with preservation of truncal subcutaneous fat, paravertebral and lateral gluteal loss, reduced fat mass and lean mass and absence of hyperinsulinaemia and dyslipidaemia, and concluded that the picture did not correspond to a generalised lipodystrophy [24].

The link to FBN1 emerged in 2010. Graul-Neumann and colleagues described a 27-year-old German woman with lipodystrophy and a progeroid appearance from birth who fulfilled the 1996 Ghent criteria with three major criteria (ectopia lentis, aortic root dilatation and dural ectasia); after excluding AGPAT2, BSCL2, CAV1, PTRF, PPARG, LMNB2, LMNA and ZMPSTE24, they found the de novo deletion c.8155_8156del in FBN1 and noted the similarity with the two patients of O'Neill [13, 25]. One of the authors had followed this patient for 25 years without a diagnosis [13]. In 2011 two cases were published in the same issue of the American Journal of Medical Genetics: Goldblatt and colleagues, in Perth, described a 20-year-old man of Irish ancestry with severe generalised lipodystrophy, a progeroid appearance since infancy and bilateral lens subluxation at 16 years, carrying the de novo deletion c.8156_8175del [9, 26]; Horn and Robinson described a 3.5-year-old girl with progeroid facial features of neonatal onset, macrocephaly with hydrocephalus, lipodystrophy and tall stature, carrying the de novo variant c.8226+1G>T in the last intron, and proposed that the truncated protein escaped NMD [27].

In 2013, Takenouchi and colleagues described a preterm Japanese girl with severe congenital lipodystrophy, a progeroid appearance, craniosynostosis and accelerated growth in height with much lower weight gain, carrying c.8175_8182del; their review of the previous cases led them to propose a cardinal triad (congenital lipodystrophy; preterm birth with accelerated linear growth disproportionate to weight; progeroid appearance with a distinctive facies) and the name “marfanoid-progeroid syndrome”, and to suggest a neomorphic effect of a highly charged C-terminal motif (ETEKHKRN) shared by three of the variants [9, 16]. In 2014, Jacquinet and colleagues re-examined the Verloes patient at 16 years: considered at birth a possible Wiedemann–Rautenstrauch variant, she had developed a marfanoid habitus, severe myopia and aortic root dilatation, and carried c.8226+1G>A de novo, with skipping of the penultimate exon demonstrated in fibroblasts and stable mRNA [4]. In the same year, Garg and Xing re-evaluated the two patients from 2007, then aged 23 and 17 years, and identified by trio exome sequencing de novo variants at the C-terminal end of FBN1 in both; they called the picture “progeroid fibrillinopathy” and noted that their patients lacked the ETEKHKRN motif, which did not support Takenouchi's hypothesis [5].

The current designation was proposed in 2016 by Passarge, Robinson and Graul-Neumann, in a review of seven patients from six publications (2010–2014) in which all variants were located in the penultimate exon of FBN1 [13]. In the same year, Romere, Chopra and colleagues, starting from two patients with 3′ truncating FBN1 variants (genotypes matching those of Garg's patients), discovered that the 140-amino-acid C-terminal product released from profibrillin-1 by furin is a fasting-induced glucogenic hormone, which they named asprosin (from the Greek aspros, white), after the reduction of white subcutaneous adipose tissue in the patients [7]. In 2017, Duerrschmid and colleagues showed that asprosin is also a central orexigenic hormone and that the patients were hypophagic, and reproduced the phenotype in a mouse heterozygous for exon 65 skipping [28]. These were followed by a CRISPR-edited rabbit model (2018) [29], the first Chinese patient and studies of NMD and fibrillin aggregation (2020) [6], the first experimental demonstration, in cells from a Japanese patient, of exon 65 skipping and NMD escape (2023) [12] and a Turkish case with musculoskeletal involvement (2024) [15].

1.3. Nomenclature and reclassifications

The nomenclature of MPL has three sources of confusion. The first is the term “neonatal progeroid syndrome”, used in the asprosin literature to designate patients with MPL and, in OMIM, as a synonym of Wiedemann–Rautenstrauch syndrome (#264090), an autosomal recessive disorder caused mainly by biallelic variants in POLR3A [7, 8, 30]. Some of the patients now classified as MPL were labelled at birth as Wiedemann–Rautenstrauch, and Smith's records that de novo variants in the penultimate exon of FBN1, in CAV1 and in SLC25A24 have been identified in patients with that diagnosis, whose neonatal progeroid and lipodystrophic phenotype is not identical to that of Wiedemann–Rautenstrauch syndrome [31]. The second is exon numbering: the articles from 2010 to 2016 and OMIM refer to variants in “exon 64” and “intron 64”, counting the coding exons of NM_000138.4; in the MANE transcript NM_000138.5, with 66 exons of which the first is non-coding, the same exon is exon 65 and the intron of the splicing variants is intron 65 [4, 10, 12, 13]. Some sources give 65 exons for FBN1, a number that corresponds to the coding exons. The third is the condition label in ClinVar: many records of FBN1 variants across the whole gene list “Progeroid and marfanoid aspect-lipodystrophy syndrome” among the conditions, through laboratory gene–disease assignment, although no MPL phenotype has been described for those variants [32].

2. Molecular Genetics and Pathophysiology

2.1. The FBN1 gene and fibrillin-1

The FBN1 gene lies at 15q21.1 and encodes fibrillin-1, an extracellular matrix glycoprotein of 2871 amino acids and about 320 kDa, composed of 47 cysteine-rich epidermal growth factor (EGF)-like domains, 43 of which bind calcium (cbEGF), interspersed with eight-cysteine modules (TB, similar to those of the transforming growth factor beta (TGF-β) binding proteins) [33]. The fibrillins polymerise into microfibrils which, associated with elastin, form the elastic fibres of the skin, vascular wall, tendons, fascia, alveoli and the ciliary zonule of the lens [33]. Microfibril assembly depends on a fibronectin matrix, which is indispensable for the C-terminal association of fibrillin-1 monomers into “beaded” structures and for their linear assembly [33]. Fibrillin-1 is synthesised as profibrillin-1 and processed by proteolysis before being incorporated into the matrix [4].

The MANE Select (Matched Annotation from NCBI and EMBL-EBI) reference transcript is NM_000138.5 (ENST00000316623.10), with 66 exons on the negative strand; the first exon is non-coding, the coding sequence starts at position 317 of the mRNA and the protein NP_000129.3 has 2871 amino acids [10, 11]. In the GRCh38 reference genome assembly, exon 65 occupies chr15:48,412,569–48,412,743 (175 nucleotides) and exon 66, the last, chr15:48,408,313–48,411,379 [10]. The literature before 2017 and OMIM use NM_000138.4 and a numbering that starts at the exon containing the initiation codon, so the penultimate exon is there “exon 64” (codons 2685–2742; c.8052–c.8226) and the last intron “intron 64” [4, 9, 13]. The c. designations of the variants do not change between the two transcript versions; only the exon number changes (Table 1).

Table 1. Correspondence of FBN1 exon numbering in the MPL region

Sources: [7, 10–13].

2.2. C-terminal processing of profibrillin-1 and asprosin

Profibrillin-1 is cleaved at the C-terminus by furin, a proprotein convertase, between residues Arg2731 and Ser2732, within the penultimate exon, at a conserved R-G-R-K-R-R recognition sequence [4, 13]. Cleavage generates mature fibrillin-1, which is incorporated into microfibrils, and a 140-amino-acid C-terminal fragment (residues 2732–2871), asprosin [7]. The first 11 amino acids of asprosin are encoded by exon 65 and the remaining 129 by exon 66; these two exons show slightly higher evolutionary conservation in vertebrates than the rest of the sequence [7]. The C-terminal globular region of fibrillin-1 is structurally similar to fibulins 3 and 4, which led Passarge and colleagues to propose that functional loss of this segment contributes to the pathogenesis [13].

Asprosin circulates at nanomolar concentrations in humans, mice and rats, migrates at about 30 kDa in plasma because it is glycosylated (it has three predicted N-glycosylation sites) and is secreted without its own signal peptide [7]. Its concentration rises with fasting and falls with feeding, shows circadian oscillation and is suppressed by glucose; white adipose tissue is the main source, and mice without adipose tissue (Bscl2−/−) have low asprosin [7]. In the liver, asprosin acts through a G protein-coupled receptor (OR4M1, murine orthologue Olfr734), with a rise in cyclic adenosine monophosphate (cAMP) and activation of protein kinase A, and stimulates hepatic glucose release without altering peripheral uptake [7, 34]. In the central nervous system it crosses the blood–brain barrier, activates agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus through a cAMP-dependent pathway and inhibits, by a GABA-dependent mechanism, the anorexigenic pro-opiomelanocortin (POMC)-expressing neurons, which stimulates appetite [28]. The orexigenic receptor identified in 2022 is receptor-type tyrosine-protein phosphatase δ (PTPRD): Ptprd−/− mice are lean, hypophagic and euglycaemic, and the soluble binding domain of PTPRD sequesters asprosin and reduces appetite and blood glucose [34]. In humans and mice with insulin resistance and obesity, asprosin is raised [7, 28].

2.3. Molecular mechanism of MPL

All the MPL variants published up to 2016 lay in a 71-base-pair segment at the 3′ end of the coding region, downstream of the last 50 nucleotides of the penultimate exon, and clustered around the furin cleavage site [7]. Later variants keep the pattern: small frameshifting deletions or insertions in exon 65 or at the start of exon 66, and intron 65 donor-site variants that cause skipping of exon 65 (175 nucleotides, a number that is not a multiple of three) and an altered reading frame [6, 12]. Under the general rule of NMD, a premature termination codon located in the last exon or less than about 50–55 nucleotides from the last exon–exon junction does not trigger mRNA degradation; the mutant transcript is translated and produces a truncated profibrillin-1 with an altered C-terminus and without a functional cleavage site [4, 6, 7].

The evidence for NMD escape has four levels. Jacquinet and colleagues demonstrated in fibroblasts skipping of the penultimate exon caused by c.8226+1G>A, with stable mRNA [4]. Lin and colleagues used an in silico predictor (NMDEscPredictor) and predicted that all the truncating MPL variants escape NMD, whereas the control variant from a patient with classic Marfan syndrome, c.7785del p.(Tyr2596ThrfsTer86), whose termination codon lies in MANE exon 64, was predicted to be subject to NMD [6]. Romere and colleagues measured plasma asprosin in two patients and found values lower than expected for a heterozygote, lower than those of patients with more N-terminal truncations subject to NMD; overexpression of the truncated profibrillin in normal cells reduced asprosin secretion, which suggests a dominant-negative effect on the normal allele [7]. Moriwaki and colleagues obtained in 2023 the first experimental proof in patient material: in lymphoblastoid lines from a child with c.8226+5G>A, cDNA amplification showed a 230-base-pair product in addition to the normal 405-base-pair one, corresponding to exon 65 skipping, and treatment with cycloheximide, a translation inhibitor that blocks NMD, did not change the ratio of the two products, indicating that the mutant transcript is not degraded [12].

Lin and colleagues also studied fibrillin aggregation in HEK293T cells co-transfected with the normal and mutant alleles in a 1:1 ratio. Profibrillin carrying the MPL variant prevented native aggregation of normal fibrillin, which remained in the monomeric fraction, suggesting an intracellular dominant-negative effect, whereas the Marfan syndrome mutant reduced the aggregated fraction, in a pattern compatible with haploinsufficiency; both truncating mutants and the missense control p.Gly2003Arg increased SMAD2 phosphorylation [6]. The authors propose a mechanism lying between gain of function and a dominant-negative effect, rather than simple loss of function [6]. Takenouchi's hypothesis of a neomorphic effect of a highly charged C-terminal motif (ETEKHKRN) generated by three of the variants has not been confirmed, because the variants of Garg's patients do not produce it [5, 16]. The phenotype therefore results from two components: an effect on fibrillin-1 and the microfibrils, responsible for the marfanoid features, and asprosin deficiency, to which the leanness, hypophagia and low insulin are attributed [6, 7, 28].

The cause of the lipodystrophy has not been established. Davis and colleagues showed that FBN1 expression decreases after the onset of adipocyte differentiation of human mesenchymal stem cells and is increased in the adipose tissue of obese women, and hypothesised, without proof, a failure of adipocyte differentiation or lipid accumulation [35]. The 2026 European Consortium of Lipodystrophies (ECLip) consensus defines lipodystrophy as deficient development or inadequate maintenance of adipose tissue, not attributable to nutritional deprivation or a catabolic state, and regards adipose dysfunction (insulin resistance with low HDL cholesterol, high triglycerides or metabolic dysfunction-associated steatotic liver disease, or histological change) as the hallmark of most clinically relevant forms [36]. That consensus does not classify MPL [36]. Patients with MPL have low insulin and euglycaemia, have no reported hypertriglyceridaemia or steatosis, and have measured hypophagia [7, 13, 28]; on the reading of this article, the profile is closer to a reduction of adipose tissue with a component of hormonal appetite deficiency than to a lipodystrophy with adipose failure, an interpretation that none of the authors has formulated in those terms. Moriwaki and colleagues stress that the aged appearance does not reflect true cellular ageing but the scarcity of subcutaneous fat [12], and Romere calls the term “progeroid” a misnomer for the same reason [7].

2.4. Animal models

The Fbn1^NPS/+ mouse, created by CRISPR editing with a 10-base-pair deletion at the exon 65–intron 65 boundary that reproduces a patient's exon 65 skipping, has asprosin below 50 % of normal despite heterozygosity, extreme leanness with reduced fat mass and lean mass, normal body length, low leptin and a weight difference of about 10 g at 10 weeks [28]. These animals were protected from the obesity and diabetes induced by six months of a 60 % fat diet, had hypophagia with a compensatory reduction in energy expenditure, normal heart rate, blood pressure, temperature and thyroid axis, and AgRP neurons with reduced activity and no response to fasting; a single subcutaneous dose of recombinant asprosin corrected the hypophagia and intracerebroventricular injection restored AgRP neuron activity [1, 28]. The authors attribute the reduction in lean mass to the marfanoid component [28]. An asprosin-neutralising antibody given to these mice (250 µg, five animals per group) did not change blood glucose, appetite or weight, which is compatible with the already very low asprosin [37].

The hypomorphic mgR mouse (about 20 % of the Fbn1 transcript) has asprosin reduced by 70 %, insulin twice as low and hypoglycaemia after 24 hours of fasting, corrected by a dose of asprosin [7]. The rabbit with a CRISPR-induced C-terminal truncation in exon 65 (26 of 28 kits edited) showed a thin face, eyelid anomalies, enophthalmos, thin limbs, lower weight and high mortality (pulmonary infections, pneumothorax and ascending aortic dilatation in the animals that died), reduced microfibrils with intracellular retention of fibrillin-1, fibrillin-poor zonules, a corneal epithelial defect, aortic dilatation with elastic fibre fragmentation at 2–4 months, reduced white and brown adipose tissue, fasting euglycaemia but worse glucose tolerance, and lower insulin and glucagon [29]. The animal models support the dual mechanism, but the mortality and aortopathy findings in the rabbit do not translate directly to humans.

2.5. Variant spectrum

Table 2 brings together the variants published in patients with MPL and a described phenotype, described according to the Human Genome Variation Society (HGVS) recommendations, normalised in VariantValidator on NM_000138.5 (GRCh38) and with the ClinVar classification consulted on 29 October 2026.

Table 2. FBN1 variants described in MPL

Notes: for the intron 65 variants, VariantValidator does not predict the protein (p.?); the published protein consequences are the authors' inferences from exon 65 skipping, and the difference between p.(Glu2742Glufs*43) and p.(His2685Ilefs*9) reflects annotation conventions for the same event [6, 11]. Garg's notation “c.8206_8027insA” contains an error in the interval (it must be 8206_8207) and Passarge transcribes “c.8206_8026insA”; the normalised form is c.8206dup [5, 11, 13]. The variant c.8222T>C was considered likely benign by the predictors used by Garg and has conflicting interpretations in ClinVar; the causal variant in patient 2 is c.8226+1G>T [5, 9].

The variant c.8226+5G>A has been described in two further patients, cited by Moriwaki, without the MPL label: a child identified in a genome-based craniosynostosis screen, with exorbitism, ligamentous laxity, recurrent inguinal hernias, tall stature, lens subluxation, mild aortic dilatation at 8 years and sagittal and metopic synostosis, and a patient presented at a cardiovascular genetics meeting, with poor weight gain, a marked progeroid appearance, arachnodactyly, hypermobility, motor delay, frequent pulmonary infections and a normal aortic root [12]. These cases were read only through Moriwaki's description.

2.6. Genotype–phenotype correlation and limits of the rule

In Marfan syndrome, genotype–phenotype correlations are limited: cysteine substitutions in EGF domains are associated with ectopia lentis, variants in exons 24–32 (of the old transcript) with the early-onset severe form, variants with a premature termination codon with less ectopia lentis and more skeletal and skin manifestations, and variants at the ends of the gene, including exons 59–65, with milder or incomplete forms [14, 33]. Passarge and colleagues list the recognised correlations — the neonatal region in exons 24–32, geleophysic and acromicric dysplasias in exons 41–42, stiff skin syndrome in exon 37 — and propose MPL as the fourth [13]. MPL is a qualitative exception to the tendency towards mild phenotypes at the 3′ end: the consequence depends on whether the variant escapes NMD and alters the cleavage site, and not only on its position. Not all variants of the penultimate exon nor all truncating or splicing variants of the 3′ exons of FBN1 give a progeroid phenotype [13], and the same variant c.8226+5G>A has been associated with phenotypes ranging from Marfan syndrome with craniosynostosis to a marked progeroid picture [12]. For this reason, a novel variant in exon 65, intron 65 or the start of exon 66 should be interpreted in the light of the phenotype and, where possible, of RNA studies.

2.7. Inheritance, penetrance and variability

Inheritance is autosomal dominant [1, 2]. In all probands with parental testing the variant arose de novo: eight of eight in Lin's series and in Moriwaki's patient [6, 12]. In Graul-Neumann's patient the variant was absent from the parents, the unaffected sister and 150 controls, and multiplex ligation-dependent probe amplification (MLPA) excluded a deletion of the other allele [13]. No vertical transmission has been described, so there are no penetrance data; the expressivity of the marfanoid manifestations varies between patients with the same variant, as the two carriers of c.8226+1G>T show [6, 13]. No genetic modifiers have been described.

2.8. Allelic disorders

MPL shares its gene with the type 1 fibrillinopathies, which range from “tall” phenotypes (Marfan syndrome, ectopia lentis, MASS) to “short” phenotypes with reduced stature and joint stiffness (Weill–Marchesani type 2, acromicric and geleophysic dysplasias, stiff skin) [14, 22]. GeneReviews lists MPL among the allelic FBN1 disorders to be considered in the differential diagnosis of Marfan syndrome [14].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limits

Clinical knowledge of MPL rests on isolated case reports. The two tabulated syntheses available are those of Passarge and colleagues, with seven patients from six publications between 2010 and 2014 [13], and of Lin and colleagues, who added an eighth patient [6]; Moriwaki and colleagues counted nine cases published up to 2023 [12], and in 2024 a Turkish case was published whose clinical content was not accessible [15]. Anthropometric values are expressed as standard deviations (SD) relative to the reference for age and sex. Ages at last observation range from 3.5 to 27 years, which makes it difficult to compare age-dependent manifestations such as aortic dilatation, scoliosis or ectopia lentis [13]. There are no cohorts, registries or natural history studies; no patient has received mechanism-directed therapy, so everything that follows is natural history with symptomatic treatment. The two summary tables differ in some fields (for example, mitral prolapse in the Horn and Robinson patient), and the discrepancies are indicated.

Table 3. Frequency of manifestations in the published series

Dashes indicate that the field is absent from the source, not that the manifestation is absent.

3.2. Prenatal and neonatal period

Intrauterine growth restriction and preterm birth are constant: in Passarge's seven patients gestational age ranged from 28 to 39 weeks, birth weight from 1040 to 1780 g, length from 40 to 45 cm and head circumference from 28.5 to 32 cm [13]. In Jacquinet's patient, born at 39 weeks, the pregnancy was complicated in the third trimester by growth restriction and oligohydramnios, and birth weight was 1720 g (−4 SD), with a length of 45 cm (−2.5 SD) [4]. In Moriwaki's patient, fetal growth stopped at around 32 weeks, with suspected placental insufficiency, and caesarean section at 35 weeks and 2 days delivered a newborn girl of 1556 g (−2.6 SD), 45.4 cm (0.0 SD) and head circumference 33.2 cm (+1.0 SD) [12]. The disproportion between a near-normal length and a very low weight, with a relatively large head circumference, is already visible at birth.

The neonatal appearance described includes almost complete absence of subcutaneous fat, moderate muscle wasting, thin skin with visible veins, relative macrocephaly with a wide anterior fontanelle, hypoplasia of the facial bones, long narrow hands and feet, mild arthrogryposis of the large joints and laxity of the small ones [1, 4]. Eyelid entropion was described in two patients, requiring surgery at 1 year and at 1 year and 4 months [4, 12]. Jacquinet's patient had no natal teeth, a feature that helps distinguish Wiedemann–Rautenstrauch syndrome [4, 31].

3.3. Growth, adipose tissue and energy balance

The growth pattern is one of the elements of Takenouchi's triad: accelerated growth in height with much lower weight gain [16]. Jacquinet's patient measured 86.5 cm (+2.25 SD) and weighed 8.2 kg (−2.25 SD) at 19 months, 166 cm (+3.5 SD) and 29.7 kg at 12 years, and 177 cm (+3 SD) and 41.8 kg (−2 SD) at 16 years [4]. Moriwaki's patient had, at 9 years and 7 months, 151.6 cm (+2.8 SD), 29.0 kg (−0.3 SD), a body mass index (BMI) of 12.6 kg/m² and 9.4 % body fat [12]. The Chinese patient is a partial exception: at 4 years she measured 101 cm (25th centile) and 12 kg (−3 SD) and at 9 years 136 cm (50th centile) and 20.5 kg (−3 SD), with a BMI of 11.1 kg/m² [6]. Across the series, BMI ranged from 9.8 to 13.5 kg/m² [6].

Fat distribution is not uniform. Orphanet describes a generalised absence except for the breast and iliac region [2]. Whole-body magnetic resonance imaging (MRI) of O'Neill's two patients showed loss of fat in the face and distal extremities, with subcutaneous fat preserved in the chest and abdomen, and dual-energy X-ray absorptiometry (DEXA) showed reduced fat mass and lean mass [24]. In adulthood, total body fat by DEXA was 20.5 %, 27.7 % and 28.4 % in three women [5, 6]. Jacquinet's patient had, at 19 months, a generalised absence of fat except over the genitalia and the iliac wings [4].

Energy balance was measured in the two patients studied by Duerrschmid (Table 4). Both ate much less than recommended for age and sex and had a proportionately reduced energy expenditure, a pattern that reproduces that of the Fbn1^NPS/+ mouse and that is attributed to asprosin deficiency [28]. Garg's patient 1 reported a feeling of hypoglycaemia that forced her to eat frequent meals, recurrent nausea and vomiting, and iron-deficiency anaemia requiring transfusion attributed to poor intake and menorrhagia [5]. Moriwaki's patient was referred to genetics, among other reasons, for poor appetite [12], and Jacquinet's patient had severe feeding difficulties in early childhood [4].

Table 4. Energy intake and expenditure in two adult women with MPL

Source: [28], Table 1. By genotype, the two patients correspond to the patients of Garg and Xing.

3.4. Metabolism

The absence of metabolic disturbances is part of the definition [2]. Graul-Neumann's patient had normal fasting glucose, insulin and C-peptide and normal insulin receptors in fibroblasts [13]; Jacquinet tabulated metabolic data in three of the five patients known in 2014, with normal fasting glucose, insulin and lipids in two and a normal oral glucose tolerance test in one [1]; O'Neill's patients had neither hyperinsulinaemia nor dyslipidaemia [24]. Romere measured in the two patients an insulin level after an overnight fast half that of controls, with euglycaemia [7], and Duerrschmid describes preserved insulin sensitivity [28]. This combination contrasts with the classic generalised and partial lipodystrophies, in which insulin resistance, hypertriglyceridaemia, diabetes and hepatic steatosis dominate the course [18, 39]. The series is small and without published long-term metabolic follow-up; the absence of abnormalities up to 27 years does not equate to zero metabolic risk.

3.5. Eyes

Myopia is almost constant and often severe: −11 dioptres in Graul-Neumann's patient, extreme myopia with iridodonesis without dislocation in Garg's patient 2, and severe myopia without ectopia lentis at 16 years in Jacquinet's patient [4, 5, 13]. Ectopia lentis occurred in three of seven patients, detected in adolescence (13, 16 and 17 years); Garg's patient 1 had dislocation of the left lens with lensectomy and partial vitrectomy at 17 years and developed myopic macular degeneration [5, 13]. Takenouchi's Japanese patient had at 10 years severe bilateral myopia, proptosis and enlarged optic discs, without subluxation [1]. Congenital entropion, with corneal epithelial damage, was described in two patients [4, 12], and Garg's patient 2 had mild strabismus [5].

3.6. Cardiovascular system

Aortic root dilatation was recorded in three of seven patients [13]. Graul-Neumann's patient had a root of 32 mm at 16 years and 35 mm at 27 years, both at the 97th centile for body surface area [13]. In Jacquinet's patient, the echocardiogram was normal at 12 years and showed root dilatation at 16 years, with a Z-score of 3.3 [4]. Garg's patient 2 had at 17 years 3.1 cm at the sinuses of Valsalva and 2.4 cm at the sinotubular junction (Z-score 2.29), and patient 1 had at 23 years 2.5 cm and 2.0 cm (Z-score 1.56), with myxomatous-looking mitral leaflets without significant prolapse and normal ejection fraction [5]. The patients of Takenouchi (10 years), Lin (9 years, Z 1.6) and Moriwaki (9 years) had no dilatation [1, 6, 12]. Mitral valve prolapse was recorded in three of seven patients by Passarge and in four of eight by Lin; the Chinese patient had prolapse of both leaflets with moderate regurgitation, and Moriwaki's patient mild mitral regurgitation stable since the age of 2 years [6, 12, 13]. Takenouchi's patient had arterial hypertension and hydronephrosis [6]. No aortic dissection or aortic surgery has been described, but the longest published follow-up ends at 27 years and the number of patients is small, so the absence of events gives no information on lifetime risk.

3.7. Skeleton

The marfanoid skeletal manifestations are the most constant: arachnodactyly, dolichostenomelia, finger hyperextensibility, wrist and thumb signs, high palate, pectus excavatum, flat or valgus foot and scoliosis [6, 13]. Scoliosis can be severe and early: the Chinese patient had at 4 years a right thoracic scoliosis with a Cobb angle of 117°, congenital hip dislocation and, at 9 years, bilateral metacarpophalangeal dislocation and interosseous atrophy, and underwent surgery [6]. Garg's patient 1 had thoracic and lumbar scoliosis, bilateral protrusio acetabuli and operated claw toes, and patient 2 scoliosis and hip pain [5]. Mild arthrogryposis of the large joints in the neonatal period was described in two patients [1, 4]. Moriwaki's patient had a Marfan systemic score of 5 and the Chinese patient of 7 out of 20 [6, 12]. The Chinese patient did not fulfil the revised Ghent criteria, and the Horn and Robinson patient, at 3.5 years, did not fulfil the Ghent ocular or cardiovascular criteria [6, 9].

3.8. Skull, nervous system and development

Head circumference is large relative to the face, and three patients had arrested hydrocephalus [1, 6]. Craniosynostosis was described in Takenouchi's patient (posterior sagittal suture, with scaphocephaly) and in one of the cases with c.8226+5G>A, and is rare in Marfan syndrome [1, 12]. Moriwaki's patient had dolichocephaly and a prominent forehead, and Garg's patient 1 a thickened calvarium in the frontal regions [5, 12]. Lumbosacral dural ectasia was recorded in two patients [13]. Psychomotor and intellectual development is normal in all patients described [6, 13]; Moriwaki's patient walked unaided at 18 months [12]. Both of Garg's patients had severe recurrent headaches, and the younger one had treated anxiety, depression and attention deficit, and mild unilateral hearing loss [5].

3.9. Digestive, respiratory and other systems

Jacquinet's patient had severe gastro-oesophageal reflux with Nissen fundoplication at 3 years and gastrostomy in the first year of life, frequent upper respiratory and bronchopulmonary infections, bronchial asthma, and two cosmetic maxillofacial operations in childhood [4]. Garg's patient 1 underwent partial colectomy at 16 years, for an indication not described in the article [5]. Easy bruising was recorded in three patients [6]. Both of Garg's patients had regular menstruation, one on an oral contraceptive, with menarche at 16 years in the younger [5]. The 2024 Turkish case was published as an image with musculoskeletal involvement; the text was not accessible [15].

4. Clinical Recognition and Red Flags

4.1. When to suspect

In the newborn, suspicion arises in a preterm or growth-restricted newborn with almost complete absence of subcutaneous fat, an aged facial appearance, relative macrocephaly with a wide fontanelle, proptosis, retrognathia, long narrow hands and feet and laxity of the small joints [2, 4, 13]. This presentation is shared with the other neonatal progeroid syndromes, and MPL should be part of that differential from the outset, as Jacquinet and colleagues recommended [4]. Eyelid entropion and mild arthrogryposis of the large joints strengthen the suspicion [1, 4, 12].

In childhood, the most characteristic sign is the dissociation between accelerated growth in height, often above +2 SD, and a very low weight, with a body mass index between 9.8 and 13.5 kg/m² and normal psychomotor development [4, 6, 12, 16]. The triad proposed by Takenouchi — congenital lipodystrophy, preterm birth with accelerated linear growth disproportionate to weight gain, and a progeroid appearance with a distinctive facies — is the most widely used recognition rule [16]. Persistent poor appetite in a very thin, tall child should raise the possibility of asprosin deficiency [12, 28].

In adolescence and adulthood, suspicion arises in two scenarios. The first is a patient labelled at birth with Wiedemann–Rautenstrauch syndrome or “neonatal progeroid syndrome” who develops a marfanoid habitus, severe myopia, ectopia lentis or aortic root dilatation [4, 5]. The second is a patient with Marfan features, sometimes without fulfilling the Ghent criteria, whose extreme thinness since birth and aged face are not explained by Marfan syndrome [25, 26]. Lens subluxation at 16 years was the finding that prompted FBN1 testing in Goldblatt's patient [26]. A scoliosis or aortopathy panel yielding a variant at the 3′ end of FBN1 should lead to reverse phenotyping directed at lipodystrophy and the progeroid appearance, as happened in the Chinese patient [6].

4.2. Features that distinguish MPL from other progeroid syndromes

The criteria used by Graul-Neumann to rule out the classic progerias were the absence of premature greying, hypogonadism and scleroderma-like skin [25]. The absence of natal teeth, intellectual disability and paradoxical gluteal or lumbosacral fat accumulations rules out Wiedemann–Rautenstrauch syndrome [4, 31]; the absence of muscular hypertrophy, hepatomegaly, acanthosis nigricans and hypertriglyceridaemia rules out congenital generalised lipodystrophy [39]; the absence of alopecia, acro-osteolysis and premature atherosclerosis rules out Hutchinson–Gilford progeria [40]. The presence of marfanoid features (arachnodactyly, myopia, ectopia lentis, aortic dilatation, dural ectasia) is the positive element.

4.3. Red flags and emergencies

The signs requiring urgent assessment are those of Marfan syndrome: sudden chest, back or abdominal pain (aortic dissection), sudden dyspnoea (pneumothorax), acute visual loss (lens dislocation or retinal detachment) and rapid growth of the aortic root [14]. In MPL no human dissection or pneumothorax has been described, but root dilatation in three of seven patients and the death of model rabbits with pneumothorax and ascending aortic dilatation justify the same surveillance [13, 29]. Red flags specific to this syndrome also include rapid progression of scoliosis in early childhood [6], corneal damage from entropion in the infant [12], food refusal with weight loss, recurrent vomiting or anaemia from insufficient intake [4, 5] and, in the infant, severe gastro-oesophageal reflux [4].

4.4. Newborn screening

MPL is not part of any newborn screening programme, and newborn metabolic screening was normal in Moriwaki's patient [12].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated formal diagnostic criteria. The descriptive proposals available are Takenouchi's triad (congenital lipodystrophy; preterm birth with accelerated linear growth disproportionate to weight; progeroid appearance with a distinctive facies) [16], Passarge's triad (incomplete Marfan features; progeroid appearance without other manifestations of premature ageing; lipodystrophy without metabolic disturbances) [13] and the Orphanet definition [2]. The diagnosis is molecular: it rests on a heterozygous pathogenic variant in exon 65, intron 65 or the start of exon 66 of FBN1 (NM_000138.5) in a patient with a compatible phenotype [12, 13]. The revised Ghent nosology (Loeys 2010) is not intended to diagnose MPL, but serves to describe the marfanoid component: the diagnosis of Marfan syndrome requires, in the presence of an FBN1 variant associated with Marfan syndrome, an aortic root Z-score ≥2.0 or ectopia lentis, and before the age of 20 years provisional terms are used [14]. Graul-Neumann's patient fulfilled the 1996 Ghent criteria [13]; the more recent paediatric patients had systemic scores of 5 and 7 [6, 12].

Table 5. Proposed clinical diagnostic elements

5.2. Initial assessment

Assessment of a patient with suspected MPL includes full anthropometry (weight, length or height, head circumference, arm span, upper/lower segment ratio), ophthalmological examination with slit lamp and refraction, echocardiography with measurement of the aortic root as a Z-score and assessment of the mitral valve, assessment of the spine and joints, and nutritional assessment with a dietary survey [6, 12, 14]. Body composition can be documented by DEXA (fat percentage of 9.4 % in a 9-year-old child and 20.5–28.4 % in adult women) and regional distribution by whole-body MRI [5, 6, 12, 24]. The 2016 multisociety lipodystrophy guideline bases the diagnosis of lipodystrophy on history, examination, body composition and metabolic status (class I, level B) and states that no leptin value establishes or excludes the diagnosis (class IIa, level C), because assays are not standardised and values overlap with those of the general population [18]. Baseline metabolic characterisation (fasting glucose and insulin, glycated haemoglobin, lipid profile, transaminases and liver ultrasound) documents the absence of adipose failure and serves as a reference for follow-up [13, 18]. The 2026 ECLip consensus considers adiponectin useful for distinguishing physiological thinness, in which it rises, from lipodystrophy, in which it falls [36]; there are no published adiponectin measurements in patients with MPL.

5.3. Genetic tests

The first-line test is sequencing of FBN1, alone or in a panel for Marfan syndrome, Loeys–Dietz syndrome and thoracic aortic aneurysms and dissections, or by exome or genome sequencing when the neonatal picture is indistinguishable from other progeroid syndromes [14]. In published practice, the diagnosis was made by Sanger sequencing of FBN1 after excluding other lipodystrophy genes [25], by trio exome sequencing [5, 12] and by a 564-gene congenital scoliosis panel [6]. Before the exome, Moriwaki's patient had a karyotype (46,XX) and microarray, both normal [12]. FBN1 analysis must fully cover exons 65 and 66 and the intron 65 boundaries, including position +5 of the donor site [7, 12]. In classic Marfan syndrome, FBN1 sequencing identifies a pathogenic variant in about 90–93 % of probands who fulfil the clinical criteria, and testing for deletions and duplications adds about 5 % [14]; these values measure the proportion of detectable variants in patients with Marfan syndrome and not sensitivity for MPL, in which all known variants are small and detectable by sequencing. In heritable aortopathy panels, about 20 % of results include variants of uncertain significance [33].

5.4. Limits of the tests

A negative result does not exclude the diagnosis if the laboratory did not cover the intronic positions near exon 65, if coverage of the last exon was insufficient or if the patient has somatic mosaicism with a low allele fraction. Intron 65 variants (c.8226+1 and c.8226+5) are detected only if the analysis includes the intron–exon boundaries [12]. Interpretation of a truncating variant in exon 65 or 66 should not follow the usual loss-of-function-with-NMD logic, because these variants escape NMD and act through a dominant-negative or neomorphic effect [6, 7, 12]. For novel splicing variants in the region, RNA studies (RT-PCR in lymphoblastoid lines or fibroblasts, with and without cycloheximide) can demonstrate exon 65 skipping and NMD escape [4, 12]. The condition label “Progeroid and marfanoid aspect-lipodystrophy syndrome” assigned in ClinVar to FBN1 variants in other regions of the gene results from laboratory gene–disease associations and does not demonstrate an MPL phenotype [32]. Plasma asprosin has been measured only in research, with a sandwich enzyme-linked immunosorbent assay (ELISA) developed by Romere's group [7]; there is no validated clinical test or reference range, and it should not be used as a diagnostic test.

5.5. Report content and interpretation

The report should state the gene, the transcript with version (NM_000138.5), the variant in HGVS with the predicted protein consequence or p.? for intronic variants, zygosity, the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, the location in terms of MANE exon, the prediction of NMD escape and the correspondence with the old numbering when the cited literature uses it [11, 12]. For a variant of uncertain significance in the region, segregation (confirmation that it arose de novo, with confirmed paternity), phenotypic concordance and RNA studies are the most weighty arguments. The variant c.8222T>C, found in cis with c.8226+1G>T, shows that there may be more than one de novo variant on the same allele; in that case the causal variant should be identified by functional evidence and by comparison with published cases [5].

5.6. Practical algorithm

Table 6. Diagnostic algorithm

5.7. Prenatal and preimplantation diagnosis

Third-trimester fetal growth restriction, sometimes with oligohydramnios, was the only prenatal manifestation described [4, 12]; it is not specific and does not allow ultrasound diagnosis. Because the known cases arose de novo, prenatal or preimplantation diagnosis arises only when the familial variant is known, in pregnancies of the parents of a patient (because of the possibility of germline mosaicism) or in the offspring of a patient; these tests are technically possible once the variant has been identified, as for the other FBN1 disorders [14].

6. Differential Diagnosis

The differential of MPL spans three groups: the neonatal progeroid syndromes with lipodystrophy, the congenital and progeroid lipodystrophies of later onset, and the marfanoid conditions, including the other FBN1 disorders. Table 7 summarises the distinguishing features and the test that discriminates each entity.

Table 7. Differential diagnosis of MPL

AD: autosomal dominant; AR: autosomal recessive.

6.1. Neonatal progeroid syndromes

Wiedemann–Rautenstrauch syndrome is the most important differential, because it is the label under which several patients with MPL were initially identified [4, 5, 31]. It is autosomal recessive and caused mainly by biallelic variants in POLR3A, frequently with a deep intronic splicing allele, which requires intronic analysis or genome sequencing [30, 44]; a variant in POLR3GL has been described [45]. The features that separate it from MPL are the localised fat accumulations on the buttocks and in the lumbosacral region, present in about half of patients, natal teeth, dental anomalies, usually severe intellectual disability, hypomyelination and much shorter survival: mean survival is about 7 months and, in a series of 13 patients, four died in the first weeks, two in the first year and four between 5 and 10 years [8, 31]. MPL, by contrast, has normal development, progressive marfanoid features and documented survival into adulthood [13].

De novo null variants in CAV1 cause a neonatal progeroid lipodystrophy with mottled skin, early cataracts and pulmonary arterial hypertension, distinct from congenital generalised lipodystrophy type 3, which is recessive [41, 46, 47]. The recurrent de novo variants p.Arg217His and p.Arg217Cys of SLC25A24 cause Fontaine progeroid syndrome, with craniosynostosis, severe midface hypoplasia, hypertrichosis and early death in many patients [42, 49, 50]. Craniosynostosis also occurs in MPL [1, 12], so the distinction rests on hypertrichosis, midface hypoplasia and marfanoid features. Smith's groups the patients with variants in FBN1, CAV1 and SLC25A24 as neonatal progeroid and lipodystrophic phenotypes that are not identical to Wiedemann–Rautenstrauch syndrome [31].

6.2. Congenital and progeroid lipodystrophies

In congenital generalised lipodystrophy (Berardinelli–Seip), hyperphagia, muscular hypertrophy, hepatomegaly, acanthosis nigricans and severe metabolic complications from childhood contrast with the hypophagia, reduced lean mass and normal metabolism of MPL [28, 39]. Mandibuloacral dysplasia and MDPL syndrome have later onset, their own bone changes (acro-osteolysis, clavicular osteolysis, mandibular hypoplasia) or deafness, and insulin resistance [52, 53]. Hutchinson–Gilford progeria begins after a normal neonatal period and progresses with alopecia and accelerated atherosclerosis [40]. The 2016 lipodystrophy guideline includes FBN1 among the genes of the autosomal dominant progeroid syndromes with lipodystrophy, alongside LMNA, CAV1, POLD1 and KCNJ6 [18].

6.3. Marfanoid conditions

The early-onset severe form of Marfan syndrome, formerly called “neonatal Marfan syndrome”, presents with severe valvular disease and contractures in the first year of life and has neither lipodystrophy nor a progeroid face [14, 23]. GeneReviews recommends abandoning the term “neonatal” and the Oxford Desk Reference regards this form as the extreme of a continuum [14, 54]. The marfanoid conditions with intellectual disability (Lujan–Fryns and Shprintzen–Goldberg syndromes, mosaic trisomy 8, 15q21 deletion involving FBN1 and contiguous genes) are distinguished by cognitive impairment, which MPL does not cause [23, 54]; OMIM records the phenotypic overlap of MPL with Shprintzen–Goldberg syndrome, which also involves craniosynostosis [1].

6.4. Physiological thinness and undernutrition

In an undiagnosed very thin child or adult, undernutrition and eating disorders enter the differential. The 2026 ECLip consensus states that, in thin people, the diagnosis of lipodystrophy generally requires evidence of adipose dysfunction or histological change, and that a high adiponectin in a person with little fat is a strong argument against lipodystrophy, because adiponectin rises in physiological thinness and falls in lipodystrophy [36]. In MPL, thinness is present from birth, is accompanied by a progeroid appearance and marfanoid features and is associated with hypophagia of hormonal origin [13, 28].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment directed at the mechanism of MPL, nor any specific guideline or consensus; a search of ClinicalTrials.gov on 29 October 2026 found no study of the syndrome or of asprosin as a drug [17]. Management is symptomatic and multidisciplinary and combines two sets of recommendations that have to be extrapolated with care: those for Marfan syndrome for the cardiovascular, ocular and skeletal component [14], and those of the 2016 multisociety lipodystrophy guideline for nutrition, metabolic screening, contraception and psychological support [18]. Extrapolation has limits in both directions. Patients with MPL do not have the metabolic complications that justify much of the lipodystrophy recommendations, and they have hypophagia rather than hyperphagia [13, 28]. On the other hand, the marfanoid component is incomplete and of variable severity, and there are no data on long-term aortic outcome [13].

7.2. Cardiovascular component

When there is aortic root dilatation, management follows that of Marfan syndrome, with the same extrapolated character. GeneReviews states that beta-blockers or angiotensin II receptor blockers (ARBs) reduce haemodynamic stress on the aortic wall and are started at the diagnosis of Marfan syndrome, at any age, or in the presence of progressive root dilatation; it recommends the maximum tolerated dose, regardless of blood pressure, optimising one drug before adding another, avoiding ARBs in pregnancy and not using calcium channel blockers or angiotensin-converting enzyme inhibitors because of a lack of direct evidence [14]. Meta-analyses of randomised trials in Marfan syndrome show that ARBs reduce growth of the root and ascending aorta compared with placebo or when added to a beta-blocker [14]. The paediatric and adult doses (atenolol, propranolol, metoprolol, bisoprolol, losartan, irbesartan, valsartan), the trial table and the regulatory status of these drugs are those of Marfan syndrome, in which all are used off-label. None of the published patients with MPL has documented use of a beta-blocker or ARB, aortic surgery or dissection [5, 6, 12, 13]. The decision to treat a child with MPL without aortic dilatation has no evidence base of its own; the decision to treat documented dilatation follows the Marfan criteria.

In Marfan syndrome, aortic root surgery is indicated in childhood when growth reaches about 0.5–1.0 cm per year or there is progressive severe aortic regurgitation, and after childhood and in adults when the maximum diameter approaches 5.0 cm, growth reaches about 1.0 cm per year or there is progressive severe regurgitation; the valve-sparing technique is common [14]. Current North American and European guideline thresholds add factors that bring surgery forward. Mitral prolapse with moderate regurgitation, present in the Chinese patient, is monitored and treated as in Marfan syndrome [6, 14].

7.3. Nutrition and growth

The thinness of MPL is associated with hypophagia, with measured intakes of 955 and 1336 kcal per day in two adult women, that is, about half the reference intake, and with a compensatory reduction in energy expenditure [28]. There are no studies of nutritional intervention in MPL. The applicable general recommendations are those of the lipodystrophy guideline: a diet with a balanced macronutrient composition (class IIa, level C), referral to a dietitian especially in infants and young children (IIa, C) and avoidance of overfeeding to reach a “normal” weight (IIa, C) [18]. The same guideline considers a low weight-for-length or BMI acceptable as long as linear growth is maintained, because the body composition of these patients is atypical and the reference curves do not apply [18]. In MPL, linear growth is normal or accelerated [4, 16], so a low BMI should not, by itself, prompt forced feeding; it should prompt nutritional assessment when there are signs of deficiency (anaemia, micronutrient deficiencies, weight loss or food refusal). In severe Marfan syndrome, GeneReviews notes that some children present with severe undernutrition that may require intervention by a nutritionist or gastroenterologist [14].

The interventions described in the cases were gastrostomy in the first year of life and Nissen fundoplication at 3 years for severe reflux and feeding difficulties [4], frequent meals for a feeling of hypoglycaemia, and iron and vitamin D supplements in an adult woman with iron-deficiency anaemia that required transfusion [5]. Recombinant asprosin corrected the hypophagia of the mouse model with a single subcutaneous dose, but there are no studies in humans [28].

7.4. Metabolic component and metreleptin

Metreleptin, a recombinant leptin analogue, is the only drug approved specifically for lipodystrophy [18]. The 2016 guideline recommends it as first line, with diet, for the metabolic abnormalities of generalised lipodystrophy (class I, level B) and allows it in partial lipodystrophy with leptin below 4 ng/mL and severe metabolic abnormalities (glycated haemoglobin above 8 % or triglycerides above 500 mg/dL) (IIb, B) [18]. Metreleptin reduces hyperphagia and frequently causes weight loss, and the dose should be reduced if the loss is excessive [18]. Patients with MPL do not meet these criteria, because they have no reported diabetes, hypertriglyceridaemia or steatosis, have low insulin and are hypophagic [7, 13, 28]; the anorexigenic effect of metreleptin would, in principle, worsen energy balance. No report of metreleptin use in MPL was found in the sources consulted. The indications, authorisations by jurisdiction and doses of metreleptin are those established for the genetic lipodystrophies.

7.5. Eyes, skeleton and other manifestations

The measures for the marfanoid manifestations are those of Marfan syndrome [14]. Early correction of refractive errors prevents amblyopia; ectopia lentis with a free-floating lens or with the lens edge in the visual axis is treated by lens extraction, with an intraocular lens usually after puberty [14]; in MPL, lensectomy with partial vitrectomy was performed at 17 years [5]. Entropion with corneal damage was corrected surgically at 1 year and at 1 year and 4 months [4, 12]. Scoliosis is treated with bracing or arthrodesis [14]; the Chinese patient, with 117°, underwent surgery, and Lin and colleagues stress the need to assess metabolic and nutritional status before spinal surgery in lipodystrophic patients [6]. Hernias tend to recur, and recurrent pneumothorax is treated with pleurodesis or bulla resection, as in Marfan syndrome [14].

7.6. Physical activity

The lipodystrophy guideline recommends encouraging exercise in the absence of contraindications (IIa, C) and cardiac assessment before starting exercise in the subtypes predisposed to cardiomyopathy [18]. In MPL, the restrictions of Marfan syndrome prevail when there is aortic dilatation: avoid contact and competitive sports and isometric exercise [14]; the recommendations vary with the degree of dilatation.

7.7. Physical appearance and psychological support

The lipodystrophy guideline recommends assessing distress related to the altered appearance and referring to mental health services or plastic surgery when necessary (IIa, C); for facial lipoatrophy it describes autologous fat transfer, dermal fillers or muscle grafts, with limited data [18]. Davis and colleagues stress that the lack of adipose tissue in the fibrillinopathies is a source of psychosocial problems, especially in young people [35]. Jacquinet's patient had two cosmetic maxillofacial operations in childhood [4], and one of Garg's patients had treated anxiety, depression and attention deficit [5].

7.8. Agents and circumstances to avoid

When a marfanoid component is present, the GeneReviews recommendations for Marfan syndrome apply: avoid contact or competitive sports and isometric exercise, cardiovascular stimulants (including decongestants), vasoconstrictors (including triptans), LASIK refractive surgery, breathing against resistance or positive-pressure ventilation when there is a risk of pneumothorax, and fluoroquinolones [14]. Oral oestrogens are contraindicated in lipodystrophy because of the risk of severe hypertriglyceridaemia and pancreatitis (IIa, C) [18]; in MPL, without hypertriglyceridaemia, the applicability of this contraindication has not been established (section 8.5).

7.9. Regulatory status

Table 8. Regulatory status of the relevant drugs

7.10. Research and recent developments

Research on asprosin is directed mainly at obesity and diabetes, in which the hormone is raised, and not at MPL, in which it is deficient. Table 9 summarises the relevant intervention studies, all preclinical.

Table 9. Intervention studies on the FBN1–asprosin axis

These results do not allow clinical conclusions about MPL. No comparison is possible between studies with different models and outcomes, none measured outcomes in humans and one of them (antibody in the Fbn1^NPS/+ mouse) was negative for expected reasons. The study by Shetty and colleagues, published in June 2026, indicates that restoring asprosin in the aortic wall does not improve the aneurysm of the Marfan model, which rules out asprosin deficiency as the explanation of the aortopathy [58]. The article by Kim and colleagues, from August 2026, declares holdings of the senior author in companies with intellectual property on asprosin [59]. The review by Deng and colleagues (2026) on FBN1-related disorders and the 2026 ECLip consensus on the definition of lipodystrophy are the other publications in the 12-month window; neither brings new clinical data on MPL [22, 36]. A search of PubMed and Europe PMC on 29 October 2026 identified no new clinical series of MPL published between November 2025 and October 2026, which does not exclude isolated reports not indexed with the terms used.

7.11. Transition and organisation of care

Transition from paediatric to adult medicine should ensure continuity of aortic, ophthalmological and nutritional surveillance, and transfer of information about the variant and its mechanism, because the diagnosis is rare and often unknown to adult services. The VASCERN network, through its heritable aortopathies working group, and Endo-ERN, which includes the lipodystrophies, are the European reference points [19, 20].

8. Reproductive Options and Family Counselling

8.1. Mode of transmission and de novo cases

MPL is an autosomal dominant disorder [1, 2]. In all published probands with parental testing the variant arose de novo, and no familial case or vertical transmission has been described [6, 12, 13]. In the siblings tested the variant was absent: in the unaffected sister of Graul-Neumann's patient and in two and five siblings of Garg's patients [5, 13].

8.2. Risk to the parents and siblings of a patient

When the variant is not detected in the blood of either parent, the recurrence risk for siblings is low, but higher than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in one parent; testing of leucocyte DNA does not detect all somatic mosaicism or germline-only mosaicism, and a parent with somatic mosaicism may have a mild phenotype [14]. Somatic and germline mosaicism has been described in Marfan syndrome [54]. In MPL, parental mosaicism has been neither described nor excluded, and there are no empirical recurrence data; counselling therefore uses the general principles of the FBN1 disorders [14]. Parents may opt for prenatal or preimplantation diagnosis in a subsequent pregnancy, given the residual risk of mosaicism.

8.3. Risk to the offspring of a patient

Under the autosomal dominant model, each child of a patient has a 50 % probability of inheriting the variant [14]. There are no data on fertility or offspring of patients with MPL; Garg's two adult patients had regular menstruation, one with menarche at 16 years [5]. Expression in offspring is not known, but the uniformity of the core phenotype in the patients described suggests that a carrier of the variant would have the same basic picture, with variable marfanoid severity. Once the variant has been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are technically possible; the ideal time to discuss them is before pregnancy [14].

8.4. Testing of relatives and minors

Because the cases are de novo, cascade testing is as a rule limited to confirming the de novo origin in the parents. Testing of asymptomatic siblings is not necessary when the parents are negative, because the phenotype is evident from birth; in a sibling with suggestive features, targeted testing should be performed. Counselling of an adolescent with MPL should include, before reproductive age, information on the 50 % risk to offspring and the reproductive options, and discussion of the aortic risk of any pregnancy.

8.5. Contraception and pregnancy

No pregnancy has been described in patients with MPL. In Marfan syndrome, pregnancy carries a risk of aortic dissection, especially with a root above 4.0 cm, and the third trimester, delivery and the first postpartum month are the period of greatest vulnerability [14, 23]. GeneReviews recommends preconception counselling, continuing the beta-blocker and stopping ARBs (fetal loss, oligohydramnios and developmental abnormalities in the second and third trimesters), and echocardiography every 2–3 months during pregnancy and in the immediate postpartum period; some women opt for valve-sparing surgery before pregnancy with a root below 5.0 cm [14]. Thresholds for pregnancy follow the European Marfan syndrome guidelines. A woman with MPL and aortic dilatation should be counselled according to these criteria.

The lipodystrophy guideline contraindicates oral oestrogens (risk of severe hypertriglyceridaemia and pancreatitis), recommends progestogen-only or non-hormonal contraception (class IIa, level C) and prenatal care with an obstetrician experienced in diabetes and a physician experienced in lipodystrophies (IIa, C) [18]. One of Garg's patients used an oral contraceptive, with no complications reported [5]. The contraindication of oral oestrogens rests on the metabolic risk of the lipodystrophies with adipose failure, which patients with MPL do not show; the choice of method should be based on the patient's lipid profile and, if in doubt, progestogen-only or non-hormonal methods should be preferred. Fetal growth restriction and low maternal weight, foreseeable in the pregnancy of a woman with MPL, would justify obstetric surveillance of fetal growth, extrapolating from the prenatal history of the patients themselves [13].

8.6. Perioperative period

The operations described in patients with MPL include entropion repair, lensectomy and vitrectomy, spinal arthrodesis, fundoplication with gastrostomy, partial colectomy, foot surgery and maxillofacial surgery [4–6, 12]. Before an intervention, the aortic root and mitral valve, nutritional status and metabolism should be documented [6], the scarcity of subcutaneous tissue should be taken into account in positioning and protection of bony prominences, and the Marfan syndrome precautions regarding positive-pressure ventilation should be applied when there is a risk of pneumothorax [14].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Orphanet classifies the prevalence of MPL in the class below 1 per 1,000,000 and records seven cases or families based on the 2014 articles by Jacquinet and by Garg and Xing [2]. This number corresponds to the count published in 2014 and not to the current number: by 2023 nine patients with a C-terminal variant and the MPL phenotype had been published [12], to which are added a Turkish case in 2024 [15] and two patients with c.8226+5G>A described without the MPL label [12]. These numbers count published reports and do not measure population frequency; recognition of the entity dates from 2010–2016, some patients were labelled with other diagnoses and most variants are detected only if the laboratory analyses the 3′ end of FBN1, so the true frequency is unknown. There is no incidence estimate. For comparison, Marfan syndrome has a prevalence of 1 in 5000 to 1 in 10,000, with no ethnic predominance [14].

9.2. Geographical distribution and ancestry

The published patients are of European ancestry (Germany, Belgium, Ireland, seen in Australia, United States), Hispanic (United States), Japanese (two patients), Chinese (one patient) and Turkish (one patient) [6, 9, 12, 15]. There are no founder populations or recurrent variants by region; the only repeated variant, c.8226+1G>T, occurred de novo in two unrelated patients of European ancestry [6]. In Lin's series, seven of the eight patients were female, as was Moriwaki's patient; in such a small sample this proportion has no established biological interpretation [6, 12]. The sources consulted do not include patients from Portugal or Brazil, which does not show that none exist.

9.3. Special populations

Patients are born preterm (28–39 weeks) and with very low birth weight (1040–1780 g), which exposes them to the complications of prematurity and growth restriction [13]. In children, accelerated linear growth with a very low BMI requires careful use of reference curves: the lipodystrophy guideline considers a low BMI acceptable as long as linear growth is maintained [18]. Intellectual development is normal, which allows full participation in schooling, but physical appearance may have a psychosocial impact in adolescence [13, 35]. There are no data on older adults, because the oldest patient described was 27 years old [13].

9.4. European networks and patient organisations

VASCERN (European Reference Network on Rare Multisystemic Vascular Diseases), with its heritable aortopathies working group, is the reference ERN for the aortic component [19]; Endo-ERN (European Reference Network on Rare Endocrine Conditions) includes the lipodystrophies [20]; and ERN ITHACA covers rare malformation syndromes [21]. The European Consortium of Lipodystrophies (ECLip) maintains a European registry and published in 2026 the consensus on the definition and classification of the monogenic lipodystrophies [36, 60]. Among patient organisations, The Marfan Foundation (United States) covers the FBN1 disorders and Lipodystrophy United (United States) the lipodystrophies [61, 62]. No organisation dedicated specifically to MPL was identified.

10. Illustrative Clinical Case

10.1. Japanese girl with c.8226+5G>A and proof of NMD escape (Moriwaki and colleagues, 2023)

The patient was the fourth child of non-consanguineous Japanese parents, with a 33-year-old mother and a 35-year-old father of normal stature (156.0 and 169.5 cm); the mother had had a miscarriage, and the older brother and twin sisters were healthy [12]. Fetal growth stopped at around 32 weeks, with suspected placental insufficiency, and the patient was born by repeat elective caesarean section at 35 weeks and 2 days, weighing 1556 g (−2.6 SD), measuring 45.4 cm (0.0 SD), with a head circumference of 33.2 cm (+1.0 SD) and an Apgar score of 8 at 1 minute; newborn screening for inherited metabolic diseases and brainstem auditory evoked potentials were normal [12].

In the neonatal period bilateral entropion of the upper and lower eyelids and dolichocephaly were noted; because of severe corneal epithelial damage, the entropion was corrected surgically at 1 year and 4 months [12]. Independent walking began at 18 months and psychomotor development was normal. At 2 years mild mitral regurgitation was identified, which remained stable on subsequent echocardiograms, without aortic root dilatation [12]. The first genetics clinic appointment took place at 5 years and 9 months, for an undiagnosed picture and poor appetite. Examination showed dolichocephaly, a prominent forehead, a narrow nasal bridge, mild retrognathia, reduced subcutaneous fat, operated bilateral entropion, a high palate, long fingers, positive wrist and thumb signs, flat feet and mild finger hyperextensibility; ophthalmological examination revealed myopic astigmatism (right eye −2.5 dioptres sphere with −2.5 cylinder at 90°; left eye −3.0 sphere with −2.0 cylinder at 70°) without ectopia lentis [12]. Figure 1 of the article shows the long fingers and toes, without hindfoot deformity (Figure 1 of Moriwaki 2023).

At 9 years and 7 months she measured 151.6 cm (+2.8 SD), weighed 29.0 kg (−0.3 SD), had a head circumference of 55.3 cm (+2.2 SD), an arm span of 158.0 cm, a BMI of 12.6 kg/m² and 9.4 % body fat, with a Marfan systemic score of 5 [12]. Karyotype (46,XX) and chromosomal microarray were normal. Trio exome sequencing, carried out in the Japanese Initiative on Rare and Undiagnosed Diseases (IRUD) programme, identified the heterozygous variant NC_000015.10(NM_000138.5):c.8226+5G>A in intron 65 of FBN1, absent from the parents and confirmed by Sanger sequencing [12]. In lymphoblastoid lines, cDNA amplification between exons 64 and 66 showed, in addition to the normal 405-base-pair product, a 230-base-pair product whose sequence confirmed the direct junction of exons 64 and 66 through skipping of exon 65; cycloheximide treatment did not change the ratio of the two products, demonstrating that the mutant transcript escapes NMD (Figure 2 of Moriwaki 2023) [12].

10.2. Lessons from the case

The case illustrates the features that lead to the diagnosis — late fetal growth restriction, growth in height above +2 SD with a very low BMI, poor appetite, congenital entropion and marfanoid features without ectopia lentis or aortic dilatation in the first decade — and the typical diagnostic pathway, with normal karyotype and microarray before the exome [12]. It also shows the importance of intronic coverage: the variant lies five nucleotides into intron 65 and would be missed by an analysis limited to positions ±2 [12]. The RNA study, carried out in a research setting, was the first experimental demonstration of the mechanism in patient material and is not a routine test; it is justified when a novel intronic variant in the region is of uncertain significance. The article describes no cardiovascular therapy or nutritional intervention, and gives no information on the course after 9 years [12].

10.3. Other cases with accessible figures

Passarge and colleagues bring together in Figure 1 photographs of three patients (those of Graul-Neumann, Horn and Robinson, and Jacquinet) and in Figure 2 a diagram of the clinical overlap between Marfan syndrome, progeroid syndromes and lipodystrophies (Figure 1; Figure 2) [13]. Lin and colleagues show the Chinese patient with severe scoliosis, thinness and arachnodactyly, the hand radiographs and the chromatogram of the variant, and a diagram of the FBN1 C-terminus with the position of the variants around exon 65 (Figure 1; Figure 4) [6]. The legends of these figures were read on the article pages.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Survival into young adulthood is documented (20, 23 and 27 years), with normal intellectual development [6, 13]. No deaths have been described in the published patients, but the number of patients is small, the longest follow-up ends at 27 years and there are no life expectancy data; the absence of events does not allow lifetime risk to be estimated. The main foreseeable determinant of prognosis is the marfanoid component: aortic root dilatation occurred in three of seven patients, with Z-scores of 2.29 at 17 years and 3.3 at 16 years and a diameter at the 97th centile at 16 and 27 years, and may appear in adolescence after normal echocardiograms in childhood [4, 5, 13]. No dissection has been reported. Ectopia lentis appeared in adolescence and myopia progressed to myopic macular degeneration in at least one case [5, 13]. Scoliosis can be severe and early [6]. Thinness persists into adulthood (BMI of 9.9 and 13 kg/m² at 24 and 18 years) without reported metabolic complications, but with anaemia from insufficient intake in one case [5, 28]. In the rabbit model there was mortality from pneumothorax, pulmonary infection and ascending aortic dilatation, findings that have so far no described human equivalent [29].

11.2. Surveillance

There is no MPL-specific surveillance protocol. Table 10 combines the GeneReviews Marfan syndrome surveillance [14] with the lipodystrophy guideline screening for progeroid syndromes [18]; both are extrapolations, and detailed aortic surveillance is by diameter and age.

Table 10. Proposed surveillance in MPL

The annual metabolic screening of the lipodystrophy guideline is intended for patients at risk of adipose failure; in MPL, in which no metabolic abnormality has been described, it serves mainly to document the course, and the interval may be revised if the results remain normal. Aortic and ophthalmological follow-up is what has the greatest clinical consequence.

12. Summary and Final Considerations

Marfanoid–progeroid–lipodystrophy syndrome is an autosomal dominant fibrillinopathy, described in about ten patients, almost always de novo, caused by small deletions or insertions and splicing variants in exon 65, intron 65 and the start of exon 66 of FBN1 (NM_000138.5), designated “exon 64” and “intron 64” in the literature before 2017. These variants escape nonsense-mediated decay, produce a truncated profibrillin-1 without a functional furin cleavage site and reduce circulating asprosin below what is expected for a heterozygote, through a dominant-negative effect. The picture results from the sum of an effect on the microfibrils, responsible for incomplete marfanoid features (arachnodactyly, joint hypermobility, severe myopia, ectopia lentis in three of seven patients, aortic root dilatation in three of seven, mitral prolapse, dural ectasia, scoliosis), and of asprosin deficiency, associated with hypophagia, reduced energy expenditure, low insulin and euglycaemia.

Recognition rests on the triad of congenital lipodystrophy, preterm birth with accelerated growth in height and disproportionately low weight, and a progeroid appearance with proptosis, downslanting palpebral fissures and retrognathia, with normal development and without metabolic complications. The main differential diagnosis is Wiedemann–Rautenstrauch syndrome, autosomal recessive due to POLR3A, with which MPL shared the name “neonatal progeroid syndrome”; it is followed by the neonatal progeroid lipodystrophies due to CAV1 and SLC25A24, congenital generalised lipodystrophy and the progeroid syndromes of later onset. The diagnosis requires an FBN1 analysis that covers the 3′ end and intron 65, and interpretation of truncating variants in the region does not follow the loss-of-function-with-NMD rule.

There is no targeted treatment and there are no clinical trials. Management combines, by extrapolation, Marfan syndrome surveillance and therapy for the aorta, eyes and spine, and the nutritional and screening recommendations of the lipodystrophies, bearing in mind that MPL does not have the metabolic complications that justify metreleptin and that thinness with maintained linear growth is the rule. Research on asprosin, centred on obesity and diabetes, remains preclinical, and hormone replacement has been tested only in animal models. The main gaps are the absence of data on aortic outcome after 27 years, on pregnancy, fertility and offspring, and on the true population frequency of the syndrome.

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