Autosomal recessive cutis laxa type IB (ARCL1B) is characterized by the presence of severe systemic connective tissue abnormalities, including emphysema, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels. All symptoms refer to disturbed elastic fiber formation ... Autosomal recessive cutis laxa type IB (ARCL1B) is characterized by the presence of severe systemic connective tissue abnormalities, including emphysema, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels. All symptoms refer to disturbed elastic fiber formation (summary by Hoyer et al., 2009). For a complete phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
Ades et al. (1996) reported 4 unrelated children, 3 boys and 1 girl, with congenital abnormalities of the great vessels, comprising either single or multiple arterial aneurysms, aortic and/or arterial dilation, and/or vessel tortuosity. The authors noted that ... Ades et al. (1996) reported 4 unrelated children, 3 boys and 1 girl, with congenital abnormalities of the great vessels, comprising either single or multiple arterial aneurysms, aortic and/or arterial dilation, and/or vessel tortuosity. The authors noted that each child had a distinct phenotype, but all had in common the rare finding of aneurysms of the aorta and main pulmonary artery. Progression of these abnormalities was clearly evident in the female patient, who had diffuse vessel irregularity and tortuosity involving intraabdominal, intracranial, and extracranial arteries. She presented within the first 2 months of life with airway compression, aneurysm of the ascending aorta with dilatation of the proximal aortic arch and innominate artery, massive dilatation of the pulmonary trunk beyond the pulmonary valve, proximal pulmonary arterial stenosis, and moderate pulmonary regurgitation. After surgical repair of the aortic and pulmonary trunk aneurysms at 2.5 months of age, recurrent episodes of life-threatening respiratory obstruction developed at age 7 months, at which time she was found to have a massive recurrence of aneurysm of the ascending aorta and innominate artery, requiring reoperation at 8 months of age. Cineangiography at 39 months of age showed redundant aortic arch with significant dilation of the pulmonary trunk and proximal right and left branches and a mildly tortuous abdominal aorta with tortuosity and dilation of the major abdominal arteries. Ultrasonography at 4.5 years of age showed marked tortuosity and mild fusiform dilatation of the right common carotid artery, with less marked tortuosity of the left common carotid. Cerebral angiography at 5.5 years showed extreme tortuosity and dilatation of intra- and extracranial arteries. Other features in this patient included prominent eyes, bulbous nasal tip, prominent premaxilla, highly arched palate, micrognathia, generalized mild joint hypermobility, and velvety smooth skin with normal scarring. Histologic examination of tissue from the aorta and pulmonary artery showed a marked disruption of elastic fibers with an increase in deposition of interstitial glycosaminoglycans and marked thickening of the arterial intima. Large elastic fibers were markedly reduced in number and small elastic fibers were highly irregular in distribution. Analysis of dermal fibroblasts from this patient demonstrated that the proportion of collagen forming mature crosslinks was within the normal range, as was the kinetics of crosslink formation. Baspinar et al. (2005) studied a 3-year-old boy referred for evaluation of a widened mediastinum discovered on routine chest x-ray. The boy had unusually flattened facies with a prominent forehead, depressed nasal bridge, hypertelorism, narrow nostrils, high-arched palate, pectus excavatum, and moderate hypermobility of the joints. CT of the chest revealed a dilated aortic arch; transthoracic echocardiography demonstrated an aneurysmal dilation of the ascending aorta and a high aortic arch with a kink at the isthmus level. The diameters of the aortic valve, aortic root at the sinus Valsalva level, and the ascending aorta were 1.07 cm, 2.8 cm, and 4.3 cm, respectively. Aortography showed an elongated aorta with 2 acute curves, at the arcus aorta and at the diaphragmatic level. Although the boy was asymptomatic, he was placed on beta blocker therapy due to the risk of spontaneous rupture of the ascending aorta. Baspinar et al. (2005) noted that the facial dysmorphism and multiple joint dislocations were suggestive of Larsen syndrome (150250). Hucthagowder et al. (2006) described a patient with cutis laxa and severe systemic connective tissue abnormalities. The patient, the child of unaffected nonconsanguineous parents of Iraqi descent, was born with multiple fractures at gestational age 36 weeks, after an uneventful pregnancy, although oligohydramnios was reported. Examination at age 9 months revealed generalized cutis laxa with soft, velvety, and transparent skin. Additional observations included hypotonia, emphysema, generalized arterial tortuosity, inguinal and diaphragmatic hernia, joint laxity, and pectus excavatum. Diaphragmatic plication was performed at the age of 10 months. During surgery, both arterial and venous tortuosity, emphysematous and hyperexpanded lungs, and an esophagus not fixed to the posterior chest were observed. The diaphragm contained very little muscle and mainly consisted of pleuroperitoneal membrane. Aortic root aneurysm was diagnosed at the age of 2 years. Dasouki et al. (2007) reported an infant girl with apparent arachnodactyly, mild cutis laxa, and severe systemic vascular abnormalities that were inoperable and incompatible with life; she died on day 27 of life. Autopsy findings included biventricular hypertrophy and right ventricle dilatation, aneurysmal dilation of the ascending aorta and main branches of pulmonary arteries with dissection of the wall, and intussusception-like telescoping of the inner arterial layer causing severe luminal narrowing of the main branches of the pulmonary arteries. Histopathologic examination of skin, aortic wall, and pulmonary artery revealed that elastic fibers in all 3 tissues were markedly decreased in density, fragmented, and shortened. Hoyer et al. (2009) reported the third case of cutis laxa due to FBLN4 mutation (604633.0004). The patient was an infant girl who was born of consanguineous Iraqi parents, from a pregnancy remarkable for fetal overgrowth and oligohydramnios, and who died immediately after birth with extreme bradycardia. She exhibited cutis laxa, arachnodactyly of hands and feet with contractures of the third to fifth fingers, medial rotation of feet, spina bifida of the os sacrum, microcephaly, and facial dysmorphism. Autopsy showed collapsed lungs with hypoplastic diaphragm and signs of cervical soft tissue bleeding due to vessel fragility. Histologic examination showed fragmentation of elastic fibers with formation of cystic cavities in the medial layer of the aorta and central lung vessels. Hoyer et al. (2009) stated that this case extended the phenotypic spectrum of FBLN4 mutations to include microcephaly, overgrowth, and arachnodactyly. - ARCL1B, Mappila Type Kappanayil et al. (2012) reported 22 unrelated infants, members of the Mappila Muslim group from the northern coastal Malabar region of the southern Indian state of Kerala. Eight of these patients had a family history of consanguinity; 4 families had a history of infant death. Patients presented at a median age of 1.5 months with the typical aneurysmal dilatation, elongation, tortuosity, and narrowing of the aorta, pulmonary artery and their branches seen in other patients with ARC1B. The phenotype included a variable combination of cutis laxa (52%), long philtrum with thin vermilion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long, slender digits (48%), and visible arterial pulsations (38%). Early death (at 4 months of age or less) occurred in 17 of 21 patients homozygous for the same mutation (see MOLECULAR GENETICS). Isthmic hypoplasia in 9 correlated with early death.
Hucthagowder et al. (2006) described a child with cutis laxa caused by homozygosity for a missense mutation (604633.0001) in the EFEMP2 gene (FBLN4).
Dasouki et al. (2007) identified compound heterozygosity for a missense mutation and a ... Hucthagowder et al. (2006) described a child with cutis laxa caused by homozygosity for a missense mutation (604633.0001) in the EFEMP2 gene (FBLN4). Dasouki et al. (2007) identified compound heterozygosity for a missense mutation and a 4-bp duplication in the FBLN4 gene (604633.0002 and 604633.0003, respectively) in a patient with cutis laxa, arachnodactyly, and severe systemic vascular abnormalities. Analysis of the FBLN5 (604580) gene showed no mutations. The authors noted overlapping phenotypic similarities to the patient described by Hucthagowder et al. (2006). In the infant girl with cutis laxa reported by Hoyer et al. (2009), sequencing of the FBLN4 gene revealed a homozygous missense mutation in exon 7 (604633.0004). Renard et al. (2010) sequenced the FBLN4 gene in 17 patients with prominent cutis laxa but no major cardiovascular findings, who were known to be negative for mutation in the ELN (130160) and FBLN5 genes, but detected no FBLN4 mutations. Analysis of a second cohort of 22 patients who had mild skin involvement but significant cardiovascular features, including arterial tortuosity, stenosis, and aneurysms, and who had previously tested negative for mutation in the SLC2A10 (606145), FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, revealed homozygosity or compound heterozygosity for mutations in the FBLN4 gene in 3 patients (604633.0005-604633.0008), 2 of whom had previously been described (Ades et al., 1996; Baspinar et al., 2005). Renard et al. (2010) concluded that patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms and arterial tortuosity and stenosis, and stated that these findings confirmed the important role of fibulin-4 in vascular elastic fiber assembly. Kappanayil et al. (2012) detected homozygosity for a missense mutation in exon 7 of the FBLN4 gene (604633.0009) in 21 of 22 infants from the Mappila community of southern India with characteristic arterial dilatation and tortuosity. One patient was compound heterozygous for this mutation and a de novo missense mutation on the paternal allele. Both mutations occurred in the same conserved calcium-binding EGF domain. Homozygosity was lethal in the majority; 17 of 21 died at a median age of 4 months.
EFEMP2-related cutis laxa is characterized by cutis laxa and systemic involvement. ...
DiagnosisClinical Diagnosis EFEMP2-related cutis laxa is characterized by cutis laxa and systemic involvement. Major clinical characteristics:Cutis laxa. Furrowing of the skin of the whole body that is particularly obvious in face, torso, and limbs. The face can have a “droopy” appearance with eyelid ptosis and sagging cheeks. When extended the skin can be displaced more than normal skin and shows abnormal recoil; the skin has a “doughy” consistency. It does not display redundancy as in the Ehlers-Danlos syndromes. The skin can also be normal.Arterial involvement. Arterial tortuosity with aortic and arterial aneurysms and stenosis (the isthmus aorta in particular is often stenotic); pulmonary hypertension, stenosis and dilatation of pulmonary arteries; hemorrhagic strokeRespiratory involvement. Emphysema, diaphragmatic hernia or hypoplasiaCraniofacial involvement. Midface hypoplasia, retrognathia, ocular hypertelorism, highly arched palateOther evidence of a generalized connective disorderJoint laxity or contracturesArachnodactylyPectus excavatumInguinal hernias HypotoniaBone fragilityMolecular Genetic Testing Gene. EFEMP2 (previously known as FBLN4) is the only gene in which mutations cause EFEMP2-related cutis laxa.Clinical testingSequence analysis. No large cohorts in which molecular genetic testing has been performed have been published; however, in persons with a typical clinical presentation, including congenital cutis laxa and arterial involvement, the probability of identifying two causative EFEMP2 mutations is high.Table 1. Summary of Molecular Genetic Testing Used in EFEMP2-Related Cutis LaxaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityEFEMP2Sequence analysisSequence variants 2>95%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of EFEMP2-related cutis laxa is established in individuals who meet clinical diagnostic criteria and have two mutations identified in EFEMP2. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in EFEMP2 (FBLN4). Individuals without cutis laxa ascertained based on the presence of arterial tortuosity, stenosis, and aneurysms can have mutations in EFEMP2 [Renard et al 2010]. This is considered to be a variant of the EFEMP2-related cutis laxa phenotypic spectrum with variable expression or reduced penetrance of cutis laxa rather than a distinct disorder. (See Clinical Description.)
EFEMP2-related cutis laxa (autosomal recessive cutis laxa type 1A, ARCL1A) is a highly variable disorder ranging from perinatal lethality caused by cardiopulmonary failure [Hoyer et al 2009] to manifestations limited to the vascular and craniofacial systems [Renard et al 2010]. The most common shared features besides cutis laxa include arterial tortuosity, aneurysms and stenosis; retrognathia; joint laxity; and arachnodactyly. All features present in at least two affected individuals are shown in Table 2....
Natural HistoryEFEMP2-related cutis laxa (autosomal recessive cutis laxa type 1A, ARCL1A) is a highly variable disorder ranging from perinatal lethality caused by cardiopulmonary failure [Hoyer et al 2009] to manifestations limited to the vascular and craniofacial systems [Renard et al 2010]. The most common shared features besides cutis laxa include arterial tortuosity, aneurysms and stenosis; retrognathia; joint laxity; and arachnodactyly. All features present in at least two affected individuals are shown in Table 2.Table 2. Clinical Manifestations of Persons with EFEMP2-Related Cutis LaxaView in own windowFindingPatient123456Cutis laxa++++/- 1--Retrognathia?+++--Ocular hypertelorism???-++Highly arched palate???++-Dysplastic ears--+--+Arterial tortuosity++++++Aortic aneurysm++?+++Pulmonary arterial hypoplasia-+?+--Cardiac hypertrophy-++---Bradycardia-++???Cerebral atrophy, stroke??+??+Developmental emphysema+?+---Diaphragmatic hernia/hypoplasia+?+???Oligohydramnios+-+???Joint laxity+?+++-Arachnodactyly+++--+Pectus excavatum+??-+-Fractures+-+---Age at death (months)-10--18ReferenceHucthagowder et al [2006]Dasouki et al [2007]Hoyer et al [2009]Renard et al [2010]Renard et al [2010]Renard et al [2010]? = no information1. Velvety skinOf note, several features not included in Table 2 were found in only one affected individual, highlighting the pleiotropic and variable nature of EFEMP2-related phenotypes. Unique features by patient:Patient 1. Transparent skin, low muscle tone, and inguinal hernia Patient 2. Pneumonia, pulmonary hypertension, right ventricular hypertrophy, tricuspid insufficiency, renal tubular damagePatient 3. Long birth length, absolute microcephaly, contractures, spina bifida, small palpebral fissures, soft cranial bones, bowing and elongation of the long bones, flaring of the metaphyses, soft tissue bleeding Patient 5. Flat facies In a cohort of 16 affected individuals from India almost all died from cardiopulmonary failure [Nampoothiri et al 2010]. Major clinical characteristics included marked aortic dilatation, aortic and arterial tortuosity, isthmic aortic narrowing, and dilatation/stenosis of the pulmonary arteries. Aberrant branching of the right pulmonary artery was also a frequent finding. Recurrent additional features included long philtrum with thin upper lip, prominent eyes with ocular hypertelorism, and hypotonia.
Other disorders characterized by cutis laxa are summarized in Table 3....
Differential DiagnosisOther disorders characterized by cutis laxa are summarized in Table 3.FBLN5-related cutis laxa (ARCL1B) is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias. Occasionally supravalvular aortic stenosis is observed. Rarely, diverticulae of hollow viscera have been described. Intrafamilial variability in age of onset is observed. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death. Inheritance is autosomal recessive. LTBP4-related cutis laxa (ARCL1C, cutis laxa with severe pulmonary, gastrointestinal and urinary abnormalities, Urban-Rifkin-Davis syndrome [URDS]) is characterized by abnormal pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All affected individuals had severe respiratory distress with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Cardiovascular lesions were mild and limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis and enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide anterior fontanels. The craniofacial and pulmonary phenotype of URDS is similar to EFEMP2-related cutis laxa. Differences include relatively mild cardiovascular involvement in URDS and the presence of severe gastrointestinal and urinary complications, which have not been described to date in EFEMP2-related cutis laxa.ATP6V0A2-related cutis laxa (ARCL2A) spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end. Affected individuals have furrowing of the skin of the whole body that improves with time. They may have other evidence of a generalized connective disorder, including enlarged anterior fontanel in infancy, congenital dislocation of the hips, inguinal hernias, and high myopia. In most (but not all) affected individuals, cortical and cerebellar malformations are associated with severe developmental and neurologic abnormalities including seizures. Clinical features of ARCL2A that are not observed in EFEMP2-related cutis laxa are: intellectual disability, hip dislocation, and delayed closure of the fontanel. Secondary effects of strokes (developmental delay, structural brain defects) [Hoyer et al 2009, Renard et al 2010] may complicate the distinction between ARCL2A and ARCL1A. In ARCL2A, abnormal serum transferrin (N-glycosylation test) and apolipoprotein CIII (O-glycosylation test) isoelectric focusing (IEF) may help confirm the diagnosis.ELN-related cutis laxa (ADCL) was historically considered a strictly cutaneous disorder without systemic involvement; however, it is now known that persons with ELN mutations can also have aortic aneurysms that require aortic root replacement or lead to aortic rupture in early adulthood. The aortic pathology of these aneurysms is indistinguishable from that of Marfan syndrome. It remains to be seen whether ELN is mutated in persons with thoracic aortic aneurysms and aortic dissections (TAAD) [Szabo et al 2006] (see Thoracic Aortic Aneurysms and Aortic Dissections). Adult-onset emphysema has also been reported in ADCL [Urban et al 2005]. The following manifestations distinguish EFEMP2 -related cutis laxa from ADCL: arterial tortuosity, infantile aneurysms, infantile developmental emphysema, death in infancy or early childhood, arachnodactyly, and retrognathia. Gerodermia osteodysplastica (GO). Onset occurs in infancy or early childhood (for review, see Nanda et al [2008]). Children appear older than their age as a result of sagging cheeks and jaw hypoplasia. Skin wrinkling is less severe than in persons with cutis laxa and is confined to the dorsum of the hands and feet and to the abdomen when in the sitting position. A generalized connective tissue weakness leads to frequent hip dislocation and hernias; however, GO can be distinguished from other types of cutis laxa by the presence of osteopenia/osteoporosis and fractures, most commonly vertebral compression fractures, but also fractures of the long bones. However, fractures have also been described in EFEMP2 -related cutis laxa [Hucthagowder et al 2006, Hoyer et al 2009]. Intellectual development is in the normal range. In contrast to ARCL2A, fontanel size and closure are normal; positioning of the palpebral fissures is normal; and disease manifestations do not become milder with age. Mutations in SCYL1BP1 are causative [Hennies et al 2008]. Unlike EFEMP2-related cutis laxa, GO is generally not associated with cardiovascular and pulmonary manifestations.De Barsy syndrome is characterized by a progeroid appearance, pre- and postnatal growth retardation, moderate to severe intellectual disability, corneal clouding or cataracts, and generalized cutis laxa [Guerra et al 2004]. The progeroid appearance is not caused by skin sagging, but rather by a hypoplasia of the dermis. Joint hyperlaxity, pseudo-athetoid movements, and hyperreflexia are observed. Inheritance is autosomal recessive; the causative gene is not known. Like GO, de Barsy syndrome is not associated with cardiovascular and pulmonary involvement.Table 3. Disorders to Consider in the Differential Diagnosis of Cutis LaxaView in own windowDisease NameGene SymbolOMIM #InheritanceClinical FindingsCutis Laxa EmphysemaAneurysmsIntellectual disabilityGI and GU MalformationsARCL1AEFEMP2604633AR+++++++--ARCL1B FBLN5219100AR ++++++--+ARCL1C URDSLTBP4613177AR+++++--+++ARCL2AATP6V0A2278250AR++--++-ARCL2BPYCR1612940AR+++-++-ADCLELN or FBLN5123700AD+++--GOSCYL1BP1231070AR+ +----De Barsy syndromeUnknown219150AR+--+++-
To establish the extent of disease in an individual diagnosed with EFEMP2 -related cutis laxa, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with EFEMP2 -related cutis laxa, the following evaluations are recommended:Chest roentgenogramEchocardiography3D-CT scanLung function testMR angiographyTreatment of ManifestationsHernia. Routine repair is appropriate.Pulmonary emphysema is treated symptomatically. Tracheostomy may be necessary when retrognathia leads to upper airway obstruction. Arterial abnormalities. No definitive treatment is available. Based on experience in other related disorders (e.g., Marfan syndrome), treatment with beta-blockers or angiotensin receptor blockers can be considered when aortic root dilatation is present. However, the efficacy of these interventions in EFEMP2- related disorders has not been proven.SurveillanceRegular cardiovascular and pulmonary follow-up starting at birth or at the time of diagnosis is appropriate.Agents/Circumstances to AvoidCigarette smoking can worsen emphysema and should be avoided To protect skin, sun tanning should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials related to this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. EFEMP2-Related Cutis Laxa: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEFEMP211q13.1EGF-containing fibulin-like extracellular matrix protein 2EFEMP2 homepage - Mendelian genesEFEMP2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for EFEMP2-Related Cutis Laxa (View All in OMIM) View in own window 604633EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 2; EFEMP2 614437CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IB; ARCL1BNormal allelic variants. EFEMP2 has 11 exons and produces a 2002-bp long transcript, which in turn encodes a protein of 443 amino acid residues.Pathologic allelic variants. See Table 4.Table 4. Selected EFEMP2 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid ChangeReference SequencesNormalc.775G>A 1p.Val259Ile 1NM_016938.4 NP_058634.4c.1126G>A 2p.Arg409Gln 2Pathologicc.169G>A 3p.Glu57Lys 3c.608A>C 4p.Asp203Alac.835C>T 5p.Arg279Cys 5c.1070_1073dupCCGC 5p.Asp359fs*360 5c.800G>A 6p.Cys267Tyr 6c.376G>A 7p.Glu126Lys 7c.1189G>A 7p.Ala397Thr 7c.377A>T 7p.Glu126Val 7c.577delC 7p.Gln193fs*204 7See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. rs6013142. rs618938673. Hucthagowder et al 2006]4. Nampoothiri et al [2010]5. Dasouki et al [2007]6. Hoyer et al [2009]7. Renard et al [2010]Normal gene product. Fibulin-4 is a member of the fibulin family of extracellular matrix proteins. Fibulin-4 is known to associate with tropoelastin, possibly connecting elastin to microfibrils to form elastic fibers [Kobayashi et al 2007]. Fibulin-4 also binds strongly to the N-terminal region of fibrillin-1 in the presence of Ca2+ [Ono et al 2009]. Fibulin-4 can bind lysyl oxidase, an enzyme responsible for the crosslinking of elastin and collagen required for the integrity of the extracellular matrix [Horiguchi et al 2009].Abnormal gene product. Mutations in EFEMP2 (FBLN4) impair the stability and/or secretion of fibulin-4 [Hucthagowder et al 2006], similarly to previous findings for fibulin-5 mutations [Hu et al 2006]. The resulting decrease of protein in the extracellular matrix may lead to altered interactions with fibulin-4 binding partners and, subsequently, to impaired elastogenesis. Fibulin-4 also competes with latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) for binding to fibrillin-1 [Ono et al 2009]. As such, this fibulin protein may modulate the sequestration of latent TGFβ in the extracellular matrix. Consistent with this notion, increased TGFβ signaling was found in tissues from persons with EFEMP2 mutations [Renard et al 2010] and in a murine model of fibulin-4 deficiency [Hanada et al 2007]. In addition, the resulting decrease of mutant fibulin-4 protein in the extracellular matrix may lead to defective terminal differentiation of vascular smooth muscle, as recently shown [Huang et al 2010].