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Geleophysic Dysplasia

, MD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: October 11, 2018.

Summary

Clinical characteristics.

Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. Major findings are likely to be present in the first year of life. Cardiac, respiratory, and lung involvement result in death before age five years in approximately 33% of individuals with ADAMTSL2-related geleophysic dysplasia.

Diagnosis/testing.

The clinical diagnosis of geleophysic dysplasia is based on clinical and radiographic findings. The molecular diagnosis is established in a proband who also has one of the following on molecular genetic testing: biallelic pathogenic variants in ADAMTSL2 or a heterozygous pathogenic variant in either FBN1 or LTBP3.

Management.

Treatment of manifestations: Regular physiotherapy to prevent joint limitation; cardiac valve replacement as needed; tracheostomy as required.

Surveillance: Annual multidisciplinary examination to access height and range of motion of the joints; echocardiography for evidence of valvular stenosis and/or arterial narrowing; clinical assessment for evidence of tracheal stenosis and respiratory compromise; clinical assessment and ultrasound examination, if needed, to assess liver size.

Genetic counseling.

Geleophysic dysplasia caused by biallelic pathogenic variants in ADAMTSL2 is inherited in an autosomal recessive manner. Geleophysic dysplasia caused by a heterozygous pathogenic variant in either FBN1 or LTBP3 is inherited in an autosomal dominant manner.

  • Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Autosomal dominant inheritance. To date, all individuals diagnosed with FBN1- or LTBP3-related geleophysic dysplasia have had a de novo pathogenic variant. If the FBN1 or LTBP3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism.

Once the pathogenic variant(s) in a family are known, the following are possible: carrier testing for relatives at increased risk for autosomal recessive geleophysic dysplasia, preimplantation genetic diagnosis, and prenatal testing for pregnancies at increased risk for either autosomal recessive or autosomal dominant geleophysic dysplasia.

Diagnosis

Suggestive Findings

Geleophysic dysplasia should be suspected in individuals with the following clinical and radiographic findings.

Clinical findings

  • Proportionate short stature
  • Very short hands and feet
  • Progressive joint limitation and contractures
  • Distinctive facial features: round, full face; small nose with anteverted nostrils; broad nasal bridge; thin upper lip with flat philtrum [Allali et al 2011]
  • Thickened skin
  • Progressive cardiac valvular disease diagnosed on echocardiography
  • Normal intellect
  • Additional features:
    • Hepatomegaly
    • Tracheal stenosis
    • Recurrent respiratory and middle-ear infections

Radiographic findings

  • Delayed bone age
  • Broad proximal phalanges
  • Cone-shaped phalangeal epiphyses
  • Shortened long tubular bones
  • Small capital femoral epiphyses

Establishing the Diagnosis

The clinical diagnosis of geleophysic dysplasia is based on clinical and radiographic findings (see Suggestive Findings).

The molecular diagnosis of geleophysic dysplasia is established in a proband with characteristic clinical and radiographic findings and one of the following on molecular genetic testing (Table 1):

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of geleophysic dysplasia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the diagnosis of geleophysic dysplasia is considered, molecular genetic testing approaches can include concurrent or serial single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.

1.

Perform ADAMTSL2 sequence analysis first if autosomal recessive inheritance is suspected or there is known consanguinity.

2.

If no pathogenic variant is found, perform FBN1 sequence analysis.

3.

If no pathogenic variant is found, perform LTBP3 sequence analysis.

A multigene panel that includes ADAMTSL2, FBN1, LTBP3, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

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

Option 2

When the diagnosis of geleophysic dysplasia is not considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis; however, to date no (multi)exon deletions or duplications have been detected in any of the three genes.

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

Table 1.

Molecular Genetic Testing Used in Geleophysic Dysplasia

Gene 1, 2Proportion of Geleophysic Dysplasia Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ADAMTSL2~50% 6~99%Unknown (none reported to date)
FBN1~50% 6~99%Unknown (none reported to date)
LTBP3<1% 7~99%Unknown (none reported to date)
1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

Clinical Characteristics

Clinical Description

Geleophysic dysplasia is a progressive disorder resembling a lysosomal storage disorder, involving bones and joints, cardiac valves, and skin. To date about 80 individuals have been reported: 33 affected individuals [Allali et al 2011] and 53 in case reports between 1960 and 2018 [Vanace et al 1960, Spranger et al 1971, Koiffmann et al 1984, Spranger et al 1984a, Spranger et al 1984b, Peters et al 1985, Lipson et al 1987, Shohat et al 1990, Wraith et al 1990, Lipson et al 1991, Rosser et al 1995, Figuera 1996, Hennekam et al 1996, Pontz et al 1996, Rennie et al 1997, Santolaya et al 1997, Titomanlio et al 1999, Keret et al 2002, Matsui et al 2002, Zhang et al 2004, Panagopoulos et al 2005, Scott et al 2005, Giray et al 2008, Ben-Salem et al 2013, Lee et al 2013, Porayette et al 2014, Elhoury et al 2015, García-Ortiz et al 2015, Mackenroth et al 2016, McInerney-Leo et al 2016, Li et al 2017, Cheng et al 2018].

Major findings are likely to be present in the first year of life.

A skeletal disorder is usually suspected at birth because of short stature and short hands and feet. The final height is between -3 SD and -6 SD. The progressive joint limitation and skin thickening interfere with normal joint function, leading to toe walking, contractions at large joints, and limitation of wrist and hand movement.

Cardiac findings are likely to become evident in the first year of life: 23/33 (70%) of affected children had cardiac anomalies (pulmonary stenosis, atrial septal defect) and had valvular thickening [Allali et al 2011; Authors, personal observation]; pulmonary arterial hypertension was observed in a few. The cardiac disease is progressive with dilation and thickening of the pulmonary, aortic, and mitral valves. Among those with valvular thickening, 30%-40% of affected children underwent valve replacement.

Intermittent hearing loss from otitis media is common.

Hepatomegaly, tracheal stenosis (observed in the first years of life in the more severe cases), and bronchopulmonary insufficiency with pulmonary arterial hypertension responsible for severe respiratory problems have also been observed. Note: Hepatomegaly is not associated with liver disease.

Two individuals developed glaucoma [Saricaoglu et al 2013; Author, personal data].

In the report of 33 individuals with ADAMTSL2-related geleophysic dysplasia, seven children (20%) died by age 3.6 years (average age 30 months) [Allali et al 2011]; a combination of cardiac, respiratory, and lung anomalies were reported.

The oldest living affected individual is age 30 years. In addition to progressive cardiac valvular thickening, survivors have short stature (< -3 SD), progressive joint contractures (limited range of motion of fingers, toes, wrist, and elbows, and tip-toe gait), thickened skin, and recurrent respiratory and ear infections.

Histologic examination of skin, liver, trachea, and heart shows lysosomal-like PAS-positive vacuoles, suggestive of glycoprotein and a storage disorder.

Phenotype Correlations by Gene

The clinical features of ADAMTSL2- and FBN1-related geleophysic dysplasia are indistinguishable.

Individuals with LTPB3-related geleophysic dysplasia to date have not had cardiac valvular involvement. While the absence of cardiac valvular thickening in contrast to the severity of the lung involvement may be a distinctive clinical feature for LTPB3-geleophysic dysplasia [McInerney-Leo et al 2016], confirmation awaits additional data.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Prevalence

Geleophysic dysplasia is rare; 80 individuals have been reported to date. The prevalence is not known.

Differential Diagnosis

The acromelic dysplasia group includes four rare disorders: geleophysic dysplasia, Weill-Marchesani syndrome, acromicric dysplasia, and Myhre syndrome. The clinical overlap between the four disorders is striking. Overlapping and distinguishing clinical features are summarized in Table 4. Hepatomegaly and early mortality are encountered only in the most severe forms of geleophysic dysplasia.

Table 4.

Disorders to Consider in the Differential Diagnosis of Geleophysic Dysplasia

DisorderGene(s)MOIClinical Features of the Disorder
Overlapping w/Geleophysic DysplasiaDistinguishing from Geleophysic Dysplasia
Acromicric dysplasiaFBN1
LTBP3
ADSee Table 2See Table 2
Weill-Marchesani syndromeFBN1AD
ADAMTS10
ADAMTS17
LTBP2
AR
Myhre syndromeSMAD4AD 1
  • IUGR
  • Short stature
  • Short hands & feet
  • Progressive joint limitation & contractures
  • Thickened skin
  • Heart involvement
  • Facial features w/prognathism
  • Cranial skull anomalies
  • Variable degree of cognitive impairment
  • Deafness

IUGR = intrauterine growth restriction

1.

All probands with Myhre syndrome reported to date have had a de novo SMAD4 pathogenic variant.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with geleophysic dysplasia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Height
  • Joint range of motion by an orthopedist/physiotherapist
  • Echocardiography to evaluate for evidence of valvular stenosis and/or arterial narrowing
  • Clinical history for evidence of tracheal stenosis and respiratory compromise
  • Liver size by clinical assessment and/or ultrasound examination
  • Eye examination to evaluate for evidence of glaucoma
  • Hearing assessment
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are appropriate:

  • Joint manifestations. Regular physiotherapy to prevent joint limitation
  • Heart. Valve replacement when severe
  • Tracheal stenosis. Tracheostomy when severe

Surveillance

Annual multidisciplinary examination to assess the following:

  • Height
  • Joint range of motion by an orthopedist/physiotherapist
  • Heart by echocardiography for evidence of valvular stenosis and/or arterial narrowing
  • Trachea for evidence of stenosis and respiratory compromise
  • Liver size for evidence of hepatomegaly

Evaluation of Relatives at Risk

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

Pregnancy Management

Pregnancy is unusual in women with geleophysic dysplasia. The management of a pregnant woman is complicated due to the small pelvis, cardiac anomalies, and tracheal stenosis. It is recommended that women considering a pregnancy be evaluated prior to pregnancy and followed during pregnancy in a high-risk perinatal center.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Geleophysic dysplasia caused by biallelic pathogenic variants in ADAMTSL2 is inherited in an autosomal recessive manner. Geleophysic dysplasia caused by a heterozygous pathogenic variant in either FBN1 or LTBP3 is inherited in an autosomal dominant manner.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one ADAMTSL2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with geleophysic dysplasia 1 are obligate heterozygotes (carriers) for a pathogenic variant in ADAMTSL2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ADAMTSL2 pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the ADAMTSL2 pathogenic variants in the family.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • To date, all individuals diagnosed with FBN1- or LTBP3-related typical geleophysic dysplasia have had a de novo pathogenic variant.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include physical examination for signs of geleophysic dysplasia (e.g., proportionate short stature, distinctive facial features) and molecular genetic testing if the FBN1 or LTBP3 pathogenic variant has been identified in the proband. Note: Decreased penetrance has not been reported to date in FBN1- or LTBP3-related geleophysic dysplasia.
  • If the FBN1 or LTBP3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the FBN1 or LTBP3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with autosomal dominant geleophysic dysplasia has a 50% chance of inheriting the pathogenic variant.

Other family members. Given that all probands with FBN1- or LTBP3-related geleophysic dysplasia reported to date have the disorder as a result of a de novo pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the geleophysic dysplasia-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
    Email: review.personal.info@heart.org
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
    Email: contactus@magicfoundation.org
  • French Reference Center for Skeletal Dysplasia
    Hôpital Necker-Enfant Malades
    Phone: +33 142192713
    Fax: +33 144495150
    Email: cr.moc@nck.aphp.fr
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Geleophysic Dysplasia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Geleophysic Dysplasia (View All in OMIM)

134797FIBRILLIN 1; FBN1
231050GELEOPHYSIC DYSPLASIA 1; GPHYSD1
602090LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 3; LTBP3
612277ADAMTS-LIKE PROTEIN 2; ADAMTSL2
614185GELEOPHYSIC DYSPLASIA 2; GPHYSD2
617809GELEOPHYSIC DYSPLASIA 3; GPHYSD3

ADAMTSL2

Gene structure. The 18 coding exons of ADAMTSL2 constitute a transcript of 40.6 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The pathogenic variants identified to date are located throughout the gene. The majority of pathogenic variants are missense, although nonsense and one 30-bp deletion affecting the N glycan-rich module were described [Allali et al 2011] (see Table 5).

Table 5.

Selected ADAMTSL2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.440C>T 1p.Pro147LeuNM_001145320​.1
NP_001138792​.1
c.338G>A 1p.Arg113His
c.340G>A 1p.Glu114Lys
c.2431G>A 2p.Gly811Arg
c.2586G> 2p.Trp862Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Reported as homozygous pathogenic variants

2.

Reported as compound heterozygous state

Normal gene product. ADAMTSL2 belongs to a large superfamily containing 19 ADAMTS proteases and at least five ADAMTS-like proteins. ADAMTS proteases are secreted enzymes with a conserved organization that includes a metalloprotease domain and an ancillary domain containing one or more thrombospondin type 1 repeats (TSRs). Some ADAMTS proteases participate in extracellular matrix (ECM) turnover in arthritis and others are involved in procollagen and von Willebrand factor maturation or in angiogenesis [Apte 2004].

The ADAMTS-like subfamily comprises proteins homologous to the ADAMTS ancillary domains but lacking the protease domain and hence lacking catalytic activity. ADAMTSL-1 and ADAMTSL-3 proteins are closely related secreted glycoproteins, whereas ADAMTSL-2 has a different domain structure. Indeed, ADAMTSL2 encodes a 951-amino-acid protein composed of a signal peptide, a TSR, a cysteine-rich module, a spacer module, an N-glycan-rich module, six additional TSRs, and a PLAC module. The function of these domains is currently unknown [Koo et al 2007].

ADAMTS-like 2 is a glycoprotein lacking enzymatic activity whose function is unknown. To define the molecular pathway in which ADAMTSL2 may participate, yeast two-hybrid screening of a human muscle cDNA library was performed. The human latent TGFβ-binding protein 1 (encoded by LTBP1) was identified as an ADAMTSL2 partner. The interaction of LTBP-1S (the dominant and more widely distributed protein isoform) with ADAMTSL2 was verified using immunoprecipitation [Le Goff et al 2008].

The LTBP1 protein plays a major role in the storage of latent TGFβ in the ECM and regulates its availability [Isogai et al 2003]. Owing to the interaction of ADAMTSL2 with LTPB1, the amount of total and active TGFβ in the culture medium of fibroblasts from individuals with geleophysic dysplasia was investigated. Using ELISA assays, a tenfold higher level of TGFβ was found in the culture medium of fibroblasts from affected individuals compared to controls (p<0.0003). The active TGFβ represented 85% and 92% of total TGFβ in culture medium of individuals with geleophysic dysplasia, whereas active TGFβ represented only 7% of total TGFβ in control medium [Le Goff et al 2008].

The finding of a potential interaction between LTPB1 and ADAMTSL2 suggests that ADAMTSL2 may be involved in the microfibrillar network and in TGFβ bioavailability. TGFβ is a growth factor that regulates cell proliferation, migration, differentiation, and survival in a context-dependent fashion; its activity is tightly regulated through the ECM [Isogai et al 2003].

Abnormal gene product. The functional consequences of the ADAMTSL2 pathogenic variants were tested using a myc-tagged wild type and an ADAMTSL2 mutated construct (p.Arg113His, p.Pro147Leu, and p.Gly811Arg) in parallel transfections of HEK293F cells. Western blot analyses after 48 hours of transfection confirmed that wild type ADAMTSL2 protein was secreted into the medium. All three mutated proteins were also secreted, but at reduced levels compared to wild type ADAMTSL2. Although there was no statistically significant alteration of cellular levels, a significantly decreased secretion of each mutated protein was found. Thus, the mutated proteins are likely to be synthesized, but it is possible that they are misfolded, which may interfere with their efficient secretion. An increased turnover of mutated protein or altered function of secreted mutated protein could also explain these data [Le Goff et al 2008].

FBN1

Gene structure. FBN1 is large (>600 kb) and the coding sequence is highly fragmented (65 exons). The promoter region is large and poorly characterized. High evolutionary conservation of intronic sequence at the 5' end of the gene suggests the presence of intronic regulatory elements. Three exons at the extreme 5' end of the gene are alternatively utilized and do not appear to contribute to the coding sequence (see Thoracic Aortic Aneurysms and Aortic Dissections). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. All FBN1 pathogenic variants identified to date in geleophysic dysplasia are clustered in the same region (exon 41-42) encoding the TGFβ-binding protein-like 5 (TB5) domain of FBN1. Among the 16 FBN1 pathogenic variants identified, seven were specifically identified in geleophysic dysplasia (GD), seven were specifically identified in acromicric dysplasia (AD), and two were found in individuals with either GD or AD [Le Goff et al 2011]. All pathogenic variants were located in exons 41-42 encoding the TB5 domain and altered either large aromatic components or structurally important residues. Half of the pathogenic variants created or removed a cysteine residue within this domain, which is characterized (as are the other TB domains) by eight cysteines directly involved in FBN1 folding via intradomain disulfide linkage.

Normal gene product. Fibrillins are large glycoproteins (350 kd) ubiquitously expressed. They give rise to filamentous assemblies (microfibrils) with an average diameter of 10 nm. They are grouped together with LTBPs and fibulins into a structurally related family of extracellular matrix proteins. Fibrillins have a specific modular structure that consists of 46/47 epidermal growth factor (EGF)-like domains (42/43 of which are of the calcium-binding type) interspersed with seven 8-cysteine-containing modules (TB/8-Cys). The modules with 8-Cys are specific to fibrillins and LTBPs. This molecule also contains a specific binding sequence to integrin receptors α5β1, αvβ3, and vβ6. Fibrillin assemblies thus constitute the non-collagenous architectural elements of soft- and hard-tissue matrices. The importance of fibrillin deposition for the proper storage, distribution, release, and activation of locally produced TGFβ and BMP molecules has been demonstrated.

Abnormal gene product. To analyze the consequences of FBN1 pathogenic variants, the microfibrillar structure in skin fibroblasts of individuals with GD/AD and controls was observed by indirect immunofluorescence. Staining revealed abundant long microfibrils in controls, but fibroblasts from individuals with AD/GD demonstrated a reduced number of microfibrils and complete network disorganization.

To test the effect of TB5 domain pathogenic variants on TGFβ signaling, the phospho-SMAD2/3 level in cell lysate of skin fibroblasts of individuals with GD/AD and age- and passage-matched controls was analyzed by Western blot; an enhanced signal was found. Consistent with this observation, the quantification of active and total TGFβ in the cultured medium of skin fibroblasts of individuals with GD/AD by ELISA shows a tenfold higher level of total TGFβ in the cultured medium compared to controls.

Because ADAMTSL2 pathogenic variants were previously identified in a subset of individuals with GD, a direct link between FBN1 associated with AD and (some cases of) GD and ADAMTSL2 was hypothesized. To demonstrate this interaction, a surface plasmon resonance analysis using FBN1 recombinant protein was performed. A specific interaction between FBN1 and ADAMTSL2 may provide evidence that dysregulation of the FBN1/ADAMTSL2/TGFβ interrelationship is the underlying mechanism of the short stature phenotypes.

LTBP3

Gene structure. LTBP3 comprises 28 exons; the longest transcript variant is NM_001130144.2. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Three pathogenic variants have been identified: a splice site variant, a missense variant located in an EGF-like calcium-binding domain and associated with acromicric dysplasia, and a nonstop (or stop-loss) change with loss of the normal stop codon with translation likely extending into the 3'UTR [McInerney-Leo et al 2016].

Normal gene product. The transcript NM_001130144.2 encodes the 1,303-amino-acid protein NP_001123616.1. LTBP3 belongs to TGBβ-binding protein (LTBP) family, comprising four proteins found in microfibrils of the ECM and structurally similar to fibrillins. It is incorporated into the ECM through its interaction with fibrillin-1 [Zilberberg et al 2012]. It contains 13 epidermal growth factor-like repeats and four TGFβ-binding (TB) domains (or 8-cysteine domains), which are specific to the LTBP-fibrillin superfamily. LTBP3 is involved in TGFβ secretion, trapping, and activation [Koli et al 2008]. TGFβ signaling is important in chondrogenesis and osteogenesis [Le Goff & Cormier-Daire 2015].

Abnormal gene product. The mechanism of pathogenicity for LTBP3 has not yet been fully elucidated. Pathogenic variants associated with geleophysic dysplasia are responsible for a disorganized microfibrillar network. However, TGFβ signaling is not increased [McInerney-Leo et al 2016].

References

Literature Cited

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Chapter Notes

Author History

Valérie Cormier-Daire, MD, PhD (2009-present)
Carine Le Goff, PhD; Université Paris Descartes (2009-2018)
Pauline Marzin, MD (2018-present)

Revision History

  • 11 October 2018 (bp) Comprehensive update posted live
  • 19 April 2012 (me) Comprehensive update posted live
  • 22 September 2009 (et) Review posted live
  • 5 June 2009 (vcd) Original submission
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