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 geleophysic dysplasia 1.
Diagnosis/testing.
Diagnosis is based on clinical and radiographic findings. The two genes known to be associated with geleophysic dysplasia are ADAMTSL2 (geleophysic dysplasia 1) and FBN1 (geleophysic dysplasia 2).
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.
Two forms of geleophysic dysplasia have been recently described based on the underlying gene involved, with no obvious clinical differences.
The first form is inherited in an
autosomal recessive manner and is caused by pathogenic variants in
ADAMTSL2. 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.
The second form of geleophysic dysplasia is inherited in an
autosomal dominant manner and is caused by pathogenic variants in
FBN1. Most individuals diagnosed with
FBN1-related geleophysic dysplasia represent
simplex cases (i.e., a single occurrence in a family). If a parent of the
proband has an
FBN1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. If neither parent is
affected, the empiric risk to sibs of a proband is approximately 1%-2%, most likely attributable to
germline mosaicism.
Carrier testing for relatives at risk for autosomal recessive geleophysic dysplasia and prenatal testing for pregnancies at increased risk for either form of the disorder are possible if the pathogenic variant(s) in the family are known.
Diagnosis
Clinical Diagnosis
Clinical diagnostic criteria for geleophysic dysplasia:
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:
Radiographic findings. Skeletal survey shows delayed bone age; broad proximal phalanges; cone-shaped phalangeal epiphyses; shortened long tubular bones; and small capital femoral epiphyses.
Histologic findings. Histologic examination of skin, liver, trachea, and heart shows lysosomal-like PAS-positive vacuoles, suggestive of glycoprotein and a storage disorder.
Molecular Genetic Testing
Gene.
ADAMTSL2 is the gene associated with the autosomal recessive form of geleophysic dysplasia (geleophysic dysplasia 1). FBN1 is the gene associated with the autosomal dominant form of geleophysic dysplasia (geleophysic dysplasia 2).
Clinical testing
Sequence analysis of
ADAMTSL2 or
FBN1 detects pathogenic variants in all
affected individuals to date [Authors, personal data].
Table 1.
Summary of Molecular Genetic Testing Used in Geleophysic Dysplasia
View in own window
| Gene 1 | Test Method | Variants Detected 2 | Variant Detection Frequency by Test Method 3 |
|---|
| ADAMTSL2 | Sequence analysis 4 | Sequence variants | 50% |
| Deletion/duplication analysis 5 | Exon or whole-gene deletions | Unknown; none detected 6 |
| FBN1 | Sequence analysis of select exons | Sequence variants of exons 41 and 42 7 | 50% |
Testing Strategy
To confirm/establish the diagnosis in a proband
- 1.
Physical examination
- 2.
Skeletal survey
- 3.
If autosomal recessive inheritance is suspected or there is known consanguinity:
- a.
ADAMTSL2 sequence analysis
- b.
If ADAMTSL2 sequencing does not detect any pathogenic variants, FBN1 sequence analysis
- 4.
If clinical suspicion is high and sequencing detects no pathogenic variant in either ADAMTSL2 or FBN1, consideration of ADAMTSL2 deletion/duplication analysis
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Note: Carriers for the autosomal recessive form of geleophysic dysplasia are heterozygotes 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 pathogenic variants in the family.
Clinical Characteristics
Clinical Description
Geleophysic dysplasia is a progressive disorder resembling a lysosomal storage disorder, involving bones and joints, cardiac valves, and skin. Information on 31 affected individuals was published between 1960 and 2008 [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]. More recently a series of 33 affected individuals was reported by Allali et al [2011].
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.
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.
One individual developed glaucoma.
In the recent series of 33 individuals with geleophysic dysplasia 1, seven affected children (20%) died by age 3.6 years [Allali et al 2011]; a combination of cardiac, respiratory, and lung anomalies were reported. The average age of death was 30 months.
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.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known. The clinical features of those with pathogenic variants in ADAMTSL2 are indistinguishable from the clinical features of those with pathogenic variants in FBN1.
Prevalence
Geleophysic dysplasia is rare; 55 cases have been reported to date. The prevalence is not known.
Differential Diagnosis
The acromelic dysplasia group includes three rare disorders: geleophysic dysplasia, Weill-Marchesani syndrome, and acromicric dysplasia. All three of these conditions are characterized by short stature, short hands, and stiff joints. The clinical overlap between the three disorders is striking. Indeed, in addition to the diagnostic criteria, they all share common features including delayed bone age, cone-shaped phalangeal epiphyses, thickened skin, and heart disease. In contrast, eye involvement is a characteristic of Weill-Marchesani syndrome, whereas hepatomegaly and early mortality are encountered only in the most severe forms of geleophysic dysplasia.
Acromicric dysplasia (OMIM 102370) is distinguished from geleophysic dysplasia by the less severe outcome and the absence of progressive cardiac valvular thickening and distinctive facial features. The clinical findings of 22 individuals with acromicric dysplasia from 15 families have shown additional features including:
Frequent ear, tracheal, and respiratory complications
Non-progressive heart disease in 4/22 cases (2 with bicuspid aortic valve; 2 with atrial septal defect)
Myopia (8/20)
Sixteen individuals were simplex cases (i.e., a single occurrence in a family), but the observation of vertical transmission in three families was consistent with autosomal dominant inheritance. Of note, Moore Federman syndrome is probably the same as acromicric dysplasia. FBN1 pathogenic variants have been recently identified in individuals with acromicric dysplasia [Le Goff et al 2011].
Weill-Marchesani syndrome is distinguished from geleophysic dysplasia by abnormalities of the lens of the eye. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Two modes of inheritance have been reported: autosomal dominant caused by pathogenic variants in FBN1 (fibrillin 1) and autosomal recessive caused by pathogenic variants in ADAMTS10. A review of 128 individuals with Weill-Marchesani syndrome did not identify any clinical distinction between the two forms, supporting the clinical homogeneity of the disorder [Faivre et al 2003, Dagoneau et al 2004]. Diagnosis relies on clinical findings, but molecular genetic testing can help confirm the diagnosis.
Myhre syndrome probably also belongs to this group of disorders. It is characterized by facial features with prognathism, cranial skull anomalies, and variable degree of cognitive impairment [Burglen et al 2003, van Steensel et al 2005].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with geleophysic dysplasia, the following assessments are recommended if they were not performed as part of the diagnostic evaluation:
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 for to evaluate for evidence of glaucoma
Hearing assessment
Clinical genetics consultation
Treatment of Manifestations
The following are appropriate:
Surveillance
Annual multidisciplinary examination to assess:
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
Therapies Under Investigation
Search ClinicalTrials.gov 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.
Risk to Family Members – Autosomal Recessive Inheritance
Parents of a proband
Sibs of a proband
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.
Carrier Detection
Carrier testing of at-risk relatives is possible if the pathogenic variants have been identified in the family.
Risk to Family Members – Autosomal Dominant Inheritance
Parents of a proband
Decreased
penetrance has not been reported to date in individuals with
FBN1-related GD. Recommendations for the evaluation of parents of a
proband with an apparent
de novo pathogenic variant include physical examination for signs of GD (e.g., proportionate short stature, distinctive facial features) and
molecular genetic testing if the
FBN1 pathogenic variant has been identified in the proband.
Sibs of a proband
The risk to the sibs of the
proband depends on the genetic status of the proband’s parents.
When the parents are clinically unaffected, the risk to the sibs of a
proband appears to be low.
If the
pathogenic variant found in the
proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of
germline mosaicism.
Offspring of a proband. Each child of an individual with geleophysic dysplasia 2 has a 50% chance of inheriting the pathogenic variant.
Other family members. Because geleophysic dysplasia 2 results from a de novo pathogenic variant, other family members (except possibly sibs) are not at increased risk.
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
6645 West North Avenue
Oak Park IL 60302
Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
Fax: 708-383-0899
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.
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. Recently, 12 new pathogenic variants were described [Allali et al 2011]. 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, Table 2, Table 3 (pdf)]
Table 2.
Selected ADAMTSL2 Pathogenic Variants
View in own window
| DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
| c.440C>T 1 | p.Pro147Leu | NM_001145320.1
NP_001138792.1 |
| c.338G>A 1 | p.Arg113His |
| c.340G>A 1 | p.Glu114Lys |
| c.2431G>A 2 | p.Gly811Arg |
| c.2586G> 2 | p.Trp862Ter |
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 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 TGF-β-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 TGF-β in the extracellular matrix (ECM) and regulates its availability [Isogai et al 2003]. Owing to the interaction of ADAMTSL2 with LTPB1, the amount of total and active TGF-β in the culture medium of fibroblasts from individuals affected with geleophysic dysplasia was investigated. Using ELISA assays, a tenfold higher level of TGF-β was found in the culture medium of fibroblasts from affected individuals compared to controls (p<0.0003). The active TGF-β represented 85% and 92% of total TGF-β in culture medium of individuals with geleophysic dysplasia, whereas active TGF-β represented only 7% of total TGF-β 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 TGF-β bioavailability. TGF-β is a growth factor that regulates cell proliferation, migration, differentiation, and survival in a context-dependent fashion and whose 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 h 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 [from 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 pathogenic variants 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 impact 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 TGF-β in the cultured medium of skin fibroblasts of individuals with GD/AD by ELISA shows a tenfold higher level of total TGF-β 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.
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Wraith JE, Bankier A, Chow CW, Danks DM, Sardharwalla IB. Geleophysic dysplasia.
Am J Med Genet. 1990;35:153–6. [
PubMed: 2090119]
Zhang X, Boles RG, Law SK, Lin M. Ocular findings in geleophysic dysplasia.
J AAPOS. 2004;8:198–200. [
PubMed: 15088061]
Suggested Reading
Le Goff C, Cormier-Daire V. Genetic and molecular aspects of acromelic dysplasia.
Pediatr Endocrinol Rev. 2009;6:418–23. [
PubMed: 19396027]
Chapter Notes
Revision History
19 April 2012 (me) Comprehensive update posted live
22 September 2009 (et) Review posted live
5 June 2009 (vcd) Original submission
