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.
Prevalence
Geleophysic dysplasia is rare; 80 individuals have been reported to date. The prevalence is not known.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Autosomal Recessive Inheritance – Risk to Family Members
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 of an ADAMTSL2 pathogenic variant.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the ADAMTSL2 pathogenic variants in the family.
Autosomal Dominant Inheritance – Risk to Family Members
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.
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
View in own window
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.
View in own window
|
134797 | FIBRILLIN 1; FBN1 |
|
231050 | GELEOPHYSIC DYSPLASIA 1; GPHYSD1 |
|
602090 | LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 3; LTBP3 |
|
612277 | ADAMTS-LIKE PROTEIN 2; ADAMTSL2 |
|
614185 | GELEOPHYSIC DYSPLASIA 2; GPHYSD2 |
|
617809 | GELEOPHYSIC 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
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 |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
- 2.
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].
