DiagnosisClinical Diagnosis Clinical diagnostic criteria for geleophysic dysplasia: Proportionate short stature Very short hands and feet Progressive joint limitation and contracturesDistinctive facial features: round, full face; small nose with anteverted nostrils; broad nasal bridge; thin upper lip with flat philtrum [Allali et al 2011]Thickened skinProgressive cardiac valvular disease diagnosed on echocardiographyNormal intellectAdditional features: HepatomegalyTracheal stenosisRecurrent respiratory and middle-ear infectionsRadiographic 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 testingSequence analysis of ADAMTSL2 or FBN1 detects mutations in all affected individuals to date [Authors, personal data]. Table 1. Summary of Molecular Genetic Testing Used in Geleophysic DysplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityADAMTSL2Sequence analysis Sequence variants 250%Clinical Deletion / duplication analysis 3Exonic or whole-gene deletionsUnknown; none detected 4FBN1Sequence analysis of select exons Sequence variants of exons 41 and 42 550% Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. No deletions or duplications of ADAMTSL2 have been reported to cause geleophysic dysplasia. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)5. Exons analyzed may vary by laboratoryTesting Strategy To confirm/establish the diagnosis in a proband 1.Physical examination2.Skeletal survey3.If autosomal recessive inheritance is suspected or there is known consanguinity:a.ADAMTSL2 sequence analysisb.If ADAMTSL2 sequencing does not detect any mutations, FBN1 sequence analysis 4.If clinical suspicion is high and sequencing detects no disease causing mutation in either ADAMTSL2 or FBN1, consideration of ADAMTSL2 deletion/duplication analysisCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations 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 disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in ADAMTSL2. FBN1 mutations have been identified in acromicric dysplasia, Marfan syndrome, isolated ectopia lentis, Weill-Marchesani syndrome, MASS syndrome, and thoracic aortic aneurysms and aortic dissections.}

Natural History 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.

Differential DiagnosisThe 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 complicationsNon-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 mutations 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 mutations in FBN1 (fibrillin 1) and autosomal recessive caused by mutations 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]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations 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 narrowingClinical history for evidence of tracheal stenosis and respiratory compromise Liver size by clinical assessment and/or ultrasound examinationEye examination for to evaluate for evidence of glaucoma Hearing assessmentGenetics consultationTreatment of ManifestationsThe following are appropriate: Joint manifestations: regular physiotherapy to prevent joint limitation Heart: valve replacement Tracheal stenosis: tracheostomy when severeSurveillance 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 narrowingTrachea for evidence of stenosis and respiratory compromiseLiver size for evidence of hepatomegalyEvaluation 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 for this disorder.

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. Geleophysic Dysplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFBN115q21​.1Fibrillin-1FBN1 @ LOVDFBN1ADAMTSL29q34​.2ADAMTS-like protein 2ADAMTSL2 homepage - Mendelian genesADAMTSL2Data 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 Geleophysic Dysplasia (View All in OMIM) View in own window 134797FIBRILLIN 1; FBN1 231050GELEOPHYSIC DYSPLASIA 1; GPHYSD1 612277ADAMTS-LIKE PROTEIN 2; ADAMTSL2 614185GELEOPHYSIC DYSPLASIA 2; GPHYSD2ADAMTSL2Normal allelic variants. The 18 coding exons of ADAMTSL2 constitute a transcript of 40.6 kb.Pathologic allelic variants. The pathologic allelic variants identified to date are located throughout the gene. Recently, 12 new mutations were described [Allali et al 2011]. The majority of mutations 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 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.440C>T ^{1p.Pro147LeuNM_001145320​.1
NP_001138792​.1c.338G>A 1p.Arg113Hisc.340G>A 1p.Glu114Lysc.2431G>A 2p.Gly811Argc.2586G> 2p.Trp862*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Reported as homozygous pathologic variants 2. Reported as compound heterozygous stateNormal 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 mutations were tested using a myc-tagged wild type and an ADAMTSL2 mutant 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 mutant 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 mutant protein was found. Thus, the mutant 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 mutant protein or altered function of secreted mutant protein could also explain these data [Le Goff et al 2008]. FBN1Normal allelic variants. 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].Pathologic allelic variants. All FBN1 mutations 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 mutations identified, seven were specifically identified in geleophysic dysplasia (GD), seven were specifically identified in acromicric dysplasia (AD), and two mutations were found in individuals with either GD or AD [Le Goff et al 2011. All mutations were located in exons 41-42 encoding the TB5 domain and altered either large aromatic components or structurally important residues. Half of the mutations 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 mutations, 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 mutations 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 mutations 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.}