Geleophysic Dysplasia
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 testing, 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):
- Biallelic pathogenic variants in ADAMTSL2 (~50% of affected individuals) [Le Goff & Cormier-Daire 2009, Cheng et al 2018]
- A heterozygous pathogenic variant in FBN1 (~50% of affected individuals) [Le Goff & Cormier-Daire 2009, Cheng et al 2018]
- A heterozygous pathogenic variant in LTBP3 (~<1% of affected individuals) [McInerney-Leo et al 2016]
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, 2 | Proportion of Geleophysic Dysplasia Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-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.
See Table A. Genes and Databases for chromosome locus and protein.
- 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. 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.
Le Goff & Cormier-Daire [2009], Cheng et al [2018]
- 7.
McInerney-Leo et al [2016]
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
| Disorder | Gene(s) | MOI | Clinical Features of the Disorder | |
|---|---|---|---|---|
| Overlapping w/Geleophysic Dysplasia | Distinguishing from Geleophysic Dysplasia | |||
| Acromicric dysplasia | FBN1 LTBP3 | AD | See Table 2 | See Table 2 |
| Weill-Marchesani syndrome | FBN1 | AD | ||
| ADAMTS10 ADAMTS17 LTBP2 | AR | |||
| Myhre syndrome | SMAD4 | AD 1 |
|
|
MOI = mode of inheritance
AD = autosomal dominant
AR = autosomal recessive
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 EU Clinical Trials Register 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.