joint laxity

Baker-Gordon Syndrome

Clinical Characteristics
Ocular Features: 

Poor visual acuity described as central in origin with poor eye contact.  Periorbital anomalies of low-set eyebrows and epicanthal folds are common.  The eyes have been described as "almond-shaped".  Strabismus and nystagmus are commonly present.

Systemic Features: 

The facial features ae described as "fine" with a short nose and a thin upper lip.  The forehead is unusually high. 

There is general developmental delay with impaired intellectual development, delayed or absent walking, and behavioral psychiatric manifestations such as stereotypic and unpredictable outbursts.   There are often involuntary and hyperkinetic movements with dystonia, dyskinesia, ataxia and choreoathetosis.  The EEG is often abnormal although seizures have not been reported.

Genetics

De novo heterozygous mutations in the SYT1 gene (12q21.2) have been associated with this condition.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

SYT1-associated neurodevelopmental disorder: a case series

Baker K, Gordon SL, Melland H, Bumbak F, Scott DJ, Jiang TJ, Owen D, Turner BJ, Boyd SG, Rossi M, Al-Raqad M, Elpeleg O, Peck D, Mancini GMS, Wilke M, Zollino M, Marangi G, Weigand H, Borggraefe I, Haack T, Stark Z, Sadedin S; Broad Center for Mendelian Genomics, Tan TY, Jiang Y, Gibbs RA, Ellingwood S, Amaral M, Kelley W, Kurian MA, Cousin MA, Raymond FL. SYT1-associated neurodevelopmental disorder: a case series. Brain. 2018 Sep 1;141(9):2576-2591.

PubMed ID: 
30107533

Joint Laxity, Short Stature, and Myopia

Clinical Characteristics
Ocular Features: 

Three of four brothers in one family had high myopia and two had retinal detachments as well as iris and chorioretinal colobomas.  In a second family with five sibs a teenage female was reported to have glaucoma and vision of legal blindness.  She and one brother had high myopia as well (parameters not reported).

Systemic Features: 

In one consanguineous family a brother and sister had multiple large joint dislocations including elbows, hips, knees and ankles.  The sister exhibited severe kyphoscoliosis while her brother had only mild kyphosis.  A single individual in each of the two sibships had hearing loss.

Three brothers in another consanguineous family had joint laxity and mild pectus carinatum.

Short stature was noted in all 5 affected individuals.  Cognitive development was reported as normal.

Genetics

Five individuals from 2 consanguineous Saudi sibships have been reported.  Homozygous mutations in the GZF1 gene (20p11.21) segregated as expected for an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.   Retinal detachment surgery and joint dislocation reduction should be considered in appropriate individuals.

References
Article Title: 

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

Patel N, Shamseldin HE, Sakati N, Khan AO, Softa A, Al-Fadhli FM, Hashem M, Abdulwahab FM, Alshidi T, Alomar R, Alobeid E, Wakil SM, Colak D, Alkuraya FS. GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome. Am J Hum Genet. 2017 May 4;100(5):831-836.

PubMed ID: 
28475863

Stickler Syndrome, Type II

Clinical Characteristics
Ocular Features: 

Virtually all (85%) patients have a nonprogresssive axial myopia.  The vitreous degeneration has a beaded pattern without the veils of type I, claimed by some to be important in the distinction of the two types.  Paravascular lattice retinopathy is seen in 38% of patients and 64% have cataracts, sometimes with wedge opacities similar to those in type I Stickler syndrome.  Nearly half (42%) of patients are reported to have retinal detachments.

Systemic Features: 

Hearing loss occurs early and many individuals (80%) eventually require hearing aids.    Midline clefting is present frequently with bifid uvula, a highly arched palate, or an actual cleft palate.  Joint laxity is common.

Genetics

There are reasons to classify type II Stickler syndrome as a unique disorder apart from type I (108300).  In addition to phenotypic evidence (vitreoretinal disease, amount of hearing loss, and degree of epiphyseal disease), mutation in two different genes are involved.  Type II results from a mutation in the COL11A1 (1p21) and type I (108300) in COL2A1.  Both types are inherited in autosomal dominant patterns.

Type IV (614234) with vitreoretinal changes, myopia, and a high risk of retinal detachment is inherited in an autsomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients with type II Stickler disease need lifelong ophthalmologic monitoring because of the risk of retinal detachments and cataracts with treatment as indicated.
 

References
Article Title: 

Clinical features of type 2 Stickler syndrome

Poulson AV, Hooymans JM, Richards AJ, Bearcroft P, Murthy R, Baguley DM, Scott JD, Snead MP. Clinical features of type 2 Stickler syndrome. J Med Genet. 2004 Aug;41(8):e107.

PubMed ID: 
15286167

Ehlers-Danlos Syndrome, Type VIA

Clinical Characteristics
Ocular Features: 

The globe is thin and fragile and ruptures easily.  This results from scleral fragility which is in contrast to type VIB EDS  (229200) in which the cornea seems to be more fragile.  Retinal detachment is always a risk but no quantitative assessment can be made since early case reports did not always provide good classification of EDS types.  Other ocular abnormalities such as keratoconus and structural changes in the cornea are less common but frequent changes in classification and lack of genotyping in early cases make definitive clinical correlations difficult.

Systemic Features: 

The primary clinical manifestations of this form (VIA) of Ehlers-Danlos syndrome are extraocular.   The skin is soft, thin, easily extensible, and bruises easily.  The joints are highly flexible with a tendency to dislocate.  Arterial ruptures are not uncommon, often with severe consequences.  Scoliosis begins almost at birth and often progresses to severe kyphoscoliosis.  Patients are floppy (hypotonic).  Intellect is normal and there are generally no developmental delays.  Thirty per cent of infants have a club foot at birth.

Genetics

This an autosomal recessive disorder caused by molecular defects in the PLOD1 gene (1p36.3-p36.2).  The gene product is an enzyme, lysyl hydroxylase 1, important for the normal crosslinking of collagen. Mutations in PLOD1 may result in hydroxylase dysfunction with abnormal hydroxylation of lysine, weakened crosslinks, and fragile tissue.  

The classification of Ehlers-Danlos disease is under constant revision as new mutations and clinical subtypes are found (see 130000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Joint dislocations, ocular trauma and vascular ruptures require prompt attention.  Longevity is not impacted by this syndrome.

References
Article Title: 

Marfan Syndrome

Clinical Characteristics
Ocular Features: 

Marfan syndrome typically has skeletal, ocular and cardiovascular abnormalities.  The globe is elongated creating an axial myopia and increasing the risk of rhegmatogenous retinal detachments.  Ectopia lentis is, of course, the classical ocular feature and is often if not always congenital with some progression.  The lenses most frequently dislocate superiorly and temporally and dilating the pupils often reveals broken and retracted lens zonules.  Phacodenesis and iridodenesis are commonly present even in the absence of evident lens dislocations. Cataracts develop several decades earlier than in unaffected individuals. The cornea is generally several diopters flatter than normal and there is an increased risk of open angle glaucoma.  There is considerable clinical variation among patients.

Systemic Features: 

Patients with the Marfan phenotype are usually tall with disproportionately long limbs (dolichostenomelia) and digits (arachnodactyly).   Patients frequently have scoliosis or kyphoscoliosis.  The joints are lax and hyperflexible although contractures can also occur.  The sternum is often deformed, either as a pectus excavatum, or sometimes pectus carinatum.  The hard palate is high and narrow resulting in crowding of the teeth and maloccclusion.  The defect in fibrillin is responsible for the weakness in connective tissue that leads to frequent cardiac valve malfunction, especially insufficiency of the aortic valve resulting from aortic dilatation, tear, and rupture.  The latter is often life-threatening as aortic dissection can be fatal.  Mitral valve prolapse is seen as well.  Cardiovascular disease is primarily responsible for the shortened life expectancy in this disease, more pronounced among males.

Genetics

As many as 25% of cases are caused by new mutations, but familial cases usually follow an autosomal dominant pattern of inheritance.  Autosomal recessive inheritance is claimed for several individuals in a consanguineous Turkish family.  Mutations in the fibrillin-1 gene (FBN1) on chromosome 15 (15q21.1) are considered responsible for the typical phenotype.  The exact nature of the fibrillin defect is unknown but the result is a generalized weakness in connective tissue.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani syndrome (608328) which is allelic to the Marfan syndrome.

Mutations in FBN1 have also been found in cases with isolated autosomal dominant ectopia lentis (129600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Isometric exercises such as weight lifting should be avoided as should contact sports in which blunt trauma to the chest may occur because of the weakened aortic wall due to cystic changes that predispose the athlete to aortic dissection.  A dislocated and/or cataractous lens may need to be removed from the visual axis, and, of course, periodic retinal examinations for retinal holes and retinal detachments should be made.   Beta-adrenergic blockade reduces the risk of aortic dilatation and improves survival.

Pravastatin has been reported to reduce aortic dilation in marfan mice.

References
Article Title: 

Pravastatin reduces marfan aortic dilation

McLoughlin D, McGuinness J, Byrne J, Terzo E, Huuskonen V, McAllister H, Black A, Kearney S, Kay E, Hill AD, Dietz HC, Redmond JM. Pravastatin reduces marfan aortic dilation. Circulation. 2011 Sep 13;124(11 Suppl):S168-73.

PubMed ID: 
21911808
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