short stature

Chondrodysplasia Punctata 2

Clinical Characteristics
Ocular Features: 

Early onset cataracts, often sectorial, are the major ocular feature of this syndrome.  Micropthalmia and microcornea have been observed.  There may be local vitreoretinal abnormalities leading to localized detachments and retinoschisis.

Systemic Features: 

The cartilage disease in this disorder leads to short stature that is often asymmetrical.  There is considerable variation in skeletal manifestations as the spine as well as the limbs can be involved.  The skin at birth may be scaly and erythrodermic.  Later the skin pigmentation may assume a whorled pattern and hyperkeratosis appears, often in a segmental pattern consistent with X-chromosomal mosaicism.  The skin may also be ichthyotic.  The nasal bridge is often flat with frontal bossing.  Flexion contractures are sometimes seen.  Cicatricial alopecia and coarse hair are often noted in adults.

Genetics

A number of skeletal disorders are classified as chondrodysplasia punctata, and there is considerable clinical and genetic heterogeneity (see also rhizomelic chondrodysplasia punctata [215100] in this database for an autosomal recessive form) which has yet to be worked out.  The disorder described here is an X-linked dominant disorder with lethality in males.  It results from a mutation in the EBP gene (Xp11.23-p11.22) causing difficulty in converting lanosterol to cholesterol.  The diagnosis can be confirmed by finding increased plasma accumulation of precursors of sterols 8(9)-cholestenol and 8-dehydrocholesterol. Rare severely affected males with hypotonia, seizures, cerebellar atrophy, agenesis of the corpus callosum, and developmental delays have been reported. 

The X-linked recessive (CDPX1;302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Cataract extraction may improve vision.  Sun protection is advised.

References
Article Title: 

Sorsby Macular Coloboma Syndrome

Clinical Characteristics
Ocular Features: 

Macular colobomas, usually bilateral, are the major ocular feature of this oculoskeletal disorder.  These are non-progressive and are generally heavily pigmented.  Vision is, of course, severely reduced (20/200) and horizontal or pendular nystagmus is a feature in some cases.

Systemic Features: 

The systemic features are primarily skeletal.  Patients have short-limbed dwarfism and brachydactyly of the type B variety.  The thumbs and sometimes the large toes may be broad and bifid.  The distal two phalanges sometimes short, absent, or duplicated and the nails can be dysplastic or absent. Syndactyly of several digits in both hands and feet is common.  The ears are large and protuberant and some patients have deafness.  Oligodontia may be present.  Cartilage can have diastrophic changes.  Mental development is normal.

Genetics

In the few families reported, the transmission pattern is vertical suggesting autosomal dominant inheritance but no mutation or locus has been reported.  The mutation causing brachydactyly type B1 was not present in several cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical treatment of digital anomalies can be beneficial.  Low vision aids could be helpful as well.

References
Article Title: 

Rhizomelic Chondrodysplasia Punctata

Clinical Characteristics
Ocular Features: 

Congenital cataracts are the outstanding ocular feature of this syndrome and are present in over 70% of patients.  They are usually bilateral and symmetrical and may not be present for several months after birth.

Systemic Features: 

The name of this disorder comes from the punctate calcification seen in cartilage.   The vertebrae have coronal clefting.  The cartilage abnormalities result in defective bone growth with severe growth retardation, short stature, and joint contractures.  Many infants die during the neonatal period and few survive beyond the first decade of life. However, milder forms have been reported. The skin can be ichthyotic and severe mental retardation is often accompanied by seizures.  Red cells are deficient in plasmalogens while phytanic acid and very long chain fatty acids accumulate in the plasma, a biochemical profile characteristic of RCDP1.

Other types of chondrodysplasia punctata also exist (RCDP2 and RCDP3). The X-linked recessive (CDPX1; 302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

A phenocopy sometimes results from maternal ingestion of dicoumarol in early pregnancy.

Genetics

This rare autosomal recessive condition results from mutations in the PEX7 gene (6q22-q24) causing a peroxisomal biogenesis disorder.  Some clinical features overlap with those of Zellweger syndrome (214100) and infantile Refsum disease (266510), also peroxisomal biogenesis disorders. 

Mutations in the same gene are responsible for adult Refsum disease-2 (266500).  The latter, however, has other neurological symptoms as well as clinical features of retinitis pigmentosa with night blindness and restricted visual fields.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available beyond supportive measures. Cataract removal may improve vision but the poor prognosis for longevity requires caution be used.

References
Article Title: 

Baller-Gerold Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features are a rather minor part of this syndrome and are found in less than a third of patients.  These primarily involve lids and adnexae with telecanthus, downslanting lid fissures, and epicanthal folds.  Some individuals have nystagmus while strabismus, blue sclerae, and ectropion have also been reported.

Systemic Features: 

The cardinal features of this syndrome are craniosynostosis and radial defects.  However, a large number of variable defects such as imperforate or anteriorly placed anus, rectovaginal fistula, absent thumbs, polydactyly, and mental retardation may also be present.  The radius may be completely absent or abnormally formed and occasionally the ulnar bone is involved as well.  Some patients have a conductive hearing loss.

Genetics

This syndrome is caused by a mutation in the RECQL4 gene at 8q24.3 and seems to be an autosomal recessive disorder.  Its syndromal status as a unique syndrome is in some doubt because of considerable phenotypic overlap with other entities such as Roberts (268300) and Saethre-Chotzen (101400) syndromes.  The latter however is caused by a mutation in the TWIST1 gene and the former by mutations in the ESCO2 gene.

The same gene is mutated in Rothmund-Thomson syndrome (268400) suggesting allelism of the two disorders.  The phenotype is vastly different in the two disorders however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Marshall Syndrome

Clinical Characteristics
Ocular Features: 

Myopia is a common feature.  The globes appear prominent with evident hypertelorism, perhaps in part due to shallow orbits.  The vitreous is abnormally fluid.  The beaded vitreous pattern seen in Stickler syndrome type II (604841), with which Marshall syndrome is sometimes confused, is not seen in Marshall syndrome, nor is the same frequency of retinal detachments.  Congenital or juvenile cataracts were present in Marshall’s original family.

Systemic Features: 

The midface is flat with some features of the Pierre-Robin phenotype.  The nasal root is flat and the nares anteverted.  Patients tend to be short in stature and joints are often stiff.  Small iliac wings and a thickened calvarium can be seen radiologically together with other bone deformities.  Abnormal frontal sinuses and intracranial calcifications have also been reported.  Sensorineural hearing loss may be noted during the first year of life with age-related progression.  Osteoarthritis of the knees and lumbosacral spine begins in the 4th and 5th decades.  Features of anhidrotic ectodermal dysplasia such as hypohidrosis and hypotrichosis are present in some patients.  Individuals may have linear areas of hyperpigmentation on the trunk and limbs.

Genetics

The syndromal status of Marshall syndrome as a unique entity remains uncertain inasmuch as there are many overlapping clinical features with Stickler syndrome type II (604841) and both result from mutations in the COL11A1 gene (1p21).  Autosomal dominant inheritance is common to both although autosomal recessive inheritance has been proposed for a few families with presumed Marshall syndrome. Stickler syndrome type II (604841) and Marshall syndrome may be allelic or even the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder beyond cataract removal.  Patients need to be monitored for retinal breaks and detachments.

References
Article Title: 

Kearns-Sayre Syndrome

Clinical Characteristics
Ocular Features: 

Ptosis and progressive ophthalmoplegia usually have their onset before the second decade of life.  Pigmentary retinopathy is common with a variable clinical pattern of simple salt-and-pepper pigmentation or pigmentary clumping resembling retinitis pigmentosa.

Systemic Features: 

Atrioventricular conduction defects including complete heart block, cardiomyopathy, short stature, elevated CSF protein, and ataxia are among the most frequent extraocular features seen.  Pharyngeal, facial, and skeletal muscle weakness seem to be common features.  Growth retardation, delayed sexual maturation, and mental deterioration occur in some patients. Older patients have a sensorineural hearing deficit as well.

EEG abnormalities are often present.  CT scans reveals a diffuse leukoencephalopathy as well as a variety of CNS abnormalities in the cerebellum and brain stem.  Muscle biopsies reveal 'ragged red' fibers.

This is a progressive disorder and many patients die in the third or fourth decades of life.

Genetics

Unlike many syndromes of external ophthalmoplegia with deletions in mitochondria, no nuclear DNA mutations have been associated with this disorder.  However, it is a clinically and genetically heterogeneous condition.  Exclusively maternal transmission consistent with mitochondrial disease has been observed in some familial cases.  Other familial cases suggest autosomal inheritance and in some the transmission pattern is consistent with autosomal recessive inheritance.  Many if not most cases occur sporadically.

Mitochondrial DNA defects in muscle and brain vary in size and location and even the proportion of normal to abnormal mitochondria among cells varies. This may account for some of the clinical heterogeneity.

Treatment
Treatment Options: 

Coenzyme Q(10) may decrease fatigue with improvement in eye muscle movement and a lessening in the degree of heart block.  Pacemakers may be necessary in some patients.  Exercise is recommended for patients with significant skeletal myopathy.

References
Article Title: 

Kniest Dysplasia

Clinical Characteristics
Ocular Features: 

High myopia and vitreoretinal degeneration are characteristic ocular features in this disorder.   The myopia is in the range of -7.5 to -15.25 with most patients having about -11 diopters.  Acuity may be normal but inoperable retinal detachments can lead to blindness.  The vitreous demonstrates liquefaction and syneresis and often detaches posteriorly forming a retrolental curtain.  About half of affected eyes have perivascular lattice degeneration and the same proportion of patients at some point develop a retinal detachment.  Giant tears and retinal dialysis are commonly the cause.  The lens is often dislocated and cataracts are common.

Systemic Features: 

Short stature, cleft palate, stiff joints, and conductive hearing loss are characteristic extraocular features of Kniest dysplasia.  Some patients develop frank joint contractures and many are unable to make a tight fist due to inflexibility of the interphalangeal joints.  Lumber kyphoscoliosis is common.  Epiphyseal cartilage has a 'Swiss cheese appearance' with prominent lacunae.  The facies are round and the midface is underdeveloped with a flat nasal bridge.  Mild psychomotor retardation is sometimes seen.  

High levels of keratin sulfate are found in the urine.

Genetics

Mutations in the COL2A1 gene (12q13.11-q13.2) coding for type II collagen is responsible for this autosomal dominant disorder. This is one of a number of disorders known as type II collagenopathies (see Stickler syndrome I [609508]).  The clinical features arise from a defect in type II procollagen.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the dysplasia.  Displaced lenses can be removed but the myopia and degenerated vitreous require a cautious approach.  Rhegmatogenous detachments demand prompt attention.

References
Article Title: 

Ophthalmic and molecular genetic findings in Kniest dysplasia

Sergouniotis PI, Fincham GS, McNinch AM, Spickett C, Poulson AV, Richards AJ, Snead MP. Ophthalmic and molecular genetic findings in Kniest dysplasia. Eye (Lond). 2015 Jan 16. doi: 10.1038/eye.2014.334. [Epub ahead of print].

PubMed ID: 
25592122

The Kniest syndrome

Siggers CD, Rimoin DL, Dorst JP, Doty SB, Williams BR, Hollister DW, Silberberg R, Cranley RE, Kaufman RL, McKusick VA. The Kniest syndrome. Birth Defects Orig Artic Ser. 1974;10(9):193-208.

PubMed ID: 
4214536

Weill-Marchesani Syndrome 2

Clinical Characteristics
Ocular Features: 

Glaucoma may have an infantile onset and pupillary block glaucoma is a lifelong risk.  The lenses dislocate inferiorly but may migrate into the anterior chamber.  Spherophakia occurs in 74% of patients.  Extreme myopia in the range of -13 D may be present.  There is an increased risk of retinal detachment.

Systemic Features: 

One patient had mitral valve insufficiency.  Midface hypoplasia with a protruding lower lip was found in two patients.  The elbow and perhaps other large joints have limited mobility and the interphalangeal joints are thickened with difficulty in full extension of the fingers.  Patients are short in stature and the digits are often short and stubby.  The skin is tanned and thickened in places.  Cardiac anomalies are present in 13% of patients.

Genetics

This is an autosomal dominant disorder resulting from heterozygous mutations in FBN1 (15q21.1).  It is thus allelic to the Marfan syndrome (154700).  Weill-Marchesani syndrome 1 (277600) is a clinically similar syndrome but results from homozygous mutations in ADAMTS10. Homozygous mutations in ADAMTS17 cause the Weill-Marchesani-Like syndrome (613195).

Some individuals with isolated autosomal dominant ectopia lentis (129600) have mutations in FBN1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients should be monitored for the occurrence of glaucoma and treated appropriately.  Frequent refractive checks are recommended.  Lens extraction may be indicated when the visual axis is obstructed by a displaced lens or when lens-induced glaucoma occurs.

References
Article Title: 

Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome

Faivre L, Dollfus H, Lyonnet S, Alembik Y, M?(c)garban?(c) A, Samples J, Gorlin RJ, Alswaid A, Feingold J, Le Merrer M, Munnich A, Cormier-Daire V. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A. 2003 Dec 1;123A(2):204-7. Review.

PubMed ID: 
14598350

Weill-Marchesani Syndrome 1

Clinical Characteristics
Ocular Features: 

The Weill-Marchesani phenotype is a rare connective tissue disorder manifested by short stature, brachydactyly, spherophakia and stiff joints.   As many as 94% have spherophakia and 64% have dislocated lenses.  The central corneal thickness is increased.  The small, abnormally shaped lens can migrate anteriorly causing pupillary block glaucoma and sometimes dislocates into the anterior chamber.  This may occur spontaneously or following pharmacologic mydriasis which is sometimes done to relieve the pupillary block.

Systemic Features: 

Short stature in the range of 155 cm in height for men and 145 cm for women is common.  Brachydactyly and stiff joints prevent patients from making a tight fist.   A few patients (13%) have some mild mental deficit but most have normal intelligence.  Cardiac defects include patent ductus arteriosis, pulmonary stenosis, prolonged QT interval mitral valve stenosis, and mitral valve prolapse.  Some heterozygous carriers also are short in stature and may have joint stiffness.

Genetics

Homozygous mutations in the ADAMTS10 gene (19p13.3-p13.2) cause this disorder.  Homozygous mutations in LTBP2 (14q24.3) have also been found in WMS1 and in the Weill-Marchesani-Like syndrome (613195).

Weill-Marchesani syndrome 2 (608328) is a clinically similar syndrome but results from heterozygous mutations in FBN1. Homozygous mutations in ADAMTS17 cause the Weill-Marchesani-Like syndrome (613195) .  It is not always possible to distinguish between the AR and AD forms of the disease using clinical criteria alone.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Dislocated lenses should be removed if they are interfering with vision or migrate into the anterior chamber.  A peripheral iridotomy should be considered in cases where pupillary block glaucoma occurs.  Long-term mydriasis is not recommended because of the risk of lens dislocation into the anterior chamber.  Chronic open angle glaucoma is a threat and life-long monitoring is recommended.  Measurements of the intraocular pressure should take the increased central corneal thickness into account.  Trabeculectomy should be considered when the pressure cannot be medically controlled.

References
Article Title: 

LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix

Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, Klotzle B, Mahmoudi MJ, Ebrahimian MJ, Chelich N, Taghiabadi E, Kamyab K, Boileau C, Paisan-Ruiz C, Ronaghi M, Elahi E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012 Apr 26. doi: 10.1002/humu.22105. [Epub ahead of print] PubMed PMID: 22539340.

PubMed ID: 
22539340

Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome

Faivre L, Dollfus H, Lyonnet S, Alembik Y, M?(c)garban?(c) A, Samples J, Gorlin RJ, Alswaid A, Feingold J, Le Merrer M, Munnich A, Cormier-Daire V. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A. 2003 Dec 1;123A(2):204-7. Review.

PubMed ID: 
14598350

Cohen Syndrome

Clinical Characteristics
Ocular Features: 

Patients have early onset night blindness with defective dark adaptation and corresponding ERG abnormalities.  Visual fields are constricted peripherally and central visual acuity is variably reduced.  A pigmentary retinopathy is often associated with a bull’s eye maculopathy. The retinopathy is progressive as is high myopia.  The eyebrows and eyelashes are long and thick and the eyelids are highly arched and often ‘wave-shaped’.  Congenital ptosis, optic atrophy, and ectopia lentis have also been reported.

Systemic Features: 

Affected individuals have a characteristic facial dysmorphism in which ocular features play a role.  They have a low hairline, a prominent nasal root, and a short philtrum.  The tip of the nose appears bulbous. The head circumference is usually normal at birth but lags behind in growth so that older individuals appear microcephalic.  Delays in developmental milestones are noticeable in the first year of life.  Mild to moderate mental retardation is characteristic but does not progress.  Hypotonia is common early, and many individuals are short in stature.  Low white counts and frank neutropenia are often seen and some patients have frequent infections, especially of the oral mucosa and the respiratory tract.  A cheerful disposition is said to be characteristic.

Genetics

This is an autosomal recessive disorder caused by a mutation in the COH1 (VPS13B) gene on chromosome 8 (8q22-q23).  However, a variety of mutations have been reported including deletions and missense substitutions and, since these are scattered throughout the gene, complete sequencing is necessary before a negative result can be confirmed.

There is evidence of significant clinical heterogeneity between cohorts descended from different founder mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corrective lenses for myopia can be helpful.  For patients with sufficient vision, low vision aids can be helpful.  Selected individuals may benefit from vocational and speech therapy.  Infections should be treated promptly.

References
Article Title: 

Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport

Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003 Jun;72(6):1359-69.

PubMed ID: 
12730828

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