myopia

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

Myopia 1, X-linked, Nonsyndromal

Clinical Characteristics
Ocular Features: 

Nonsyndromal high myopia of -6D to -23D has been reported in multigenerational families.  No other ocular abnormalities have been found.  Detection is usually late in the first decade of life. 

Systemic Features: 

No systemic disease has been reported.

Genetics

Only males were reported to be highly myopic in two large multigenerational Indian families.  The transmission pattern was consistent with an X-linked recessive mode of inheritance.  Only males were affected and no male-to-male transmission was observed.  In another nonAsian family, 3 brothers with myopia had 5 myopic grandsons, all offspring of their daughters.  The daughters had low grade myopia not requiring correction.

The presumed locus for MYP1 is located at Xq28, in the same location as the presumed gene for Bornholm Eye Disease (300843) in which high myopia is also found.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment beyond corrective lenses has been reported.

References
Article Title: 

Refinement of the X-linked nonsyndromic high-grade myopia locus MYP1 on Xq28 and exclusion of 13 known positional candidate genes by direct sequencing

Ratnamala U, Lyle R, Rawal R, Singh R, Vishnupriya S, Himabindu P, Rao V, Aggarwal S, Paluru P, Bartoloni L, Young TL, Paoloni-Giacobino A, Morris MA, Nath SK, Antonarakis SE, Radhakrishna U. Refinement of the X-linked nonsyndromic high-grade myopia locus MYP1 on Xq28 and exclusion of 13 known positional candidate genes by direct sequencing. Invest Ophthalmol Vis Sci. 2011 Aug 29;52(9):6814-9. Erratum in: Invest Ophthalmol Vis Sci. 2011 Oct;52(11):7909.

PubMed ID: 
21357393

X-linked form of myopia

Bartsocas CS, Kastrantas AD. X-linked form of myopia. Hum Hered. 1981;31(3):199-200.

PubMed ID: 
7262894

Myopia 25, Autosomal Dominant, Nonsyndromic

Clinical Characteristics
Ocular Features: 

Myopia in the range of -6.00 to -31.01 diopters with onset before 10 years of age are the only ocular signs reported.

Systemic Features: 

No systemic signs have been reported.

Genetics

This nonsyndromic autosomal dominant condition results from heterozygous mutations in P4HA2 (5q31.1).  A three generation Chinese family has been reported.  A variety of other mutations in the same gene have been identified in sporadic cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Correction of refractive errors should be prescribed. Periodic ocular examinations are advised to detect evidence of retinal degeneration and to ensure that changes in refraction are corrected.

References
Article Title: 

Mental Retardation, X-Linked 99, Syndromic, Female-Restricted

Clinical Characteristics
Ocular Features: 

Palpebral fissures are generally shortened and may slant up or down.  Cataracts of unknown morphology have been reported and strabismus is common.

Systemic Features: 

The systemic phenotype is highly variable.  Skull and facial anomalies are common with brachycephaly, bitemporal narrowing, and a broad low nasal bridge. There is general developmental delay in both motor and cognitive abilities.  Patients are short in stature while scoliosis, hip dysplasia, and post-axial polydactyly may be present.  The teeth may be malformed and numerous (29%) of individuals have hypertrichosis.  Nearly a third of individuals have a cleft palate/bifid uvula.   Heart malformations, primarily atrial septal defects, are found in about half of affected individuals and urogenital anomalies such as renal dysplasia are relatively common.  Feeding difficulties have been reported while anal atresia is present in about half of patients.   

Brain imaging reveals hypoplasia of the corpus callosum, enlarged ventricles, Dandy-Walker malformations, cerebellar hypoplasia, and abnormal gyration patterns in the frontal lobe.  Generalized hypotonia has been diagnosed in half of reported patients and seizures occur in 24%.

Genetics

This female-restricted syndrome is caused by heterozygous mutations in the USP9X gene (Xp11.4).  X-chromosome inactivation is skewed greater than 90% in the majority of females but the degree of skewing in one study was independent of clinical severity.  The majority of cases occur de novo.

In males, hemizygous mutations in the USP9X gene (300919) cause a somewhat similar disorder (MRX99) without the majority of the congenital malformations having mainly the intellectual disabilities, hypotonia, and behavioral problems.

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

There is no known treatment for the general disorder but individual anomalies or defects such as atrial septal defects, cleft palate, and anal atresia might be surgically corrected.

References
Article Title: 

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Reijnders MR, Zachariadis V, Latour B, Jolly L, Mancini GM, Pfundt R, Wu KM, van Ravenswaaij-Arts CM, Veenstra-Knol HE, Anderlid BM, Wood SA, Cheung SW, Barnicoat A, Probst F, Magoulas P, Brooks AS, Malmgren H, Harila-Saari A, Marcelis CM, Vreeburg M, Hobson E, Sutton VR, Stark Z, Vogt J, Cooper N, Lim JY, Price S, Lai AH, Domingo D, Reversade B; DDD Study, Gecz J, Gilissen C, Brunner HG, Kini U, Roepman R, Nordgren A, Kleefstra T. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb 4;98(2):373-81.

PubMed ID: 
26833328

Spastic Paraplegia with Psychomotor Retardation and Seizures

Clinical Characteristics
Ocular Features: 

The eyes are usually deeply set.  Nothing is known regarding visual acuity.  Strabismus is a common feature.  Retinal dystrophy (not further described) has been reported in 4 of 8 patients described.  The ERG in one individual was read as consistent with cone-rod dystrophy.

Systemic Features: 

Newborns are hypotonic and severe psychomotor retardation is evident a few months later.  Truncal ataxia and progressive lower limb spasticity are seen later.  Mobility is significantly impaired and many individuals are confined to bed or a wheelchair and never walk.  Dysarthria is frequently present and some individuals have a neurosensory hearing loss.  Myoclonic seizures may be evident.  Kyphoscoliosis, macrocephaly, and various foot deformities have been described.

CT scans of the brain may show generalized cerebral atrophy and a hypoplastic corpus callosum.  The ventricles may be enlarged and the EEG confirms the occurrence of myoclonic as well as tonic-clonic and focal epilepsy.

Genetics

This is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the HACE1 gene (6q16).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this condition but physical therapy and assistive devices such as hearing and visual aids may be helpful.

References
Article Title: 

DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9.

PubMed ID: 
26437029

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Hollstein R, Parry DA, Nalbach L, Logan CV, Strom TM, Hartill VL, Carr IM, Korenke GC, Uppal S, Ahmed M, Wieland T, Markham AF, Bennett CP, Gillessen-Kaesbach G, Sheridan EG, Kaiser FJ, Bonthron DT. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803.

PubMed ID: 
26424145

Singleton-Merten Syndrome 1

Clinical Characteristics
Ocular Features: 

Several children have been diagnosed with glaucoma in early childhood or during puberty.  Glaucoma surgery has been beneficial in some but visual damage may be severe.

Systemic Features: 

Patients have early-onset calcifications of the aorta and of the aortic and mitral valves which may be seen in childhood and can be responsible for heart failure and early death.  Osteoporosis of the limbs and widened medullary cavities have been seen.  Abnormal bone mineralization and extends to the jaws leading to tooth loss and early-onset periodontal disease.  Eruption of both primary and permanent teeth is delayed but tooth roots can be truncated as well.  The hips dislocate easily due to shallow acetabulae and patients are susceptible to tendon tears.

Hypotonia and generalized weakness may be present which is sometimes exacerbated following a febrile illness.  The skin may be dry and scaly consistent with psoriasis and there may be photosensitivity.

The forehead is broad and prominent and the hairline is high and anterior.  The philtrum is smooth and the upper vermilion is thin.

Genetics

Heterozygous mutations in the IFIH1 gene (2q24.2) are responsible for this disorder.  Another form of Singleton-Merten Syndrome (SGMRT2; 609631) is the result of mutations in the DDX58 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific problems such as fractures, glaucoma, and periodontal disease.

References
Article Title: 

A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome

Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nurnberg P, Hohne W, Crow YJ, Feigenbaum A, Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):275-82.

PubMed ID: 
25620204

Kaufman Oculocerebrofacial Syndrome

Clinical Characteristics
Ocular Features: 

Alterations in the morphology of periocular structures is the most consistent ocular feature.  These include epicanthal folds, upward-slanting lid fissures, ptosis, blepharophimosis, sparse eyebrows, and telecanthus.  However, pale optic discs, iris colobomas, microcornea, strabismus, nystagmus, and hypertelorism are variably present. 

Systemic Features: 

There is both intrauterine and postnatal growth retardation.  Hypotonia is often noted along with general psychomotor delays.  Neonatal respiratory distress and laryngeal stridor may be present.  The intellectual disability can be severe.  Corpus callosum aplasia and hypoplasia have been reported.  Microcephaly and brachycephaly with delayed suture closure are features.  The face is long and narrow and the mouth is disproportionally large.  A high arched palate can be present and the pinnae are often deformed, posteriorly rotated and may be accompanied by preauricular skin tags. The teeth appear widely spaced (diastema) and the lower jaw is underdeveloped.

Genetics

Kaufman BPIDS syndrome results from homozygous or compound heterozygous mutations in the UBE3B gene (12q23).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment is available although repair of some specific malformations is possible.

References
Article Title: 

Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome

Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miro X, White JK, Desir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmuller J, Nurnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nurnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet. 2012 Dec 7;91(6):998-1010.

PubMed ID: 
23200864

An oculocerebrofacial syndrome

Kaufman RL, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Artic Ser. 1971 Feb;7(1):135-8.

PubMed ID: 
5006210

Temtamy Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral chorioretinal colobomas may be present and involve the optic nerve in one-third of patients.  Visual acuity is not measureable but significant vision impairment is evident in most patients and may be progressive in some individuals.  Several have been reported with dislocated lenses, ptosis, microcornea, cataracts, microphthalmia, myopia, and posterior staphylomas.

Systemic Features: 

Mild, nonspecific craniofacial dysmorphism is often present.  Some form of macrocephaly, with an elongated face, low-set ears, and micrognathia has been reported.  Short stature is of the proportionate type.  Significant developmental delay is evident during childhood and patients are nonverbal. A variety of cardiovascular anomalies such as septal defects, aortic dilation, and patent ductus arteriosus have been described. MRI shows mild hypoplasia of the corpus callosum.   The gait may be ataxic and some (59%) individuals have spasticity of limb muscles with or without contractures.  Seizures develop in early childhood, usually before the age of 3 years, and are difficult to control. 

Genetics

The inconsistent and highly variable phenotype hints that this is a genetically heterogeneous condition.  Many patients seem to have an autosomal recessive condition secondary to mutations in C12orf57 (12p13.31).

A syndrome consisting primarily of colobomas, ptosis, hypertelorism, and global delay (243310) has some similar clinical features but is caused by mutations in ACTG1.

Treatment
Treatment Options: 

No therapy is available for the syndrome but attempts to control the seizures should be made. 

References
Article Title: 

Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures

Platzer K, Huning I, Obieglo C, Schwarzmayr T, Gabriel R, Strom TM, Gillessen-Kaesbach G, Kaiser FJ. Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures. Am J Med Genet A. 2014 May 5. [Epub ahead of print].

PubMed ID: 
24798461

Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia

Akizu N, Shembesh NM, Ben-Omran T, Bastaki L, Al-Tawari A, Zaki MS, Koul R, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, da Gente G, Li J, Deardorff MA, Conlin LK, Horton MA, Zackai EH, Sherr EH, Gleeson JG. Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. Am J Hum Genet. 2013 Mar 7;92(3):392-400.

PubMed ID: 
23453666

New autosomal recessive multiple congenital abnormalities/mental retardation syndrome with craniofacial dysmorphism absent corpus callosum, iris colobomas and connective tissue dysplasia

Temtamy SA, Salam MA, Aboul-Ezz EH, Hussein HA, Helmy SA, Shalash BA. New autosomal recessive multiple congenital abnormalities/mental retardation syndrome with craniofacial dysmorphism absent corpus callosum, iris colobomas and connective tissue dysplasia. Clin Dysmorphol. 1996 Jul;5(3):231-40. Review.

PubMed ID: 
8818452

Retinal Cone Dystrophy 3B

Clinical Characteristics
Ocular Features: 

This is a degenerative disorder in which patients have a progressive deterioration of visual acuity and color vision.  Most patients have significant myopia.  Visual difficulties begin in early childhood with acuity of 20/100 or worse by the second decade of life.  Color vision deficits can be detected in the second decade but nyctalopia occurs later in young adults.  Photophobia is a prominent symptom.  The ERG shows reduced and delayed cone responses.  Rod responses to low intensity flashes are undetectable but increased stimulus intensity leads to an abrupt increase in amplitude, often exceeding the upper limits of normal.

The fundus appears normal in some patients but foveal or parafoveal atrophy, a macular bull’s eye, hyperfluorescence anomalies, and a generalized fine pigmentary retinopathy have been reported.  There may be some temporal pallor in the optic nerves.  Nystagmus and strabismus may be present.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the KCNV2 gene (9p24.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this dystrophy.  Low vision aids and tinted lenses may be helpful.

References
Article Title: 

Knobloch Syndrome 2

Clinical Characteristics
Ocular Features: 

In an 18 month infant, ectopia lentis, cataract, and myopia with poor vision were noted.  This individual subsequently developed retinal degeneration and a serous retinal detachment.

Systemic Features: 

Only one patient has been reported.  While the clinical signs resemble Knobloch 1 syndrome, brain imaging does not reveal malformations in this syndrome.  The only systemic sign, in addition to an occipital encephalocele, is a minor delay in fine motor skills.

Genetics

This autosomal recessive disorder results from homozygous loss of function mutations in the ADAMTS18 gene (16q23.1).  The gene product has been found in the lens and retina in the murine eye.

Mutations in ADAMTS18 have also been found in the syndrome of Micorcornea, Myopia, Chorioretinal atrophy, and Telecanthus.  It may also be responsible for a retinal dystrophy.

Knobloch 2 syndrome was identified in a single female born to consanguineous parents.

This disorder is separate to Knobloch 1 syndrome (267750) based on the causative mutations.  A third type, KNO3, has been proposed since the Knobloch clinical features were found in a 4-generation consanguineous Pakistani family but the phenotype mapped to 17q11.2.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The skull defect can be closed and the lenses can be removed if indicated.

References
Article Title: 

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