high arched palate

Myopathy, Mitochondrial Anomalies, and Ataxia

Clinical Characteristics
Ocular Features: 

Ocular findings are variable.  One of three individuals with compound heterozygous mutations had a pigmentary retinopathy with pallor of the optic nerve but no visual abnormalities.  Her sister had only optic nerve pallor.  The eyes are described as "small" and "close-set".

No ocular findings were reported for the family with autosomal dominant inheritance.

Systemic Features: 

Ataxia, short stature, and gait difficulties from an early age are consistent findings.  Some patients are never able to walk.  Motor development is generally delayed.  Truncal and limb ataxia is a feature.  Some degree of intellectual disability is generally present and speech is often delayed.  

The face is long with a myopathic appearance.  Both micrognathia and a prominent jaw may be seen.  The palate is highly arched.  Patients are described as hypotonic and there is generalized muscle weakness both proximal and distal.  Distal sensory impairment has been described in the family with presumed dominant inheritance and there may be psychiatric symptoms of anxiety, depression, and schizophrenia.  Dysmetria with dysdiadochokinesis is often present and a fine intention tremor has been observed.

Mitochondria in fibroblasts exhibit abnormal dynamics and occur in a fragmented network.  Muscle biopsies reveal changes consistent with myopathy.  Serum creatine kinase may be elevated.

Genetics

Compound heterozygous mutations in the MSTO1 gene (1q22) have been found in two families with 3 affected individuals suggesting autosomal recessive inheritance.  In a third family, heterozygous mutations in the same gene were found in a mother and 3 of her adult children, consistent with autosomal dominant transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Rubinstein-Taybi Syndrome 2

Clinical Characteristics
Ocular Features: 

Highly-arched and bushy eyebrows are often seen.  The lashes are long and bushy and lid fissures tend to slope downward.

The ocular phenotype has not been fully described no doubt due to the rarity of cases.  Individuals with type 1 (RSTS1) have been described with congenital glaucoma, nystagmus, corneal abnormalities of shape (such as keratoglobus, sclerocornea, megalocornea), pigmentary retinopathy, and VEP evidence of rod and cone dysfunction have been described.

Systemic Features: 

The phenotype of RSTS2 is more variable than the somewhat similar RSTS1.  Less than 10% of individuals with Rubinstein-Taybi syndrome have type 2 while over 50% have type 1.  The facial dysmorphism nay be less severe in RSTS2.

Mild to moderate intellectual disability with psychosocial problems such as autism is nearly universal.  Microcephaly, a broad nasal bridge, a beaked nose, high-arched palate and some degree of micrognathia are characteristic.  The lower lip often appears 'pouty' and protrudes beyond the upper lip while the hard palate is highly arched.  Pregnancy may be complicated by pre-eclampsia and growth restriction.  Swallowing and feeding issues are common.  Syndactyly is often present and there is considerable variability in the size of the toes and thumbs.  Some patients with RSTS2 do not have evidence of the classic broad thumbs and toes characteristic of RSTS1.

Genetics

Heterozygous mutations in EP300 (22q13.2) have been found in this condition.  Virtually all cases occur de novo.  Rubinstein-Taybi Syndrome 1 (180849) is a phenotypically similar disorder resulting from a different mutation (CREBBP).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for this condition.

References
Article Title: 

Heart and Brain Malformation Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia is the cardinal ocular malformation.  Hypertelorism has been described.  Poor vision without further description has also been reported.   

Systemic Features: 

The ears are low-set, malformed, and posteriorly rotated.  The forehead is prominent and there is usually a wide anterior fontanel.  The nasal bridge is wide and frequently depressed while the lower lip is full and may be everted and split.  The palate is highly arched.  Physical growth is slow.  A ventricular septal defect is often present while the valves are hypoplastic and the aortic arch can be interrupted.

Microcephaly is often present and there may a profound delay in psychomotor development with truncal hypotonia and hyperreflexia in the limbs.   Brain imaging shows generalized atrophy with decreased myelination.  Cerebellar vermis hypoplasia has been reported.  Two of 5 patients were reported to have Dandy-Walker malformations, and a thin corpus callosum.  Seizures may occur.

Genetics

Homozygous mutations in the SMG9 gene (19q13.31) are responsible for this condition so far reported in 5 individuals in two unrelated consanguineous Arab families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice

Shaheen R, Anazi S, Ben-Omran T, Seidahmed MZ, Caddle LB, Palmer K, Ali R, Alshidi T, Hagos S, Goodwin L, Hashem M, Wakil SM, Abouelhoda M, Colak D, Murray SA, Alkuraya FS. Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice. Am J Hum Genet. 2016 Apr 7;98(4):643-52.

PubMed ID: 
27018474

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

Barber-Say Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features consist mainly of skin changes in the lids including hyperlaxity and redundancy.  There may be ectropion of the lower eyelids and sparsity of the eyebrows.  Some evidence of micro- or ablepharon is often present.  Hypertelorism and exophthalmia have been described.

Systemic Features: 

Multiple external congenital anomalies are present at birth including skin laxity, hypertrichosis (especially of the forehead, neck and back), and low-set and malformed pinnae.  Macrostomia and thin lips with redundant facial skin are often evident.  The nose appears bulbous.  The thoracic skin can be atrophic and the nipples may be hypoplastic.  Hypospadias has been reported.  A highly arched or cleft palate may be present and some individuals have a conductive hearing loss.  The teeth are small and eruption may be delayed.  Cognitive deficits may be present and mental retardation has been reported. 

Genetics

Based on genotyping and the limited number of reported pedigrees, inheritance most likely follows an autosomal dominant pattern.  Direct parent to child transmission has been reported.  Detailed examination of parents sometimes reveals mild features that are easily missed.  Mutations in the TWIST2 gene have been found in 10 unrelated individuals with Barber-Say syndrome.

TWIST2 mutations have also been found in Setleis syndrome (227260) and in ablepharon-macrostomia syndrome (200110).  These conditions have some clinical features in common with Barber-Say syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for this disorder but correction of selected anomalies such as ectropion and cleft palate may be indicated.

References
Article Title: 

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, Markello TC. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110.

PubMed ID: 
26119818

Kabuki Syndrome 2

Clinical Characteristics
Ocular Features: 

The facial features are characteristic primarily because of the appearance of the periocular features.  The eyebrows are highly arched and sparse.  The lid fissures are long with eversion of the lateral portion of the lower eyelid.  The eyelashes are bushy.  Nystagmus and strabismus have been reported.

Systemic Features: 

Only a small number of individuals with Kabuki syndrome 2 have been reported and the phenotype is incompletely described.  Most of the features in type 2 are similar to those in type 1 with defects in multiple organs.  There are often cardiac malformations including septal defects.  Otitis media and hearing loss are common.  The pinnae are large and cupped.  A highly arched or cleft palate may be present and the teeth are usually small.  The joints are highly mobile and general hypotonia is often present. The fifth finger is often short and clinodactylous.  Persistent fetal fingerpads are common.  The amount of intellectual disability varies considerably with some patients functioning normally.  Urogenital anomalies are less common than found in Kabuki syndrome 1 and anal malformations do not seem to be a feature.

Genetics

Kabuki syndrome 2 is an X-linked disorder, usually as the result of a mutation in the KDM6A gene (Xp11.3).   Patients with the X-linked form of Kabuki represent about 5-10% of cases.   

Kabuki syndrome 1 (147920) is an autosomal dominant condition caused by heterozygous mutations in the KMT2D gene but remaining heterogeneity is suggested by the fact that a substantial proportion (30%) of individuals with Kabuki syndrome features has neither of these mutations.

In a 3 generation family two males had the typical Kabuki phenotype whereas their mother and grandmother (all had the KMT2D mutation) had various attenuated features.

Treatment
Treatment Options: 

Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients

Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, De Nittis P, Pellico MT, Mandriani B, Fischetto R, Boccone L, Silengo M, Biamino E, Perria C, Sotgiu S, Serra G, Lapi E, Neri M, Ferlini A, Cavaliere ML, Chiurazzi P, Monica MD, Scarano G, Faravelli F, Ferrari P, Mazzanti L, Pilotta A, Patricelli MG, Bedeschi MF, Benedicenti F, Prontera P, Toschi B, Salviati L, Melis D, Di Battista E, Vancini A, Garavelli L, Zelante L, Merla G. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014 Jul;35(7):841-50.

PubMed ID: 
24633898

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

Craniofacial-Deafness-Hand Syndrome

Clinical Characteristics
Ocular Features: 

This rare syndrome has anomalies in periocular structures but not in the eye itself.  The lid fissures are downward slanting with telecanthus and hypertelorism.  The nasolacrimal duct was missing in several individuals.

Systemic Features: 

The midface is generally flat with underdeveloped maxillary bones and absent or small nasal bones but there may be frontal bossing.  The nose appears hypoplastic with a broad, flat root resulting in dystopia canthorum.  Micrognathia and a high arched palate are sometimes present.   The sinuses are often underdeveloped.  There may be ulnar deviation of the hands and fingers while flexion contractures and clinodactyly of the 5th finger are often present.  A sensorineural hearing loss is present in many individuals.  No poliosis has been reported.

Genetics

This is an autosomal dominant condition secondary to mutations in the PAX3 gene (22q36.1) in at least some patients.  Changes in the same gene are responsible for types 1 and 3 of the Waardenburg syndrome (193500, 148820).  In fact, the major mutation, a heterozygous C-to-G transversion, has been identified in the same codon in both CDHS and Waardenburg 3 (148820) patients.

More patients need to be genotyped to clarify the clinical features distinctive of Waardenburg types 1 and 3 (193500, 148820) and CDHS syndrome.  Should we consider these conditions allelic or simply the result of variable expressivity?  The appearance of the nasal root and associated structures is similar and both conditions are associated with sensorineural hearing loss.  Type 3 Waardenburg syndrome (148820) often has a cleft palate and musculoskeletal deformities of the upper limbs and fingers.  So far, no pigmentation changes have been reported in CDHS.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical release of contractures could be considered.

References
Article Title: 

Orofaciodigital Syndrome IX

Clinical Characteristics
Ocular Features: 

Multiple forms of orofaciodigital syndrome are recognized but this one (type IX, originally reported as VIII) is of ophthalmological interest because of the retinal anomalies.  Gurrieri’s original report calls these “retinochoroideal lacunae of colobomatous origin” similar to those found in Aicardi syndrome (304050).  These were further described as hypopigmented and atrophic appearing.  Synophyrs and hypertelorism have been noted and the ears may be low-set.

Systemic Features: 

Facial, oral, digital, psychomotor delays, and skeletal anomalies are major systemic features of OFD IX.  The oral manifestations include a high arched palate, cleft lip (sometimes subtle), bifid tongue, hemartomas on the tongue, abnormal tongue frenulation, and dental anomalies (supernumerary teeth).  Digital anomalies consist of mild syndactyly and occasionally polydactyly, brachydactyly, and bifid large toes.  Some patients have short stature.  Psychomotor delay is common and some patients have been described as mentally retarded.

Genetics

This is most likely an autosomal recessive condition since multiple sibs of both sexes have been identified.  Nothing is known of the locus or specific mutation.

Gurrieri’s name is attached to another syndrome (Gurrieri syndrome [601187]) with entirely different oculoskeletal features.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Specific malformations may need correction but there is no treatment for the overall disease.

References
Article Title: 

Megalocornea, Ectopia Lentis, and Spherophakia

Clinical Characteristics
Ocular Features: 

Patients have megalocornea and mobile lenses.  Corneal diameters are at least 13 mm in diameter.  Some lenses are spherophakic (refractive errors may be in the +11-12 diopter range) and sometimes displace into the anterior chamber or cause pupillary block glaucoma.  The clinical picture often resembles congenital glaucoma in young children but the elevated pressure is usually secondary to hypermobility of the lens and/or its spherical shape.  Haab striae are not present but cloudy corneas have been reported in a few patients.

Many patients develop phthisis or have severe reductions in vision.

Systemic Features: 

Some but not all patients have several physical features of the Marfan syndrome (154700) such as high arched palate, tall stature, and narrow face but those tested do not have mutations in the FBN1 gene.

Genetics

This is an autosomal recessive disorder.  Parental consanguinity is common.  Homozygous mutations in the LTBP2 gene (14q24.3) are found in affected individuals.

LTBP2 competes with LTBP1 (ADAMTSL2) for binding to the gene product of FBN1 in which mutations are associated with the Marfan syndrome (154700) and may account for the variable skeletal signs sometimes found in patients with this megalocornea syndrome.  Both gene products are important to the structure of the extracellular matrix proteins of the ciliary processes, lens capsule, and lens epithelial layer.  The different modes of inheritance and the unique mutations, of course, argue for separateness of the two disorders.

Mutations in LTBP2 have also been found in a family with microspherophakia and ectopia lentis but corneal diameters were described as normal suggesting clinical heterogeneity.

This is a unique disorder which previously has been classified as Glaucoma, Congenital Primary D (613086).  The usual occurrence of ectopia lentis,  the sometimes spherophakic nature of the lenses, the congenital presence of megalocornea without corneal edema in the absence of elevated intraocular pressure, and the lack of breaks in the Descemet membrane strongly suggest that this is not a primary congenital glaucoma.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Urgent lensectomy is necessary for lenses that migrate into the anterior chamber.  Patients have to be monitored as lens dislocations can occur at any age.

References
Article Title: 

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

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