telecanthus

Axenfeld-Rieger Syndrome, Type 4

Clinical Characteristics
Ocular Features: 

The ocular features of this syndrome are similar to types 1-3 and primarily involve the anterior segment.  The iris stroma is hypoplastic and the pupil location may be eccentric.  Full thickness defects in the iris can lead to pseudopolycoria.   There may be anterior displacement of the angle structures with posterior embryotoxon and localized corneal opacification.    Glaucoma is a common feature and it may be present in early childhood, associated with tearing, a hazy cornea, and buphthalmos.  Vitreous condensation was noted in all 4 reported individuals.

Systemic Features: 

The midface is flat due to maxillary underdevelopment and the teeth may be abnormally small.  Micrognathia has been reported while the nasal root is abnormally broad.  The umbilical defect consists of redundant skin that failed to involute normally.  Congenital hip anomalies of undetermined nature and a hearing defect were reported in 2 of 4 individuals.

Genetics

Heterozygous mutations in the PRDM5 gene (4q25-q26) are responsible for this condition.  Mutations in CYP1b1, PITX2, and FOXC1 were not present.  One extended pedigree with 4 affected individuals from Pakistan has been reported. 

Type 1 Axenfeld-Rieger syndrome (180500) results from heterozygous mutations in PITX2, RIEG2 (601499) from heterozygous mutations in 13q14, and RIEG3 (602482) from heterozygous mutations in the FOXC1 gene.  Thus in three types of Axenfeld-Rieger syndrome (1,3, and 4) the responsible mutation occurs in a transcription factor gene which may explain why the phenotype is highly variable with considerable overlap in clinical signs.

Autosomal recessive brittle cornea syndrome type 2 (614170) is also caused by mutations in the PRDM5 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at correction of individual problems such as glaucoma and dental anomalies.  One patient required surgery for a retinal detachment. Lifelong ocular monitoring is recommended. 

References
Article Title: 

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

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

Tenorio Syndrome

Clinical Characteristics
Ocular Features: 

The eyebrows appear bushy.  Inflammation of the limbus and keratoconjunctivitis sicca are often present and reported to resemble Sjogren syndrome.

Systemic Features: 

Infants appear large at birth with a large forehead and macrocephaly.  Birth weight, length, and head circumference are usually above the 97th percentile. The mandible appears large and the lips are full and ‘fleshy’.  Dentition is delayed.  Recurrent stomatitis and gastroesophageal reflux have been noted.  Closure of the fontanels is delayed.  Hypotonia and hyperflexible joints can be a feature.

Multiple brain anomalies have been described including cortical atrophy, dilated and asymmetrical ventricles, and mild hydrocephalus.  Psychomotor development and milestones are delayed.  Intellectual disabilities, syncope, hypoglycemia, seizures, apneic episodes, mood anomalies, abnormal gait, and general clumsiness may be present.  There was considerable clinical variation among the six reported patients. 

Genetics

Heterozygous mutations in RNF125 (18q12.1) are responsible for this syndrome. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

A new overgrowth syndrome is due to mutations in RNF125

Tenorio J, Mansilla A, Valencia M, Martinez-Glez V, Romanelli V, Arias P, Castrejon N, Poletta F, Guillen-Navarro E, Gordo G, Mansilla E, Garcia-Santiago F, Gonzalez-Casado I, Vallespin E, Palomares M, Mori MA, Santos-Simarro F, Garcia-Minaur S, Fernandez L, Mena R, Benito-Sanz S, del Pozo A, Silla JC, Ibanez K, Lopez-Granados E, Martin-Trujillo A, Montaner D; SOGRI Consortium, Heath KE, Campos-Barros A, Dopazo J, Nevado J, Monk D, Ruiz-Perez VL, Lapunzina P. A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 Dec;35(12):1436-41.

PubMed ID: 
25196541

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: 

Microcornea, Myopia, Telecanthus and Posteriorly-Rotated Ears

Clinical Characteristics
Ocular Features: 

Small corneas measuring 9.8 – 10.5 mm are characteristic.  Acuity is usually 20/60 or better in older children but even younger children maintain steady fixation.  Refractive errors of -6 to -12.75 diopters are usually present but may be much less in other children.  Axial lengths range from 22.42 to 26.84 mm corresponding to the amount of myopia.  The degree of myopic chorioretinal change correlates roughly with the amount of axial myopia.  Telecanthus is present in all individuals.  

Systemic Features: 

The ears are rotated posteriorly.

Genetics

Five males with this syndrome occurred in four consanquineous/endogamous Saudi families suggesting autosomal recessive inheritance.  Homozygous mutations in ADAMTS18 (16q23.1) have been found in these four families.  However, one child had a similarly affected father suggesting to some that this may be a pseudodominant disorder.

Mutations in the same gene are responsible for Knobloch syndrome 2 (KNO2) (608454).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported although correction of the refractive error should be made in early childhood.  It would seem prudent to monitor the vitreoretinal system for further degeneration.

References
Article Title: 

Waardenburg Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Waardenburg syndrome is a disorder of pigmentation, sensorineural deafness, and a characteristic facial (nasal root) morphology.  Some have neural tube defects.  Based on clinical criteria, the syndrome has been divided into types 1, 2, 3, and 4, with subtypes of 2 and 4.  Types 1 and 3 are caused by mutations in the same gene.

Patients often have a white forelock and iris heterochromia.  The latter may be partial in individual irides, or the entire iris in one eye with the fundus hypopigmentation often matching the iris pattern.  The fundus may also have segmental areas of pigmentary changes corresponding to the iris heterochromia. The hypopigmented portion of the iris is often a brilliant blue.  Dystopia canthorum is a prominent and nearly constant (>95%) feature of type 1, and together with the prominent nasal root and increased intercanthal distance may suggest hypertelorism.  Synophrys is often present and the medial portions of the eyebrows can be exceptionally bushy.  Sometimes the poliosis involves the lashes and eyebrows.

Systemic Features: 

Congenital sensorineural deafness is an important feature.  Individuals with type 1 often have a white forelock (29%), premature graying (44%), and hypopigmented skin patches (55%).  A few patients have cleft palate and/or lip. Neural tube defects have also been reported. The considerably more rare type 3 is caused by mutations in the same gene as type 1, but it is claimed by some to be a separate disorder because of the association of limb anomalies. 

Genetics

Autosomal dominant inheritance is typical for the Waardenburg syndrome.  Types 1 and 3 are caused by mutations in the PAX3 gene (2q35) and, of these, type 1 is far more common.  Type 1 is caused by a heterozygous mutation whereas type 3 may result from either a heterozygous, compound heterozygous, or homozygous mutation.  Both types have been reported to occur in the same pedigree.  PAX genes act as transcription factors that attach to specific sections of DNA and regulate protein production.  PAX3 gene products, among other things, specifically influence neural crest cells important to the development of cranialfacial bones and melanocytes.  Paternal age plays a role in new mutations which probably account for many sporadic cases.

Waardenburg syndrome is an excellant example of genetic heterogeneity as types 1 (193500), 2 (193510), 3 (148820  and 4 (277580) can all result from mutations in different genes.  In addition, types 2 and 4 are each caused by mutations in several different genes. 

A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3. Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations. In addition the face showed marked patchy pigmentation. One parent contributed the MITF mutation and the other added the mutation in PAX3.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No ocular treatment is necessary.  Patients may benefit from cochlear implants.

References
Article Title: 

Donnai-Barrow Syndrome

Clinical Characteristics
Ocular Features: 

A number of ocular features have been described in this disorder, including telecanthus, hypertelorism, and iris hypoplasia with marked iris transillumination.  Myopia is commonly present and retinal detachments are a risk.  Several patients had iris colobomas.  Cataracts, small optic nerves, and macular hypoplasia have been reported as well.  The lid fissures usually slant downward. 

Systemic Features: 

The facial dysmorphology, in addition to the periocular malformations, includes a prominent brow or frontal bossing, posterior rotation of the ears, a flat nasal bridge and a short nose.  Sensorineural hearing loss is universal and at least some patients have complete or partial agenesis of the corpus callosum, and an enlarged anterior fontanel.  Diaphragmatic and umbilical hernias often occur together.  Low-molecular-weight proteinuria in the absence of aminoaciduria is a frequent feature.  Developmental delays are often seen but occasional patients have normal intellect.  Rare patients have seizures. 

Genetics

This is a rare autosomal recessive disorder caused by homozygous mutations in the LRP2 (low-density lipoprotein receptor-related protein 2 or megalin) gene located at 2q24-q31.  Some patients have an ocular phenotype resembling the Stickler syndrome (609508).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is focused on specific manifestations such as cataract and retinal detachment surgery. Patients need to be monitored throughout life for retinal disease.  Omphaloceles and diaphragmatic hernias need to be repaired.  Hearing aids may be beneficial. 

References
Article Title: 

Oculodentodigital Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been reported as small and sometimes appear deep-set.  The epicanthal folds are prominent and the lid fissures are small.  Microcornea and evidence of anterior chamber dysplasia including posterior synechiae, anterior displacement of Schwalbe’s line, and stromal hypoplasia in the peripupillary area may be present.  Many eyes have some persistence of the pupillary membrane. Nystagmus and strabismus has been seen in some individuals.  A few patients have evidence of a persistent hyperplastic primary vitreous, even bilaterally. Cataracts may be present as well and a few patients have been reported with open angle glaucoma.  Most patients have normal or near normal visual acuity.

Systemic Features: 

The clinical features of this syndrome are highly variable.  Hair is sparse and the nails are usually dysplastic.  The nose appears small and peaked with underdevelopment of the nasal alae, and the mandible may be broad.  The cranial bones are often hyperostotic and the long bones as well as the ribs and clavicle are widened.  The middle phalanges of the digits are usually hypoplastic or may be absent.  Syndactyly of fingers and toes is often a feature and camptodactyly is common.  The teeth are small and carious with evidence of enamel dysplasia.   Hair often grows slowly and is sparse.  A variety of neurological deficits have been reported but no consistent pattern has been recognized.  However, white matter lesions and basal ganglia changes have been documented on MRI.

Genetics

Both autosomal recessive and autosomal dominant inheritance have been proposed but in both cases the mutations are in the same gene, GJA1, located at 6q21-q23.2.

This disorder is allelic to Hallermann-Streiff syndrome (234100).

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general condition is available.  Cataracts and glaucoma require attention when present, of course.

References
Article Title: 

Potter Disease, Type I

Clinical Characteristics
Ocular Features: 

As part of the facial morphology said to be characteristic of Potter disease, there is usually hypertelorism, telecanthus and epicanthal folds.  Cataracts and angiomas of the optic disc area have also been described.

Systemic Features: 

Polycystic kidney disease and hepatic system anomalies are major features of Potter disease.   Pulmonary hypoplasia with neonatal respiratory distress, however, is often the most immediate cause of death in most infants.  Antenatal oligohydramnios and low birth weight are commonly present.  As many as 33% of fetuses die in utero, often the result of bilateral renal agenesis.  Infants that survive can have chronic lung disease and renal dysfunction.  Congenital heart malformations are common, including septal defects, tetralogy of Fallot and patent ductus arteriosis.  Vertebrae may have a ‘butterfly’ shape but other skeletal findings include hemivertebrae and sacral agenesis.  The neck has been described as short and the skull is brachycephalic.

The facial appearance, known as Potter facies, is said to be characteristic and may be helpful in distinguishing this type of polycystic kidney disease.  In addition to the ocular findings, the nares are often anteverted, and the external ears are large and often posteriorly rotated.

Genetics

The uniqueness of this syndrome remains to be established.  There are several polycystic kidney disorders which have a monogenic basis. These often have overlapping renal features with the condition described here but lack the facial features said to be characteristic of Potter type I disease.  Autosomal recessive inheritance has been suggested on the basis of several reported families with affected sibs from consanguineous parents but so far no gene locus or mutation has been identified.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the condition but symptoms of respiratory distress and renal failure may need to be addressed acutely.  Long-term therapy for pulmonary disease and renal dysfunction can be considered for older individuals.  Many infants die in the neonatal period.

References
Article Title: 

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p

Hallermann C, M?ocher G, Kohlschmidt N, Wellek B, Schumacher R, Bahlmann F, Shahidi-Asl P, Theile U, Rudnik-Schoneborn S, M?ontefering H, Zerres K. Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p. Am J Med Genet. 2000 Jan 17;90(2):115-9. Review.

PubMed ID: 
10607948

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