synophrys

Mental Retardation, AD 34

Clinical Characteristics
Ocular Features: 

Patients may have upslanting lid fissures, epicanthus, ptosis, synophrys, and cortical visual impairment.

Systemic Features: 

Among the three reported individuals with the COL4A3BP mutation, one had postnatal microcephaly, widely spaced teeth, synophrys, and intellectual disability. Another had trunk hypotonia, global developmental delay, wide intermamillary distance, 2-3 toe syndactyly, tonic-clonic seizures, and myopathic facies. The third had a broad-based gait, coarse and curly hair, tonic-clonic seizures, and global developmental delay. 

Genetics

In a screening study of 1133 children with severe undiagnosed developmental conditions, three males were found with heterozygous mutations in the COL4A3BP gene (5q13).  Family history data are not given for these three individuals but autosomal dominant transmission seems to be a reasonable assumption.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive care is required but no other treatment has been reported.

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: 

Gorlin-Chaudhry-Moss Syndrome

Clinical Characteristics
Ocular Features: 

Orbital hypoplasia, short, abnormally slanted (up or down) lid fissures, and sometimes lid notching (colobomas?) are characteristic facial features as are bushy eyebrows and synophrys.  Lacrimal duct stenosis has been noted.  The eyes are described as 'small' but no ophthalmological examination has been performed to document microphthalmia or other ocular anomalies.  No mention is made of visual problems.

Systemic Features: 

Premature closure of the coronal suture and midface hypoplasia lead to striking brachycephaly.  The scalp hairline is low and scalp hair is abundant and coarse.  In fact, hypertrichosis is seen throughout the body.  Hypo- and microdontia with irregularly spaced teeth and a high arched palate are common features.  Clefts of the soft palate has been observed.  The ears can be small and rotated posteriorly.  The labia majora are hypoplastic as are the distal phalanges of the fingers and toes.  Mild syndactyly of the second and third fingers and toes have been described.  The nails may be abormally small.  Conductive hearing loss may be present.  Growth and psychomotor development seem to be normal although some patients have been described to have a 'stocky' build.  The facial features tend to coarsen over time.

Genetics

Autosomal recessive inheritance has been suggested but nothing is known about the gene locus.  All 5 reported patients have been female.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Cornelia de Lange Syndrome

Clinical Characteristics
Ocular Features: 

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes.  Synophrys is often prominent.  However, some also have significant ptosis, nystagmus, and high refractive errors.  Optic pallor and a poor macular reflex have also been reported.

Systemic Features: 

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%).  Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions.  The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set.  The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities.  It is stated that the middle phalanx of the index finger is always hypoplastic.  Other limb abnormalities of both upper (95%) and lower extremities are common.  Urinary tract abnormalities have been found in 41% of patients.  Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex.  Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion.  Hence, even autosomal recessive inheritance has been suggested in some families.  Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar.  The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25).  Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No genetic treatment is available.

References
Article Title: 

Waardenburg Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

This type of Waardenburg syndrome is distinguished from type 1 and 3 (193500) by the fact that it is caused by mutations in a different gene and in the absence of dystopia canthorum.  It has been claimed that hearing loss is more common and severe in type 2 (77%) as is heterochromia of the iris (47%) while skin and hair hypopigmentation are less common.

Families with WS2A may have the full spectrum of eye findings seen in X-linked ocular albinism I (300500) including decreased acuity, photophobia, nystagmus, translucent irides, hypermetropia, and albinotic fundi with foveal hypoplasia.  Indeed, such families have been considered to have 'albinism, ocular, with sensorineural deafness' (103470).  Such families might be considered to have an autosomal dominant form of ocular albinism.

Systemic Features: 

Congenital sensorineural hearing loss is an important and common feature.  Also characteristic are the white forelock, poliosis, and hypopigmented skin patches.

Genetics

Waardenburg syndrome is an excellent example of genetic heterogeneity as types 1 and 3 (193500, 148820), 2 (193510), and 4 (277580) are all caused by mutations in different genes. 

Type 2 described here is a genetically heterogeneous autosomal dominant disorder.  WS2A is caused by a mutation in MITF (microphthalmia-associated transcription factor) (3p14.1-p12.3).  This is the same disorder described as 'Albinism, ocular, with sensorineural deafness' in OMIM (103470)  (WS2-OA).

A locus at 1p21-p13.3 is associated with WS2B (600193) and WS2C (606662) maps to 8p23.  In addition, homozygous SNAI2 mutations at 8q11 have been found in several patients with WS2D (608890) suggesting autosomal recessive inheritance but the normal parents were not studied.  Recent evidence suggests that SOX10 mutations can also play a role via MITF promoter modulation (WS2E) (611584).

Type 4 is also the result of mutations in at last three 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 but assistive hearing devices can be helpful.

References
Article Title: 
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