hypertelorism

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: 

Basal Cell Nevus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelid basal-cell carcinomas are the most common ocular finding of this syndrome.  These malignancies may be multiple and may occur on the neck, chest, back, arms and elsewhere on the face.   Those on the eyelids generally have their onset in the postpubertal period, usually by age 35 years, and are often multiple.  Their indolent nature can result in considerably delay in diagnosis, however, and local recurrences are common.  Deformities of the skull often result in the appearance of hypertelorism and proptosis.  Epidermal cysts are found in one-fourth of patients, especially on the palms, but may occur in the tarsal conjunctiva as well.  Intratarsal keratinous eyelid cysts occur in 40% of patients.  Less common reported ocular findings are colobomas, glaucoma, nystagmus, strabismus, and cataracts but these may simply be associations.

Systemic Features: 

This disorder is one of a few in which a disposition to neoplasia is associated with skeletal deformities.  These include bifid ribs, scoliosis, skull deformities such as frontal bossing, increased occipitofrontal circumference, broad nasal root with hypertelorism, mandibular prognathia, and bony cysts.  Medulloblastoma is an infrequent but important sign.  Palmar and/or plantar pits are often present.  Basal cell carcinomas and jaw cysts occur in over 90% of patients by the age of 40 years.  Invasive oral tumors are found in 78% of individuals.

Genetics

This is an autosomal dominant disorder, caused by heterozygous mutations in the PTCH1 gene located on chromosome 9 (9q22.3).  Interestingly, somatic mutations in the PTCH1 gene have also been found in isolated cases with only basal cell carcinoma or medulloblastoma.  Perhaps 40% of cases arise de novo, i.e., without a family history, and older paternal age at conception increases the risk of new mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the location of clinical disease with excision of basal cell carcinomas having the highest priority.  Patients must be monitored throughout life for new lesions as well as recurrence at treated sites. Radiotherapy and non-essential diagnostic X-rays should probably be avoided due to sensitivity to ionizing radiation.

Oral administration of an experimental small molecule signaling inhibitor (GDC-0449 or Vismodegib; Genetech) of the Hedgehog signaling pathway has shown promise in reduction of the number of new lesions as well as shrinkage of existing skin lesions.  BCC lesions have been successfully treated with ingenol mebutate in a single patient.

References
Article Title: 

Eyelid Cysts in Gorlin Syndrome: A Review and Reappraisal

Wolkow N, Jakobiec FA, Yoon MK. Intratarsal Keratinous Eyelid Cysts in Gorlin Syndrome: A Review and Reappraisal. Surv Ophthalmol. 2017 Dec 26. pii: S0039-6257(17)30236-9. doi: 10.1016/j.survophthal.2017.12.007.

PubMed ID: 
29287708

Basal cell nevus syndrome: a brave new world

Goldberg LH, Firoz BF, Weiss GJ, Blaydorn L, Jameson G, Von Hoff DD. Basal cell nevus syndrome: a brave new world. Arch Dermatol. 2010 Jan;146(1):17-9. PubMed PMID: 20083687.

PubMed ID: 
20083687

Axenfeld-Rieger Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features.  Common to all types are the presence of ocular, dental, facial, skeletal abnormalities and autosomal dominant inheritance.  Anterior chamber dysgenesis of some form is universally present and severe glaucoma occurs in 50% of patients.  This may have its onset in childhood with typical symptoms of congenital glaucoma such as photophobia, excessive tearing and corneal clouding.  Hypoplasia of the iris is common and when progressive may result in an ectopic pupil and/or pseudopolycoria.  Iris insertion and Schwalbe's line are often anteriorly displaced with iridocorneal adhesions, a pattern that leads to the inclusion of this disorder among those with iridogoniodysgenesis or anterior chamber dysgenesis.  Pupillary ectropion of the posterior pigmented layer of the iris may be seen.

There is considerable clinical overlap among conditions with iris dysgenesis.  Some patients with typical systemic features of Axenfeld-Rieger syndrome may even have typical anterior chamber features of Axenfeld-Rieger anomaly in one eye and severe iris hypoplasia resembling aniridia in the other.

Systemic Features: 

Dental anomalies and mid-facial hypoplasia secondary to underdeveloped maxillary sinuses are among the most common systemic features in type 1.  The nasal root often appears abnormally broad and the lower lip appears to protrude. The teeth are frequently small and conical in shape with wide spaces between them (diastema).  Some teeth may be missing.  The umbilicus may fail to involute normally and retains excessive, redundant skin that sometimes leads to the erroneous diagnosis of an umbilical hernia for which unnecessary surgery may be performed.  Hypospadius is frequently present while cardiac defects, sensorineural deafness, and anal stenosis are less common.

Genetics

There is clinical and genetic heterogeneity in this syndrome and precise classification of many families remains elusive without knowing the genotype.  Mutations in at least four genes are responsible and all are are responsible for phenotypes transmitted in autosomal dominant patterns.  Type 1 discussed here is caused by a mutation in the homeobox transcription factor gene, PITX2, located at 4q25-q26.  A type of iris hypoplasia (IH)/iridogoniodysgenesis (IGDS) (IRID2; 137600) disorder has been classified separately but is caused by a mutation in PITX2 as well and many cases have the same systemic features.  Mutations in the same gene have also been found in ring dermoid of the cornea (180550) and in some cases of Peters anomaly (604229).

RIEG2 (601499) is rare but a deletion of 13q14 has been reported in several cases.  Mapping in a large family with 11 affected individuals yielded a locus in the same region.  Clinical signs overlap types 1 and 3 with dental, craniofacial, and ocular features, but with hearing impairment and rare umbilical anomalies.

Mutations in the FOXC1 gene (6p25) may be responsible for RIEG3 (602482).  However, a family has been reported with a severe 'Axenfeld-Rieger phenotype' in which a digenic etiology may have been responsible: patients had mutations in both FOXC1 and PITX2. 

Heterozygous mutations in the PRDM5 gene (4q25-q26) have been identified in 4 members of a Pakistani family with typical features of the Axenfeld-Rieger syndrome. It is labeled type 4 Axenfeld-Rieger syndrome in this database. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The presence of glaucoma requires prompt and vigorous treatment but control is difficult with blindness too often the result.  Oral surgery may be beneficial for dental problems.  Low vision aids can be useful.

References
Article Title: 

Axenfeld-Rieger syndrome

Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017 Oct 3. doi: 10.1111/cge.13148. [Epub ahead of print] Review.

PubMed ID: 
28972279

The Rieger syndrome

Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet. 1978;2(3):307-18.

PubMed ID: 
263445

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