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Retinitis Pigmentosa, Deafness, Mental Retardation and Hypogonadism

Clinical Characteristics
Ocular Features: 

Only two families with this presumed disorder have been reported.  The retinal picture resembles retinitis pigmentosa with ‘bone spicule’ pigment clumps, vascular attenuation, and pale optic nerve heads.  Cataracts and nystagmus have been observed.  Vision is usually limited to light perception by the middle of the first decade of life.

Systemic Features: 

Small testes and gynecomastia are found in males while females have oligo- or amenorrhea.  The hands and feet appear broad and the face has a coarse appearance with a depressed nasal bridge and a broad nose.  Insulin-resistant diabetes and hyperinsulinemia are present.  Acanthosis nigricans, keloids, obesity, and hearing loss are also features.  All patients have significant developmental delays and evident mental retardation.

Genetics

No locus has been identified although autosomal recessive inheritance seems likely: the parents in one family were first cousins and there was no parent to child transmission.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment although cataract surgery might be considered if lens opacities are visually significant.

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: 

Gurrieri Syndrome

Clinical Characteristics
Ocular Features: 

Tapetoretinal degeneration has been described in several patients.  Some patients have keratoconus with lens and corneal opacities.  Visual acuities have not been reported.  The full ocular phenotype must be considered unknown since most patients have not had full ophthalmic evaluations.

Systemic Features: 

Features of an osteodysplasia are among the most striking in this syndrome.  Short stature, brachydactyly, delayed bone age, osteoporosis, and hypoplasia of the acetabulae and iliac alae are usually present.  Birth weight is often low.  Joints may be hyperflexible as part of the generalized hypotonia. The eyes are deep-set, the nasal bridge is prominent, the midface is flat, and the supraorbital ridges are prominent giving the face a rather coarse look.  Prognathism with a prominent lower lip and dental malocclusion reinforce this appearance.  Seizures beginning in early childhood may be difficult to control.  Most patients have severe psychomotor retardation and never acquire speech.

Genetics

The genetics of this familial disorder remain unknown.  No locus or mutation has been identified but one patient had an absent maternal allele of the proximal 15q region as found in Angelman syndrome.

Orofaciodigital syndrome IX (258865) is another autosomal recessive syndrome sometimes called Gurrieri syndrome.  In Gurrieri’s original description of two brothers, chorioretinal lacunae, similar to those seen in Aicardi syndrome (304050), were present.  The systemic features are dissimilar, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Familial Internal Retinal Membrane Dystrophy

Clinical Characteristics
Ocular Features: 

Folds in the internal limiting membrane are commonly seen, especially in the macula.  Intraretinal edema is seen throughout but may be most evident in the macula which often appears cystic.  Superficial microcystic changes in the retina are concentrated in the posterior pole.  The internal limiting membrane often appears thickened and filamentous material may be present in areas where it is separated from the retina.  The inner retina may have schisis cavities.  Visual acuity remains good until midlife.

This disorder is considered by some to result from a primary defect in Muller cells resulting in permeability defects on the retinal surface.  Evidence for this hypothesis comes from ERG studies in which light adapted responses showed a delayed and reduced b-wave, with broad and delayed ON and OFF responses and a missing flicker response.  However, responses may be inconsistent between the two eyes and more studies are needed.

Histologic studies show endothelial cell swelling, pericyte degeneration, and basement membrane thickening in retinal capillaries.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Several families with transmission patterns characteristic of autosomal dominant inheritance have been reported.  However, no locus or mutation has been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Macular Dystrophy, Fenestrated Type

Clinical Characteristics
Ocular Features: 

The earliest fundus findings consisting of a yellowish refractile sheen (about 1 disc diameter in size) with red fenestrations in the central macula were found in a 4 year old.  Changes in macular pigmentation were noted at the age of 16 years.  Visual acuity remains normal.  By the third decade of life an annular zone of hypopigmentation could be seen around the sheen and this gradually enlarged.  The sheen seemed to emanate below the retinal vessels but anterior to the RPE.  At the center a ‘bull’s eye’ pattern of hyperpigmentation appeared.  By the 6th decade of life paracentral scotomas were present causing some visual disturbance.  Fluorescein angiography reveals no abnormalities in the sensory retina or retinal vasculature but an annular zone of window defects around the ‘bull’s eye’ can be seen.  The scotopic ERG can be normal while the amplitudes of the photopic ERG may show a mild reduction in amplitude and the EOG light-dark ratio can also be slightly reduced.  Mild red-green color deficits can be demonstrated.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

No locus or mutation has been identified but the transmission pattern is compatible with autosomal dominant inheritance in the two reported families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Oculomotor Apraxia

Clinical Characteristics
Ocular Features: 

This is a disorder of impaired smooth ocular pursuit movements.  Voluntary horizontal eye movements are absent or defective while vertical gaze and random eye movements are usually retained.  Patients learn early to compensate by sharply turning the head in a jerky, thrusting fashion.  The head turn often overshoots because the eyes tend to deviate in the opposite direction as a result of the vestibular reflex.  Blinking is also sometimes employed to initiate eye movements.  The condition is likely congenital in onset but it is not progressive.  In fact, the ability to look from side to side improves in at least some patients.

Systemic Features: 

The small number of reported patients has limited description of the full phenotype but this seems to be a generalized neurological disorder.  Patients have been reported with global developmental delay, hypotonia, cognitive delays, ataxia/clumsiness, and speech difficulties.  Neuroimaging may reveal abnormalities in various brain stuctures including the cerebellum, cerebrum, vermis, and corpus callosum in 40% of patients.       

Genetics

The genetics of isolated oculomotor apraxia is unknown since no responsible mutation has been identified.  However, familial cases are known, including twins and sibling offspring of consanguineous matings, as well as multigenerational cases.  This condition may be genetically heterogeneous since autosomal recessive and autosomal dominant transmission patterns seem equally likely.  It may also be possible that the Cogan-type oculomotor apraxia is not a isolated entity but simply an associated sign as part of more generalized neurological disease.

Oculomotor apraxia may also be seen in ataxia-telangiectasia (208900), ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600) and in Gaucher disease (203800).  It may be the presenting sign in the latter disease.  

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study

Wente S, Schroder S, Buckard J, Buttel HM, von Deimling F, Diener W, Haussler M, Hubschle S, Kinder S, Kurlemann G, Kretzschmar C, Lingen M, Maroske W, Mundt D, Sanchez-Albisua I, Seeger J, Toelle SP, Boltshauser E, Brockmann K. Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study. Orphanet J Rare Dis. 2016 Jul 29;11(1):104. doi: 10.1186/s13023-016-0486-z.

PubMed ID: 
27473762

Spastic Ataxia, Optic Atrophy, Mental Retardation

Clinical Characteristics
Ocular Features: 

Optic atrophy is generally but not always present.  Internuclear ophthalmoplegia and nystagmus have been reported. 

Systemic Features: 

This progressive neurodegenerative disorder has its onset in early childhood with delayed psychomotor development, spastic ataxia of the limbs, and dysarthria.  Tremor, dysmetria, and poor coordination of fine movements are often present.  A sensorineural hearing loss has been found in several individuals.  Peripheral neuropathy has been reported as well.  The nature and degree of cognitive impairment has not been quantified.

Genetics

The presence of consanguinity in one family and affected sibs in another suggest autosomal recessive inheritance but nothing is known about the genotype.  The signs and symptoms resemble those found in other spastic ataxias and this may not be a unique disorder.

Optic atrophy is also found in autosomal recessive SPAX4 (613672) and in autosomal dominant SPAX7 (108650).      

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Optic Nerve Edema, Splenomegaly, Cytopenias

Clinical Characteristics
Ocular Features: 

Persistent optic nerve edema is eventually followed by some degree of optic atrophy.  The nerve edema may be seen early in the first decade of life and is not associated with increased lumbar puncture pressure.  Peripapillary hemorrhages may be seen.  Visual acuity may decrease somewhat by the end of the first decade of life and becomes functionally significant in early adolescence and may be reduced to counting fingers.  The ERG, which shows minimal dysfunction early, eventually appears nearly flat without photopic or scotopic responses.  The retinal vessels become markedly attenuated and the macula may be mildly edematous and show pigmentary changes.  Pigment clumping is not seen.  Visual fields show a central or cecocentral scotoma, enlargement of the blind spot, and eventually severe peripheral constriction.  The vitreous and aqueous humor sometimes have an increased number of cells.   Lenticular opacities requiring cataract surgery has been reported.  One patient developed a phacomorphic angle closure attack at the age of 19 years.

Systemic Features: 

Splenomegaly is a consistent sign and is usually present in the first decade of life but histology shows primarily cellular congestion of the red pulp cords.  Bone marrow biopsies show mild erythroid hyperplasia. Peripheral blood counts show mild neutropenia and thrombocytopenia.  Occasional atypical lymphocytes may be seen.  Patients often complain of mildly to moderately severe migraine headaches.  Urticaria and anhidrosis are common features.

Genetics

Only a single report of this condition has been published.  A mother and two daughters (half sisters) had the symptoms described here and this is the basis for consideration of autosomal dominant inheritance.  Nothing is known regarding the etiology or the mechanism of disease.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Topical, intravitreal, oral, and subtenon application of steroids apparently have no impact on the progression of the intraocular disease.  Cataracts may need to be removed.

References
Article Title: 

An inherited disorder with splenomegaly, cytopenias, and vision loss

Tantravahi SK, Williams LB, Digre KB, Creel DJ, Smock KJ, Deangelis MM, Clayton FC, Vitale AT, Rodgers GM. An inherited disorder with splenomegaly, cytopenias, and vision loss. Am J Med Genet A. 2012 Mar;158A(3):475-81. doi: 10.1002/ajmg.a.34437. Epub 2012 Feb 3.

PubMed ID: 
22307799

Spherophakia with Inguinal Hernia

Clinical Characteristics
Ocular Features: 

Individuals with this condition have small spherical lenses that are usually displaced superiorly.  Myopia, both lenticular and axial, is often present and retinal detachments can occur.  Glaucoma was reported in one patient but this followed surgery for a retinal detachment.  Iridodenesis and nystagmus may be present.  The single report mentions strong zonules that created difficulties during intracapsular lens removal.  None of the spherical lenses were reported to migrate into the anterior chamber nor was lens-induced glaucoma present.

Systemic Features: 

Inguinal hernias are the only systemic manifestation of this disorder.  Four of 11 affected individuals in the family reported required surgery.  Physical examination and skeletal measurements were used to rule out the Marfan and Weill Marchesani syndromes.

Genetics

A single family with 11 affected individuals in 4 generations has been reported.  The four generation pedigree suggested autosomal dominant inheritance but nothing is known regarding the mutation or locus.

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).  Autosomal recessive isolated spherophakia (251750) has been found in several families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens extraction may be necessary for vision rehabilitation if it is partially displaced.

References
Article Title: 

Dominant microspherophakia

Johnson VP, Grayson M, Christian JC. Dominant microspherophakia. Arch Ophthalmol. 1971 May;85(5):534-7.

PubMed ID: 
5087595

Spherophakia and Metaphyseal Dysplasia

Clinical Characteristics
Ocular Features: 

The corneas and anterior chambers were normal in the son but the lenses were small and spherical and had colobomatous defects.  The father developed a retinal detachment in one eye and elevated intraocular pressure. The morphology of the lenses in the father is unknown.

Systemic Features: 

The diaphyses of the long bones are thickened with relative sparing of the small bones in the extremities.  The epiphyses become more irregular later in life.  The vertebrae are deformed with flattening.  The result is brachymelia and moderately severe dwarfism.  Pigeon breast deformity can be present.

Genetics

A father and son have been reported with this combination of findings suggesting autosomal dominant inheritance.  No locus or mutation has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Unknown.

References
Article Title: 

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