autosomal recessive?

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: 

Chorioretinopathy, Ataxia, and Hypogonadism

Clinical Characteristics
Ocular Features: 

The retinal pigment epithelium changes may be seen as early as the first decade of life with pigment deposition resembling bone spicules.  These changes as well as atrophy of the choriocapillaris are most apparent in the posterior pole and extend into the midperiphery.  Retinal vessels may be attenuated.  Progressive loss of vision, dyschromatopsia, and photophobia are the primary ocular symptoms. Night blindness and constricted visual fields are noted by some patients.  The ERG shows subnormal and sometimes absent photopic and scotopic responses.  Nystagmus is present in more than half of individuals. 

Systemic Features: 

Difficulties with balance, intention tremors, and scanning speech are evident in adolescence or early adult life.  Cerebellar ataxia is present in nearly 40 percent of individuals.  However, there is marked variability in the rate of progression.  Many patients have atrophy of the superior and dorsal areas of the cerebellar vermis and atrophy of the cerebellar hemispheres as noted on MRIs. Hypogonadotrophic hypogonadism is a feature with delayed puberty noted in 26 percent.  In the absence of exogenous hormone administration, secondary sexual characteristics fail to develop.

Genetics

Autosomal recessive inheritance has been suggested on the basis of consanguinity in three families, multiple affected sibs born to normal parents, and a 1:1 sex ratio.  Homozygous and compound heterozygous mutations in PNPLA6 (19p13.2) have been found in several patients.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Trichomegaly Plus Syndrome (275400), in this database.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The use of appropriate hormones can stimulate the development of normal secondary sexual characteristics and may restore reproductive function.   At least two female patients gave birth to a child following hormone substitution.

Low vision aids could be helpful in selected patients.

References
Article Title: 

Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature

Tarnutzer AA, Gerth-Kahlert C, Timmann D, Chang DI, Harmuth F, Bauer P, Straumann D, Synofzik M. Boucher-Neuhauser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature. J Neurol. 2014 Oct 31. [Epub ahead of print].

PubMed ID: 
25359264

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum

Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schols L, Lima-Martinez MM, Farooq A, Schule R, Stevanin G, Marques W Jr, Zuchner S. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2013 Dec 19. [Epub ahead of print].

PubMed ID: 
24355708

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: 

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

Foveal Hypoplasia and Anterior Chamber Dysgenesis

Clinical Characteristics
Ocular Features: 

This is a congenital disorder with poor vision (20/120-20/400) and nystagmus from birth according to family history.  Three of five patients in one family had a posterior embryotoxon and two had Axenfeld anomaly.  No glaucoma was present although no individuals were older than 15 years of age at the time of examination.  The foveal reflex was absent and there was a poorly defined foveal avascular zone with no distinction of the foveomacular area.   Reduced ERG amplitudes and similar VEP responses were found in 4 affected individuals but these recordings were normal in the parents.  Chiasmal misrouting has been reported in two affected members of one family.  The combination of foveal hypoplasia and decussation defects is characteristic of disorders of pigmentation (albinism) but no iris defects or other evidence of pigmentary anomalies have been found in this condition of foveal hypoplasia.

Systemic Features: 

No systemic abnormalities were described.

Genetics

Consanguinity has been reported.  A region containing 33 genes at 16q23.2-24.2 co-segregates with the disorder but no mutation has been identified.  Mutations in FOXC2 and PAX6 (that code for transcription factors) have been specifically ruled out in selected families.  However, the phenotype is consistent with dysfunction of some other as yet unidentified transcription control factor or promotor region.    

An autosomal dominant disorder with somewhat similar features known as anterior segment mesenchymal dysgenesis (107250) has been described but its unique status remains to be established.  Foveal hypoplasia has not been reported but an associated mutation in FOXE3 could be responsible. 

Isolated foveal hypoplasia without anterior chamber malformations (136520) has been reported among families of Jewish Indian ancestry in which homozygous mutations SLC38A8 cosegregated.

With the widespread utilization of OCT measurements, it has become apparent that underdevelopment of the fovea can be a feature of numerous ocular disorders (more than 20 in this database).  In most conditions, the foveal dysplasia is part of a disease complex as in this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known.

References
Article Title: 

A new recessively inherited disorder composed of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis maps to chromosome 16q23.3-24.1

Al-Araimi M, Pal B, Poulter JA, van Genderen MM, Carr I, Cudrnak T, Brown L, Sheridan E, Mohamed MD, Bradbury J, Ali M, Inglehearn CF, Toomes C. A new recessively inherited disorder composed of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis maps to chromosome 16q23.3-24.1. Mol Vis. 2013 Nov 1;19:2165-72. PubMed PMID: 24194637;

PubMed ID: 
24194637

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: 

KID Syndrome

Clinical Characteristics
Ocular Features: 

Superficial punctate keratopathy leads to recurrent corneal erosions and eventually scarring and neovascularization.  Progressive opacification requiring PK often occurs.  These individuals may also suffer loss of eyebrows and eyelashes with trichiasis and thickening of the lid margins.  Corneal erosions and keratoconjunctivitis sicca cause incapacitating symptoms.

Systemic Features: 

The skin may be diffusely erythematous and scaly.  This often becomes patchier with well-demarcated areas especially in skin folds of the neck, axillae, and groin.  Older patients with likely autosomal recessive disease have hepatomegaly and may suffer cirrhosis and liver failure.  Short stature and mental retardation have also been noted.  The hearing loss is neurosensory in type.  Epidermal glycogen deposition has been found in one patient with the presumed recessive disorder.

In the presumed autosomal dominant disease, growth failure, mental retardation and liver disease do not seem to be present.  However, oral and skin squamous cell carcinomas, as well as malignant pilar tumors of the scalp may lead to early death.

Genetics

It is uncertain if one or more entities are represented by the KID syndrome.  Many cases are sporadic but others seem to be transmitted in autosomal recessive or autosomal dominant patterns.  The locus of the mutation is unknown in the recessive form.  In the dominant form, a mutation has been found in the connexin-26 gene, GJB2, gene located at 13q12.11.

See Hereditary Mucoepithelial Dysplasia (158310) for a somewhat similar but unique genodermatosis.  Another is IFAP (308205) but cataracts and hearing loss are not features.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The use of ocular lubricating preparation may supply significant relief from symptoms but scarring may eventually necessitate penetrating keratoplasty.  The threat of skin cancers and fatal hepatic failure requires monitoring throughout life.

References
Article Title: 

Blue Diaper Syndrome

Clinical Characteristics
Ocular Features: 

A single patient has been reported with microcornea, optic nerve hypoplasia, and 'abnormal' eye movements.  The full ocular phenotype is unknown but 'visual problems' are sometimes mentioned in other reports.

Systemic Features: 

Nephrocalcinosis and blue urine are the major systemic manifestations of blue diaper syndrome.  Symptoms of fever, constipation, poor weight gain, failure to thrive, and irritability can also be part of the syndrome.

Genetics

This is considered an autosomal recessive disorder although an X-linked defect cannot be ruled out since reported patients have been male.  Parental consanguinity is present in some families.  Nothing is known about the mutation or its locus.  Intestinal transport of tryptophan is defective and bacterial degradation results in excessive indole production.  Oxidation in the urine to indigo blue results in the characteristic discoloration.        

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restriction of dietary tryptophan has been suggested.

References
Article Title: 

Heimler Syndrome 2

Clinical Characteristics
Ocular Features: 

Several cases have been reported with macular dystrophy and 'salt-and-pepper' mottling of the RPE extending to the midperiphery with foveal sparing.  Autofluorescence with hyper- and hypo-autofluorescent dots has been observed in the mottled areas of the RPE.  Spectral domain OCT has shown loss of the inner/outer segment boundary with RPE thinning and multiple retinal cysts but the ERG does not show rod-cone dysfunction. Visual acuity and the ocular fundus were normal in one patient until the age of 29 years when her vision dropped to 20/200 in one eye and 20/40 in the other.

Systemic Features: 

Primary dentition may be normal but secondary teeth have enamel hypoplasia (amelogenesis imperfecta).  The nails have Beau lines (transverse ridges) and leukonychia (white spots).  Severe sensorineural hearing loss develops sometime in the first year or two of life and it may be unilateral. At least one patient was documented to have had normal audiological test results until the age of 3 years.

Psychomotor development is normal at least until sensory deprivation occurs.

Genetics

This is a rare syndrome of ectodermally derived tissue which results from compound heterozygous mutations in the PEX6 gene (6p21.1).  A pair of monozygotic twin girls with this syndrome has been reported.  Parents are phenotypically normal.  No instance of parent-to-child transmission has been noted and it seems likely that this is an autosomal recessive disorder.

Another form of Heimler syndrome (234580) but with compound heterozygous mutations in the PEX1 gene (7q21.2) has been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

One patient has been treated with carbonic anhydrase inhibitors with apparent stabilization of vision.  Low vision aids and assistive hearing devices are likely of benefit for at least some patients.

References
Article Title: 

Spectrum of PEX1 and PEX6 variants in Heimler syndrome

Smith CE, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet. 2016 Nov;24(11):1565-1571.

PubMed ID: 
27302843

Macular dystrophy in Heimler syndrome

Lima LH, Barbazetto IA, Chen R, Yannuzzi LA, Tsang SH, Spaide RF. Macular dystrophy in Heimler syndrome. Ophthalmic Genet. 2011 Jun;32(2):97-100.

PubMed ID: 
21366429

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