Ocular albinism with late-onset sensorineural deafness is a rare, X-linked inherited subtype of ocular albinism characterized by severe visual impairment, translucent pale-blue irises, a reduction in the retinal pigment and moderately severe deafness with onset ranging from adolescence to fourth or fifth decade of life.


Ocular anomalies-axonal neuropathy-developmental delay syndrome

A rare mitochondrial disease characterized by signs and symptoms within a phenotypic and metabolic spectrum that includes global developmental delay, hypotonia, intellectual disability, optic atrophy, axonal neuropathy, hypertrophic cardiomyopathy, lactic acidosis, and increased excretion of Krebs cycle intermediates. Other variable features are spasticity, seizures, ataxia, congenital cataract, and dysmorphic facial features. Age of onset is in the neonatal period or infancy.


A rare inflammatory eye disease characterized by sub-epithelial blistering manifesting with bilateral, asymmetrical, chronic or recurrent conjunctivitis and aberrant tissue regeneration leading to progressive conjunctival fibrosis, secondary corneal vascularization and, in some cases, blindness. Patients typically present with conjunctival redness, increased lacrimation, burning and/or foreign body sensation, edema, limbitis and/or varying degrees of ocular pain. Ankyloblepharon may be observed in end stages of the disease.


Ocular cystinosis is the benign, adult form of cystinosis (see this term), a metabolic disease characterized by an accumulation of cystine crystals in the cornea and conjunctiva responsible for tearing and photophobia and associated with no other additional manifestations.


Ocular motor apraxia, Cogan type is characterised by impairment of voluntary horizontal eye movements and compensatory head thrust. Around 50 cases have been described so far. The oculomotor manifestations tend to improve with age but the syndrome may also be associated with learning and speech difficulties, or, in some cases, cerebral malformations. Both sporadic and familial forms have been described, with sporadic forms being more frequent. The mode of transmission of the familial form has not yet been clearly established. A gene located on the long arm of chromosome 2, near to the NPHP1 gene involved in nephronophthisis, may be associated with ocular motor apraxia, Cogan type.


A rare congenital malformation syndrome, most commonly presenting with hemifacial microsomia associated with ear and/or eye malformations and vertebral anomalies of variable severity. Additional malformations involving the heart, kidneys, central nervous, digestive and skeletal systems may also be associated.

Summary:
Epidemiology
The prevalence at birth is less than 1/26,000 in Europe, with a slight male predominance.
Clinical description
The phenotypic spectrum ranges from isolated mild facial asymmetry to severe bilateral craniofacial microsomia and additional multiple extracranial abnormalities. Craniofacial involvement is typically unilateral; the most common manifestations are auricular abnormalities, preauricular appendages and/or fistulas, hypoplasia of the mandible, maxilla, malar bone, and/or zygomatic arch, and epibulbar dermoids. Although exceptional, airway obstruction due to mandibular and maxillary hypoplasia can be life threatening. Auricular abnormalities are usually unilateral and include microtia, ear malpositioning and external auditory canal atresia or stenosis, with or without hearing loss. Ocular involvement may range from an upper eyelid coloboma to micro/anophthalmia in severe cases. Facial palsy, asymmetric palatal elevation, impairment of extraocular movements and trigeminal anesthesia have been reported. Congenital heart defects, such as tetralogy of Fallot, septal defects, transposition of the great vessels, aortic arch anomalies, situs inversus, and dextrocardia are not uncommon. Additional features may include renal (unilateral kidney agenesis, double ureter, renal ectopia, hydronephrosis, hydroureter) and central nervous system (developmental delay, microcephaly, encephalocele, hydrocephaly, corpus callosum hypoplasia, Arnold-Chiari malformation, holoprosencephaly) anomalies. Intelligence is typically normal.
Etiology
The etiology is poorly understood but is suspected to be heterogeneous and multifactorial. The gene MYT1 (20q13.33) has been Implicated in a few rare cases, and chromosomal abnormalities have been associated with some of the congenital malformations associated with this condition.
Diagnostic methods
Diagnosis is based on clinical findings. Microtia and/or mandibular hypoplasia with a preauricular tag have been suggested as diagnostic; however, there are no established guidelines for the minimum diagnostic criteria.
Differential diagnosis
Differential diagnosis includes syndromes associated with microtia and mandibular hypoplasia, including Treacher Collins syndrome, Townes-Brocks syndrome, CHARGE syndrome, branchio-oto-renal spectrum disorders, mandibulofacial dysostosis with microcephaly, and Wildervanck syndrome.
Antenatal diagnosis
Prenatal diagnosis of craniofacial microsomia is uncommon. Where there is a family history, non-invasive prenatal diagnosis is advised. Fetal ultrasound allows detection of severe extracranial anomalies and some cases with severe mandibular hypoplasia, whereas 3D ultrasound scans may enable identification of cases with milder defects.
Genetic counseling
The condition usually occurs sporadically, but autosomal dominant inheritance has been reported. To assess recurrence risk, parents and siblings should be evaluated for the clinical manifestations. Due to the phenotypic heterogeneity of the disease, predicting the severity in offspring is difficult. In cases where no family history or chromosomal abnormality exists, sibling recurrence risk is estimated at 2-3%.
Management and treatment
Treatment is multidisciplinary and should be divided into stages, according to the patient's age, and tailored according to the extent and severity of observed abnormalities. A full evaluation is necessary to assess skeletal, renal, cardiac, dental and auricular involvement. Prompt treatment may be required for airway obstruction and extracranial abnormalities. Correction of malformations usually requires a longitudinal, multistage and coordinated treatment plan. Surgeries for facial asymmetry may be complicated by temporomandibular joint aplasia/hypoplasia. The timing and most effective interventions for mandibular correction is still controversial. Many professionals currently advocate for intervention after completion of facial growth where possible, thereby avoiding relapses and numerous surgeries.
Prognosis
Outcome depends on the complexity of the abnormalities, as well as the timing of diagnosis and interventions. Long-term outcomes may be hard to predict.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Carrie HEIKE  - Dr Daniela LUQUETTI


Oculopalatocerebral syndrome is characterised by the association of four anomalies: intellectual deficit, microcephaly, palate anomalies and ocular abnormalities.

Summary:
Epidemiology
It has been described in five patients (three boys and two girls).
Clinical description
Maternal hypertension, oligoamnios and intrauterine growth retardation (IUGR) are often noted during pregnancy. The clinical manifestations are evident from birth. The palate anomaly is usually cleft palate. In the majority of cases, postnatal growth is marked by statural (between -2.5 and -4 SD) and ponderal retardation. Microcephaly is present in all patients (between -2 and -5.6 SD). Persistent hyperplastic primary vitreous (uni- or bilateral) was present in all cases reported so far and may be associated with microphthalmia, cataract or optic atrophy. Facial dysmorphology is characterised by full cheeks, a bulbous nasal tip, and long ears with thickened helices. Hands and feet are small. Anomalies of the external genitalia were reported in some of the male patients, with two of the boys displaying cryptorchidism. Skeletal anomalies include pectus excavatum, joint hyperlaxity and kyphoscoliosis. Intellectual deficit (moderate to severe) is a constant feature and is associated with cerebral atrpohy or quadriplegia in some cases. Hearing difficulties may also be present and a tendency for atopy is often noted.
Etiology
So far, neither a causative gene nor locus has been identified.
Diagnostic methods
Diagnosis is based in the clinical manifestations, in particular on the presence of a persistent hyperplastic primary vitreous in association with other malformations.
Differential diagnosis
Differential diagnosis should include cerebro-oculo-nasal syndrome (see this term) and other syndromes associated with a persistent hyperplastic primary vitreous.
Antenatal diagnosis
Prenatal diagnosis is possible but relies on detection of the malformations and growth retardation by foetal ultrasound.
Genetic counseling
Familial reoccurrence and evidence of consanguinity in two of the three reported families are suggestive of autosomal recessive inheritance. Genetic counselling of families with an affected child should take into account a risk of reoccurrence of 25%.
Management and treatment
Treatment should include surgical correction of the palate anomalies and management of the visual problems. Physical and speech therapy should also be recommended.
Prognosis
Although no data are available on the long-term prognosis, the nature of the anomalies suggests that life expectancy for these patients is normal.

                            Last update:
                            January 2007

                            - Expert reviewer(s):
                            Pr Pierre SARDA


Oculoauricular syndrome, Schorderet type is a rare, genetic developmental defect during embryogenesis syndrome characterized by various ophthalmic anomalies (including congenital microphthalmia, microcornea, cataract, anterior segment dysgenesis, ocular coloboma and early onset rod-cone dystrophy) and abnormal external ears (low-set pinna with crumpled helix, narrow intertragic incisures, abnormal bridge connecting the crus of the helix and the antihelix, narrow external acoustic meatus, and lobule aplasia).


A rare dysostosis syndrome characterized by vertical, median craniofacial clefting of fronto-naso-maxillary structures associated with auriculo-mandibular malformations, manifesting with highly variable craniofacial features which include hypertelorism, eyelid colobomas, orbital dystopia, epibulbar dermoids, nasal anomalies (e.g. wide nasal bridge, bifid nose, widely separated, slit-like nares, nasal bone dysplasia), auricular and middle ear dysplasia (microtia, aural stenosis, pre-auricular skin tags/pits), cleft lip/palate, mandibular/maxillary hypoplasia and facial asymmetry. Intracranial abnormalities and extra-craniofacial features are frequently associated.


Oculoauriculovertebral spectrum with radial defects

A rare branchial arches and limb primordia development disorder characterized by variable degrees of uni- or bilateral craniofacial malformation and radial defects that result in extremely variable phenotypic manifestations. Characteristic features include low postnatal weight, short stature, vertebral defects, hearing loss, and facial dysmorphism (incl. facial asymmetry, external, middle, and inner ear malformations, orofacial clefts, and mandibular hypoplasia). These features are invariably associated with radial defects, such as preaxial polydactyly, thumb and/or radius hypoplasia/agenesis, or triphalangeal thumb. Cardiac, pulmonary, renal, and central nervous system involvement has also been reported.


Oculocerebral hypopigmentation syndrome, Cross type is a rare congenital syndrome characterized by cutaneous and ocular hypopigmentation, various ocular anomalies (e.g. corneal and lens opacity, spastic ectropium, and/or nystagmus), growth deficiency, intellectual deficit and other progressive neurologic anomalies such as spastic tetraplegia, hyperreflexia, and/or athetoid movements. The clinical picture varies among patients and may also include other anomalies such as urinary tract abnormalities, Dandy-Walker malformations, and/or bilateral inguinal hernia.


Oculocerebral hypopigmentation syndrome, Preus type is a rare congenital syndrome characterized by skin and hair hypopigmentation, growth retardation, and intellectual deficit that are associated with a combination of various additional clinical anomalies such as ocular albinism, cataract, delayed neuropsychomotor development, sensorineural hearing loss, dolicocephaly, high arched palate, widely spaced teeth, anemia, and/or nystagmus.


A rare neurologic disease typically characterized by the triad of eye, central nervous system and skin malformations, and often associated with an intellectual disability.

Summary:
Epidemiology
Prevalence is unknown, but around 40 cases have been reported to date. Oculocerebrocutaneous syndrome (OCCS) is predominantly found in males.
Clinical description
Neonates, predominantly boys, typically present with an orbital cyst or cystic microphthalmia, often in combination with eyelid colobomata. Cutaneous features often include striated muscle hamartoma, multiple cutaneous tags in the periorbital region (pedunculated/finger-like), and focal aplasia/hypoplasia (mainly on the neck, face and scalp). Developmental delay and intellectual disability may vary from very mild to profound. About half of the patients have a history of epileptic seizures, however they are well controlled in most cases. OCCS has a wide spectrum of clinical symptoms beyond the typical clinical triad, with skull, rib and vertebral anomalies, craniofacial clefts including a defect of the nasal ala in some cases, and abnormal ear pinnae. Cryptorchidism is occasionally reported.
Etiology
Etiology remains elusive. OCCS is hypothesized to be a postzygotic mosaic condition.
Diagnostic methods
Diagnosis is based on the presence of the triad of eye, central nervous system (CNS) and cutaneous clinical features. It is confirmed on magnetic resonance imaging (MRI) by the demonstration of : 1) mainly asymmetrical forebrain malformations with polymicrogyria (PMG), periventricular nodular heterotopias located beneath the PMG, interhemispheric or intraventricular cysts, enlarged ventricles or hydrocephalus, and partial or complete agenesis of the corpus callosum; and 2) provisionally unique mid-hindbrain malformations, characterized by giant tectum, absent or severely malformed vermis and posterior fossa malformation with cerebellar hypoplasia and widening of the fourth ventricular outflow tract. Electroencephalogram (EEG) is abnormal in 50% of cases.
Differential diagnosis
Differential diagnosis includes encephalocraniocutaneous lipomatosis, but the multitude of mesenchymal tumors (in particular lipomas, and choristomas) and CNS anomalies exclude it from OCCS. The brain malformations overlap substantially with those seen in Aicardi syndrome although the mid-hindbrain malformation is unkown in Aicardi syndrome and the typical chorioretinal lacunae associated with Aicardi syndrome are unknown in OCCS. Goldenhar syndrome, focal dermal hypoplasia and microphthalmia with linear skin defects should also be considered. The mid-hindbrain malformations may be confused with Dandy-Walker malformation, but are often complex and severe in OCCS.
Genetic counseling
OCCS occurs sporadically. The preponderance of males suggests that OCCS may be an X-linked disorder.
Management and treatment
Management should involve a multidisciplinary team composed of an ophthalmologist, neurologist and pediatrician. Removal of the orbital cyst may be done by aspiration and dissection from the adjacent periocular region. Sclerosing therapy with ethanolamine oleate may be used. Because of the cerebral or cerebellar malformations and consequent manifestations, a neurological evaluation is necessary before deciding on a surgical intervention.
Prognosis
OCCS has been fatal in 15% of the reported cases. Most surviving patients have significant psychomotor deficiencies but a normal development has been reported in at least 15% of the cases.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Ute MOOG


Oculocerebrofacial syndrome, Kaufman type

A rare, genetic, syndromic intellectual disability characterized by severe intellectual disability, distinctive craniofacial features and variable multiple congenital anomalies including ocular, brain, urogenital and skeletal abnormalities.

Summary:
Epidemiology
To date, 19 molecularly diagnosed cases have been described in the scientific and medical literature.
Clinical description
The most prominent clinical findings are severe intellectual disability, pre-and postnatal growth retardation, microcephaly, and typical craniofacial features which include non-progressive microcephaly of prenatal onset, prominence of the zygomatic region of the face, full cheeks, prominent frontal tubers, sparse and arched eyebrows, blepharophimosis with epicanthal folds, upslanted palpebral fissures, preauricular skin tags, underdeveloped and abnormally folded ears, wide nasal base, low nasal bridge, anteverted nares, long and flat philtrum and retrognathia. Hypotonia, feeding difficulties, failure to thrive and poor speech development are universal findings. Many patients require tube-feeding. Perceptive language is better than expressive, some patients acquire a few words and basic ambulation skills such as eating and dressing independently. Brain abnormalities may include absent or hypoplastic corpus callosum and changes in white matter signal intensity on MRI, but major structural brain malformations are absent. Epilepsy may occur. Ocular abnormalities include short and narrow palpebral fissures, microcornea/microphtalmos, refractive errors and strabismus. Other less frequently observed congenital anomalies include hearing loss, urogenital abnormalities (hypoplastic external genitals, hypospadias, vesicoureteral reflux, duplicated renal pelvis), skeletal abnormalities (including clinodactyly, hypoplastic or absent distal phalanges of some digits, pectus carinatum, coxa valga, pes talus varus and scoliosis). Ectodermal anomalies include thin, sparse hair, and light colored, fine skin. Gastroesophageal reflux is a frequent problem. Congenital heart malformations and breathing problems (tracheo/laryngomalacia, subglottic stenosis) are frequent. About half of patients have abnormal cholesterol levels (low total HDL/LDL levels). Patients have an overall friendly disposition.
Etiology
The syndrome is caused by biallelic inactivating mutations in the UBE3B gene (12q24.11), which encodes ubiquitin protein ligase E3B, a putative calmodulin-regulated mitochondria-associated enzyme involved in the protein ubiquitination pathway.
Diagnostic methods
Diagnosis is established in a proband with developmental delay/intellectual disability, characteristic craniofacial anomalies and biallelic UBE3B pathogenic variants.
Differential diagnosis
Differential diagnosis principally includes other syndromes featuring association of blepharophimosis and intellectual disability (e.g. blepharophimosis-intellectual disability syndrome, Maat-Kievit Brunner type), as well as Toriello-Carey syndrome, Smith-Lemli-Opitz syndrome, and DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and Seizures) if digital anomalies are present.
Antenatal diagnosis
Prenatal testing for at risk pregnancies is possible where the UBE3B pathogenic variants have been identified previously in a family member.
Genetic counseling
Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Full multisystem evaluation should be performed following the diagnosis, and growth, developmental progress, vision, hearing and contractures/scoliosis should be regularly followed up. Educational intervention and speech therapy should start as early as possible. Intervention for feeding problems may be needed. Treatment of the encountered congenital and functional anomalies is standard.
Prognosis
Prognosis depends on the severity of symptoms; however, data is limited.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Katalin SZAKSZON | ITHACA*

                                * European Reference Network


A rare multisystem disorder characterized by congenital cataracts, glaucoma, intellectual disabilities, seizures, postnatal growth retardation and renal tubular dysfunction with chronic renal failure.

Summary:
Epidemiology
The estimated prevalence is 1/500,000 and males are almost exclusively affected.
Clinical description
Oculocerebrorenal syndrome of Lowe (OCRL) is a congenital disorder characterized by ocular abnormalities (bilateral congenital discoid cataracts, glaucoma with or without buphthalmos, strabismus, hypermetropia and corneal and conjunctival cheloids), neurological involvement (developmental delay, seizures, hypotonia present at birth typically with absence of deep tendon reflexes), stereotypic behavior (temper tantrums, aggressiveness and obsessive compulsive behavior), postnatal growth retardation, mild to severe intellectual disability (mean IQ 40-50), stereotypic hand movements, renal dysfunction of the Fanconi type (proximal tubular acidosis; phosphate wasting leading to renal rickets, osteomalacia and pathological fractures) and progressive decline in kidney function leading to end-stage renal failure in adulthood. Subtle cataracts are obligate findings in female carriers after puberty. Other clinical manifestations include facial dysmorphism (frontal bossing, deep-set eyes, chubby cheeks, fair complexion), destructive teno-synovitis in older patients, short stature, mucocutaneous anomalies (eruptive vellus hair cysts, tricoepithiloma, excess skin folds and eruption cysts in oral cavity), dental malformations, cryptorchidism and bleeding tendency due to platelet dysfunction.
Etiology
OCRL results from mutations in OCRL (Xq25), leading to phosphatidylinositol (4,5) bisphosphate accumulation, defective membrane trafficking and disturbed actin cytoskeleton remodeling. In the kidney, disturbed endosomal trafficking impairs protein reabsorption and digestion in the proximal tubules. In the eye, abnormal actin remodeling leads to disorganization of embryonic lens epithelium and abnormal development of the trabecular meshwork that regulates aqueous humor outflow from the eye.
Diagnostic methods
Diagnosis of OCRL is based on specific ophthalmologic, neurologic and renal abnormalities. Laboratory findings reveal features of renal Fanconi syndrome and elevations in plasma creatine kinase, lactate dehydrogenase and transaminases levels. The presence of low-molecular weight proteinuria is the first renal abnormality and is invariably present after birth. Brain imaging reveals brain atrophy, delayed myelination, pachygyrias, hydrocephalus as well as white matter lesions suggestive of periventricular leukomalacia. Diagnosis is confirmed by genetic screening of OCRL.
Differential diagnosis
Differential diagnosis includes Dent disease type 2 (an allelic disease with a milder phenotype), congenital infections (such as congenital rubella syndrome), Nance-Horan syndrome, Smith-Lemli-Opitz syndrome, muscle-eye-brain disease, cystinosis and peroxisomal disorders.
Antenatal diagnosis
Prenatal testing is possible and unless the mutation in the family has been defined previously, assay of enzyme activity is preferred. Elevated maternal serum and amniotic fluid alpha-fetoprotein or presence of cataract on ultrasound may be used for prenatal screening.
Genetic counseling
The pattern of inheritance is X-linked and genetic counseling is recommended for affected families. If the mother is a carrier, 50% of her sons will inherit the disease whereas 50% of her daughters will be carriers. De novo mutations are reported in 30% of affected males.
Management and treatment
Treatment of OCRL includes early cataract extraction to avoid amblyopia, glaucoma control by either medications or surgery and postoperatively, eye glasses. Contact lenses are contraindicated. Nasogastric tube feedings or feeding gastrostomy may be required. Treatment also includes physical and speech therapy, use of drugs (clomipramine, paroxetine and risperidone) for behavioral problems, correction of tubular dysfunction by alkali supplements, phosphate, potassium and water. Potassium citrate may be useful to prevent nephrocalcinosis.
Prognosis
Quality of life depends on extent of neurological and renal manifestations. Life span rarely exceeds 40 years and death occurs between 20-40 years, as a consequence of renal disease, hypotonia, increased susceptibility to infectious disease, seizures and sudden death. Glaucoma is often difficult to control.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Arend BÖKENKAMP


A form of oculocutaneous albinism (OCA) characterized by a spectrum of hypopigmentation of skin hair and eyes, ranging from little or no pigmentation to localized pigementation. Nystagmus, photophobia and reduced visual acuity are frequently present. The subtypes include OCA1A, OCA1B, type 1 minimal pigment oculocutaneous albinism (OCA1-MP) and type 1 temperature sensitive oculocutaneous albinism (OCA1-TS).


A severe form of oculocutaneous albinism type 1 (OCA1) characterized by complete absence of melanin and manifesting as white hair and skin, blue, fully translucent irises, nystagmus and misrouting of the optic nerves.

Summary:
Epidemiology
The worldwide prevalence of OCA1 is estimated at 1/40,000. OCA type 1A (OCA1A) is considered to account for about half of the overall OCA1 cases among non-Hispanic, Caucasian patients.
Clinical description
Patients have white skin and hair at birth. Irises are blue to pink and fully translucent. These features do not change throughout a patient's life. Nystagmus may be present at birth or it may develop in the first 3 to 4 months of life. It continues throughout life but usually slows down after childhood and is less noticeable when a person is relaxed and well rested. Visual acuity ranges from 20/100 and 20/400 and an alternating strabismus is often present. The reduction in visual acuity is associated with foveal hypoplasia. Severe photophobia is common. Nevi and ephelides are common but are unpigmented and pink. Patients do not tan, and if proper sun protection methods are not followed, skin becomes rough, coarse, thickened and can have solar keratoses. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.
Etiology
OCA1A is caused by a mutation in the TYR gene (11q14.2) encoding tyrosinase. The mutation leads to a completely inactive or incomplete tyrosinase enzyme polypeptide. Melanocytes contain no melanin, as without this enzyme the melanin biosynthetic pathway is blocked.
Diagnostic methods
The characteristic clinical findings along with confirmatory genetic testing are used to diagnose OCA1A. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing is usually necessary to make the correct diagnosis of this subtype.
Differential diagnosis
Differential diagnoses include the other forms of OCA and X-linked ocular albinism (XLOA) as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndromes 1-11, Chediak-Higashi syndrome, Griscelli syndromes 1-3, and Waardenburg syndrome type II.
Antenatal diagnosis
Prenatal testing is possible for at risk pregnancies by molecular genetic testing.
Genetic counseling
This disorder is inherited autosomal recessively. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Annual ophthalmologic examination is necessary and corrective lenses or glasses are given to improve visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.
Prognosis
OCA1A is not life threatening, unless malignancies develop, and remains stable after childhood. The medical and social consequences can however have major impacts on a patient's daily life.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI


A form of oculocutaneous albinism type 1 (OCA1) characterized by skin and hair hypopigmentation, nystagmus, reduced iris and retinal pigment and misrouting of the optic nerves.

Summary:
Epidemiology
The worldwide prevalence of OCA1 is estimated at 1/40,000. OCA1B is considered to account for about half of all overall OCA1 cases among non-Hispanic, Caucasian patients
Clinical description
Newborns have white or very light yellow hair but with age the hair can darken to blond or light brown. Eyelash hair can be darker than scalp and eyebrow hair. Skin remains creamy white but a minimal amount of tanning is possible along with freckles and pigmented nevi. Nystagmus is sometimes visible at birth but in others not until 3 to 4 months of age. It continues throughout life but becomes less rapid with age and is usually more noticeable in times of stress, anger or tiredness. Iris color is blue at birth and can change to brownish tan or greenish hazel or remain unchanged. Visual acuity ranges from 20/100 to 20/200. With time, skin can become rough, coarse and thickened if sun protection procedures are not followed. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.
Etiology
OCA1B is caused by a mutation in the TYR gene located on chromosome 11q14.2 encoding tyrosinase. The mutation causes the production of a partially active or hypomorphic tyrosinase enzyme that leads to minimal melanin formation in melanocytes.
Diagnostic methods
The characteristic clinical findings along with confirmatory genetic testing are used to diagnose OCA1B. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing is necessary to obtain a definitive diagnosis, as some OCA1B patients have a certain degree of phenotypical variation which may lead to confusion in distinguishing it from other OCAs. This overlap of clinical symptoms emphasizes the importance of genetic analysis in the diagnosis of albinism.
Differential diagnosis
Differential diagnoses include the other forms of OCA and X-linked recessive ocular albinism (XLOA) as well as syndromes with albinism as a feature, such as Hermansky-Pudlak syndromes 1-11, Chediak-Higashi syndrome, Griscelli syndromes 1-3, and Waardenburg syndrome type II.
Antenatal diagnosis
Prenatal testing is possible for at risk pregnancies by molecular genetic testing.
Genetic counseling
This disorder is inherited autosomal recessively and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Annual ophthalmologic examination is necessary and corrective lenses or glasses are given to improve visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.
Prognosis
OCA1B is not life threatening and remains stable after childhood. The medical and social consequences can however have major impacts on a patient's daily life.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI


A form of oculocutaneous albinism characterized by variable hypopigmentation of the skin and hair, numerous characteristic ocular changes and misrouting of the optic nerves at the chiasm.

Summary:
Epidemiology
The prevalence of Oculocutaneous albinism type 2 (OCA2) is estimated at 1/38,000-1/40,000 in most populations throughout the world except in the African population that has a higher prevalence of 1/3,900-1/1,500.
Clinical description
Skin and hair pigmentation ranges from minimal to near normal. Most infants develop nystagmus before the age of 3-4 months, which may start off as rapid but usually slows down over time. Strabismus and visual inattention is also present in the first six months of life. Adult visual acuity usually ranges from 20/60-20/100 and does not worsen over time. Iris color ranges from blue to brown. Newborns all have pigmented hair ranging from light yellow to light brown and skin color is creamy white. Hair color may darken over time but does not change after adolescence. In Africans, a phenotype of light brown hair and skin and gray irises occurs, known as brown OCA (BOCA), which is part of the spectrum of OCA2. Patients of other ethnicities with BOCA have almost normal pigmentation. Exposure to sun can overtime lead to rough, coarse and thickened skin along with solar keratoses. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.
Etiology
OCA2 is caused by a mutation in the OCA2 gene (15q12-q13), encoding the OCA2 protein. The precise function of this protein is unknown, however, several studies have reported possible roles in the maintenance of proper intramelanosomal pH or the melanosomal structural matrix. Patients with OCA2 have melanocytes that still produce small amounts of melanin, but it is mostly yellow pheomelanin.
Diagnostic methods
The characteristic clinical findings along with genetic testing are used to diagnose OCA2. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing for a mutation in the OCA2  gene can confirm diagnosis of OCA2 and distinguish it from other forms of OCA.
Differential diagnosis
Differential diagnoses include the other forms of OCA and X-linked recessive ocular albinism (XLOA) as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II. The BOCA phenotype can also be seen in OCA3.
Antenatal diagnosis
Prenatal testing is possible when the disease causing mutation in the parent is known.
Genetic counseling
OCA2 is inherited autosomal recessively and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation), informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
No curative treatment has been found for OCA to date. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions. Periodical ophthalmologic examination is necessary and corrective lenses or glasses are given to improve visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons.
Prognosis
The disease is not life threatening and stabilizes after childhood. However, the medical and social consequences can have an impact on patient's daily life.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI


A form of oculocutaneous albinism (OCA) characterized by rufous or brown albinism and occurring mainly in the African population.

Summary:
Epidemiology
Oculocutaneous albinism type 3 (OCA3) has an estimated prevalence of 1/8,500 individuals in Africa. It is rarely seen in other populations.
Clinical description
Visual anomalies, such as nystagmus, are frequently undetectable and patients usually present with one of two phenotypes: rufous OCA (ROCA), characterized by red-bronze skin color, blue or brown irises and ginger-red hair, or brown OCA (BOCA), characterized by light to brown hair and a light to brown or tan skin color. The clinical features of OCA3 have been considered as rather mild, and in the rare cases of non-African patients, reddish hair color has been reported. A Japanese girl was reported with having OCA3 who presented with blond hair and light skin (with a small Mongolian spot), was able to tan and was negative for nystagmus.
Etiology
OCA3 is caused by a mutation in the tyrosinase-related protein 1, TYRP1, gene located on chromosome 9p23. The majority of BOCA cases are seen in OCA2, but a few BOCA phenotypes have been reported with mutations in the TYRP1 gene, indicating OCA3.
Diagnostic methods
The clinical findings along with genetic testing are used to diagnose OCA3. Hypopigmentation of hair and skin are milder than other forms of OCA and some degree of tanning may be possible. Red reflex on transillumination of the iris and nystagmus are important clues to the diagnosis, however, some patients lack nystagmus or strabismus. Molecular genetic testing for a mutation in the TYRP1  gene can confirm diagnosis of OCA3 and distinguish it from other forms of OCA.
Differential diagnosis
Differential diagnoses include the milder forms of OCA (except for OCA1A), as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II.
Antenatal diagnosis
Prenatal testing is theoretically possible when the disease causing mutation in the parent is known, however, there are no reports of it having been performed.
Genetic counseling
OCA3 is inherited autosomal recessively and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation), informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Annual ophthalmologic examination is necessary and corrective lenses or glasses may be given when the patients have impaired visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.
Prognosis
OCA3 is not life threatening and stabilizes after childhood. However, the medical and social consequences can have an impact on patient's daily life.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI


A form of oculocutaneous albinism characterized by varying degrees of skin and hair hypopigmentation, numerous ocular changes and misrouting of the optic nerves at the chiasm.

Summary:
Epidemiology
The estimated world prevalence of oculocutaneous albinism type 4 (OCA4) is 1/100,000 but it is more common in Japan.
Clinical description
Cutaneous hypopigmentation is often visible at birth and signs of nystagmus and strabismus present in the first year of life. Nystagmus is not always present at birth and can develop at 3 to 4 months of age. It can start off as rapid and slow down in later life and it is usually more noticeable when patients are tired, stressed, anxious or angry. Foveal hypoplasia is associated with a reduction in visual acuity. Alternating strabismus and reduced stereoscopic vision are also noted. Visual changes are not progressive and usually stabilize after childhood. A wide range of clinical phenotypes can be found with OCA4. Iris color can range from blue to brown. Photophobia is common. Hair color in newborns ranges from silvery white to light yellow. It may darken slightly with time (to light brown) but usually remains relatively unchanged. Skin color is usually creamy white. Over time, skin can become coarse, thickened and rough and solar keratoses are common in those who have not limited their exposure to the sun. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.
Etiology
OCA4 is caused by mutations in the membrane-associated transporter protein (MATP) gene, SLC45A2 (5p13.2), encoding a transporter protein which is thought to mediate melanin synthesis. Melanocyte cultures established from a mouse model of OCA4 have demonstrated that tyrosinase processing and trafficking is disrupted before delivery to melanosomes. Patients with OCA4 have melanocytes that still produce small amounts of melanin, but it is mostly yellow pheomelanin.
Diagnostic methods
The characteristic clinical findings along with genetic testing are used to diagnose OCA4. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing for a mutation in the SLC45A2 gene can confirm diagnosis of OCA4 and distinguish it from other forms of OCA.
Differential diagnosis
Differential diagnoses include the other forms of OCA and X-linked recessive ocular albinism (XLOA) as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndromes 1-7, Chediak-Higashi syndrome , Griscelli syndrome, and Waardenburg syndrome type II.
Antenatal diagnosis
Prenatal diagnosis is possible when a parent has been identified to have the disease causing mutation, but it is rarely performed.
Genetic counseling
OCA4 is inherited autosomal recessively and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Ophthalmic care is ongoing and glasses or contact lenses can usually improve visual acuity. In some cases strabismus surgery may be performed. Patients must avoid exposure to sun as this can lead to pachydermia, premalignant lesions and an increased risk of developing skin cancer. A hat with a brim can protect the skin and eyes from the sun's harmful rays and patients should always wear sunscreen and cover exposed skin when outside. Dark glasses can be used to alleviate photophobia. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.
Prognosis
The disease is not life threatening and usually remains stable after childhood. The medical and social consequences can however have an impact on a patient's daily life.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI


A form of oculocutaneous albinism characterized by white skin, golden hair, photophobia, nystagmus, foveal hypoplasia and impaired visual acuity, that affects males and females equally. Patients have been reported only in a consanguineous Pakistani family. The responsible gene has not yet been detected.


A form of oculocutaneous albinism characterized by light hair at birth that darkens with age, white skin, transparent irides, photophobia, nystagmus, foveal hypoplasia and reduced visual acuity.


A form of oculocutaneous albinism (OCA) characterized by skin and hair hypopigmentation (light blond to dark brown), nystagmus, iris transillumination, visual acuity ranging from 6/9 to 3/60 and hypopigmentation of the peripheral ocular fundus. Photophobia is not a major feature.


A type of oculocutaneous albinism characterized by mild hypopigmentation of the skin, hair, and eyes with moderate reduction of visual acuity and nystagmus. The ocular phenotype includes moderate foveal hypoplasia, iris transillumination, and hypopigmentation of the retina.


A group of rare genetic hypopigmentation disorders characterized by a generalized reduction in pigmentation of hair, skin and eyes and variable ocular findings including nystagmus, reduced visual acuity and photophobia. Variants include OCA1A (the most severe form), OCA1B, OCA1-minimal pigment (OCA1-MP), OCA1-temperature sensitive (OCA1-TS), OCA2, OCA3, OCA4, OCA5, OCA6, OCA7 and OCA8.


Oculodental syndrome, Rutherfurd type is a rare genetic disorder that is primarily characterized by the classical triad of gingival fibromatosis, non-eruption of tooth and corneal dystrophy (bilateral corneal vascularization and opacity). Abnormally shaped teeth have also been reported. The syndrome is transmitted as an autosomal dominant trait.


A rare congenital malformation syndrome characterized by craniofacial, ocular, dental, digital anomalies and neurologic symptoms.

Summary:
Epidemiology
Less than 300 cases have been described worldwide, predominantly in Caucasian families. There are some reports in the Asian population.
Clinical description
Oculodentodigital dysplasia (ODDD) is characterized by great phenotypic variability. Typical craniofacial anomalies include thin nose with hypoplastic alae nasi, small anteverted nares and a prominent columella, mandibular overgrowth, cleft palate, and microcephaly. Limb malformations include syndactyly type 3 (involving the fourth and fifth fingers) and/or syndactyly of second to fourth toes, camptodactyly, and clinodactyly due to hypoplasia or aplasia of the middle phalanges. Cranial hyperostosis and broad tubular bones can occur. Ophthalmological anomalies include decreased visual acuity, microphthalmia, microcornea, cataracts, glaucoma, iris abnormalities and optic atrophy. Less often, nystagmus, palpebral fissure hypoplasia, epicanthal folds and convergent strabismus are found. Most patients have abnormal primary and permanent dentition with microdontia, partial anodontia, enamel hypoplasia, multiple caries and early tooth loss. Frequent neurological manifestations vary and include dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures. Some patients have dysplastic ears and conductive hearing loss. Mild global development delay has been described. Brain magnetic resonance imaging may show white matter abnormalities. Brittle nails and hair abnormalities (hypotrichosis and slow growth) may be present. Cardiac anomalies, including arrhythmias or congenital malformations (ventricular septal defect) have been described.
Etiology
ODDD is caused by mutations in the GJA1 gene (6q22-q23), encoding Cx43 protein. Around 70 causative mutations have been identified, resulting in variable ODDD phenotypes. Most missense variants are located in the connexin domain.
Diagnostic methods
Diagnosis is based on clinical findings. Careful phenotype evaluation of facial dysmorphism and digital anomalies, ophthalmological and dental examination, and hand X-ray are required. Neurological symptoms might also be present. The clinical diagnosis can be confirmed by molecular analysis of GJA1 gene.
Differential diagnosis
Differential diagnosis includes syndromes presenting with skeletal, ocular, dental and neurological features. Syndactyly type 3 is also linked with GJA1 mutations.
Antenatal diagnosis
Genetic prenatal diagnosis is theoretically possible if GJA1 mutation has been identified in the family.
Genetic counseling
Inheritance is mostly autosomal dominant (AD) with high penetrance and variable expression. Genetic counselling should be offered to affected individuals and their families. For AD variants, the risk for each pregnancy is 50 %. GJA1 variants may occur de novo. Advanced paternal age has been noted in sporadic cases. A few families with autosomal recessive inheritance have been reported in the recent years.
Management and treatment
Management is multidisciplinary. Early recognition is crucial to prevent and treat the variety of clinical manifestations. Follow-up should include a complete eye, neurological, hearing and dental evaluation. As blindness due to glaucoma can occur, patients at risk should receive anti-glaucoma treatment. Neurological symptoms may be subtle or appear only late in life. Instrumental tests can detect structural anomalies if no symptoms are present. Cardiac arrhythmias have been associated with ODDD and may require cardiologist monitoring. Plastic or orthopedic surgery is indicated for severe limb malformations.
Prognosis
Prognosis varies based on the severity. Functional, social and psychological care help to lessen the impact on the everyday life. Life expectancy depends on other system (neurological and cardiac) involvement. In cases of cardiac involvement, there is a risk of progressive heart failure. However, further understanding of cardiac anomalies in ODDD is needed.

                            Last update:
                            August 2021

                            - Expert reviewer(s):
                            Dr Ausra MATULEVICIENE | ITHACA*

                                * European Reference Network


A rare ectodermal dysplasia characterized by the association of epibulbar dermoids and aplasia cutis congenital.


Oculo-facio-cardio-dental syndrome (OFCD) is a very rare multiple congenital anomaly syndrome characterized by dental radiculomegaly, congenital cataract, facial dismorphism and congenital heart disease.

Summary:
Epidemiology
To date, 20 cases have been reported worldwide.
Clinical description
The most consistent and pathognomic dental finding of OFCD is radiculomegaly (extremely long roots), particularly of the canines and occasionally of other teeth including premolars and incisors. The dental eruption in both the deciduous and the permanent dentition is consistently slow and delayed. Oligodontia, fused teeth, supernumerary teeth, malformed permanent teeth, enamel defects, root dilacerations, malposition and malocclusion, have also been reported. Ocular abnormalities include bilateral congenital cataracts, microphthalmia, regressive vision impairment, secondary glaucoma, and ptosis. Exotropia is very common. The facial features described include a long narrow face, high nasal bridge, broad nasal tip with separated nasal cartilages, laterally curved and thick eyebrows, long philtrum, clefts of the hard/soft palate. Cardiac defects reported include ventricular septal defect, atrial septal defect, mild cardiomegaly, ventricular and atrial hypertrophy, benign peripheral pulmonic stenosis, mitral valve prolapse. Occasional reports have noted skeletal findings (syndactly of the second and third toes, hammer-type flexion of the second and fourth toes, radio-ulnar synostosis, and vertebral and rib anomalies), intestinal malrotation, hearing impairment, intellectual and psychomotor deficit.
Etiology
The BCOR gene on chromosome Xp11.4 is causative, however its exact function remains unknown.
Diagnostic methods
Diagnosis of OFCD is hard for medical specialists and the syndrome is often unrecognized. The specific dental findings (visible on a panoramic radiograph of the jaws) can be easily diagnosed by an orthodontist or a dentist.
Genetic counseling
OFCD is an X-linked dominant syndrome that is lethal in males.
Management and treatment
Management requires appropriate cardiac, ophthalmic and dental care.

                            Last update:
                            November 2007

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Oculogastrointestinal muscular dystrophy is an extremely rare autosomal recessively inherited neuromuscular disease characterized by ocular manifestations such as ptosis and diplopia followed by chronic diarrhea, malnutrion and intestinal peudo-obstruction.


Oculomaxillofacial dysostosis is a rare, genetic bone developmental disorder characterized by short stature, orbital region and ocular abnormalities (e.g. asymmetric orbits, anophthalmia, down-slanted and S-shaped palpebral fissures, sparse eyebrows/eyelashes, abnormal eyelids, ectropion, symblepharon, corneal leukoma), abnormal nose (e.g. broad and abnormally modeled nasal root, bridge and tip, lateral deviation), malar hypoplasia, cleft lip/palate, and oblique facial clefts. Intellectual disability, microcephaly, micrognathia and limb anomalies (e.g. hemimelia, abnormal scapular girdle, brachydactyly, syndactyly, broad halluces) have also been reported.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by short stature and particularly pronounced shortening of the third to fifth metacarpals and metatarsals, congenital anodontia, sparse hair, dyspigmentation of the skin, hypoplastic nipples and underdeveloped external genitals in females, and multiple ocular abnormalities (such as distichiasis, strabismus, nystagmus, lenticular opacities, and severe myopia, among others). Dysmorphic craniofacial features include brachycephaly, downslanting palpebral fissures, broad nasal root, low-set ears, and small maxilla and prominent mandible. There have been no further descriptions in the literature since 1968.


A contiguous gene syndrome comprising otodental syndrome (characterized by globodontia and sensorineural high-frequency hearing deficit) associated with eye abnormalities including, typically, iris and chorioretinal coloboma, as well as, on occasion, microcornea, microphtalmos, lenticular opacity, lens coloboma and iris pigment epithelial atrophy.


A rare, adult-onset, progressive myopathy characterized by progressive eyelid ptosis, ophthalmoplegia, dysphagia, dysarthria and proximal limb weakness.

Summary:
Epidemiology
Oculopharyngeal muscular dystrophy (OPMD) occurs worldwide with varying prevalence rates. The estimated prevalence rate in Europe is 1/100,000-200,000. The highest prevalence rate of 1/1,000 is found in French Canadians in Quebec and 1/600 in Israel's Bukharan Jews.
Clinical description
Disease onset occurs in the fifth to sixth decade of life. Early signs include ptosis, ophthalmoplegia without diplopia, limb weakness, dysarthria and dysphagia. Symptoms usually begin after the age of 45 years, and ptosis is the most common presenting feature. Other signs that occur as the disease progresses include tongue weakness and atrophy, proximal upper and lower extremity weakness, dysphonia, dysarthria, facial muscle weakness, and limitation of upward gaze. In several cases, limb weakness has preceded dysphagia. In 5-10% of patients, the disease is more severe, with ptosis and dysphagia presenting before the age of 45 and incapacitating distal leg weakness occurring before the age of 60. The manifestations of autosomal recessive OPMD usually present later (after the age of 60) than those of the autosomal dominant form.
Etiology
OPMD is caused by an expansion in the polyalanine tract in the PABPN1 gene (14q11.2), which leads to overexpression of a mutant protein, polyadenylate-binding protein 2, and consequently to the accumulation of nuclear aggregates in the muscles.
Diagnostic methods
OPMD is diagnosed by genetic confirmation of a mutation in the PABPN1 gene. Supportive evidence comes from the family history, late-onset clinical characteristics, and muscle biopsy findings (tubulofilamentous inclusions in the nuclei of myocytes using electron microscopy, as well as muscle fibers containing rimmed vacuoles). However, a muscle biopsy is not needed for diagnosis and is nowadays rarely performed. Creatine kinase (CK) levels can be slightly elevated and electromyogram (EMG) studies may suggest a mild myopathic process.
Differential diagnosis
Differential diagnoses include first and foremost myasthenia gravis, mitochondrial myopathies, and myotonic dystrophy type 1. Other less likely but possible differential diagnoses are oculopharyngodistal myopathy, proximal myotonic myopathy, congenital fibrosis of extraocular muscles, blepharophimosis-epicanthus inversus-ptosis syndrome, and autosomal dominant distal myopathy.
Antenatal diagnosis
Prenatal diagnosis is possible, but as this condition presents in adulthood, it is very rarely performed.
Genetic counseling
OPMD is inherited autosomal dominantly in the vast majority of cases, but can be found recessively in certain regions. Genetic counseling is possible when a PABPN1 mutation has been identified in a family.
Management and treatment
No pharmacological treatment is presently available, but surgical treatments are offered that can help with ptosis and dysphagia. A blepharoplasty can treat ptosis when the eyelids cover more than 50% of the pupils or when neck pain is present. A cricopharyngeal myotomy or botulinum toxin injection of the cricopharyngeal muscle can be performed to achieve normal swallowing, but dysphagia usually recurs years after surgery. The intake of dietary supplements and a diet of foods that are soft and easy to swallow are often necessary. Some patients may need a wheelchair if muscle atrophy is severe.
Prognosis
Ptosis and dysphagia typically recur within five to fifteen years after surgery. There is usually no decrease in life expectancy, but quality of life can be reduced in those where the disease is debilitating. Premature death, if it happens, is usually due to aspiration pneumonia or malnutrition (with severe weight loss) in elderly patients.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr John VISSING


A rare, genetic neuromuscular disease characterized by progressive external ocular, facial and pharyngeal muscle weakness, leading to variable degrees of ptosis, ophthalmoparesis, facial muscle atrophy, dysarthria and dysphagia, as well as distal muscle weakness and atrophy of lower and upper extremities. Respiratory muscle involvement is common, but sensorineural hearing loss, asymmetrical extremity weakness and severe proximal weakness are rare.


A rare ciliopathy characterized by congenital cataract with secondary glaucoma, developmental delay, short stature, multiple skeletal abnormalities (spinal deformities, limb anomalies, delayed bone age), dental anomalies (oligodontia, enamel defects), dysmorphic facial features (including coarse facies, low hairline, epicanthal folds, flat and broad nasal bridges, and retrognathia), and stroke. Other recurrent manifestations are hearing loss and nephrocalcinosis.


Oculotrichoanal syndrome is a form of rare, multiple congenital anomalies/dysmorphic syndrome characterized by a combination of various nose, eye, gastrointestinal and genitourinary abnormalities. Clinical presentation is variable and often includes bifid and broad nasal tip, aberrant anterior hairline, coloboma, cryptophthalmos or unilateral anophthalmia, anal anomalies, and omphalocele. Intelligence and global development is normal.


A rare ectodermal dysplasia syndrome characterized by bilateral retinitis pigmentosa, trichodysplasia (generalized hypotrichosis, structural changes), dental anomalies, onychodysplasia, and dry and scaly skin. There have been no further descriptions in the literature since 1988.


Odonto-onycho dysplasia-alopecia syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by almost total alopecia with only sparse, thin, brittle, slow-growing scalp hair, fair and sparse eyebrows and eyelashes, absent axillary and pubic hair, fragile and brittle fingernails, thick and brittle toenails (both with a subungual corneal layer), hypodontia, microdontia, widely spaced teeth with hypoplastic enamel, mild palmoplantar keratosis, café-au-lait spots and areolae anomalies. There have been no further descriptions in the literature since 1985.


A rare, genetic, ectodermal dysplasia syndrome characterized by dental abnormalities (primarily agenesis of the permanent and deciduous teeth with cone-shaped incisors and canines), onychodysplasia, palmoplantar hyperkeratosis, dry skin and, more variably, hypotrichosis, and sweat gland dysfunction (hyper- or hypohidrosis).


A rare ectodermal dysplasia syndrome characterized by neonatal teeth, trichodystrophy (with straw-like, discolored and fragile hair), onychodystrophy, and malformation of the hands and feet consisting of simian-like hands with transverse palmar creases and prominent interdigital folds, brachydactyly, and marked shortness of the first metacarpal and metatarsal bones with hypoplasia of the distal phalanges. There have been no further descriptions in the literature since 1997.


A rare primary bone dysplasia characterized by the association of spondylometaphyseal dysplasia, generalized joint laxity, and dentinogenesis imperfecta. Main skeletal abnormalities comprise short stature, narrow chest, scoliosis, mesomelic limb shortening, and brachydactyly. Radiographic features include severe metaphyseal irregularities of the tubular bones, platyspondyly with coronal clefts, cone-shaped epiphyses of the hands, square iliac wings, and coxa valga. Additional extraskeletal manifestations like pulmonary hypoplasia, cystic renal disease, and non-obstructive hydrocephalus have also been reported.


A particular form of hypophosphatasia (HPP) characterized by reduced activity of unfractionated serum alkaline phosphatase, premature exfoliation of primary and/or permanent teeth and/or severe dental caries, in the absence of skeletal system abnormalities.

Summary:
Epidemiology
The prevalence of odonto-HPP is not known. It is thought that odonto-HPP is the most frequent form of HPP because 74% of the cases are heterozygotes.
Clinical description
The main feature of odontohypophosphatasia is premature exfoliation of fully rooted primary teeth and/or severe dental caries. The anterior deciduous teeth are most commonly affected along with the incisors. X-rays reveal reduced alveolar bone, reduced thickness of dentin, and enlarged pulp chambers and root canals. Patients with other forms of HPP often have dental manifestations but these are always associated with skeletal abnormalities and other manifestations.
Etiology
Mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. Specific mutations are thought to underlie this phenotype and its variable severity.
Diagnostic methods
Diagnosis is based on clinical presentation, dental panorex and laboratory findings, and can be confirmed by genetic testing.
Differential diagnosis
Other causes for premature exfoliation should be excluded. The presence of bone symptoms (osteomalacia, fractures) distinguish adult HPP from odontohypophosphatasia.
Genetic counseling
Autosomal recessive and autosomal dominant patterns of inheritance are reported in odonto-HPP.
Management and treatment
Management is with observation and supportive measures such as implementation of an oral health program, protection of the existing teeth, and aesthetic and functional restoration of the mouth (with braces or other dental devices).
Prognosis
Loss of teeth may have functional and aesthetic consequences. Overall prognosis is generally good.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Severine BACROT  - Dr Etienne MORNET


Odontomatosis-aortae esophagus stenosis syndrome

Odontoma-dysphagia syndrome is a malformation syndrome, characterized by odontomas (undifferentiated mass of the esophagus) and severe dysphagia.

Summary:
Epidemiology
Less than ten cases have been reported so far.
Clinical description
Three of the reported patients manifested multiple odontomas. Occasionally, cardiac (stenosis of the intrathoracic descendent aorta, interstitial myocarditis), renal (pyelonephritis) and hepatic (hepatic sclerosis) involvement has been described.
Etiology
Hypertrophy and dysmotility of the esophageal smooth muscles is suggested to have causative role for dysphagia.
Genetic counseling
In several cases, autosomal dominant inheritance has been suspected. Currently, there are no genes associated with this condition.

                            Last update:
                            July 2009

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


A rare, hereditary ectodermal dysplasia syndrome characterized by involvement of teeth and nails - precocious eruption and shedding of deciduous dentition, precocious eruption of secondary dentition with short, rhomboid roots, and short, thin, slow growing nails.


A rare genetic disease characterized by intellectual disability, growth delay, absence deformities of upper and lower limbs, hypotrichosis, hypoplastic nails, abnormal dentition, abnormal auricles, hypoplastic nipples, thyroid enlargement, and abnormalities of tyrosine and/or tryptophane metabolism. Hypogonadism and cleft lip have also been reported. No new cases have been confirmed since 1970.


Off-periods in Parkinson disease not responding to oral treatment

A rare clinical situation occurring in the context of Parkinson disease characterized by return or worsening of symptoms (including motor and/or non-motor symptoms) under antiparkinsonian therapy. Types of off-periods are Morning Off (experienced before the first dose of the day), Delayed On (occurring more frequently after the first dose of the day or after meals), Wearing Off (end-of-dose deterioration), Sudden Off (sudden transition from on to off), and Dose Failure.


Ogden syndrome is a rare, genetic progeroid syndrome characterized by a variable phenotype including postnatal growth delay, severe global developmental delay, hypotonia, non-specific dysmorphic facies with aged appearance and cryptorchidism, as well as cardiac arrthymias and skeletal anomalies. Patients typically present with widely opened fontanels, mainly truncal hypotonia, a waddling gait with hypertonia of the extremities, small hands and feet, broad great toes, scoliosis and redundant skin with lack of subcutaneous fat.


Oguchi disease is an autosomal recessive retinal disorder characterized by congenital stationary night blindness (see this term) and the Mizuo-Nakamura phenomenon.

Summary:
Epidemiology
Oguchi disease is a very rare condition with approximately 50 cases described in the literature to date. It was originally discovered in Japan where the prevalence is the highest but has been found occasionally in European, American, Pakistani and Indian patients.
Clinical description
The disease is characterized by congenital stationary night blindness and the Mizuo-Nakamura phenomenon which is a unique morphological and functional abnormality of the retina that presents with a typical golden-yellow or silver-gray discoloration of the fundus in the presence of light that disappears after dark-adaptation and appears again after the onset of light. Patients have non progressive night blindness since young childhood with normal day vision, but they often claim improvement of light sensitivities when they remain a long time in a dark environment. Eye fundus shows the Mizuo-Nakamura phenomenon as the only fundus feature. A prolonged dark adaptation of 3 hours or more leads to disappearance of the Mizuo-Nakamura phenomenon fundus changes. No evidence of spicules, macular changes or chorioretinal atrophy is observed. Normal visual acuity, normal caliber of retinal blood vessels and usually normal cone response on electroretinogram (ERG) recording suggest retinal dysfunction rather than degeneration.
Etiology
Oguchi disease is caused by mutations in the SAG gene coding for arrestin located on chromosome 2q37(Oguchi type 1) or by mutations in the GRK1 gene that codes for the rhodopsin kinase located on the chromosome 13q34 (Oguchi type 2). Remarkably, some mutations in the SAG gene are associated with Oguchi disease and retinitis pigmentosa (RP) in the same family. Some mutations in SAG lead to RP.
Diagnostic methods
The diagnosis is clinical and is based on the presence of night blindness and the observation of the Mizuo-Nakamura phenomenon by funduscopy and electroretinography (ERG). The clinical diagnosis is confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes Stargardt disease, RP in female carriers, juvenile retinoschisis, and progressive cone dystrophy (see these terms). All these conditions may have fundus changes but without the classical Mizuo-Nakamura phenomenon.
Genetic counseling
Oguchi disease is an autosomal recessive condition. Brothers and sisters of an affected case have a 25% risk to be also affected.
Management and treatment
To date, there is not a specific treatment for Oguchi disease.
Prognosis
In Oguchi disease the visual prognosis is good in absence of progression of symptoms. Although Oguchi disease is categorized as a stationary condition it can lead to reduced visual acuity or constricted visual fields, especially in older patients.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Elena ALLER  - Dr Carmen AYUSO  - Dr José María MILLÁN SALVADOR


A rare multiple congenital anomalies syndrome characterized by the association of uni- or bilateral radial defects, uni- or bilateral Duane anomaly (congenital limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure), renal abnormalities, sensorineural and/or conductive hearing loss, and, less frequently, imperforate anus and scoliosis.

Summary:
Epidemiology
To date, 125 patients from 38 families have been reported.
Clinical description
Okihiro syndrome has been originally characterized by the association of radial defects, Duane anomaly and deafness. Uni- or bilateral radial defects are observed in more than 90% of the patients and range from isolated thenar hypoplasia and/or hypoplasia or aplasia of the thumbs (40%) to hypoplasia or aplasia of the radii (30%), with sometimes ulnar or humeral hypoplasia (10%). Triphalangeal thumbs and pre-axial polydactyly have also been reported (20%). Duane anomaly is observed in 50% of the patients (bilateral in 20%). Renal abnormalities may include kidney ectopia, and rarely renal hypoplasia or horseshoe kidney. Sensorineural or conductive deafness is observed in 30% of the patients, sometimes associated with ear dysplasia. Heart defects (10%), such as ventricular or atrial septal defects, tetralogy of Fallot, or conduction disturbances (5%) have also been reported. Scoliosis is observed in 10% of patients. Gastrointestinal manifestations (anal stenosis, imperforate anus, choanal atresia) could be associated.
Etiology
Okihiro syndrome is caused by heterozygous variants in SALL4 gene (20q13.2). The phenotypes caused by SALL4 deletions are not different from those caused by point mutations.
Diagnostic methods
Okihiro syndrome is suspected on clinical findings and sometimes on family history. Careful clinical examination (sometimes upper limb defects can be mild, such as thenar hypoplasia), a complete eye examination by an ophthalmologist with special attention to extraocular movements, and hearing tests are required. Abdominal and cardiac ultrasound, spinal X-rays and complete blood cell count should be performed to look for associated features, sometimes suggesting a differential diagnosis. The clinical suspicion can be confirmed by SALL4 molecular analysis.
Differential diagnosis
The phenotype overlaps with Holt-Oram syndrome, Townes-Brocks syndrome Fanconi anemia, VACTERL/VATER association, isolated Duane retraction and fetal valproate syndrome.
Antenatal diagnosis
Some features can be diagnosed during pregnancy, such as severe limb involvement, heart defects or renal abnormalities. Genetic prenatal diagnosis is possible if the pathogenic variant has previously been identified in a family member.
Genetic counseling
Okihiro syndrome is an autosomal dominant genetic condition. Genetic counseling should be provided to affected individuals and their families informing them that, for each pregnancy, there is a 50% risk of disease transmission from an individual with a pathogenic variant to their offspring. The phenotype is highly variable and mostly fully penetrant. SALL4 variants may occur de novo. Parental segregation analysis should be performed, even in absence of symptoms, to determine genetic counselling.
Management and treatment
Management is multidisciplinary and includes, at diagnosis, ophthalmological, cardiac, renal, hearing and genetic evaluations. Treatment depends on manifestations: limb, eye and/or heart surgery, occupational therapy, limb prothesis, orthoptic reeducation, physiotherapy, hearing aids, pacemaker. Surveillance depends on manifestations. Electrocardiogram is recommended regularly for adults. The social and psychological impact of the condition should be assessed and assisted. Women with Okihiro syndrome and cardiac defects should be evaluated by a cardiologist to determine what monitoring and care may be needed during pregnancy.
Prognosis
Prognosis is highly variable, according to the severity of the clinical manifestations, and their functional, social and psychological impacts in everyday life. Life expectancy depends on the severity of heart defects and renal function.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Clémence VANLERBERGHE | ITHACA*

                                * European Reference Network


A rare inflammatory rheumatic disease characterized by juvenile onset arthritis that affects fewer than 5 joints during the first 6 months after disease onset.

Summary:
Epidemiology
The incidence of juvenile idiopathic arthritis in Caucasians is 8.3/100,000. Oligoarticular juvenile idiopathic arthritis is the most common form in North America and Europe, comprising 30% to 60% of children with juvenile idiopathic arthritis. It affects girls more than boys and is rare in individuals of African, Native American or Sourthern Asian descent.
Clinical description
The disease is typically asymmetrical, affecting between one to four joints, predominantly those of the lower limbs (knee or foot) although the wrist and elbows could be rarely affected. Onset occurs between the ages of 2 and 4. The disease is divided into persistent oligoarthritis, in which there is no more than 4 joints involved after the first six months of illness, and extended oligoarthritis, in which there is involvement of more than 4 joints involved after the first six months. Pain is not a constant feature in young children and the most common reasons for seeking medical advice are an increase in the volume of the joint and/or limping. The association of this form of arthritis with nonsymptomatic iridocyclitis (no pain or visible redness) is a specific feature that is present in a third of cases. Systemic manifestations other than uveitis are characteristically absent. Therefore, fever, rash, or other constitutional symptoms suggest a different diagnosis.
Etiology
The etiology is not currently known. All juvenile idiopathic arthritis subtypes are most likely complex genetic traits as they lack single-gene, Mendelian patterns of inheritance. Inherited risk factors for both disease susceptibility and disease severity have been reported; the highly polymorphic HLA genes confer the strongest genetic effects.
Diagnostic methods
Diagnosis is based on the clinical manifestations, and exclusion of other potential causes. The presence of iridocyclitis and/or antinuclear antibodies without fever or psoriasis are strong diagnostic indicators. Exclusion criteria includes presence of systemic arthritis, psoriasis, ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient or a first-degree relative. In addition, HLA B27-positivity in males with onset of arthritis after 6 years of age and presence of rheumatoid factor IgM must be excluded.
Differential diagnosis
Differential diagnosis principally includes the other subtypes of juvenile idiopathic arthritis as well as Lyme disease, inflammatory bowel disease, pigmented villonodular synovitis, malignancy, plant thorn synovitis, septic arthritis, osteomyelitis, or tuberculosis.
Management and treatment
First step of treatment is non-steroidal anti-inflammatory agent (NSAID) , but their efficacy is quite rare. Intra-articular glucocorticoids injections are often necessary and effective. Methotrexate and, if ineffective, biologics are recommended for children with disease that extends to involve five or more joints or require repeat injections.
Prognosis
Several long-term complications may occur, the most frequent and significant ones being temporomandibular joint arthritis with retrognatism, uveitis complications (glaucoma or synechia), leg-length discrepancy in case of delayed diagnosis. Arthritis may extend to involve five or more joints within several years of diagnosis.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Chantal DESLANDRE


Oligoastrocytoma is a type of low-grade glioma with a mixed astrocytoma and oligodendroglioma histology, manifesting with headaches, speech and motor problems, seizures and, in some, subarachnoid haemorrhage.


A rare non-progressive form of cone photoreceptor dysfunction syndrome characterized by reduced visual acuity, normal fundus appearance and absent or reduced cone responses on electroretinography. In contrast to all other forms of cone dysfunction color vision is normal.

Summary:
Epidemiology
The syndrome is very rare with less than 15 cases reported in the literature so far.
Clinical description
Individuals with this disorder have reduced visual acuity from a young age and usually have a mild degree of photophobia. Best corrected visual acuity is usually in the range of 6/12 to 6/36. Fundus examination is normal. Electroretinography demonstrates absent or markedly abnormal cone responses; rod responses are normal. Color vision testing is usually normal but some patients show a very mild reduction in color discrimination. This is in contrast to other forms of inherited cone dystrophy where color vision is severely impaired.
Etiology
The causative gene has not been identified. There have been a few reports of patients with a similar phenotype who have mutations in genes normally associated with achromatopsia but the phenotype is atypical and more suggestive of an incomplete form of achromatopsia. One suggestion is that oligocone trichromacy (OT) is a very mild form of incomplete achromatopsia but this is not supported by current molecular genetic data. The reason for the presence of normal color vision despite the reduced visual acuity and electrophysiological evidence of severe cone dysfunction is uncertain. It has been proposed that patients with OT may have reduced numbers of normal functioning cones with preservation of the three cone types in normal proportions thereby enabling normal color vision (trichromacy). This hypothesis is supported by the findings of adaptive optics scanning laser ophthalmoscopic imaging (AOSLO) of the cone mosaic in patients with OT where there are reduced numbers of functioning cones in the fovea.
Diagnostic methods
Diagnostic methods include color vision testing, retinal imaging and electroretinography (ERG). Molecular genetic testing is also helpful in excluding other forms of cone dystrophy.
Differential diagnosis
Differential diagnosis should include other cone dysfunction syndromes, namely achromatopsia, Blue cone monochromatism and X-linked cone dysfunction syndrome with myopia, where there is reduced or absent color vision. The disorder also needs to be distinguished from bradyopsia where extended ERG testing beyond the ISCEV (International Society for Clinical Electrophysiology of Vision) standard needs to be performed to distinguish this rare disorder from OT. Molecular genetic testing using next generation sequencing of retinal disease gene panels will also help distinguish these disorders (where the molecular genetic basis is known) from OT.
Genetic counseling
Although most reported cases are sporadic, the disorder is likely to be inherited as an autosomal recessive trait as a number of affected sibling pairs have been reported. One family has been reported in which there may be dominant inheritance with incomplete penetrance. Affected individuals and their families should be counselled on the basis that the inheritance is likely to be autosomal recessive (unless the family history suggests otherwise).
Management and treatment
There is no effective treatment for the underlying retinal disorder. Patients should be provided with accurate visual aids: eyeglasses that can be tinted if photophobia is a prominent feature. The minority of patients with more severe visual loss may benefit from low vision aids.
Prognosis
Although few patients with this disorder have been followed up long term, it appears that the prognosis is good as the disorder is usually non-progressive.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Tony MOORE


Oligodendrogliomas are cerebral tumors that are differentiated from other gliomas on the basis of their unique genetic characteristics and better response to chemotherapy. These tumors are classified according to their grade (low grade oligodendrogliomas: grade II of the WHO classification and anaplastic oligodendrogliomas: grade III of the WHO classification) and according to their pure or mixed histology (oligoastrocytomas).

Summary:
Epidemiology
Until now, the incidence of these tumors has been largely underestimated. Oligodendrogliomas may represent up to 30% of all adult gliomas. Annual incidence can therefore be estimated at around one new case per 100,000 individuals per year. Prevalence is estimated at 1/300,000.
Clinical description
Low grade tumors are usually diagnosed after a prolonged history of seizures and headaches. Clinical presentation of malignant forms is usually more acute with rapidly progressive neurological deficits and signs of intracranial hypertension (headaches and vomiting). Malignant forms can arise from transformation of a benign tumor several years after its diagnosis. These tumors may develop anywhere in the central nervous system but arise most frequently in the cerebral hemispheres.
Etiology
The etiology is not known but no hereditary forms of oligodendroglioma have been reported. However, specific genetic characteristics, such as loss of chromosomes 1p and 19q, are observed.
Diagnostic methods
MRI may reveal infiltration of the brain parenchyma. Enhancement after contrast injection is indicative of an aggressive and malignant oligodendroglioma.
Differential diagnosis
The differential diagnosis should include low grade astrocytomas (see this term).
Management and treatment
Treatment starts with surgery. Radiotherapy is mandatory for malignant tumors, regardless of the extent of the surgical resection. Chemotherapy is beneficial and is often used during treatment of the initial tumor and for treatment of a recurring malignant oligodendroglioma. In the case of low grade partially resected tumors, chemotherapy now tends to replace radiotherapy as thefirst-line treatment. Management requires a multidisciplinary team with experience in neuro-oncology. The treatment protocol should follow the recommendations resulting from prospective studies.
Prognosis
The prognosis is usually better than that for other gliomas, such as astrocytomas. As a result of combined treatment with surgery, chemotherapy and radiotherapy, survival rates in patients without recurrence are also good, even for patients with malignant (anaplastic) tumors.

                            Last update:
                            November 2007

                            - Expert reviewer(s):
                            Dr Jacques GRILL


A rare glial tumor characterized by a highly cellular lesion that is diffusly infiltrating at the periphery and consists of evenly-spaced monomorphic cells with the oligodendroglial phenotype. It typically occurs in the supratentorial white matter. Histologically, the cells are uniformly round to oval with round nuclei, delicate chromatin and small nucleoli. Most patients present with seizures.


A rare, genetic, odontologic disease characterized by congenital absence of six or more permanent teeth (excluding the third molars) in association with an increased risk for malignancies, ranging from gastrointestinal polyposis to early-onset colorectal cancer and/or breast cancer. Ectodermal dysplasia (manifesting with sparse hair and/or eyebrows) may also be associated.


Oligodontia is a rare developmental dental anomaly in humans characterized by the absence of six or more teeth.

Summary:
Epidemiology
The prevalence of isolated oligodontia is unknown. In European populations the estimated prevalence of both syndromic and non-syndromic oligodontia varies from 1/625 to 1/1,250 depending on the studies.
Clinical description
Clinical features of oligodontia include six or more missing teeth, lack of development of maxillary and mandibular alveolar bone height and reduced lower facial height. Variation in tooth morphology is also observed along with problems in tooth development, eruption and exfoliation.
Etiology
Possible causes of oligodontia include viral disease during pregnancy, genetic predisposition, metabolic imbalances, developmental abnormalities and environmental factors. Autosomal dominant mutations in PAX9 and MSX1 have been found in patients with molar non-syndromic oligodontia. The most recent gene identified as causing oligodontia is an autosomal recessive mutation in LTBP3 which was found in one case. WNT10A gene mutations, responsible for autosomal recessive forms of HED, odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (see these terms) are also seen in a substantial proportion (30 to 50% cases according to studies) of non-syndromic oligodontia cases. EDA and EDARADD, genes involved in different forms of X-linked and hypohidrotic ectodermal dysplasia (HED, see this term), are also mutated in non-syndromic oligodontia. The dental phenotype associated with autosomal dominant HED is usually less severe than that seen in autosomal recessive HED. Oligodontia-cancer predisposition syndrome (see this term) is due to AXIN2 gene mutations. IKBKG gene mutations are also associated to syndromic oligodontia, observed in incontinentia pigmenti and HED with immunodeficiency (see these terms).
Diagnostic methods
Clinical examination along with a panoramic radiograph (and intra-oral X-rays if needed) is performed when teeth are thought to be missing. Delayed eruption of teeth, persistence of primary teeth, alveolar bone hypotrophy, and the presence of diastemas all suggest a diagnosis of oligodontia. In normal conditions all primary teeth and crypts of permanent first molars are visible on radiography at birth and crowns of permanent teeth (except third molars) at 6 years of age. When more than six teeth are absent then a diagnosis of oligodontia is given.
Differential diagnosis
Isolated oligodontia should be distinguished from syndromic forms. Oligodontia is seen in X-linked hypohidrotic ectodermal dysplasia with immunodeficiency (HED), ECC syndrome, orofaciodigital syndrome type I and oral facial clefting syndromes such as Van Der Woude syndrome, Ellis-Van Creveld syndrome or Rapp-Hodgkin syndrome, hidrotic ectodermal dysplasia, focal facial dermal dysplasia (see these terms), oligodontia-taurodontism-hypotrichosis syndrome or trichothiodystrophies.
Antenatal diagnosis
Genetic antenatal diagnosis is possible but is never performed.
Genetic counseling
Genetic counseling is necessary to exclude syndromic oligodontia and discuss issues related to inheritance.
Management and treatment
Treatment of oligodontia requires a multidisciplinary approach. Prosthetic treatment includes removable partial dentures, fixed partial dentures and over dentures. Osseointegrated dental implants are also possible when there is adequate bone height as they offer a more stable, long-term solution. Early implant therapy consists of the placement of 2 symphyseal implants from the age of 6 years old, allowing for the stabilization of a mandibular prosthesis that will be modified regularly to follow mandibular bone growth. Maxillary implants are placed upon the completion of skeletal growth.
Prognosis
With proper dental treatment, patients can have normal dentition and orofacial functions

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN  - Dr François CLAUSS


A rare kidney malformation characterized by a reduction of 80% in nephron number and a marked hypertrophy of the glomeruli and tubules.

Summary:
Epidemiology
Prevalence is unknown. The male to female ratio is of 3:1.
Clinical description
Oligomeganephronia is usually detected on routine ultrasound screening with small but normal shaped kidneys. Birth weight is often below the average value. Patients may present at birth with polyuria/polydipsia or signs of kidney dysfunction. During the first year of life, the usual symptom is persistent anorexia with vomiting, fever, and growth delay. Chronic kidney disease typically occurs during childhood or adolescence. Adult-onset oligomeganephronia has been reported in some rare cases.
Etiology
The etiology of oligomeganephronia is not fully understood, but is hypothesized to be caused by premature termination of nephrogenesis. This may be linked to the same factors as renal hypoplasia, but with a more severe reduction in nephron numbers. Such factors include intrauterine growth restriction, maternal diseases (diabetes, hypertension), maternal drug intake (inhibitors of the renin-angiotensin system or non-steroidal anti-inflammatory drugs (NSAIDs)) or intoxication (smoking and alcohol). Premature birth (before the 36th week) is also a risk factor due to incomplete nephrogenesis. Oligomeganephronia can occur as part of a multi-organ syndrome such as renal coloboma syndrome, which is caused by mutations in the PAX2 gene (10q24.31), or can be caused by chromosomal disorders including 22q11 deletion syndrome or Wolf-Hirschhorn syndrome.
Diagnostic methods
Diagnosis can be suspected by bilateral, small and echogenic kidneys on ultrasound. CT-scan may, in addition to small, normal-shaped kidneys, show a thickened cortex and medulla with striated nephrograms. The diagnosis is confirmed histologically by a reduced number of nephrons, hypertrophic glomeruli with diameters being two to three times the normal size, hypertrophic tubules and thickening of Bowman's capsule. Both kidneys are symmetrically affected.
Differential diagnosis
Differential diagnosis includes renal dysplasia, nephronophthisis, autosomal dominant tubulointerstitial kidney disease, kidney infarction or ischemic kidney disease, and diffuse kidney parenchymal disease.
Antenatal diagnosis
Antenatal ultrasonographic screening allows detection of oligomeganephronia from midway through gestation.
Genetic counseling
Most cases are sporadic, but familial occurrence has been described.
Management and treatment
Angiotensin-converting-enzyme inhibitors may slow the progression of the disease. Once having reached the stage of kidney failure, management includes a dialysis-transplantation program.
Prognosis
With the increasing metabolic demands on the kidney during growth, a decline in kidney function is seen resulting in chronic kidney disease at a mean age of 10 years (range 6 months to 20 years).

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr M.F. [Michiel] SCHREUDER | ERKNet*

                                * European Reference Network


Oliver syndrome is a very rare syndrome characterized by intellectual deficit, postaxial polydactyly, and epilepsy.

Summary:
Epidemiology
To date, seven individuals in three families have been reported.
Clinical description
Facial features are not characteristic except for a prominent jaw. Concordant features in all subjects are postaxial polydactyly, which in four individuals affect also the feet, and intellectual deficit, which is usually severe, with absent or indistinct speech. Seizures are common with onset in the first months of life or in early childhood. Cutaneous syndactyly, camptodactyly and clinodactyly of fingers and brachydactyly and syndactyly of the toes have been recorded.
Genetic counseling
The condition is probably hereditary, and transmitted as an autosomal recessive trait.

                            Last update:
                            March 2010


Olivopontocerebellar atrophy-deafness syndrome is characterised by infancy-onset olivopontocerebellar atrophy, sensorineural deafness and speech impairment. It has been described in less than 15 children. Most cases were sporadic, but autosomal recessive inheritance was suggested in three cases.


A rare primary bone dysplasia characterized by multiple enchondromas (benign cartilage-forming tumors). The lesions are generally unilateral or asymmetrically distributed. The most common affected site is the appendicular skeleton.

Summary:
Epidemiology
Prevalence of Ollier disease (OD) is estimated at 1/100,000, but mild presentations without skeletal deformities may be underdiagnosed. OD is approximately evenly represented in both sexes.
Clinical description
Clinical expression of the disease is variable, it can involve a single bone segment or multiple limbs. The lesions develop during childhood and adolescence (median age of 13), but presentation in adulthood is also possible. It usually manifests with painless bony masses, which mostly occur in an asymmetric bilateral fashion, albeit symmetrical distribution has been described. The most frequently affected sites are the bones of the appendicular skeleton, in particular the hands (phalanges and metacarpals) and the metaphyses and diaphyses of the long tubular bones (i.e. femur, tibia, humerus). Rarely, spine, ribs, sternum, and skull can be involved. Pelvis involvement can lead to scoliosis. Patients present with multiple swelling, leading to apparent morphological abnormalities. Rarely, bone shortening can be the only presenting feature. Deformity around the joints, angular deformity, genu valgus, cubitus varus, joint mobility limitation, leg-length discrepancy, pathological fractures, facial asymmetry, and cranial nerve palsy can also be associated. OD is associated with an increased risk of malignancies compared to the general population such as chondrosarcoma (variably estimated but as high as 50% in some studies), central nervous system tumors, and occasionally gliomas, acute myeloid leukemia, and juvenile granulosa cell tumors.
Etiology
The disease is due to somatic variants in IDH1 (2q34), IDH2 (15q26.1) and, more rarely, PTH1R (3p21.31), coding for isocitrate dehydrogenase 1, 2 and parathyroid hormone 1 receptor, respectively. Mutations are limited to the involved tissues. No familial case has been reported.
Diagnostic methods
The diagnosis relies on clinical features and imaging findings, in particular conventional radiological evaluation. Enchondromas appear as slow growing, radiolucent defects that originate in the metaphyses. Both CT and MRI are useful for monitoring the disease, with MRI allowing evaluation of intraosseous and soft tissue involvement.
Differential diagnosis
The differential diagnoses include multiple hereditary exostosis (also known as multiple osteochondromas), osteitis fibrosa cystica, chondroma and chondrosarcoma.
Management and treatment
No specific therapy exists for OD. The management is usually conservative, but surgical approach can be proposed and is at present the only option when complications (e.g. pathological fractures) occur. Because of the risk of malignant transformation, annual monitoring of patients is recommended. Scintigraphy, ultrasound or biopsy for histological examination can be indicated for surveillance of lesions that become symptomatic (pain, increase in size) or suspected of malignant transformation. No specific guideline is available for the surveillance of other cancers risk due to the small number of patients reported and the limited data about the real incidence of other neoplasms in OD.
Prognosis
Prognosis is difficult to assess due to the wide clinical expression and variability of the disease. Depending on the extent of skeletal involvement, OD may result in severe deformities with functional and quality of life repercussions. Negative predictors are early onset, gross asymmetrical distribution, with severe shortening or deformity of the skeletal segment involved (e.g. limb asymmetry or phalangeal deformity) and malignant transformation (which is the most serious complication, potentially affecting the life span).

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Dr Luca SANGIORGI | ERN BOND*

                                * European Reference Network