microphthalmia

Lowe Oculocerebrorenal Syndrome

Clinical Characteristics
Ocular Features: 

Lens development is abnormal from the beginning secondary to abnormal migration of lens epithelium which has been described in fetuses by 20-24 weeks of gestation.  This leads to some degree of opacification in 100% of affected males.  The lens opacities may be polar or nuclear in location but complete opacification also occurs.   Leukocoria, miosis, microphthalmos and a shallow anterior chamber has been noted in neonates.  The cataractous lenses may be small and abnormally formed.  Glaucoma is present in more than half of affected males with onset by the age of 6 years and may be difficult to control.  Conjunctival and corneal keloids are found in about one-fourth of patients.

Adult female carriers characteristically have peripheral cortical opacities, appearing in a radial configuration.  These 'snowflake' opacities seldom cause visual symptoms.   It has been proposed that slit lamp examinations for such opacities can accurately determine the carrier status of females.

Systemic Features: 

Mental retardation, hypotonia, short stature, and developmental delays are common.  Seizures and behavior problems are seen in older children.  The renal defect secondary to defective phosphatidylinositol 4, 5-biphosphate 5- phosphatase results in a Fanconi-type aminoaciduria beginning late in the first year of life.  The phosphaturia leads to hypophosphatemia and eventually renal rickets.  Proteinuria, polyuria, as well as bicarbonate, sodium and potassium wasting with tubular acidosis are all part of the urinary profile.  Some patients have dental cysts and/or defective dentin.

Genetics

The mutation causing this X-linked disorder is in the OCRL gene located at Xq26.1.  New mutations have been found among nearly one-third of affected males.  

Another X-linked disorder with similar but less severe kidney disease, Dent disease 2 (300555), has been found to have mutations in the same gene.  However, none of the ocular features are present.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts need to be removed before sensory nystagmus and amblyopia develop.  Fluid and electrolyte balance must be maintained.  Growth hormone can be used in selected patients.  Supportive systemic care is necessary in most cases.  Lifelong kidney and ocular monitoring is recommended.

References
Article Title: 

Hallermann-Streiff Syndrome

Clinical Characteristics
Ocular Features: 

Nearly all patients (80+ %) have microphthalmia and bilateral congenital cataracts.  Microcornea is common.  The eyebrows may be hypoplastic and the eyelashes likewise are sparse.  The lid fissures often slant down and telecanthus has been noted.  The distance between the two eyes appears reduced.  Blue sclerae, nystagmus, strabismus, and glaucoma are present in 10 to 30% of patients.

Systemic Features: 

The facies are sometimes described as 'bird-like' with a beaked nose, brachycephaly, and micrognathia.  Microstomia with a shortened ramus and forward displacement of the termporomandibular joints is characteristic. Upper airway obstruction may occur with severe respiratory distress.  The forehead is relatively prominent, the palate is highly arched, and the teeth are often small and some may be missing with misalignment of others.  A few teeth may even be present at birth (natal teeth).  Children appear petite and are often short in stature.  Scalp hair is thin, especially in the frontal and occipital areas, and the skin is atrophic.  Developmental delays are common but most patients have normal or near-normal intelligence.

Genetics

Most cases are sporadic but some have mutations in the GJA1 gene (6q21-q23.2).  Both autosomal dominant and autosomal recessive inheritance have been postulated.  Reproductive fitness may be low but rare affected individuals have had affected offspring.  Males and females are equally affected.

This disorder is allelic to oculodentodigital dysplasia (257850, 164200).

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Airway obstruction may require intervention and its risks must be considered during administration of general anesthesia.  Lens opacification may be severe even early in life and requires prompt surgical intervention to prevent amblyopia.

References
Article Title: 

Cerebrooculofacioskeletal Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts and microphthalmia are frequent findings in this disorder.  Delayed mental development and early death in childhood have limited full delineation of the ocular phenotype.  Photosensitivity, nystagmus, optic nerve atrophy, and pigmentary retinopathy have been reported.  The eyes may appear deeply-set.

Systemic Features: 

Microcephaly, flexion contractures, prominent nasal root and an overhanging upper lip are common features.  Severe developmental and growth delays are evident early followed by progressive behavioral and intellectual deterioration.  Both hypotonia and hyperreflexia have been described.    Kyphosis and scoliosis are common.  CT scans may show intracranial calcifications and brain histology shows severe neurodegeneration with neuronal loss and gliosis.  Respiratory distress may also occur and some individuals have died in the first decade of life.

Genetics

Homozygous mutations in the ERCC6 gene (10q11) seem to be responsible for this autosomal recessive disorder.  Several sets of parents have been consanguineous.  Mutations in the same gene are responsible for Cockayne type B syndrome (133540) and some suggest that the variable phenotype represents a spectrum of disease rather than individual entities. Cerebrooculofacioskeletal syndrome represents the more severe phenotype in this spectrum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 

Focal Dermal Hypoplasia

Clinical Characteristics
Ocular Features: 

Features have considerable heterogeneity and few patients have all of them.  Some ocular abnormalities are found in 40% of patients.  Microphthalmia is common and many patients (30%) have colobomas of the iris and choroid.  Some patients have dislocated lenses.  Distinctive peripheral corneal lesions consisting of discrete vascularized subepithelial opacities have been described.  Occasional patients have conjunctival or lid margin papillomas.  Strabismus and nystagmus are common.

Systemic Features: 

This disorder has a wide variety of clinical features and many occur in only a few patients.  The skin has focal areas of hypoplasia with hypopigmentation, often appearing in a streak or linear pattern.  These areas may be present at birth and contain bullae or urticarial lesions with signs of inflammation.  Telangiectases and herniated fat may appear in these areas.   Oral, esophageal, and laryngeal fibrovascular papillomas occur but they may also be seen in the perineal, vulvar, and perianal areas.  These may be large, friable, and recurrent.  The teeth erupt late and are usually hypoplastic.  The nails are often dysplastic and the hands and feet may be 'split' with syndactyly of the third and fourth fingers giving a 'lobster claw' appearance.  Polydactyly may be present.  Most have thin 'protruding' ears.  A variety of skeletal anomalies have been reported including absence of metatarsals and metacarpals.  A considerable number of patients have mild to moderate mental deficits.  Severely affected females may die in infancy.

Genetics

This is considered an X-linked dominant disorder with lethality in males.  However, numerous affected males (>30) and rare instances of father-to-daughter transmission have been reported and it has been suggested that half-chromatid mutations or postzygotic somatic mosaicism in these males might be responsible.  Mutations in the PORCN gene (Xp11.23) have been associated with FDH.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Surgery may be required for the papillomas if they are obstructive.

References
Article Title: 

Norrie Disease

Clinical Characteristics
Ocular Features: 

Norrie disease often presents at birth or soon thereafter with leukocoria.  There may be no response to light even at this early stage.  Microphthalmos, iris atrophy, and synechiae are often noted as well.  The posterior chamber contains a whitish-yellow mass associated with retinal folds and sometimes retinal detachment (pseudoglioma).  The vitreous may appear membranous and fibrovascular, often with traction on the retina.  Cataracts frequently develop early.  These signs may be unilateral or bilateral.  Corneal abnormalities such as opacities or sclerocornea may be present.  The mass in the posterior pole has to be distinguished from a retinoblastoma but the appearance may also resemble familial exudative vitreoretinopathy, Coats disease, persistent hyperplastic vitreous retinopathy, or retinopathy of prematurity.

Histology shows hemorrhagic necrosis of an undifferentiated glial mass.  The primary defect seems to lie in the neuroretina with absence of the ganglion cells and dysplasia of the remaining layers.  Many eyes become phthisical.

Systemic Features: 

Many individuals have growth and developmental delays with cognitive impairment and/or behavioral disorders (50%).  Frank psychoses have been reported in some patients.  Approximately 10% of patients have a chronic seizure disorder. Sensorineural deafness of some degree develops by the second decade in up to 100% of individuals.

Peripheral vascular disease (varicose veins, venous stasis ulcers, and erectile dysfunction) is present in nearly all men over the age of 50 years, perhaps the result of small vessel angiopathy.  Its age of onset is similar to that of the hearing deficit and the time course of progression is similar.

Genetics

This is an X-linked disorder as a result of mutations in the NDP gene (Xp11.4) encoding norrin.  Many mutations causing Norrie disease are novel or at least rare as might be expected for a disorder that leads to a marked reduction in reproductive fitness in males.  Carrier females usually do not have any evidence of disease.

Mutations in NDP also are responsible for a sex-linked form of familial exudative vitreoretinopathy, EVR2 (305390).  They have also been found in some cases of persistent hyperplastic primary vitreous and even in Coates' disease.  The latter conditions are usually present unilaterally, however, and some consider bilaterality to be a characteristic of NDP-related retinopathies.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Mutations in the Norrie disease gene

Schuback DE, Chen ZY, Craig IW, Breakefield XO, Sims KB. Mutations in the Norrie disease gene. Hum Mutat. 1995;5(4):285-92.

PubMed ID: 
7627181

Cataracts, Congenital, Facial Dysmorphism, and Neuropathy

Clinical Characteristics
Ocular Features: 

Cataracts, microphthalmia, and microcornea (mean diameter ~7.5 mm) are present at birth and precede the onset of neurological symptoms.  The lens opacities often consist of anterior and posterior subcapsular opacities but the entire lens may be opaque as well.  Some adults have bilateral ptosis.  The pupils are often small and have sluggish responses to light and mydriatics.  Strabismus and horizontal pendular nystagmus are common.  Visual impairment may be severe.

Systemic Features: 

The neuropathy is primarily motor and usually begins in the lower extremities but is progressive and eventually involves the arms as well.  Motor development is slow and walking is often unsteady from the start.  Speaking may not have its onset until 3 years of age.   Mild, nonprogresssive cognitive defects and mental retardation are often present.  Sensory neuropathy with numbness and tingling develops in the second decade.  Mild chorea, upper limb tremor, mild ataxia, and extensor plantar responses may be seen.  Deafness has been described.  Nerve conduction studies and biopsies have documented a demyelinating polyneuropathy while MRIs demonstrate cerebral and spinal cord atrophy which may be seen in the first decade of life.  The MRI in many patients reveals diffuse cerebral atrophy, enlargement of the lateral ventricles and focal lesions in subcortical white matter.  Most individuals have mild cognitive deficits while psychometric testing reveals borderline intelligence in a minority.

Patients are susceptible to acute rhabdomyolysis following viral infections.  Most are severely disabled by the third decade.

The facial dysmorphism appears in childhood and consists of a prominent midface, hypognathism, protruding teeth, and thickening of the lips.  Spinal deformities occur in the majority of individuals along with foot and hand claw deformities.  All patients are short in stature.  Hypogonadotropic hypogonadism is a common feature and females may be infertile.  Amenorrhea is often present by the age of 25-35 years.

Genetics

This is an autosomal recessive disorder found primarily among European Gypsies.  It is caused by mutations in the CTDP1 gene (18q23-qter).  It is sometimes confused with Marinesco-Sjogren syndrome (248800) with which it shares some clinical features but the two are genetically distinct.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts often require removal in the first decade of life. Scoliosis and foot deformities may benefit from surgical correction.  Supportive care and physical therapy can be helpful.

References
Article Title: 

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations

Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol. 1999 Jun;45(6):742-50.

PubMed ID: 
10360766

Cryptophthalmos

Clinical Characteristics
Ocular Features: 

It may be that ankyloblepharon occurs in the absence of other abnormalities but in most cases the globes are small and malformed as well.  The combination of upper and lower lid fusion associated with microophthalmia effectively precludes visualization of the globes in many cases, hence the term cryptophthalmos. Lid colobomas may be present in patients with incomplete fusion of the lid margins.  There are often adhesions between the lids and cornea while the anterior chamber may have features of Peters anomaly.  Posterior chamber abnormalities such as optic nerve hypoplasia and retinal dysplasia with other tissues such as bone may also be present.  Rarely patients may respond to bright lights.  The condition may be unilateral or bilateral. The lacrimal drainage system may be malformed or absent while the eyebrows are often missing as well.  In severe cases, the forehead skin appears to be continuous with that of the cheeks.

Cryptophthalmos is also feature of other malformation syndromes most notably that described by Fraser (219000).

Systemic Features: 

The type of cryptophthalmos described here is sometimes called simple or isolated since no systemic malformations are associated.  It should be noted, however, that other ocular abnormalities are almost always associated and the clinical features of the hidden eye are anything but isolated or simple.

Genetics

A small number of families with a vertical pattern of inheritance suggest that at least some cases are inherited in an autosomal dominant pattern but no locus has been identified.  This pattern distinguishes such cases from those with the Fraser cryptophthalmos syndrome (219000) which has an autosomal recessive pattern of inheritance.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Attempts have been made to surgically create a lid fissure but the lack of conjunctival cul de sacs and fusion of the lids to the cornea in many cases can lead to irreparable complications.

References
Article Title: 

Isolated and syndromic cryptophthalmos

Thomas IT, Frias JL, Felix V, Sanchez de Leon L, Hernandez RA, Jones MC. Isolated and syndromic cryptophthalmos. Am J Med Genet. 1986 Sep;25(1):85-98. Review.

PubMed ID: 
3099574

Incontinentia Pigmenti

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of skin, teeth, hair, and the central nervous system but 35% of patients have important ocular features.  The iris is variably atrophic and has pigmentary anomalies often with posterior synechiae.  Nystagmus, strabismus, and limited vision are often present.  The majority (up to 90%) of individuals have significant retinal disease.  The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others.  Preretinal fibrosis and retinal detachments may suggest the presence of a retinoblastoma.  Cataracts are common in patients who have a retinal detachment and some patients have microphthalmia. The retinal pigment epithelium is often abnormal with various-sized patches of sharply demarcated depigmentation.  Cases with uveitis, papillitis and chorioretinitis have been observed and it has been suggested that the observed retinal and choroidal changes result from prior inflammatory disease, perhaps even occurring in utero. There is a great deal of asymmetry in the clinical findings in the two eyes.

Systemic Features: 

Skin changes consisting of erythematous eruptions in a linear pattern are often present at birth and this may be followed by a verrucous stage.  The acute, early findings of inflammatory disease eventually subside, ultimately resulting in pigmentary changes that appear in a 'marbled pattern' in young adults.  Hypodontia and anodontia may be present.  Alopecia and CNS abnormalities are found in nearly half of patients.  Skeletal and structural deformities are common in patients with severe neurological deficits.  The only sign of this disorder in adult women may be a whorled pattern of scarring alopecia.

As many as 30% of patients have neurological features which may be present in the neonatal period.  Seizures of various types occur in 30% of patients.  MRI findings include periventricular and subcortical white matter changes, as well as corpus callosum hypoplasia, cerebral atrophy, and cerebellar hypoplasia.

 

Genetics

The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur.  The mutation occurs as a genomic rearrangement of the IKK-gamma gene, also known as NEMO (IKBKG) located at Xq28.  There is evidence from skin cultures that cells with the mutant X chromosome inactivated are preferentially viable.  It has been proposed that cells with the mutant bearing X chromosome as the active one are gradually replaced by those in which the normal X chromosome is active accounting for the post-natal course of the skin disease.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

No treatment for the generalized disorder is available although ocular surgery might be beneficial in rare cases with cataracts and detachments.

References
Article Title: 

Strømme Syndrome

Clinical Characteristics
Ocular Features: 

The core complex of Stromme syndrome consists of intestinal atresia and ocular abnormalities of the anterior segment.  The ocular anomalies consist of variable amounts of angle dysgenesis, anterior synechiae, corneal leukoma, iris colobomas and hypoplasia, sclerocornea, cataracts, and sometimes microcornea.  However, microphthalmia, tortuous retinal vessels, and optic nerve hypoplasia may also be present.  Hypertelorism and deep-set eyes have been described.  Glaucoma has not been reported.  Only about 10 cases have been reported since Stromme 's first report in 1993.  Most patients have been too young for reliable acuity testing. 

Systemic Features: 

The phenotype is highly variable.  The ears are often large and low-set.  Microcephaly is often present along with a cleft palate and micrognathia.  The intestinal atresia seems to involve the jejunum primarily and is usually surgically correctable.  The duodenum may also be involved and intestinal malrotation has been described.  Myopathic changes in the myocardium have been seen along with small cardiomyoctes.  Microcephaly seems to be progressive.  Short stature has been noted and the amount of developmental delay is highly variable.  Renal hypodysplasia and hydronephrosis have been described.

Some patients seem to develop and function almost normally while more severely affected individuals may not live beyond early infancy or childhood.

Genetics

Compound heterozygous mutations in the CENPF gene (1q41) segregate with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Infants do well following intestinal surgery.  Ocular surgery has not been reported.

References
Article Title: 

Stromme Syndrome: New Clinical Features

Stromme Syndrome: New Clinical Features Bayram Ali Dorum, Irmak Tanal Sambel, Hilal Ozkan, Irfan Kiristioglu, Nilgun Koksal APSP J Case Rep. 2017 Mar-Apr; 8(2): 14. Published online 2017 Mar 18.

PubMed ID: 
5371687

Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF

Filges I, Bruder E, Brandal K, Meier S, Undlien DE, Waage TR, Hoesli I, Schubach M, de Beer T, Sheng Y, Hoeller S, Schulzke S, Rosby O, Miny P, Tercanli S, Oppedal T, Meyer P, Selmer KK, Stromme P. Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF. Hum Mutat. 2016 Jan 28. doi: 10.1002/humu.22960. [Epub ahead of print].

PubMed ID: 
26820108

Oculocerebral Syndrome with Hypopigmentation

Clinical Characteristics
Ocular Features: 

Patients have severe ocular malformations which so far lack full characterization.  Nearly complete scleralization of the cornea prevents internal evaluation in most cases.  There may be extensive neovascularization of corneal clouding.  Anterior synechiae and cataracts have been described.  Other patients presumed to have the same disorder have normal fundi or diffuse pigmentary changes.  No limbal landmarks can be seen.  The central cornea can be more transparent but no iris can be visualized.  The eyes are microphthalmic as well.  Slow, wandering eye movements are constant.  Spastic ectropion of the lower lids is present. Lashes and eyebrows have minimal pigmentation and like the scalp hair have a slight yellowish tinge.  There is no response to bright light in severe cases whereas in other more mildly affected individuals presumed to have this disorder there is only hypoplasia of the fovea with diffuse retinal pigmentary changes.

Systemic Features: 

Individuals have severe mental retardation from birth and never respond to environmental cues beyond having a marked startle response to auditory stimuli.  Grasp and sucking responses persist at least into the second decade.  The developmental delay persists from birth and patients never achieve normal milestones.  Athetoid, writhing movements are prominent.  The limbs are spastic, and deep tendon reflexes are hyperactive. Contractures are common.  Hypodontia, diastema, and gingival hyperplasia are usually present and the hard palate is highly arched.  The skin is hypopigmented but pigmented nevi may be present and the distribution of melanocytes is uneven microscopically. Cerebellar hypoplasia has been reported in some patients.

Genetics

This is a presumed autosomal recessive disorder based on its familial occurrence and parental consanguinity in some families.  An interstitial deletion [del(3)(q27.1-1q29)] has been identified in the paternal chromosome of a 4-year-old female but the molecular defect remains unknown. 

Clinically heterogeneous cases from Africa, Germany, Italy, Great Britain, and Belgium may not all have the same disorder and evidence for a distinctive phenotype remains elusive.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None available

References
Article Title: 

Oculocerebral syndrome with hypopigmentation (Cross

De Jong G, Fryns JP. Oculocerebral syndrome with hypopigmentation (Cross syndrome): the mixed pattern of hair pigmentation as an important diagnostic sign. Genet Couns. 1991;2(3):151-5.

PubMed ID: 
1801851

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