autosomal recessive

Microphthalmia with Limb Anomalies

Clinical Characteristics
Ocular Features: 

Patients have either microphthalmia or anophthalmia which may be present unilaterally or bilaterally.  The MRI in several patients has revealed complete absence of the globes, optic nerves, chiasm, and optic tracts.  The eyelashes are often sparse with shortened palpebral fissures and broad lateral eyebrows.

Systemic Features: 

Global developmental delays, failure to thrive, and mild to moderate mental retardation are common.   Syndactyly, polydactyly, and oligodactyly with hypoplasia of the long bones are present to a variable degree.  Synostosis in the digits, ankles, and wrist is often seen.  A split hand (lobster-claw deformity) is variably present.  Other anomalies such as the kidneys (horseshoe kidney), undescended testes, anomalous venous circulation and deformed vertebrae have been reported.  The midface is often flattened.  A high palate, cleft lip, and mild scoliosis may be seen.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the SMOC1 gene (14q24.2) but there is some evidence of genetic heterogeneity as the disorder has been mapped to 10p11.23 in several families.  However, no causative mutations were found in this region.  Consanguinity among parents is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment in most cases for the ocular malformations.  Some of the limb anomalies may be surgically correctable.

References
Article Title: 

SMOC1 is essential for ocular and limb development in humans and mice

Okada I, Hamanoue H, Terada K, Tohma T, Megarbane A, Chouery E, Abou-Ghoch J, Jalkh N, Cogulu O, Ozkinay F, Horie K, Takeda J, Furuichi T, Ikegawa S, Nishiyama K, Miyatake S, Nishimura A, Mizuguchi T, Niikawa N, Hirahara F, Kaname T, Yoshiura K, Tsurusaki Y, Doi H, Miyake N, Furukawa T, Matsumoto N, Saitsu H. SMOC1 is essential for ocular and limb development in humans and mice. Am J Hum Genet. 2011 Jan 7;88(1):30-41.

PubMed ID: 
21194678

A locus for ophthalmo-acromelic syndrome mapped to 10p11.23

Hamanoue H, Megarbane A, Tohma T, Nishimura A, Mizuguchi T, Saitsu H, Sakai H, Miura S, Toda T, Miyake N, Niikawa N, Yoshiura K, Hirahara F, Matsumoto N. A locus for ophthalmo-acromelic syndrome mapped to 10p11.23. Am J Med Genet A. 2009 Mar;149A(3):336-42.

PubMed ID: 
19208380

Aphakia, Congenital Primary

Clinical Characteristics
Ocular Features: 

There is complete absence of the lens and with it aplasia of the anterior segment including complete absence of the iris, ciliary body, and trabecular meshwork.  In an autopsied case, the cornea was thinned and lacked endothelium, Bowman layer, and Descemet membrane while the retina was dysplastic.  In the single family reported, 2 sibs had sclerocornea and one had megalocornea.  Normal pressure was reported in several eyes but a single eye in one patient at the age of 3 years developed buphthalmos with elevated pressure.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Homozygosity of a nonsense mutation in the FOXE3 transcription factor gene (1p32) seems to be responsible for this autosomal recessive disorder.  The same gene has been implicated in rare cases of Peters anomaly (604229) and in anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known to restore vision.

References
Article Title: 

Microphthalmia, Syndromic 9

Clinical Characteristics
Ocular Features: 

Both microphthalmia and clinical anophthalmia have been described in this syndrome.  However, autopsy has shown true anophthalmia in a few cases who were stillborn or died in the neonatal period.  At least one eye can be cystic. The optic nerves are often hypoplastic and may be absent.  High, upward-arching eyebrows may be seen.

Systemic Features: 

An early manifestation of this disorder is neonatal pulmonary distress.  The lungs are usually hypoplastic or malformed. Cardiac malformations such as patent ductus arteriosus, septal and valvular defects, tetralogy of Fallot, and single ventricles are often present.  Diaphragmatic hernias or defects are common but hiatal hernias and frank eventration of abdominal contents have also been reported.  Renal anomalies and intrauterine growth retardation have been noted.         

Some infants have micrognathia, low-set ears, a broad nasal bridge, brachycephaly, and midline clefts of the palate.  Cerebral malformations are seldom present.

Genetics

Homozygous mutations in the STRA6 gene (15q24.1) have been found in a few cases which suggests autosomal recessive inheritance.  Parental consanguinity has been reported in some families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at the repair of the organ defects in selected cases that have survival potential.   Survival rates are poor but those less severely affected may live for a decade.

References
Article Title: 

The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew-Wood syndrome): report of eight cases including a living child and further evidence for autosomal

Chitayat D, Sroka H, Keating S, Colby RS, Ryan G, Toi A, Blaser S, Viero S, Devisme L, Boute-B?(c)n?(c)jean O, Manouvrier-Hanu S, Mortier G, Loeys B, Rauch A, Bitoun P. The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew-Wood syndrome): report of eight cases including a living child and further evidence for autosomal recessive inheritance. Am J Med Genet A. 2007 Jun 15;143A(12):1268-81.

PubMed ID: 
17506106

Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation

Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, N?ornberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, Houge G, Fern?degndez-Mart??nez L, Keating S, Mortier G, Hennekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, N?ornberg P, Reis A, Rauch A. Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet. 2007 Mar;80(3):550-60.

PubMed ID: 
17273977

Iridogoniodysgenesis and Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Megalocornea, congenital glaucoma, a concave iris with stromal atrophy and corectopia, and deep anterior chambers are typical ocular features.  High myopia has been reported and retinal detachments have been observed.  Glaucoma control can be difficult to achieve and there is a significant risk of cataracts and phthisis bulbi following surgery.  Posterior embryotoxon has not been observed.

Systemic Features: 

Facial features seem to be consistent.  The forehead is wide, the nose appears broad with a large nasal tip and broad nares although the bridge appears narrow.  The philtrum is long and wide.  The ears may appear large and the neck is short.  The thorax is abnormally wide and the nipples are widely spaced and umbilicated.  The long bones are slender with thin cortices and wide metaphyses.  There is generalized osteopenia.  Vertebral bodies are cuboid-shaped with narrow vertebral canals and enlarged apophyses

Genetics

Two non-consanguineous families each with 3 sibs have been reported suggesting autosomal recessive inheritance.  Nothing is known about the mutation or its locus.

The ocular features may resemble Rieger or Axenfeld anomaly but these are inherited in autosomal dominant patterns and the skeletal features are dissimilar.       

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Vigorous treatment of glaucoma is indicated but successful control, even with surgery, is difficult to achieve.

References
Article Title: 

Stickler Syndrome, Type IV

Clinical Characteristics
Ocular Features: 

Evidence of vitreoretinal degeneration is common and the risk of retinal detachment is high.  High myopia is common.  Cataracts are not a feature in contrast to types I and II Stickler syndrome.

It is likely that the ocular phenotype will be expanded with the report of additional families.

Systemic Features: 

Sensorineural hearing loss and short stature are often present. The latter is not usually a feature in other types of Stickler syndrome.  However, midface hypoplasia and micrognathia may be present in all types as well as in Marshall syndrome.  Midline clefting usually does not occur.

Genetics

A reported pedigree suggests autosomal recessive inheritance based on parental consanguinity and the lack of parent-to-child transmission.  Affected individuals have homozygous deletion mutations leading to loss of function in COL9A2 (1p33-p32) while parents are heterozygous.  A family with mutations in COL9A1 (6q12-q14), usually causing multiple epiphyseal dysplasia, has been reported to have autosomal recessive Stickler syndrome as well.  Homozygous individuals had typical ocular and auditory findings of autosomal dominant Stickler syndrome but with evidence of epiphyseal dysplasia.

Type I Stickler syndrome (108300, 609508) is an autosomal dominant disorder with somewhat similar ocular manifestations resulting from mutations in COL2A1.

Type II Stickler syndrome (604841) with a somewhat similar ocular phenotype is also an autosomal dominant disorder but caused by mutations in COL11A1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The myopia and hearing loss can be corrected.  Lifelong vigilance and prompt treatment are required for the vitreoretinal disease.

References
Article Title: 

Glaucoma, Congenital Primary D

Clinical Characteristics
Ocular Features: 

Evidence of glaucoma can appear in early childhood but may appear much later.  However, typical signs such as enlarged corneas or frank buphthalmos, cloudiness of the corneas, tearing and photophobia are present only when the pressure is elevated due to pupillary block or when the lens migrates into the anterior chamber.  Most patients have additional signs such as ectopia lentis and spherophakia.

Systemic Features: 

Some patients have osteopenia, a high arched palate, and a marfanoid habitus.

Genetics

This form of congenital glaucoma has been described primarily in Middle Eastern and Asian as well as Roma/Gypsy families and is inherited in an autosomal recessive pattern.  The mutations occur in the LTBP2 gene (14q24) which is in close proximity to GLC3C, another putative gene with mutations causing congenital glaucoma. 

Mutations in other genes are also associated with primary congenital glaucoma such as in CYP1B1 causing type A (231300) and in GLC3B causing type B (600975).

THIS IS NOT A PRIMARY GLAUCOMA DISORDER.  Microspherophakia and ectopia lentis are not features of primary congenital glaucoma.  Elevated pressures in these patients are found only when there is a pupillary block or when the lens dislocates into the anterior chamber.  The enlarged cornea is clear and has no breaks in the Descemet membrane.  THIS CONDITION IS THEREFORE RECLASSIFIED AS "MEGALOCORNEA, ECTOPIA LENTIS, AND SPHEROPHAKIA".     

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The usual surgical and pharmacological treatments for glaucoma apply but vision preservation is a challenge.  The spherophakic or dislocated lenses may need to be removed.

References
Article Title: 

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Azmanov DN, Dimitrova S, Florez L, Cherninkova S, Draganov D, Morar B, Saat R, Juan M, Arostegui JI, Ganguly S, Soodyall H, Chakrabarti S, Padh H, L??pez-Nevot MA, Chernodrinska V, Anguelov B, Majumder P, Angelova L, Kaneva R, Mackey DA, Tournev I, Kalaydjieva L. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet. 2011 Mar;19(3):326-33.

PubMed ID: 
21081970

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Wilson Disease

Clinical Characteristics
Ocular Features: 

The cornea and lens have visible copper deposition.  This is responsible for the classic (though non-pathognomonic) copper-colored Kayser-Fleischer ring in the cornea where evidence of copper deposition can be visualized in the posterior stroma and in the endothelium.  About 50-60% of patients at any point have evidence of such copper deposition but the number rises to 90% in patients with neurologic and psychiatric symptoms.  Copper deposition in the lens leads to a ‘sunflower’ or 'sunburst' cataract consisting of a greenish central disc in the anterior capsule with spoke-like radial cortical opacities.  Eye involvement in Wilson disease usually does not lead to significant impairment of vision.

Systemic Features: 

This is a disorder of copper metabolism.  It is associated with severe liver disease, often beginning with signs of recurrent jaundice, sometimes a hepatitis-like illness, and often culminating in liver failure.  Hepatobiliary malignancies are a significant risk, occurring in more than 1 percent of patients.  Neurologic toxicity leads to various movement disorders such as tremors, poor coordination, dystonia, and choreoathetosis.  Many patients have mental symptoms such as depression, neurotic behavior, and personality disturbances.  Some have a mask-like facies and pseudobulbar symptoms.  Symptoms can appear anytime from 3 years of age to over 50.  Other organs such as kidney, pancreas, heart and even joints may also be involved.

Patients often have a low serum ceruloplasmin, low copper levels, increased urinary excretion of copper, and increased concentration of copper in the liver.

Genetics

This is an autosomal recessive disorder caused by homozygous or doubly heterozygous mutations in the ATP7B gene (13q14.3).  Heterozygotes usually do not develop symptoms but may have reduced serum ceruloplasmin levels.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Zinc and/or copper chelating agents such as D-penicillamine or trientine have long been used with benefit but the treatment must be used throughout life.  Reduced copper intake may also be helpful.  An orthotopic liver transplant can prolong life in selected patients.

References
Article Title: 

Hepatobiliary malignancies in Wilson disease.

Pfeiffenberger J, Mogler C, Gotthardt DN, Schulze-Bergkamen H, Litwin T, Reuner U, Hefter H, Huster D, Schemmer P, Czlonkowska A, Schirmacher P, Stremmel W, Cassiman D, Weiss KH. Hepatobiliary malignancies in Wilson disease. Liver Int. 2014 Nov 4. [Epub ahead of print].

PubMed ID: 
25369181

A practice guideline on Wilson disease

Roberts EA, Schilsky ML; Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guideline on Wilson disease. Hepatology. 2003 Jun;37(6):1475-92. Erratum in: Hepatology. 2003 Aug;38(2):536.

PubMed ID: 
12774027

Oculoauricular Syndrome

Clinical Characteristics
Ocular Features: 

This rare malformation syndrome affects primarily the eyes and ears.  The globes are small and usually have colobomas of both anterior and posterior segments.  The corneas likewise are small and often have opacities.  The anterior segment is dysplastic with anterior and/or posterior synechiae.  Glaucoma may be present.  The lenses may be small and often become cataractous.  There is a progressive rod-cone dystrophy associated with a pigmentary retinopathy.  Chorioretinal lacunae have been seen in the equatorial region.  The retinal degeneration is progressive, beginning with rod dysfunction but followed by deterioration of all receptors.  The onset in early childhood results in poor vision and nystagmus. 

Systemic Features: 

The external ears are abnormal.  The earlobes may have colobomas or may be aplastic.  The intertragic notch is often underdeveloped.  Audiograms and vestibular function tests, however, show normal function and MRI of the middle and inner ears likewise reveals no anatomic abnormalities.       

Among the few patients reported, dental anomalies, spina bifida oculta, and mild dyscrania have been noted in individual patients.

Genetics

This rare disorder has been reported in only a few families.  Based on parental consanguinity and homozygosity of mutations in the HMX1 gene (4p16.1) in affected sibs, this is an autosomal recessive disorder.  In one family there was a homozygous 26 bp deletion and in another a homozygous missense mutation.  The parents are heterozygous for the deletion.

HMX1 is a homeobox gene and the deletion abolishes its function by establishing a stop codon at position 112.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the extraocular malformations.  Glaucoma treatment and cataract surgery should be considered although permanent visual rehabilitation is unlikely given the progressive nature of the rod-cone dystrophy.

References
Article Title: 

Cataracts, Congenital, Autosomal Recessive 3

Clinical Characteristics
Ocular Features: 

This type of congenital cataract has been reported in two unrelated Pakistani families.  The phenotype was dissimilar in the two families.  In one, only posterior subcapsular opacification was present.  In the other the cataract was membranous and accompanied by a corneal opacity, microcornea, and nystagmus.  Nothing is known about the course of the opacification.

Systemic Features: 

No systemic disease is apparently present.

Genetics

Consanguinity was reported for both families.  Fine mapping identified a locus at 1p34.3-p32.2 that cosegregates with the lens opacities but the mutation is unknown.  This region is distinct from the locus containing the mutation(s) causing Volkmann (115665) and posterior polar (116600) autosomal dominant cataracts.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Visually significant lens opacities could be removed.

References
Article Title: 

Wolfram Syndrome 2

Clinical Characteristics
Ocular Features: 

As in Wolfram syndrome 1, only insulin dependent diabetes mellitus and optic atrophy are essential to the diagnosis. The optic atrophy is progressive over a period of years and can be the presenting sign.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, anemia, seizures, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Hydroureter is often present.

Diabetes insipidus may be present in patients with Wolfram syndrome 1 (222300) but has not been reported in patients reported with Wolfram syndrome 2.   Upper GI ulceration and bleeding were present in several individuals.

Genetics

This is an autosomal recessive disorder similar to Wolfram syndrome 1 (WFS1; 222300) but caused by mutations in the CISD2 gene (4q22-q24).  The gene codes for a small protein (ERIS) localized to the endoplasmic reticulum. It seems to occur less commonly than WFS1.

Some patients have mutations in mitochondrial DNA as the basis for their disease (598500).  Combined with evidence that point mutations at the 4p16.1 locus predisposes deletions in mtDNA, this suggests that at least some patients with Wolfram syndrome have a recessive disease caused by mutations in both nuclear and mitochondrial genes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is supportive for specific organ disease.  Low vision aids may be helpful in selected individuals.

References
Article Title: 

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