hearing impairment (sensorineural)

Alström Syndrome

Clinical Characteristics
Ocular Features: 

Progressive failure of rods and cones begins in the first year of life and inevitably leads to blindness.  Central vision is lost first and nystagmus in early childhood results.   Photophobia can be evident in the first year of life.  Early ERGs show severe impairment of cone responses with little or no rod dysfunction.  In the second and third decades all rod and cone responses are extinguished.  Vision can be less than 20/400 by the age of 10 years and usually all light perception is lost by the beginning of the third decade.  Pale optic nerves with retinal arteriorlar narrowing and posterior subcapsular cataracts have been seen.

Systemic Features: 

This is a multisystem disease with onset in the first year of life.  Infants may have a normal birth weight but develop truncal obesity in the first year.  Hearing loss is evident in the first decade.  Insulin resistant type 2 diabetes mellitus with hyperinsulinemia often occurs in childhood and may be accompanied by hypothyroidism and hypogonadotropic hypogonadism.  Acanthosis nigricans and some degree of pulmonary dysfunction are common.  The majority of individuals (70%) develop restrictive or dilated cardiomyopathy, many in the first months of life, resulting in cardiac failure.  The liver may become cirrhotic and renal failure occurs late.  Intelligence is usually normal but many patients (25-30%) have early delays in their developmental milestones perhaps secondary to growth hormone deficiency which has been reported (98% are short in stature).  Lifespan is short and many die in childhood.  Few live beyond the age of 40 years.

Alstrom syndrome has some similarities to Bardet-Biedl syndrome (209900) but differs in the absence of mental deficiency and polydactyly.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the ALMS1 gene on chromosome 2 (2p13).  The ALMS1 protein product is found in many cells throughout the body and is located in centrosomes and the base of cilia.  Its function is unknown.

More than 320 mutations have been reported. However, many cases remain in which no mutation has been found suggesting additional genetic heterogeneity remains.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic disease.

References
Article Title: 

Alström Syndrome: Mutation Spectrum of ALMS1

Marshall JD, Muller J, Collin GB, Milan G, Kingsmore SF, Dinwiddie D, Farrow EG, Miller NA, Favaretto F, Maffei P, Dollfus H, Vettor R, Naggert JK. Alstrom Syndrome: Mutation Spectrum of ALMS1. Hum Mutat. 2015 Apr 2. doi: 10.1002/humu.22796. [Epub ahead of print].

PubMed ID: 
25846608

Alström syndrome

Marshall JD, Beck S, Maffei P, Naggert JK. Alstrom syndrome. Eur J Hum Genet. 2007 Dec;15(12):1193-202.

PubMed ID: 
17940554

Albinism, Oculocutaneous, Type I

Clinical Characteristics
Ocular Features: 

Oculocutaneous albinism is a genetically and clinically heterogeneous condition.  It is congenital in origin and the combination of foveal hypoplasia and anomalous decussation of neuronal axons in the chiasm results in a permanent reduction of vision in the range of 20/50-20/200.  Most individuals have nystagmus, photophobia, and strabismus.  The iris usually is light blue and transmits light.  The retina lacks pigmentation as well.  The ocular features are similar in types IA and IB.  The iris may darken with age in type IB (606952 ). 

Systemic Features: 

There are generally no systemic abnormalities in these pigmentation disorders with the exception of sensorineural hearing loss in some, and, of course, complete absence of pigment in skin and hair.  Anomalous decussation of axons in the auditory system has been demonstrated in such cases and otic pigment is lacking in albinos.  The skin contains amelanic melanocytes but these cells contain granules similar to those of normal cells.   Some patients with residual tyrosinase activity (type 1B, 606952 ) develop some pigmentation of hair and skin, especially in cooler areas of the body such as the extremities. 

Genetics

This type of oculocutaneous albinism is caused by mutations in the TYR gene (11q14-q21) and inherited in an autosomal recessive pattern. 

Type IA (OCA1A) has no demonstrable tyrosinase activity while type IB (OCA1B, 606952) has a reduction in enzyme activity.  Yet other patients with mutations in TYR have a variant called 'yellow albinism' in which tyrosinase activity resembles that found in type IB.  To explain the difference in skin color, it has been suggested that an individual's background ethnicity may impact the pigmentation phenotype.

Other types also transmitted as autosomal recessive conditions are OCA2 (203200), OCA3 (203290), AND OCA4 (606574). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the basic disease but low vision aids may be helpful for some patients.  Dark glasses provide comfort for photophobic individuals.  The skin should be protected against sunburn. 

References
Article Title: 

A new hypothesis of OCA1B

Chiang PW, Drautz JM, Tsai AC, Spector E, Clericuzio CL. A new hypothesis of OCA1B. Am J Med Genet A. 2008 Nov 15;146A(22):2968-70.

PubMed ID: 
18925668

Oculocutaneous albinism

Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

Axenfeld-Rieger Syndrome, Type 3

Clinical Characteristics
Ocular Features: 

The most important ocular feature is glaucoma, found in greater than 50% of patients.  It is frequently difficult to control and blindness is far too common.  The ocular phenotype has many similar features found in type 1 (RIEG1) but is discussed separately in this database since it is caused by a different mutation (see Axenfeld-Rieger syndrome, type 1 for a full description of the phenotype).  It has the typical findings of anterior segment dysgenesis including anterior displacement of Schwalbe's line, iris stromal hypoplasia, correctopia, and, of course, glaucoma.

Systemic Features: 

Patients with this type of Axenfeld-Rieger disorder are less likely to have the systemic anomalies such as craniofacial and dental defects often seen in RIEG1.  However, they often have a sensorineural hearing impairment and many have cardiac valvular and septal defects not usually seen in RIEG1.

Genetics

This is an autosomal dominant disorder resulting from a mutation in the FOXC1, a transcription factor gene located at 6p25.  Mutations in the same gene also cause iris hypoplasia/iridogoniodysgenesis (IGDA) (IRID1) 601631) which is sometimes reported as a unique disorder but is either allelic or the same disorder as the type of Axenfeld-Rieger syndrome discussed here.

Type 1 Axenfeld-Rieger syndrome (180500) results from mutations in the PITX1 transcription factor gene and type 4 from mutations in PRDM5, also a transcription factor gene.  However, digenic cases have also been reported with mutations in both PITX1 and FOXC1 genes.

The mutation responsible for type 2 Axenfeld-Rieger syndrome (601499) has as yet not been identified.  Diagnosis is best made by ruling out mutations in PITX1 and FOXC1 although it is claimed that maxillary hypoplasia and umbilical defects are less common in type 2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All patients with Axenfeld-Rieger syndromes must be monitored and treated for glaucoma throughout their lives.

References
Article Title: 

Axenfeld-Rieger syndrome

Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017 Oct 3. doi: 10.1111/cge.13148. [Epub ahead of print] Review.

PubMed ID: 
28972279

Alport Syndrome (Collagen IV-Related Nephropathies)

Clinical Characteristics
Ocular Features: 

X-linked Alport syndrome is a basement membrane disease with important ocular manifestations.  The lens is usually normal at birth but lens opacities eventually occur in a significant number of individuals with the most characteristic type being anterior polar in location.  Involvement of the anterior lens capsule often results in bilateral anterior lenticonus (25%) and may be progressive.  It is claimed that the severity of the lenticonus is a valuable marker in judging the overall disease severity.  In early stages it may be difficult to detect but its presence is suggested by an 'oil droplet' reflex during retinoscopy or slit lamp examination.  All males with anterior lenticonus should be evaluated for Alport syndrome. 

Posterior polymorphous corneal dystrophy and posterior subcapsular opacities have also been noted.  The defect in basement membranes may lead to recurrent corneal erosions, even in children, which can be incapacitating and difficult to treat.  Involvement of Bruch's membrane has been considered the source of retinal pigment epithelial changes described as a flecked retina, or 'fundus albipunctatus', found in 85% of patients.  More recent evidence using OCT suggests that the dot-and-fleck retinopathy results primarily from abnormalities in the internal limiting membrane and the nerve fiber layer.  The yellowish and/or whitish flecks are most commonly located in the posterior pole and particularly in the macula.  There is no night blindness or visual impairment from the retinal involvement.  Fluorescein angiography shows patchy areas of hyperfluorescence.  The amount of visual impairment depends primarily on the extent of lens involvement.

Termporal macular thinning occurs to some extent in all types of Alport syndrome based on OCT findings.   In one series all patients with X-linked disease had temporal thinning suggesting that this might be a useful diagnostic sign.  However, similar thinning is also seen in Leber hereditary optic neuropathy (535000), and dominant optic atrophy (165500).

Systemic Features: 

Nephritis with hematuria secondary to basement membrane disease of the glomeruli is the most life threatening aspect of this disorder.  It occurs in both sexes but more commonly in males in which it has an earlier onset.  Progressive sensorineural hearing loss beginning with high frequencies occurs in many patients, often with subtle onset in childhood, but many adults retain some hearing capacity.  In males, the onset of hearing loss often occurs before kidney disease is evident.  Hearing loss is less frequent and less severe in females.  However, there is considerable clinical and genetic heterogeneity and not all patients have the complete syndrome of nephritis, deafness and ocular disease.  In fact, it has been suggested that Alport syndrome can be subtyped into at least six categories based on the extent of organ involvement.

Genetics

Alport syndrome is a member of a group of disorders known as collagen IV-related nephropathies.  It is a genetically heterogeneous disease with 85% inherited in an X-linked pattern and most of the remainder occurring in an autosomal recessive pattern and only a few seemingly autosomal dominant.  All result from a defect in type IV collagen found in basement membranes.  About 80% of cases have a mutation in the COL4A5 gene which is located at Xq22.3.  Males seem to be more severely affected than females in the X-linked form of the disease but clearly this disorder affects both sexes reflecting the genetic heterogeneity, much of which remains to be delineated.  The autosomal disease generally results from mutations in the COL4A3 or COL4A4 genes and has been seen in both recessive and dominant patterns of transmission.

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

Renal transplantation can be lifesaving but a minority of individuals develop a specific antiglomerular basement membrane antibody (anti-GBM) that may lead to graft rejection.  Allograft survival rates are generally excellent though.  Lens extraction is beneficial where the media is compromised.

References
Article Title: 

Alport syndrome: a genetic study of 31 families

M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L,
Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic
study of 31 families. Hum Genet. 1992 Dec;90(4):420-6.

PubMed ID: 
1483700
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