autosomal dominant

Noonan Syndrome

Clinical Characteristics
Ocular Features: 

Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility most commonly of the levator.  Ptosis and strabismus are present in nearly half of patients. Amblyopia has been found in one-third of patients and almost 10% have nystagmus.  Corneal nerves are prominent and a substantial number of individuals have optic nerve abnormalities including drusen, hypoplasia, colobomas and myelinated nerves.  Evidence of an anterior stromal dystrophy, cataracts, or panuveitis is seen in a minority of patients.  About 95% of patients have some ocular abnormalities.

Systemic Features: 

Patients are short in stature.  Birth weight and length may be normal but lymphedema is often present in newborns.  The neck is usually webbed (pterygium colli) and the ears low-set.  The sternum may be deformed.  Cardiac anomalies such as coarctation of the aorta, pulmonary valve stenosis, hypertrophic cardiomyopathy, and septal defects are present in more than half of patients.  Dysplasia of the pulmonic valve has been reported as well.  Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.  Cryptorchidism is common in males.  Some patients have intellectual disabilities with speech and language problems.  Most have normal intelligence.   

Parents of affected children often have subtle signs of Noonan Syndrome.

Genetics

This is an autosomal dominant disorder that can result from mutations in at least 8 genes.  Nearly half are caused by mutations in the PTPN11 gene (12q24.1) (163950).  Mutations in the SOS1 gene (2p22-p21) cause NS4 (610733) and account for 10-20% of cases, those in the RAF1 gene (3p25) causing NS5 (611553) for about the same proportion, and mutations in the KRAS gene (12p12.1) (NS3; 609942) cause about 1%.  Mutations in BRAF (7q34) causing NS7 (613706), NRAS (1p13.2) responsible for NS6 (613224), and MEK1 genes have also been implicated and it is likely that more mutations will be found.  The phenotype is similar in all individuals but with some variation in the frequency and severity of specific features.  New mutations are common. 

Several families with autosomal recessive inheritance (NS2) (605275) patterns have been reported with biallelic mutations in LZTR1.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for most of the developmental problems but some patients benefit from special education. Cardiac surgery may be required in some cases to correct the developmental defects.  Bleeding problems can be treated with supplementation of the defective coagulation factor.  Growth hormone therapy can increase the growth velocity.

References
Article Title: 

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018 Oct;20(10):1175-1185.

PubMed ID: 
29469822

Update on turner and noonan syndromes

Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on turner and noonan syndromes. Endocrinol Metab Clin North Am. 2012 Dec;41(4):713-34. Epub 2012 Sep 28.

PubMed ID: 
23099266

Myotonic Dystrophy 2

Clinical Characteristics
Ocular Features: 

Polychromatic lens opacities and posterior subcapsular sclerosis are found in 15-30% of patients. 

Ptosis, ophthalmoplegia and strabismus are not features of DM2.As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

Systemic Features: 

Symptoms of myotonia usually appear in the third and fourth decades of life while evidence of limb girdle muscle weakness usually appears much later.  There is no infancy or childhood form of the disease and developmental delays do not occur.   In some patients the proximal muscles seem to be more affected than distal muscles and such cases are sometimes referred to as PROMM disease.  In these patients the neck and finger flexors may be the first to be affected.  However, there is considerable clinical variability.  Facial weakness is minimal.  Eventually both proximal and distal muscles weaken.  Myalgia of a burning, tearing nature can be debilitating.  Cardiac arrhythmias occur in a minority of patients.  Frontal balding is characteristic.  The long-term prognosis is better than in patients with myotonic dystrophy 1 (160900), and some but not all reports suggest fewer individuals experience age-related cognitive decline.  Insulin insensitivity and testicular failure occur in approximately half of patients.

PROMM disease and DM2 are now generally accepted as the same disease and the latter designation is preferred.

Genetics

Like classic myotonic dystrophy 1 (160900), this disorder also results from an abnormal number of repeats (in this case of CCTG).  Up to 30 tetranucleotide repeats in CNBP (3q21.3) is normal but patients with myotonic dystrophy 2 may have 11,000 or more and the number increases with age.  The repeat length may diminish with generational transmission.  Unlike DM 1, the repeat number does not seem to correlate with disease severity.  Both DM1 and DM2 are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the muscle disease but many patients require analgesic medication for muscle pain.  Visually significant cataracts should be removed.  Some patients require supportive care.

References
Article Title: 

Myotonic Dystrophy 1

Clinical Characteristics
Ocular Features: 

Posterior subcapsular cataracts may be seen at any age, often with striking iridescent opacities in the overlying cortex as well.  These polychromatic lens changes can be diagnostic but are present in only 50% of young adults with myotonic dystrophy.  When present, they are almost always bilateral.  Proximal muscle involvement leads to ptosis, strabismus, weakness of the orbicularis oculi, and sometimes ophthalmoplegia.  Such muscle weakness may lead to exposure keratitis. 

As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

A low IOP and even hypotony is sometimes seen.  The mean IOP in a series of 51 patients has been reported as 10.9 compared with 15.4 in controls.  Using ultrasound biomicroscopy, ciliary body detachments were found in at least one quadrant of all eyes.

Systemic Features: 

In the congenital form, hypotonia, generalized weakness, mental retardation and respiratory insufficiency are often present.  There is a great deal of clinical heterogeneity among patients.  Those with mild disease may have only cataracts and mild myotonia with a normal life expectancy.  Those with more severe disease (classical myotonic dystrophy) have these signs plus marked muscle weakness and wasting.  Cardiac conduction defects with secondary arryhthmias are a significant cause of mortality. Such patients tend to become disabled in adulthood.  Symptoms become evident in the second decade or later.  Deep muscle pain is common and can be severe.  Distal muscle weakness usually begins before facial muscle weakness is apparent.  Myotonia often involves the tongue while proximal muscle weakness can cause dysphagia and dysarthria.  Such patients may also suffer respiratory distress. Reproductive fitness is reduced in males who can have gonadal atrophy.  Frontal balding is common.  Some age-related cognitive decline occurs.

Over 60% of patients have a hearing impairment and more than half of these have auditory brainstem response abnormalities.  Vestibular hypesthesia is present in 37.5%.

Genetics

Myotonic dystrophy 1 is an autosomal dominant disorder caused by a trinucleotide (CTG) repeat expansion in a region of the DMPK gene (19q13.2-q13.3).  The number of repeats varies widely and is roughly correlated with severity of disease.  Infants with congenital myotonia usually have the highest number of repeats and have the most severe cognitive deficits.  The number can expand during gametogenesis each generation (resulting in the phenomenon of anticipation) and females generally transmit larger numbers.  Most infants with congenital myotonia are offspring of affected mothers.  Reduced fetal movement and hydramnios are often noted during such pregnancies.

Affected males have few offspring secondary to gonadal atrophy.  Affected heterozygous females, however, do not have the expected ratio of affected offspring because of the dynamic nature of the number of repeats.  The risk of an affected offspring for a nulliparous afflicted female is only 3-9% and she has a 20-40% risk of recurrence after the birth of an affected child.

In a study of sibships with myotonic dystrophy, 58% of offspring were affected when the transmitting parent was male and 63% when the transmitting parent was female.

At least some of the variable transmission risks and clinical heterogeneity may be explained by somatic instability of the CTG repeat numbers.  The degree of instability, moreover, may also be heritable.  Age of onset, for example, is modified by the level of somatic instability.  Further, patients in whom the repeat expands more rapidly develop symptoms earlier. 

A similar disorder, myotonic dystrophy 2 (602668), is caused by a tetranucleotide repeat expansion in the CNBP gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A variety of pharmaceutical agents have been tried for pain management without consistent results.  No treatment improves the muscle weakness.  Cholesterol lowering drugs such as statins should be avoided.  Physical therapy may be helpful.

Cardiac conduction and structural defects are a significant threat even in asymtomatic patients and require constant monitoring for the development of arrythmias.

References
Article Title: 

Inner ear dysfunction in myotonic dystrophy type 1

Balatsouras DG, Felekis D, Panas M, Xenellis J, Koutsis G, Kladi A, Korres SG. Inner ear dysfunction in myotonic dystrophy type 1. Acta Neurol Scand. 2012 Nov 5. doi: 10.1111/ane.12020. [Epub ahead of print].

PubMed ID: 
23121018

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

les F, Couto JM, Higham CF, Hogg G, Cuenca P, Braida C, Wilson RH, Adam B, Del Valle G, Brian R, Sittenfeld M, Ashizawa T, Wilcox A, Wilcox DE, Monckton DG. Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet. 2012 May 16. [Epub ahead of print].

PubMed ID: 
22595968

Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1

Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Becane HM, Lazarus A, Behin A, Laforet P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2016 Dec 9. pii: ehw569. [Epub ahead of print] PubMed.

PubMed ID: 
27941019

Keratoconus 4

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a ‘scissoring’ pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  Mutations at the 2p24 locus on chromosome 2 seem to cause KTCN4 based on genome-wide linkage analysis in families from multiple out-bred populations.  The pattern of inheritance is autosomal dominant.

Other forms of hereditary keratoconus caused by different mutations are:  Mutations in VSX1 (20p11.2) cause KTCN1, KTCN2 (608932) is linked to a mutation on chromosome 16 (16q22.3-q23.1), and KTCN3 (608586) results from a mutation on chromosome 3 (3p14-q13).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 3

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  KTCN3 seems to be caused by a mutation located at 3p14-q13 as determined from linkage studies in a 2 generation Italian family.  It is inherited in an autosomal dominant pattern.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN1 (148300) caused by mutations in the VSX1 gene at 20p11.2), KTCN2 (608932) from a mutation on chromosome 16 (16q22.3-q23.1), and KTCN4 (609271) caused by a mutation on chromosome 2 (2p24).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 2

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  KTCN2 seems to be caused by a mutation located at 16q22.3-q23.1 as determined from linkage studies in 20 Finnish families.  It is inherited in an autosomal dominant pattern.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN1 (148300) caused by a mutation in the VSX1 gene (20p11.2), KTCN3 (608586) from a mutation on chromosome 3 (3p14-q13), and KTCN4 (609271) caused by a mutation on chromosome 2 (2p24).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 1

Clinical Characteristics
Ocular Features: 

The cornea progressively thins mostly in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy may show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively often thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse.

Genetics

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and other chromosomal disorders. It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years. Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder. Only keratoconus associated with single gene mutations are considered here.

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  Mutations in the VSX1 homeobox gene (20p11.2) have been found in what is called KTCN1 keratoconus (the same gene is mutant in posterior polymorphous corneal dystrophy 1 [122000]), inherited as an autosomal dominant trait.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN2 (608932) linked to a mutation on chromosome 16 (16q22.3-q23.1), KTCN3 (608586) by a mutation on chromosome 3 (3p14-q13), KTCN4 (609271) caused by a mutation on chromosome 2 (2p24), KTCN5 (614622) mapped to 5q14.1-q21.3, KTCN6 (614623) mapped to 9q34, KTCN7 (614629) mapped to 13q32, KTCN8 (614628) mapped to 14q24, and KTCN9 (617928) associated with a mutation in the TUBA3D gene located at 2q21.1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

VSX1: a gene for posterior polymorphous dystrophy and keratoconus

Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, Priston M, Dorval KM, Chow RL, McInnes RR, Heathcote G, Westall C, Sutphin JE, Semina E, Bremner R, Stone EM. VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet. 2002 May 1;11(9):1029-36.

PubMed ID: 
11978762

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: 

Tuberous Sclerosis 2

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  They are seldom of clinical significance although optic atrophy has been reported.  The ocular phenotype is similar in types 1 and 2.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

There is some evidence that the clinical disease is more severe in this type (TSC2) than in type 1 (191100).  TSC2 has more hypomelanotic patches and brain tubers.  Cognitive defects are more severe.  Those with TSC2 mutations also have an earlier onset of seizures and a higher incidence of infantile spasms.

Genetics

This is the more severe and more common of the two tuberous sclerosis complex phenotypes.  It is caused by mutations in the TSC2 gene encoding tuberin on chromosome 16p13.3.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish between types 1 and 2.

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC (191100) is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Tuberous Sclerosis 1

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  These are seldom of clinical significance although optic atrophy has been reported. The iris may have hypopigmented areas.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

Genetics

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

A more severe phenotype, tuberous sclerosis 2 (613254), is caused by mutations in the TSC2 gene on chromosome 16p13.3 and accounts for the majority of cases of tuberous sclerosis complex.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish clinically between types 1 and 2.

New mutations are responsible for 50-70% of cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34

van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805-8.

PubMed ID: 
9242607

Tuberous sclerosis

Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. Review.

PubMed ID: 
18722871

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