autosomal dominant

Angiopathy, Hereditary, with Nephropathy, Aneurysms, and Muscle Cramps

Clinical Characteristics
Ocular Features: 

Tortuosity of second and third order arterioles is usually present bilaterally but does not involve first order branches.  Intraretinal hemorrhages may also be seen and are sometimes associated with minor stress and trauma.  No fluorescein leakage is present.  Vision usually remains good but transient vision loss may be reported if the retinal hemorrhages involve the fovea and parafoveal areas.

Systemic Features: 

Nail bed capillaries may appear tortuous.  Aneurysms of the internal carotid and middle cerebral arteries can be present and cerebrovascular accidents sometimes occur.  Brain imaging may show degrees of leukoencephalopathy.  Large renal cysts, mild hematuria both microscopic and gross, and mild renal failure are sometimes seen.  Some patients experience Raynaud phenomena.  Muscle cramps lasting seconds to hours are not uncommon.  Some patients have supraventricular cardiac arrhythmias.

Alterations in basement membrane morphology can be seen on electron microscopy in many areas of the body but that of the glomeruli is normal even though the filtration rate is decreased.

Genetics

This is an autosomal dominant condition as the result of heterozygous mutations in COL4A1 (13q34).  Mutations in the same gene have also been found in a simpler autosomal dominant disease known as Retinal Arteriolar Tortuosity (180000).  The latter may be an allelic condition or the same disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the underlying disease although symptomatic relief for cramps, arrhythmias, and renal failure may be beneficial.

References
Article Title: 

Ataxia with Oculomotor Apraxia 4

Clinical Characteristics
Ocular Features: 

Oculomotor apraxia is usually noted after the ataxia and dystonia are apparent.

Systemic Features: 

The mean age of first symptoms is 4.3 years with dystonia being the first symptom.  Cerebellar ataxia is usually the second symptom to appear.  Cognitive impairment is present in most but not all patients with this condition.  This can progress to severe dementia in some individuals.  Dystonia may become attenuated with time.  Peripheral neuropathy with decreased vibration sense and areflexia is often present.  Cerebellar atrophy is present in all patients.

Motor difficulties such as weakness and muscle atrophy may lead to loss of independent mobility by the second to third decades.

Genetics

Homozygous or compound heterozygous mutations in the PNKP gene (19q13.33) are responsible for this disorder.

Mutations in this gene have also been associated with an infantile form of epileptic encephalopathy, microcephaly, and developmental delay (613402).

See also Ataxia with Oculomotor Apraxia 1 (208920) with hypoalbuminemia, Ataxia with Oculomotor Apraxia 2 (606002), and Ataxia with Oculomotor Apraxia 3 (615217).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this condition but physical therapy may be helpful in the early stages.

References
Article Title: 

Singleton-Merten Syndrome 2

Clinical Characteristics
Ocular Features: 

Glaucoma has been diagnosed in multiple members of 4 a generation Korean family in which various features of this disorder were found.  The glaucoma is likely congenital in origin as it has been diagnosed in patients as young as 3 years of age

Systemic Features: 

Calcification of the aorta and other large vessels may be identified in childhood.  The aortic valve and coronary arteries may become calcified in young adults as well, sometimes resulting in aortic stenosis.  Arthritis resulting from calcified tendons as well as ligaments of the interphalangeal and metacarpophalangeal joints may occur in young adults.  The skin is often scaly and dry with psoriatic lesions.  The terminal tufts of the digits have evidence of erosion.

Genetics

Heterozygous mutations in the DDX58 gene (9p21.1) have been associated with this disorder.  Some of the clinical features overlap those of Singleton-Merten Syndrome 2 (182250) but this is a unique disorder caused by a different mutation (IFIH1).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma should be treated with pressure-lowering drugs and surgery.  It may be possible to decalcify cardiovascular structures in select patients and to perform valve replacement.

References
Article Title: 

Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome

Jang MA, Kim EK, Now H, Nguyen NT, Kim WJ, Yoo JY, Lee J, Jeong YM, Kim CH, Kim OH, Sohn S, Nam SH, Hong Y, Lee YS, Chang SA, Jang SY, Kim JW, Lee MS, Lim SY, Sung KS, Park KT, Kim BJ, Lee JH, Kim DK, Kee C, Ki CS. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):266-74.

PubMed ID: 
25620203

Singleton-Merten Syndrome 1

Clinical Characteristics
Ocular Features: 

Several children have been diagnosed with glaucoma in early childhood or during puberty.  Glaucoma surgery has been beneficial in some but visual damage may be severe.

Systemic Features: 

Patients have early-onset calcifications of the aorta and of the aortic and mitral valves which may be seen in childhood and can be responsible for heart failure and early death.  Osteoporosis of the limbs and widened medullary cavities have been seen.  Abnormal bone mineralization and extends to the jaws leading to tooth loss and early-onset periodontal disease.  Eruption of both primary and permanent teeth is delayed but tooth roots can be truncated as well.  The hips dislocate easily due to shallow acetabulae and patients are susceptible to tendon tears.

Hypotonia and generalized weakness may be present which is sometimes exacerbated following a febrile illness.  The skin may be dry and scaly consistent with psoriasis and there may be photosensitivity.

The forehead is broad and prominent and the hairline is high and anterior.  The philtrum is smooth and the upper vermilion is thin.

Genetics

Heterozygous mutations in the IFIH1 gene (2q24.2) are responsible for this disorder.  Another form of Singleton-Merten Syndrome (SGMRT2; 609631) is the result of mutations in the DDX58 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific problems such as fractures, glaucoma, and periodontal disease.

References
Article Title: 

A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome

Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nurnberg P, Hohne W, Crow YJ, Feigenbaum A, Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):275-82.

PubMed ID: 
25620204

Cole-Carpenter Syndrome 1

Clinical Characteristics
Ocular Features: 

The bony orbits are shallow and the eyes appear prominent as part of the facial and skull bone deformities.  The proptosis may be progressive and eventually interfere with blinking and normal surface wetting of the cornea. 

Systemic Features: 

This condition may superficially resemble osteogenesis imperfecta with osseous deformities and frequent fractures.  However, the occurrence of craniosynostosis and hydrocephalus helps to distinguish it.  Cranial sutures may be slow to fuse and macrocephaly has been described.  Communicating hydrocephalus can be a feature and may require shunting.  Some patients have osteopenia of the long bones that fracture easily.

The facial features are said to be distinctive with midface hypoplasia, low-set ears, micrognathia, and, of course, prominent globes.  Growth may be subnormal and a variety of limb bone and digital anomalies have been described.  Intelligence is normal, however.

Genetics

This condition is the result of heterozygous mutations in the P4HB gene (17q25.3) (PDI family).

See Cole-Carpenter Syndrome 2 (616294) for a somewhat similar disorder that is recessively inherited.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A frontal craniectomy may be necessary during early childhood to relieve the proptosis particularly when blinking is impaired.  Patients must be followed for the development of communicating hydrocephalus.  Long bone fractures require prompt treatment. 

References
Article Title: 

Kaufman Oculocerebrofacial Syndrome

Clinical Characteristics
Ocular Features: 

Alterations in the morphology of periocular structures is the most consistent ocular feature.  These include epicanthal folds, upward-slanting lid fissures, ptosis, blepharophimosis, sparse eyebrows, and telecanthus.  However, pale optic discs, iris colobomas, microcornea, strabismus, nystagmus, and hypertelorism are variably present. 

Systemic Features: 

There is both intrauterine and postnatal growth retardation.  Hypotonia is often noted along with general psychomotor delays.  Neonatal respiratory distress and laryngeal stridor may be present.  The intellectual disability can be severe.  Corpus callosum aplasia and hypoplasia have been reported.  Microcephaly and brachycephaly with delayed suture closure are features.  The face is long and narrow and the mouth is disproportionally large.  A high arched palate can be present and the pinnae are often deformed, posteriorly rotated and may be accompanied by preauricular skin tags. The teeth appear widely spaced (diastema) and the lower jaw is underdeveloped.

Genetics

Kaufman BPIDS syndrome results from homozygous or compound heterozygous mutations in the UBE3B gene (12q23).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment is available although repair of some specific malformations is possible.

References
Article Title: 

Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome

Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miro X, White JK, Desir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmuller J, Nurnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nurnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet. 2012 Dec 7;91(6):998-1010.

PubMed ID: 
23200864

An oculocerebrofacial syndrome

Kaufman RL, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Artic Ser. 1971 Feb;7(1):135-8.

PubMed ID: 
5006210

Tenorio Syndrome

Clinical Characteristics
Ocular Features: 

The eyebrows appear bushy.  Inflammation of the limbus and keratoconjunctivitis sicca are often present and reported to resemble Sjogren syndrome.

Systemic Features: 

Infants appear large at birth with a large forehead and macrocephaly.  Birth weight, length, and head circumference are usually above the 97th percentile. The mandible appears large and the lips are full and ‘fleshy’.  Dentition is delayed.  Recurrent stomatitis and gastroesophageal reflux have been noted.  Closure of the fontanels is delayed.  Hypotonia and hyperflexible joints can be a feature.

Multiple brain anomalies have been described including cortical atrophy, dilated and asymmetrical ventricles, and mild hydrocephalus.  Psychomotor development and milestones are delayed.  Intellectual disabilities, syncope, hypoglycemia, seizures, apneic episodes, mood anomalies, abnormal gait, and general clumsiness may be present.  There was considerable clinical variation among the six reported patients. 

Genetics

Heterozygous mutations in RNF125 (18q12.1) are responsible for this syndrome. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

A new overgrowth syndrome is due to mutations in RNF125

Tenorio J, Mansilla A, Valencia M, Martinez-Glez V, Romanelli V, Arias P, Castrejon N, Poletta F, Guillen-Navarro E, Gordo G, Mansilla E, Garcia-Santiago F, Gonzalez-Casado I, Vallespin E, Palomares M, Mori MA, Santos-Simarro F, Garcia-Minaur S, Fernandez L, Mena R, Benito-Sanz S, del Pozo A, Silla JC, Ibanez K, Lopez-Granados E, Martin-Trujillo A, Montaner D; SOGRI Consortium, Heath KE, Campos-Barros A, Dopazo J, Nevado J, Monk D, Ruiz-Perez VL, Lapunzina P. A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 Dec;35(12):1436-41.

PubMed ID: 
25196541

Jackson-Weiss Syndrome

Clinical Characteristics
Ocular Features: 

The facial malformation such as the flattened midface with maxillary hypoplasia leads to shallow orbits with the result that the eyes appear proptotic.  Some but not all individuals have strabismus, usually exotropia.  Optic atrophy has not been reported. 

Systemic Features: 

Infants usually present at birth with skull deformities resembling some variant of acrocephalosyndactyly.  Some or all of the skull sutures may be fused.  In some individuals craniectomy is necessary while others have normal brain development.  Few patients have evidence of abnormal neurological development and psychometric testing reveals IQ's in the normal range.  The midface is flattened with sometimes severe maxillary hypoplasia.  No hand deformities are present. 

There may be cutaneous syndactyly of the second and third toes.  Variable tarsal fusion is often present. The great toe may be abnormally broad and deviated medially.  The first metatarsals and proximal phalanges of the great toes are generally broad.

The phenotype is highly variable and even among individuals in genetically more homogeneous populations such as the Old Order Amish the range of facial, skull, and digital anomalies include features found among all of the craniosynostosis syndromes except for Apert syndrome.

Genetics

Heterozygous mutations in the FGFR2 gene (10q26.13) are likely responsible for this autosomal dominant condition. 

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Beare-Stevenson Syndrome (123790), Crouzon Syndrome (123500), Pfeiffer Syndrome (101600), Apert Syndrome (101200), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment beyond surgical correction of selected malformations. The risk of exposure keratitis requires constant vigilance and appropriate corneal lubrication.

References
Article Title: 

Fibrosis of Extraocular Muscles with Synergistic Divergence

Clinical Characteristics
Ocular Features: 

This is an ocular motility disorder with restrictive ophthalmoplegia and anomalous eye movements.  Some individuals exhibit Marcus Gunn jaw winking and downgaze fixation along with ptosis.  MRI imaging may reveal hypoplasia of the oculomotor nerve and absence of the abducens nerve.  Sometimes one or more extraocular muscles are replaced with fibrous tissue.  Globe retraction may accompany the abduction movement.  Forced duction testing may reveal severe restriction and Bell's phenomenon may be absent.  Vertical nystagmus and jerky eye motions may accompany attempted fixation.  There is considerable asymmetry to the extraocular movements of the two eyes. 

Systemic Features: 

Some patients have oculocutaneous hypopigmentation.

Genetics

No specific mutation has been identified.  Several examples of parent to child transmission have been reported suggesting autosomal dominant inheritance.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM1 (135700), CFEOM2 (602078), CFEOM3C (609384), and CFEOM5 (616219), although the eye movement phenotype may vary.  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ptosis and strabismus surgery may be of benefit.

References
Article Title: 

Fibrosis of Extraocular Muscles, CFEOM3C

Clinical Characteristics
Ocular Features: 

Bilateral ptosis is present at birth and the superior rectus muscle movements are limited.  Two of the 4 affected members of the 3 generation family reported also had bilateral excyclotropia.  The extraocular muscle movement restrictions were not progressive.  On computed tomography the extraocular muscles appeared normal.

Systemic Features: 

One affected member of the pedigree had an unbalanced translocation with asymmetric facial dysmorphism with exophthalmia and ptosis. She also had physical and mental growth delay, kyphosis, pectus excavatum, limited speech, ophthalmoplegia, regression of motor skills and peripheral hypertonia with brisk reflexes.  Other members with ophthalmoplegia had no systemic findings. 

Genetics

In the reported family a balanced translocation, t(2;13)(q37.3;q12.11), was present in 3 affected. The 4th patient with syndromal ophthalmoplegia had an unbalanced translocation.  The transmission pattern of t(2;13) is consistent with autosomal dominant inheritance.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM1 (135700), CFEOM2 (602078), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ptosis surgery can be helpful.

References
Article Title: 

Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3)locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes

Aubourg P, Krahn M, Bernard R, Nguyen K, Forzano O, Boccaccio I, Delague V, De Sandre-Giovannoli A, Pouget J, Depetris D, Mattei MG, Philip N, Levy N. Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3)locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes. J Med Genet. 2005 Mar;42(3):253-9.

PubMed ID: 
15744040

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