autosomal dominant

Macular Dystrophy, Patterned 2

Clinical Characteristics
Ocular Features: 

Abnormal pigmentation of yellow, white, or black color accumulates in the central area of the macula.  The deposition of pigment appears in the retinal pigment epithelium (RPE) level in a pattern more or less resembling the wings of a butterfly.  The peripheral retina has diffuse pigment mottling.  Drusen-like structures may be seen at the peripheral borders of the macular pigmentation.  Visual fields are normal usually but there may be some decrease in central sensitivity.

However, this is a generalized retinal disorder as revealed by the abnormal mass response (decreased light/dark ratio) of the electrooculogram (EOG).   Patients may not have visual symptoms until their late 20s or early 30s even though the pigmentation may be evident in the second decade.  Color vision, dark adaptation and the ERG are normal.  Younger patients may have normal vision.

Systemic Features: 

No systemic associations have been reported.

Genetics

This condition results from heterozygous mutations in the CTNNA1 gene (5q31).  For a similar disorder see Macular Dystrophy, Patterned 1 (169150).

As many as 25% of patients with myotonic dystrophy 1 (160900) and myotonic dystrophy 2 (602668) have a patterned pigmentary maculopathy.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment.

References
Article Title: 

Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity

Saksens NT, Krebs MP, Schoenmaker-Koller FE, Hicks W, Yu M, Shi L, Rowe L, Collin GB, Charette JR, Letteboer SJ, Neveling K, van Moorsel TW, Abu-Ltaif S, DeBaere E, Walraedt S, Banfi S, Simonelli F, Cremers FP, Boon CJ, Roepman R, Leroy BP, Peachey NS, Hoyng CB, Nishina PM, den Hollander AI. Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity. Nat Genet. 2016 Feb;48(2):144-51.

PubMed ID: 
26691986

Takenouchi-Kosaki Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype consists of mild ptosis, synophrys, exotropia, and eversion of the lower eyelids.  One of two reported patients was described as having bilateral retinal dysplasia and a falciform retinal detachment in one eye.  Visual acuity is significantly impaired.

Systemic Features: 

Affected individuals may be of normal birth weight but skeletal growth is subnormal and there is general developmental delay.  Congenial cardiac anomalies such as persistent ductus arteriosus may be present.  Lymphedema has been noted at one year of age and probably persists throughout life.  Protein-losing enteropathy secondary to intestinal lymphangiectasia was present in one individual.  The same patient had pericardial effusion, hydrothorax, and ascites.  Intellectual disability may be severe although there is no evidence of progression.  Neurosensory hearing loss has been described in one patient.

Thrombocytopenia is a consistent finding and has been described as early as one year of age.  Platelet numbers as low as 52,000/microL have been recorded and appear larger than normal. 

Genetics

Both unrelated female patients reported have heterozygous missense mutations in the CDC42 gene (1p36). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Cleft Palate, Psychomotor Retardation, and Distinctive Facial Features

Clinical Characteristics
Ocular Features: 

The facial dysmorphism is present at birth together with the cleft palate.  Downslanting lid fissures, widely spaced eyes, and ptosis may be present.  Eyebrows have been described as sparse in one patient.  Strabismus and ocular apraxia are present in some children. 

Systemic Features: 

Three patients have been reported, one of whom also had a second deletion in a gene implicated in the Kabuki syndrome.  This individual had hypertrichosis and synophyrys whereas the others had sparse eyebrow and temporal hair.  The teeth are malformed with some conically shaped and widely spaced.  The forehead is prominent and the fingers are tapered and brachydactylous with 5th finger clinodactyly.

There are significant delays in achieving developmental milestones.  Hypotonia has been described.  Speech and walking in particular may be delayed for several years.   Physical growth may be delayed as well.  A variety of brain anomalies have been seen in some but not all individuals.  Hypospadius and cryptorchidism have been described.  All children reported have palatal anomalies.

Genetics

Heterozygous mutations in the KDM1A gene have been identified in two patients.  In another report a single patient had an out-of-frame 3-nucleotide deletion in the ANKRD11 gene (as sometimes found in Kabuki syndrome) plus a mutation in the KDM1A gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, Rauch A, Saenz MS, Boltshauser E, Patterson KE, Nickerson DA, Bamshad MJ. Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet Med. 2015 Dec 10. doi: 10.1038/gim.2015.161. [Epub ahead of print].

PubMed ID: 
26656649

Behcet-Like Familial Autoinflammatory Syndrome

Clinical Characteristics
Ocular Features: 

A minority of reported patients (3 of 14) have had Behcet-like uveitis with retinal vasculitis and chorioretinal lesions.  In two of the 3 patients with uveitis the inflammation was anterior but the authors reported significant visual loss.

Systemic Features: 

Fourteen patients in 6 unrelated families have been reported.  Onset usually occurs during the first or second decades of life.  Patients usually developed oral and genital ulcers.  Other features variably present were polyarthritis, a skin rash and inflammatory disease or ulcerations in the GI tract.  Several patients had periodic fevers and hemolytic anemia was present in one.  The majority of individuals have been female.

Three patients in a single family had lupus anticoagulant and three others had antinuclear antibodies.

Genetics

This syndrome results from heterozygous mutations in the TNFAIP3 gene (6q23.3) with loss of function leading to A20 haploinsufficiency.  Changes in the TNFAIP3 gene have also been identified in rheumatoid arthritis, systemic lupus erythematosis, and idiopathic juvenile arthritis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Several patients have responded positively to treatment with tumor necrosis factor inhibitors or colchicine.

References
Article Title: 

Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, P Hanson E, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gul A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016 Jan;48(1):67-73.

PubMed ID: 
266422433

Macular Dystrophy, Patterned 3

Clinical Characteristics
Ocular Features: 

This condition has been found in an extended pedigree among peoples originating in the West Indies.  Vision loss is noted after the age of 50 years but clinical evidence can be seen in the fourth or fifth decades. The findings are primarily in the retinal pigment epithelium but Bruch's membrane is also involved.  Choroidal neovascularization and macular scarring may be present. The fundus pigmentary pattern has been described as resembling "dried-out soil" or crocodile skin.  In late stages the fundus picture resembles retinitis pigmentosa with loss of the RPE and photoreceptors.  The loss of photoreceptors continues throughout life. An 85 year old woman with light perception only has been described. 

In early stages the full-field ERG can be nomal but later rod and cone responses are severely reduced.  The OCT may show scalloped elevation at the borders of the scalloped patches corresponding to the irregular thickness of the RPE and Bruch membrance.

Knockout mice have both thickened and thinned areas of the Bruch membrane.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This autosomal dominant condition results from heterozygous mutations in MAPKAPK3 (3p21.3), a mitogene-activated kinase of the p38 signaling pathway.  It is highly expressed in the RPE.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium

Meunier I, Lenaers G, Bocquet B, Baudoin C, Piro-Megy C, Cubizolle A, Quiles M, Jean-Charles A, Cohen SY, Merle H, Gaudric A, Labesse G, Manes G, Pequignot M, Cazevieille C, Dhaenens CM, Fichard A, Ronkina N, Arthur SJ, Gaestel M, Hamel CP. A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum Mol Genet. 2016 Mar 1;25(5):916-26.

PubMed ID: 
26744326

Axenfeld-Rieger Syndrome, Type 4

Clinical Characteristics
Ocular Features: 

The ocular features of this syndrome are similar to types 1-3 and primarily involve the anterior segment.  The iris stroma is hypoplastic and the pupil location may be eccentric.  Full thickness defects in the iris can lead to pseudopolycoria.   There may be anterior displacement of the angle structures with posterior embryotoxon and localized corneal opacification.    Glaucoma is a common feature and it may be present in early childhood, associated with tearing, a hazy cornea, and buphthalmos.  Vitreous condensation was noted in all 4 reported individuals.

Systemic Features: 

The midface is flat due to maxillary underdevelopment and the teeth may be abnormally small.  Micrognathia has been reported while the nasal root is abnormally broad.  The umbilical defect consists of redundant skin that failed to involute normally.  Congenital hip anomalies of undetermined nature and a hearing defect were reported in 2 of 4 individuals.

Genetics

Heterozygous mutations in the PRDM5 gene (4q25-q26) are responsible for this condition.  Mutations in CYP1b1, PITX2, and FOXC1 were not present.  One extended pedigree with 4 affected individuals from Pakistan has been reported. 

Type 1 Axenfeld-Rieger syndrome (180500) results from heterozygous mutations in PITX2, RIEG2 (601499) from heterozygous mutations in 13q14, and RIEG3 (602482) from heterozygous mutations in the FOXC1 gene.  Thus in three types of Axenfeld-Rieger syndrome (1,3, and 4) the responsible mutation occurs in a transcription factor gene which may explain why the phenotype is highly variable with considerable overlap in clinical signs.

Autosomal recessive brittle cornea syndrome type 2 (614170) is also caused by mutations in the PRDM5 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at correction of individual problems such as glaucoma and dental anomalies.  One patient required surgery for a retinal detachment. Lifelong ocular monitoring is recommended. 

References
Article Title: 

CHOPS Syndrome

Clinical Characteristics
Ocular Features: 

There is usually some degree of proptosis and apparent hypertelorism.  The eyebrows are bushy and the eyelashes are luxurious.  One of three patients had cataracts and another had mild optic atrophy.

Systemic Features: 

The overall facial appearance may resemble Cornelia de Lange syndrome with hypertrichosis and a coarse, round facies.  Head circumference is low normal.  Septal defects and a patent ductus arteriosus are often present.  Laryngeal and tracheal malacia predispose to recurrent pulmonary infections and chronic lung disease.  Skeletal dysplasia includes brachydactyly and anomalous vertebral bodies resulting in short stature (3rd percentile).  Genitourinary abnormalities include cryptorchidism, horseshoe kidney, and vesiculoureteral reflux.  Delayed gastric emptying and reflux have been reported.

Genetics

Heterozygous mutations in the AFF4 gene (5q31.1) have been identified in 3 unrelated individuals with this condition.  No familial cases have been identified.  The gene is a core component of the super elongation complex that is critical to transcriptional elongation during embryogenesis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the general disorder.  Tracheostomy was required in 2 of three reported patients. 

References
Article Title: 

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44.

PubMed ID: 
25730767

Mandibulofacial Dysostosis with Alopecia

Clinical Characteristics
Ocular Features: 

The extensive dysplasia of the facial bones involves those of the orbital rims and zygomatic arches.  The orbital rims can be malformed and there is often a broad depression at the inferolateral region of the eyes.  Hypoplasia or even aplasia of the eyelids maybe present and some individuals have colobomas of the lower eyelids.  The lacrimal punctae may be temporally displaced.  The eyebrows and eyelashes are often sparse as part of the generalized alopecia.

Systemic Features: 

This is a disorder of craniofacial development resulting in extensive malformations of facial bones and skin.  Different rates of development among these structures leads to facial asymmetry in many patients. Maxillary, zygomatic arch, and mandibular bones are dysplastic resulting in micrognathia and a flat midface.   The temporomandibular joints are absent and the external ear canals are often incompletely formed.  Conductive hearing loss is common with hypoplastic ossicular chains while the pinnae are low-set, crumpled and abnormally cupped.  There may be preauricular tags or pits present.  Tooth eruption is often delayed and there may be agenesis of many permanent teeth.  The maxillary sinuses may be absent.  Cleft palate is often present.

Genetics

Heterozygous mutations in the EDNRA gene (4q31) are responsible for this condition.  No familial cases have been reported and it can be assumed that the mutations arise de novo. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual anomalies such as the colobomas, dental deformities and cleft palate may be surgically repaired.  Upper airway obstruction may require tracheostomy in infants.

References
Article Title: 

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia

Gordon CT, Weaver KN, Zechi-Ceide RM, Madsen EC, Tavares AL, Oufadem M, Kurihara Y, Adameyko I, Picard A, Breton S, Pierrot S, Biosse-Duplan M, Voisin N, Masson C, Bole-Feysot C, Nitschke P, Delrue MA, Lacombe D, Guion-Almeida ML, Moura PP, Garib DG, Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ, Kurihara H, Saal HM, Weaver DD, Katsanis N, Lyonnet S, Golzio C, Clouthier DE, Amiel J. Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am J Hum Genet. 2015 Apr 2;96(4):519-31.

PubMed ID: 
25772936

Hypotrichosis-Lymphedema-Telangiectasia-Renal Defect Syndrome

Clinical Characteristics
Ocular Features: 

Sparse hair can be noted at birth and by several years of age the alopecia of the eyelids and eyebrows is complete.  The upper eyelids may be swollen at birth as well. 

Systemic Features: 

The facial features are unusual.  The nose appears long and may have a broad nasal root.  The lips are full and the lower jaw is prominent. Evidence of developmental delay has been reported in one patient.

The scrotum can be edematous at birth and sometimes contains large hydroceles.  Hair is sparse in infancy but within a few years alopecia is complete.  Telangiectases on the scalp, scrotum, and limbs are evident at several years of age.  Pulmonary vascular congestion and lymphangiectasia may be present in some individuals antenatally.  Renal failure, sometimes with hypertension can occur at any time from early childhood to young adulthood.  Renal biopsy has shown histologic features consistent with membranoproliferative glomerulonephritis and thrombotic microangiopathy.  This may be preceded by proteinuria in infants as young as 2 years. 

Genetics

This condition is the result of heterozygous mutations in the SOX18 gene (20q13.33). 

Homozygous mutations in the same gene may be responsible for a somewhat similar disorder (HLTS) (607823) which has many of the same facial and systemic features but lacks the renal disease. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some patients have benefitted from renal transplantation.

References
Article Title: 

Gracile Bone Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been described as small.  Aniridia may be present.

Systemic Features: 

This is a usually fatal form of skeletal dysplasia with splenic and ocular features as well.  In utero death is not uncommon while newborns may not survive the neonatal period.  The face has been described as dysmorphic with a high forehead, flat nasal bridge, a cloverleaf-shaped skull, and hypoplastic cranial bones with premature suture closure.  The long bones are dysplastic as well with thinned diaphyses (sometimes fractured in utero), growth plate disorganization, excessive remodeling, and signs of arrested growth.  The ribs share in the dysplasia but pulmonary hypoplasia has also been described.  Most individuals have short limbs.

The spleen can be hypoplastic or aplastic and ascites has been noted in several infants.  Failure to thrive is common and seizures have been reported.  Males may have micropenis and hypospadias while females have been described with labial fusion.  

Low parathyroid hormone levels and hypocalcemia has been reported in most individuals.

Genetics

Heterozygous mutations in the FAM111A gene (11q12.1) have been associated with this disorder.  The functional role of FAM111A products is unknown but likely play a role in calcium metabolism, parathyroid hormone secretion, and osseous development.

Mutations in the same gene can be responsible for the allelic autosomal dominant Kenny-Caffey syndrome (127000) with some similar features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

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