cardiac septal defects

Carey-Fineman-Ziter Syndrome

Clinical Characteristics
Ocular Features: 

Abnormal eye movements with prominent external ophthalmoplegia are hallmarks of this disease.  An oculomotor nerve palsy with limited abduction and some degree of facial palsy are usually present.  The Moebius sequence is present in many patients.  Epicanthal folds, downslanting lid fissures, and ptosis are frequently seen.

Systemic Features: 

Clinical signs are highly variable.  Unusual facies with features of the Pierre Robin complex are characteristic.  Micrognathia and retrognathia are often present with glossoptosis.  Hypotonia and failure to thrive are commonly seen.  Dysphagia and even absent swallowing likely contribute to this.  Respiratory insufficiency can be present from birth, often with laryngostenosis, and some patients develop pulmonary hypertension and restrictive lung disease as adults.  Progressive scoliosis may contribute to this.  Many patients have club feet with joint contractures.  Skull formation consisting of microcephaly, or macrocephaly, or plagiocephaly is commonly seen.  Cardiac septal defects are common.

Intellectual disability is present in some but not all individuals.  Neuronal heterotopias, enlarged ventricles, reduced white matter, a small brainstem, microcalcifications, and enlarged ventricles have been observed.

Genetics

Homozygous or compound heterozygosity of the MYMK gene (9q34) is responsible for this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.

References
Article Title: 

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bonnemann CG, Olson EN; Moebius Syndrome Research Consortium, Carey JC, Robertson SP, Manoli I, Engle EC. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.

PubMed ID: 
28681861

Möbius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome

Verloes A, Bitoun P, Heuskin A, Amrom D, van de Broeck H, Nikkel SM, Chudley AE, Prasad AN, Rusu C, Covic M, Toutain A, Moraine C, Parisi MA, Patton M, Martin JJ, Van Thienen MN. Mobius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome. Am J Med Genet A. 2004 Jun 15;127A(3):277-87.

PubMed ID: 
15150779

Arthrogryposis, Perthes Disease, and Upward Gaze Palsy

Clinical Characteristics
Ocular Features: 

Upward gaze is restricted and attempts to do so are associated with exotropia.

Systemic Features: 

Arthrogryposis with restricted joint mobility is present in both proximal and distal joints, including hips, elbows, hands, and knees.  It is usually evident early in infancy when parents note "tight joints".  Other joint deformities present to some degree are "trigger finger" deformities found in the middle fingers and thumbs.  Hip pain and difficulty walking as early as 3 years of age can be signs of avascular necrosis of the femoral head (Perthes disease).   

Pyloric stenosis can lead to severe, recurrent vomiting.  Pulmonic stenosis is commonly present and there are often cardiac septal defects as well as valvular malfunctions.  Bronchial asthma is a feature.

Genetics

One extended consanguineous Saudi family with three affected females has been reported.  No similar findings are present in the parents and the condition is most likely transmitted as an autosomal recessive.  A homozygous mutation in NEK9 (14q24) has been associated with this condition.

Heterozygous mutations in the same gene have been identified in 3 patients with nevus comedonicus (617025).  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Flexion deformities may be at least partially alleviated by surgery and is especially beneficial for digital function.  Pyloric stenosis and cardiac valve disease may respond to surgery.

References
Article Title: 

Mutations in NEK9 Cause Nevus Comedonicus

Levinsohn JL, Sugarman JL; Yale Center for Mendelian Genomics, McNiff JM, Antaya RJ, Choate KA. Somatic Mutations in NEK9 Cause Nevus Comedonicus. Am J Hum Genet. 2016 May 5;98(5):1030-7.

PubMed ID: 
27153399

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, ALMoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M, Alfaleh K, Alshammari M, Alhashem A, Alangari AA, Salih MA, Kircher M, Daza RM, Ibrahim N, Wakil SM, Alaqeel A, Altowaijri I, Shendure J, Al-Habib A, Faqieh E, Alkuraya FS. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med. 2016 Jul;18(7):686-95.

PubMed ID: 
26633546

Hypotonia, Infantile, with Psychomotor Retardation

Clinical Characteristics
Ocular Features: 

Abducens nerve palsy with characteristic strabismus (esotropia) can be present.

Systemic Features: 

Mothers may note decreased fetal movements.  Severe generalized hypotonia may be evident at birth, requiring tube feeding and respiratory assistance.  Death may occur before 6 months of age but with intense supportive care children may live for several years.  Brain imaging may show enlarged lateral ventricles and thinning of the corpus callosum in some individuals but no abnormalities in others.  Muscle biopsies can show severe myopathic changes with increased fibrosis, variation in fiber size, and small atrophic fibers.  Cardiac septal defects have been reported.  Delayed psychomotor development is a common feature.

Genetics

Homozygous mutations in the CCDC174 gene (3p25.1) are responsible for this condition so far reported in only two families with 6 children affected.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for this condition.

References
Article Title: 

CDC174, a novel

Volodarsky M, Lichtig H, Leibson T, Sadaka Y, Kadir R, Perez Y, Liani-Leibson
K, Gradstein L, Shaco-Levy R, Shorer Z, Frank D, Birk OS. CDC174, a novel
component of the exon junction complex whose mutation underlies a syndrome of
hypotonia and psychomotor developmental delay
. Hum Mol Genet. 2015 Nov
15;24(22):6485-91.

PubMed ID: 
26358778

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

Basel-Vanagaite-Smirin-Yosef Syndrome

Clinical Characteristics
Ocular Features: 

The eyes appear abnormally far apart.  Ptosis, microcornea, congenital cataracts, sparse eyebrows, and strabismus are usually present.  Epicanthal folds are often seen.

Systemic Features: 

Psychomotor development is severely delayed and with delay or absence of milestones.  DTRs are often hyperactive but some infants are described as hypotonic.  Some individuals have seizures.  There may be a nevus flammeus simplex lesion on the forehead and body hair is sparse.  Cleft palate, cardiac septal defects, hypospadius, thin corpus callosum and cerebral ventricular dilation have been observed.  The upper lip may have a tented morphology with everted lower lip vermilion. A short philtrum is common. 

Genetics

A homozygous missense mutation in the MED25 gene (19q13.33) has been reported and the transmission pattern is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No known treatment has been reported.

References
Article Title: 

Homozygous MED25 mutation implicated in eye-intellectual disability syndrome

Basel-Vanagaite L, Smirin-Yosef P, Essakow JL, Tzur S, Lagovsky I, Maya I, Pasmanik-Chor M, Yeheskel A, Konen O, Orenstein N, Weisz Hubshman M, Drasinover V, Magal N, Peretz Amit G, Zalzstein Y, Zeharia A, Shohat M, Straussberg R, Monte D, Salmon-Divon M, Behar DM. Homozygous MED25 mutation implicated in eye-intellectual disability syndrome. Hum Genet. 2015 Jun;134(6):577-87.

PubMed ID: 
25792360

Carpenter Syndrome

Clinical Characteristics
Ocular Features: 

A variety of ocular anomalies have been reported in Carpenter syndrome with none being constant or characteristic.  The inner canthi are often spaced widely apart and many have epicanthal folds and a flat nasal bridge.  Other reported abnormalities are nystagmus, foveal hypoplasia, corneal malformations including microcornea, corneal opacity, and mild optic atrophy and features of pseudopapilledema.

Systemic Features: 

Premature synostosis involves numerous cranial sutures with the sagittal suture commonly involved causing acrocephaly (tower skull).  Asymmetry of the skull and a 'cloverleaf' deformity are often present.  The polydactyly is preaxial and some degree of syndactyly is common especially in the toes.  The digits are often short and may be missing phalanges.  Some patients are short in stature.  Structural brain defects may be widespread including atrophy of the cortex and cerebellar vermis.  Septal defects in the heart are found in about one-third of patients.  The ears can be low-set and preauricular pits may be seen.  Some but not all patients have obesity and a degree of mental retardation.

Genetics

This is an autosomal recessive syndrome caused by a mutation in the RAB23 gene (6p12.1-q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment of the ocular defects is necessary in most cases. Craniectomy may be required in cases with severe synostosis.

References
Article Title: 

Carpenter syndrome

Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. J Craniofac Surg. 2009 Jan;20(1):254-6.

PubMed ID: 
19165041

RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity

Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007 Jun;80(6):1162-70. Erratum in: Am J Hum Genet. 2007 Nov;81(5):1114. Josifiova, Dragana [corrected to Josifova, Dragana].

PubMed ID: 
17503333

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
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