wide nasal bridge

Sweeney-Cox Syndrome

Clinical Characteristics
Ocular Features: 

 Periorbital and facial anomalies were present in the two reported patients.  Pseudoproptosis (considered secondary to deficiency of the bony orbits) accentuated by midface hypoplasia, and upper lid colobomas have been observed.  The globes were described as "small" although there were no "concerns" regarding vision in the single male patient.  Electrodiagnostic tests were "normal."    

Systemic Features: 

Multiple anomalies and malformations were present in the two reported patients, an unrelated male and female.  Severe facial dysmorphism secondary to uneven skull bone formation and suture closures is present.  The metopic ridge is prominent, the orbital bones are deficient, the occiput is flattened, the anterior fontanel and coronal sutures are wide.  Midfacial hypoplasia is present.  The neck is broad and the shoulders are narrow.  The fingers are long and the distal phalanges may be fixed in flexion.  The ears are low-set, small, and cupped.  The palate is high and may be cleft.  Cutaneous syndactyly of the fingers has been observed.  Variable developmental delays/learning difficulties are present.

The male had an imperforate anus, undescended testes and a 60 dB hearing loss.  The female had a midline cleft palate with choanal atresia requiring a tracheostomy from birth and required fundoplication and gastrostomy for gastroesophageal reflux.

Genetics

Heterozygous missense mutations in the TWIST1 gene (7p21.1) were found in both reported individuals.  These appear to have arisen de novo.

Mutations in the same gene have also been found in the Saethre-Chotzen Syndrome (101400) in which some of the same skeletal features are found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported for the general condition but individual malformations may require attention.  The lid colobomas were repaired in the female but corneal exposure remained and corneal scarring and phthisis developed in the right eye.  The left eye retained some vision ("able to see large objects").

References
Article Title: 

Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans

Kim S, Twigg SRF, Scanlon VA, Chandra A, Hansen TJ, Alsubait A, Fenwick AL, McGowan SJ, Lord H, Lester T, Sweeney E, Weber A, Cox H, Wilkie AOM, Golden A, Corsi AK. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Hum Mol Genet. 2017 Jun 1;26(11):2118-2132.

PubMed ID: 
28369379

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, Wall SA, Noons P, Rees KE, Tidey EA, Craft J, Taylor J, Taylor JC, Goos JA, Swagemakers SM, Mathijssen IM, van der Spek PJ, Lord H, Lester T, Abid N, Cilliers D, Hurst JA, Morton JE, Sweeney E, Weber A, Wilson LC, Wilkie AO. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

PubMed ID: 
27884935

Sweeney-Cox Syndrome

Clinical Characteristics
Ocular Features: 

Ophthalmologic examinations have not been reported.  However, periorbital and facial anomalies were present in the two reported patients.  Pseudoproptosis (considered secondary to deficiency of the bony orbits) accentuated by midface hypoplasia, and upper lid colobomas have been observed.  The globes were described as "small" although there were no "concerns" regarding vision in the single male patient.  Electrodiagnostic tests were "normal."    

Systemic Features: 

Multiple anomalies and malformations were present in the two reported patients, an unrelated male and female.  Severe facial dysmorphism secondary to uneven skull bone formation and suture closures is present.  The metopic ridge is prominent, the orbital bones are deficient, the occiput is flattened, the anterior fontanel and coronal sutures are wide.  Midfacial hypoplasia is present.  The neck is broad and the shoulders are narrow.  The fingers are long and the distal phalanges may be fixed in flexion.  The ears are low-set, small, and cupped.  The palate is high and may be cleft.  Cutaneous syndactyly of the fingers has been observed.  Variable developmental delays/learning difficulties are present.

The male had an imperforate anus, undescended testes and a 60 dB hearing loss.  The female had a midline cleft palate with choanal atresia requiring a tracheostomy from birth and required fundoplication and gastrostomy for gastroesophageal reflux.  

Genetics

Heterozygous missense mutations in the TWIST1 gene (7p21.1) were found in both reported individuals.  These appear to have arisen de novo.

Mutations in the same gene have also been found in the Saethre-Chotzen Syndrome (101400) in which some of the same skeletal features are found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported for the general condition but individual malformations may require attention.  The lid colobomas were repaired in the female but corneal exposure remained and corneal scarring and phthisis developed in the right eye.  The left eye retained some vision ("able to see large objects").

References
Article Title: 

Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans

Kim S, Twigg SRF, Scanlon VA, Chandra A, Hansen TJ, Alsubait A, Fenwick AL, McGowan SJ, Lord H, Lester T, Sweeney E, Weber A, Cox H, Wilkie AOM, Golden A, Corsi AK. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Hum Mol Genet. 2017 Jun 1;26(11):2118-2132.

PubMed ID: 
28369379

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, Wall SA, Noons P, Rees KE, Tidey EA, Craft J, Taylor J, Taylor JC, Goos JA, Swagemakers SM, Mathijssen IM, van der Spek PJ, Lord H, Lester T, Abid N, Cilliers D, Hurst JA, Morton JE, Sweeney E, Weber A, Wilson LC, Wilkie AO. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

PubMed ID: 
27884935

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

Mowat-Wilson Syndrome

Clinical Characteristics
Ocular Features: 

Most reports of Mowat-Wilson disorders provide only incomplete ocular findings and the full phenotype remains to be described.  Most of the reported findings are part of the facial phenotype, such as downward slanting palpebral fissures, and 'wedge-shaped' eyebrows with the medial portion visibly wider than the temporal region.  Hypertelorism, strabismus and telecanthus have also been noted.  However, optic nerve atrophyor aplasia, RPE atrophy, microphthalmia, ptosis, and cataracts are sometimes present while strabismus is more common.  Iris and other uveal colobomas may be present and at least one patient has been reported with retinal aplasia.  There may be considerable asymmetry in the features among the two eyes.

Systemic Features: 

This is a highly complex dysmorphic developmental disorder with unusual progression of facial features.  Birth weight and length are usually normal but later there is general somatic and mental growth delay with microcephaly (pre- and post natal), short stature, intellectual disability, and epilepsy (70%).  Hypotonia has been noted at birth.  A significant proportion (~50%) of patients have Hirschsprung disease with megacolon.  Congenital heart defects are common, many involving septal openings.  Hypospadias is often present with or without other genitourinary anomalies.  Teeth are often crowded and crooked.  The earlobes may be flattened and may have a central depression.

The facial features are present in early childhood but as they mature the upper half of the nasal profile becomes convex, while the nasal tip becomes longer and overhangs the philtrum.  The eyes appear more deeply set.  The chin lengthens and prognathism becomes apparent.  IQ levels cannot be determined but many individuals exhibit behavioral or emotional disturbances.

Genetics

Heterozygous mutations in ZEB2 (2q22.3) are responsible for most cases (81%) of this disorder.  A large number of molecular mutations, many of the nonsense type, have been reported. About 2-4% of patients have cytogenetic alterations involving the 2q22 region.

Another disorder with microcephaly, intellectual disability and Hirschsprung disease is Goldberg-Shprintzen syndrome (609460) with mutations in the KIAA1279 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment may be directed at specific defects but there is no treatment for the general disorder. Individuals can live to adulthood. Treatment is largely symptomatic.  Physical and speech treatment can be helpful if initiated early.

References
Article Title: 

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and

Ivanovski I, Djuric O, Caraffi SG, Santodirocco D, Pollazzon M, Rosato S,
Cordelli DM, Abdalla E, Accorsi P, Adam MP, Ajmone PF, Badura-Stronka M, Baldo C,
Baldi M, Bayat A, Bigoni S, Bonvicini F, Breckpot J, Callewaert B, Cocchi G,
Cuturilo G, De Brasi D, Devriendt K, Dinulos MB, Hjortshoj TD, Epifanio R,
Faravelli F, Fiumara A, Formisano D, Giordano L, Grasso M, Gronborg S, Iodice A,
Iughetti L, Kuburovic V, Kutkowska-Kazmierczak A, Lacombe D, Lo Rizzo C, Luchetti
A, Malbora B, Mammi I, Mari F, Montorsi G, Moutton S, Moller RS, Muschke P,
Nielsen JEK, Obersztyn E, Pantaleoni C, Pellicciari A, Pisanti MA, Prpic I,
Poch-Olive ML, Raviglione F, Renieri A, Ricci E, Rivieri F, Santen GW, Savasta S,
Scarano G, Schanze I, Selicorni A, Silengo M, Smigiel R, Spaccini L, Sorge G,
Szczaluba K, Tarani L, Tone LG, Toutain A, Trimouille A, Valera ET, Vergano SS,
Zanotta N, Zenker M, Conidi A, Zollino M, Rauch A, Zweier C, Garavelli L.
Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and
recommendations for care
. Genet Med. 2018 Jan 4. doi: 10.1038/gim.2017.221. [Epub
ahead of print].

PubMed ID: 
29300384

Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome

Bourchany A, Giurgea I, Thevenon J, Goldenberg A, Morin G, Bremond-Gignac D, Paillot C, Lafontaine PO, Thouvenin D, Massy J, Duncombe A, Thauvin-Robinet C, Masurel-Paulet A, Chehadeh SE, Huet F, Bron A, Creuzot-Garcher C, Lyonnet S, Faivre L. Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome. Am J Med Genet A. 2015 Apr 21. [Epub ahead of print]

PubMed ID: 
25899569

The behavioral phenotype of Mowat-Wilson syndrome

Evans E, Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M. The behavioral phenotype of Mowat-Wilson syndrome. Am J Med Genet A. 2012 Feb;158A(2):358-66. doi: 10.1002/ajmg.a.34405.

PubMed ID: 
22246645

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature

Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti L, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R, Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S, Wakamatsu N, Neri G. Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature. Am J Med Genet A. 2009 Mar;149A(3):417-26. Review.

PubMed ID: 
19215041

Clinical and mutational spectrum of Mowat-Wilson syndrome

Zweier C, Thiel CT, Dufke A, Crow YJ, Meinecke P, Suri M, Ala-Mello S, Beemer F, Bernasconi S, Bianchi P, Bier A, Devriendt K, Dimitrov B, Firth H, Gallagher RC, Garavelli L, Gillessen-Kaesbach G, Hudgins L, K?SS?SSri?SSinen H, Karstens S, Krantz I, Mannhardt A, Medne L, M?ocke J, Kibaek M, Krogh LN, Peippo M, Rittinger O, Schulz S, Schelley SL, Temple IK, Dennis NR, Van der Knaap MS, Wheeler P, Yerushalmi B, Zenker M, Seidel H, Lachmeijer A, Prescott T, Kraus C, Lowry RB, Rauch A. Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet. 2005 Apr-Jun;48(2):97-111

PubMed ID: 
16053902
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