downslanting palpebral fissures

Al Kaissi Syndrome

Clinical Characteristics
Ocular Features: 

Reported facial dysmorphism features include periocular anomalies of ptosis, hypertelorism, down-slanting lid fissures, and epicanthal folds.  

Systemic Features: 

The phenotype is somewhat variable.  Intrauterine and postnatal growth retardation with hypotonia are common.   Moderate to severe intellectual disability is usually present and speech may be severely delayed.  The forehead is narrow, the nasal tip is broad, the nasal bridge is depressed, and the ears are low-set and posteriorly rotated.   Small hands and sometimes joint laxity are commonly present.  Cervical spine abnormalities including clefting, improper fusion, and segmentation anomalies are common.

Brain MRI may be normal but a small corpus callosum was present in some patients.

Genetics

Homozygous mutations in the CDK10 gene (16q24.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Windpassinger C, Piard J, Bonnard C, Alfadhel M, Lim S, Bisteau X, Blouin S, Ali NB, Ng AYJ, Lu H, Tohari S, Talib SZA, van Hul N, Caldez MJ, Van Maldergem L, Yigit G, Kayserili H, Youssef SA, Coppola V, de Bruin A, Tessarollo L, Choi H, Rupp V, Roetzer K, Roschger P, Klaushofer K, Altmuller J, Roy S, Venkatesh B, Ganger R, Grill F, Ben Chehida F, Wollnik B, Altunoglu U, Al Kaissi A, Reversade B, Kaldis P. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am J Hum Genet. 2017 Sep 7;101(3):391-403.

PubMed ID: 
28886341

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

Retinitis Pigmentosa With or Without Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Downward slanting lid fissures may be detectable at birth as part of the general craniofacial dysmorphism.  Some degree of night blindness causes symptoms by the second decade of life and constricted visual fields with pigmented retinopathy and vessel narrowing can be detected.  The ERG shows reduced or absent responses.  The retinal phenotype is progressive.   

Systemic Features: 

Most but not all patients have skeletal anomalies.  Nonspecific craniofacial dysmorphology features are frequently present including frontal bossing, macrocephaly, low-set ears, large columella, hypoplastic nares, and malar hypoplasia.  A short neck, brachydactyly, and overall shortness of stature are often present.  Some individuals have nail dysplasia.  The proximal femoral metaphyses sometimes show chondrodysplasia.

There is often some degree of intellectual disability and there may be delays in speech, feeding, and walking.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the CWC27 gene (5q12.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No general treatment has been reported.  Low vision aids and night vision devices may be helpful, especially for educational activities.

References
Article Title: 

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Xu M, Xie YA, Abouzeid H, Gordon CT, Fiorentino A, Sun Z, Lehman A, Osman IS, Dharmat R, Riveiro-Alvarez R, Bapst-Wicht L, Babino D, Arno G, Busetto V, Zhao L, Li H, Lopez-Martinez MA, Azevedo LF, Hubert L, Pontikos N, Eblimit A, Lorda-Sanchez I, Kheir V, Plagnol V, Oufadem M, Soens ZT, Yang L, Bole-Feysot C, Pfundt R, Allaman-Pillet N, Nitschke P, Cheetham ME, Lyonnet S, Agrawal SA, Li H, Pinton G, Michaelides M, Besmond C, Li Y, Yuan Z, von Lintig J, Webster AR, Le Hir H, Stoilov P; UK Inherited Retinal Dystrophy Consortium., Amiel J, Hardcastle AJ, Ayuso C, Sui R, Chen R, Allikmets R, Schorderet DF. Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. Am J Hum Genet. 2017 Apr 6;100(4):592-604.

PubMed ID: 
28285769

Intellectual Disability with Dysmorphic Facies and Ptosis

Clinical Characteristics
Ocular Features: 

The eyes appear widely spaced and the lid fissures slant downward.  Ptosis and blepharophimosis are present.  Strabismus is an uncommon feature.

Systemic Features: 

The characteristic facial profile (round, flat) is evident at birth. Microcephaly has been seen in some children.  Low birthweight is common.  Most infants feed poorly with general growth delay and short stature becoming evident in childhood.  Hypotonia and joint hypermobility are constant features.  Gross and fine motor movements appear uncoordinated.  Expressive language is delayed and impaired.  Intellectual disability is mild and achievement of developmental milestones may be delayed.  Seizures are seen in about half of affected individuals.  Brain MRIs may reveal mild white matter anomalies.  Spinal fusion among cervical vertebrae is common.

Individuals may live to adulthood.

Genetics

Heterozygous mutations in the BRPF1 gene (3p25) are responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Mattioli F, Schaefer E, Magee A, Mark P, Mancini GM, Dieterich K, Von Allmen G, Alders M, Coutton C, van Slegtenhorst M, Vieville G, Engelen M, Cobben JM, Juusola J, Pujol A, Mandel JL, Piton A. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis. Am J Hum Genet. 2017 Jan 5;100(1):105-116.

PubMed ID: 
27939639

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Yan K, Rousseau J, Littlejohn RO, Kiss C, Lehman A, Rosenfeld JA, Stumpel CT, Stegmann AP, Robak L, Scaglia F, Nguyen TT, Fu H, Ajeawung NF, Camurri MV, Li L, Gardham A, Panis B, Almannai M, Sacoto MJ, Baskin B, Ruivenkamp C, Xia F, Bi W; DDD Study.; CAUSES Study., Cho MT, Potjer TP, Santen GW, Parker MJ, Canham N, McKinnon M, Potocki L, MacKenzie JJ, Roeder ER, Campeau PM, Yang XJ. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. Am J Hum Genet. 2017 Jan 5;100(1):91-104.

PubMed ID: 
27939640

ZTTK Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are deep-set and the palpebral fissures slant downward.  Optic atrophy is often present.  The majority of individuals have poor visual responses which may also be attributed to central or cortical impairment.  Strabismus and nystagmus are frequently present.

Systemic Features: 

ZTTK syndrome is multisystem malformation and developmental disorder with a heterogeneous clinical presentation.  The facial features might suggest the diagnosis at birth but most of the signs are nonspecific including frontal bossing, underdevelopment of the midface, facial asymmetry, low-set ears, broad and/or depressed nasal bridge, and a short philtrum.  Poor feeding and hypotonia in the neonatal period are usually present and physical growth is subnormal resulting in short stature.

Brain imaging may show abnormal gyral patterns, ventriculomegaly, hypoplasia of the corpus callosum, cerebellar hypoplasia, arachnoid cysts, and loss of periventricular white matter.  About half of patients develop seizures and many have intellectual disabilities.  Spinal anomalies include hemivertebrae with scoliosis and/or kyphosis.  Other skeletal features include joint laxity in some patients and contractures in others.  Arachnodactyly, craniosynostosis, and rib anomalies have been reported.  There may be malformations in the GI, GU, and cardiac systems while immune and coagulation abnormalities have also been reported.

Genetics

Heterozygous mutations in the SON gene (21q22.11) have been identified in patients with this condition.  They may cause truncation of the gene product with haploinsufficiency or, in other patients, a frameshift in the reading.  The SON gene is a master RNA splicing regulator that impacts neurodevelopment.

Virtually all cases are the result of de novo mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.  Physical therapy and assistive devices may be helpful.

References
Article Title: 

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive

Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Kury S, Besnard T, Isidor B, Latypova X, Bezieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, Walkiewicz MA. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive. Am J Hum Genet. 2016 Sep 1;99(3):720-7.

PubMed ID: 
27545676

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Kim JH, Shinde DN, Reijnders MR, Hauser NS, Belmonte RL, Wilson GR, Bosch DG, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CT, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BB, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortum F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Behunova J, Rehder H, Gordon CT, Rio M, Romana S, Tang S, El-Khechen D, Cho MT, McWalter K, Douglas G, Baskin B, Begtrup A, Funari T, Schoch K, Stegmann AP, Stevens SJ, Zhang DE, Traver D, Yao X, MacArthur DG, Brunner HG, Mancini GM, Myers RM, Owen LB, Lim ST, Stachura DL, Vissers LE, Ahn EY. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711-9.

PubMed ID: 
27545680

Rubinstein-Taybi Syndrome 2

Clinical Characteristics
Ocular Features: 

Highly-arched and bushy eyebrows are often seen.  The lashes are long and bushy and lid fissures tend to slope downward.

The ocular phenotype has not been fully described no doubt due to the rarity of cases.  Individuals with type 1 (RSTS1) have been described with congenital glaucoma, nystagmus, corneal abnormalities of shape (such as keratoglobus, sclerocornea, megalocornea), pigmentary retinopathy, and VEP evidence of rod and cone dysfunction have been described.

Systemic Features: 

The phenotype of RSTS2 is more variable than the somewhat similar to RSTS1.  Less than 10% of individuals with Rubinstein-Taybi syndrome have type 2 while over 50% have type 1.  The facial dysmorphism nay be less severe in RSTS2.

Mild to moderate intellectual disability with psychosocial problems such as autism is nearly universal.  Microcephaly, a broad nasal bridge, a beaked nose, high-arched palate and some degree of micrognathia are characteristic.  The lower lip often appears 'pouty' and protrudes beyond the upper lip while the hard palate is highly arched.  Pregnancy may be complicated by pre-eclampsia and growth restriction.  Swallowing and feeding issues are common.  Syndactyly is often present and there is considerable variability in the size of the toes and thumbs.  Some patients with RSTS2 do not have evidence of the classic broad thumbs and toes characteristic of RSTS1.

Genetics

Heterozygous mutations in EP300 (22q13.2) have been found in this condition.  Virtually all cases occur de novo.  Rubinstein-Taybi Syndrome 1 (180849) is a phenotypically similar disorder resulting from a different mutation (CREBBP).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for this condition.

References
Article Title: 

Developmental Delay with Short Stature, Dysmorphic Features, and Sparse Hair

Clinical Characteristics
Ocular Features: 

Patients may have downward-slanting lid fissures, hypertelorism, epicanthal folds, and sparse eyebrows and eyelashes.

Systemic Features: 

Patients have scaphocephaly with or without craniosynostosis and facial dysmorphism with a depressed nasal bridge and micrognathia.  Short stature, sparse hair, and developmental delay are characteristic.  Hypoplastic toenails and dental anomalies are present.  Brain imaging may show Dandy-Walker malformations and cerebellar vermis hypoplasia.  The kidneys may have focal interstitial nephritis and there may be intermittent hematuria and proteinuria in the presence of otherwise normal renal function.  Cardiac septal defects have been noted.

Genetics

Homozygous mutations in the DPH1 gene (17p13.3) are responsible for this disorder.  Two families have been reported with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Matching two cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies

Loucks CM, Parboosingh JS, Shaheen R, Bernier FP, McLeod DR, Seidahmed MZ, Puffenberger EG, Ober C, Hegele RA, Boycott KM, Alkuraya FS, Innes AM. Matching two independent cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. Hum Mutat. 2015 Oct;36(10):1015-9.

PubMed ID: 
26220823

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families

Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA, Faqeih E, Alhashem A, Bashiri FA, Al-Owain M, Kentab AY, Sogaty S, Al Tala S, Temsah MH, Tulbah M, Aljelaify RF, Alshahwan SA, Seidahmed MZ, Alhadid AA, Aldhalaan H, AlQallaf F, Kurdi W, Alfadhel M, Babay Z, Alsogheer M, Kaya N, Al-Hassnan ZN, Abdel-Salam GM, Al-Sannaa N, Al Mutairi F, El Khashab HY, Bohlega S, Jia X, Nguyen HC, Hammami R, Adly N, Mohamed JY, Abdulwahab F, Ibrahim N, Naim EA, Al-Younes B, Meyer BF, Hashem M, Shaheen R, Xiong Y, Abouelhoda M, Aldeeri AA, Monies DM, Alkuraya FS. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 Jan 13;10(2):148-61.

PubMed ID: 
25558065

Acrofacial Dysostosis, Cincinnati Type

Clinical Characteristics
Ocular Features: 

The periocular features are part of the general facial dysmorphism.  The lid fissures slant downward, and the orbits appear inferiorly displaced.  'Clefts' (colobomas?) of the lower eyelids and sometimes the upper may be evident.  The medial eyelashes were absent in one patient. 

Systemic Features: 

The extraocular features reported so far are based on only three patients and there is considerable variation.  The head is usually small and patients may be short in stature.  The zygomatic arches, the maxillae and the mandibles are hypoplastic as is the midface.  There may be anotia and severe conductive hearing loss.  The pinnae can be large and are sometimes low-set.  Inconsistent short limbs with hip dysplasia and femoral bowing have been reported.  Brachydactyly is also a feature.

Genetics

Heterozygous mutations in the POLR1A gene (2p11) seem to be responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the overall condition but individual anomalies such as lid 'clefts' can be surgically repaired. Severe micrognathia may require tracheostomy at birth.

References
Article Title: 

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

Cole-Carpenter Syndrome 2

Clinical Characteristics
Ocular Features: 

Postnatally the eyes are prominent and hypertelorism has been reported.  The palpebral fissures slant downward and the root of the nose is angular. 

Systemic Features: 

This is primarily a skeletal disorder with impaired skull ossification and multiple bone fractures of prenatal origin.  It is sometimes confused with forms of osteogenesis imperfecta.  The skull is poorly ossified and frequent diaphyseal fractures of the long bones occur leading to motor delays and short stature.  Rib fractures are sometimes seen. Intelligence seems to be normal.  A receding chin has been noted and the hard palate is highly vaulted.  The midface is flat.

Genetics

This disorder results from compound heterozygous mutations in the SEC24D gene (4q26).  Only a few patients have been reported.

For a somewhat similar but autosomal dominant disorder see Cole-Carpenter Syndrome 1 (112240).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical activity should be restricted to noncontact sports and where the cranium has ossification defects a helmet should be worn.  Fractures should be appropriately treated.

References
Article Title: 

Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

Garbes L, Kim K, Riess A, Hoyer-Kuhn H, Beleggia F, Bevot A, Kim MJ, Huh YH, Kweon HS, Savarirayan R, Amor D, Kakadia PM, Lindig T, Kagan KO, Becker J, Boyadjiev SA, Wollnik B, Semler O, Bohlander SK, Kim J, Netzer C. Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta. Am J Hum Genet. 2015 Mar 5;96(3):432-9.

PubMed ID: 
25683121

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