developmental delay

Pontocerebellar Hypoplasia 11

Clinical Characteristics
Ocular Features: 

Some patients are reported to have poor eye contact, hyperopia, and strabismus.  Three individuals had colobomas.  Strabismus, poor eye contact, and hyperopia have been noted in some individuals.   

Systemic Features: 

Microcephaly and large ears may be noted at birth.  Some patients have general hypotonia while others have spastic hypertonia.  Neurological features include markedly delayed psychomotor development, truncal and appendicular ataxia, and cognitive delays.  Developmental milestones such as walking, sitting, and speech are delayed.  Some patients have seizures.  A variety of behavior abnormalities have been reported including stereotypical movements, autistic behavior, repetitive motor movements, and poor communication.  Dysarthria and dysphagia are sometimes present.  There seems to be little progression of the neurological manifestations.

Brain MRIs reveal cerebellar hypoplasia and hypoplasia or agenesis of the corpus callosum in most patients.

Genetics

Homozygous mutations in the TBC1D23 gene (3q12.1q12.2) cause this disorder

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, de Saint Martin A, Runge K, Iqbal Z, Spitz MA, Laura M, Drouot N, Gerard B, Deleuze JF, de Brouwer APM, Razzaq A, Dollfus H, Assir MZ, Nitchke P, Hinckelmann MV, Ropers H, Riazuddin S, Najmabadi H, van Bokhoven H, Chelly J. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet. 2017 Sep 7;101(3):428-440.

PubMed ID: 
28823707

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

Encephalopathy, Progressive, Early-Onset, wtih Brain Atrophy and Spasticity

Clinical Characteristics
Ocular Features: 

Optic atrophy or cortical visual impairment with lack of visual tracking have been described in all patients.

Systemic Features: 

Microcephaly is evident at birth with global developmental delay and hearing loss.  One patient of 3 reported in 2 unrelated families had brief flexion seizures at 5 months.  Developmental regression and stagnation may become evident within the first months of life.  The EEG showed a hypsarrhythmia pattern.  Truncal hypotonia, spasticity, dystonia and/or myoclonus, scoliosis, and dysphagia are also features.  Two of the three reported patients had seizures. 

Brain MRI showed a pattern of pontine hypoplasia, partial agenesis of the corpus callosum, modified frontal gyri and diffuse cortical atrophy with enlarged ventricles have been described.  The cerebellum seems to be spared.

Genetics

Homozygous or compound heterozygous mutations in the TRAPPC12 gene (2p25.3) were found in 3 children in 2 unrelated families with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

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

Gabriele-de Vries Syndrome

Clinical Characteristics
Ocular Features: 

A number of nondiagnostic signs occur in the periocular structures as part of the general facial dysmorphism.  There is a general fullness to the periocular area, most evident in the upper eyelids.  The lid fissures slant downward and the eyebrows are sparse.  Strabismus is often present.  Ptosis has been noted in a few individuals.

Systemic Features: 

Systemic signs are inconsistent and highly variable.  Intrauterine growth is usually below average.  Feeding problems are evident from birth.  The facial dysmorphology is highlighted by a high, broad forehead and accentuated by micrognathia and midface hypoplasia.  The ears are posteriorly rotated.  General development is delayed and milestones, if achieved, are delayed.  Behavioral problems can be manifest as anxiety and some individuals have features of the autism spectrum.  Abnormal movements such as tremor and dystonia are sometimes present.

Brain imaging may reveal delayed myelination, frontal gliosis, white matter abnormalities, and enlarged ventricles.

Genetics

Heterozygous mutations in the YY1 gene (14q32) have been identified in this condition.  The gene is a transcription factor that acts both as a repressor and an activator in specific circumstances.  Virtually all cases occur de novo.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective generalized treatment has been reported.

References
Article Title: 

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Gabriele M, Vulto-van Silfhout AT, Germain PL, Vitriolo A, Kumar R, Douglas E, Haan E, Kosaki K, Takenouchi T, Rauch A, Steindl K, Frengen E, Misceo D, Pedurupillay CRJ, Stromme P, Rosenfeld JA, Shao Y, Craigen WJ, Schaaf CP, Rodriguez-Buritica D, Farach L, Friedman J, Thulin P, McLean SD, Nugent KM, Morton J, Nicholl J, Andrieux J, Stray-Pedersen A, Chambon P, Patrier S, Lynch SA, Kjaergaard S, Torring PM, Brasch-Andersen C, Ronan A, van Haeringen A, Anderson PJ, Powis Z, Brunner HG, Pfundt R, Schuurs-Hoeijmakers JHM, van Bon BWM, Lelieveld S, Gilissen C, Nillesen WM, Vissers LELM, Gecz J, Koolen DA, Testa G, de Vries BBA. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. Am J Hum Genet. 2017 Jun 1;100(6):907-925.

PubMed ID: 
28575647

Neurodevelopmental Disorder with Progressive Microcephaly, Spasticity, and Brain Anomalies

Clinical Characteristics
Ocular Features: 

 Examined patients have optic atrophy with nystagmus and roving eye movements.

Systemic Features: 

There are extensive and, in most cases, progressive CNS abnormalities resulting in severe neurodevelopmental deficits.  Infants at birth have progressive truncal hypotonia and limb spasticity.  Motor deficits result in little spontaneous movement, resulting in poor sucking, and respiratory difficulties.  Language does not develop and there is profound mental retardation. Progressive microcephaly is a characteristic finding.  There are often extrapyramidal signs such as rigidity and dystonic posturing.

Dysmorphic features include a short nose, high-arched palate, low-set and posteriorly rotated ears, micrognathia, postaxial polydactyly, hirsutism, pectus carinatum, contractures of large joints, and hyperextensibility of small joints.

Brain imaging shows a progressive leukoencephalopathy, cerebral and cerebellar atrophy, and delayed myelination.  The corpus callosum is often thin and the ventricles appear enlarged.  The lifespan is generally short with death occurring in infancy or early childhood.

Genetics

This autosomal recessive disorder results from homozygous mutations in the PLAA gene (9p21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins

Hall EA, Nahorski MS, Murray LM, Shaheen R, Perkins E, Dissanayake KN, Kristaryanto Y, Jones RA, Vogt J, Rivagorda M, Handley MT, Mali GR, Quidwai T, Soares DC, Keighren MA, McKie L, Mort RL, Gammoh N, Garcia-Munoz A, Davey T, Vermeren M, Walsh D, Budd P, Aligianis IA, Faqeih E, Quigley AJ, Jackson IJ, Kulathu Y, Jackson M, Ribchester RR, von Kriegsheim A, Alkuraya FS, Woods CG, Maher ER, Mill P. PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. Am J Hum Genet. 2017 May 4;100(5):706-724.

PubMed ID: 
28413018

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Falik Zaccai TC, Savitzki D, Zivony-Elboum Y, Vilboux T, Fitts EC, Shoval Y, Kalfon L, Samra N, Keren Z, Gross B, Chasnyk N, Straussberg R, Mullikin JC, Teer JK, Geiger D, Kornitzer D, Bitterman-Deutsch O, Samson AO, Wakamiya M, Peterson JW, Kirtley ML, Pinchuk IV, Baze WB, Gahl WA, Kleta R, Anikster Y, Chopra AK. Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. Brain. 2017 Feb;140(Pt 2):370-386.

PubMed ID: 
28007986

Gaze Palsy, Familial Horizontal, with Progressive Scoliosis 2

Clinical Characteristics
Ocular Features: 

Strabismus is present at birth.  Horizontal eye movements are restricted but vertical gaze can be normal.  The optic nerves appear normal.

Systemic Features: 

Hypotonia may be noted at birth but ankle clonus and spasticity can develop later.  Progressive kyphoscoliosis has been diagnosed as early as the age of 4 years and may result in restrictive lung disease requiring spine surgery by the second decade of life.  Developmental milestones such as walking and talking are delayed and intellectual development is subnormal.  Mirror movements may be present.  Gait may be unsteady but can be normal.

Brain MRI reveals a variety of malformations.  Agenesis of the corpus callosum is present and the white matter tracts appear disorganized.  The superior cerebellar peduncles fail to decussate and transverse pontine fibers may be absent.  The pons and midbrain are hypoplastic while there is a midline cleft throughout the brainstem resulting in a butterfly-shaped medulla.

Genetics

Homozygous mutations in the DCC gene (18q21) are responsible for this condition.  Three patients in 2 unrelated consanguineous families have been reported.  Studies suggest that the DCC gene product is important for forebrain and brainstem midline crossing of neurons.

See Gaze Palsy, Familial Horizontal, with Progressive Scoliosis 1 (607313) for another disorder with somewhat similar features.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic mutations in human DCC cause developmental split-brain syndrome

Jamuar SS, Schmitz-Abe K, D'Gama AM, Drottar M, Chan WM, Peeva M, Servattalab S, Lam AN, Delgado MR, Clegg NJ, Zayed ZA, Dogar MA, Alorainy IA, Jamea AA, Abu-Amero K, Griebel M, Ward W, Lein ES, Markianos K, Barkovich AJ, Robson CD, Grant PE, Bosley TM, Engle EC, Walsh CA, Yu TW. Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet. 2017 Apr;49(4):606-612.

PubMed ID: 
28250456

PEHO-Like Syndrome

Clinical Characteristics
Ocular Features: 

Poor visual fixation and attention has been noted during the first 6 months of life.  Optic atrophy has been described and epicanthal folds may be present.

Systemic Features: 

General hypotonia with developmental delay and progressive microcephaly are evident in the first 6-12 months of life.  Seizures may be present at birth or within the first month of life.  Edema of the feet, hands, and face are also present at birth.  Cognitive deficits and motor delays are usually evident during infancy.  The central hypotonia may be accompanied by peripheral spasticity.  Kyphoscoliosis often develops.  Other dysmorphic features include micrognathia, narrow forehead, short nose, and open mouth.

Brain imaging reveals coarse pachygyria, polymicrogyria, and dilated ventricles with hypoplastic corpus callosum and pons.  Cerebellar hypoplasia was found in one child. 

Genetics

This presumed autosomal recessive disorder is associated with homozygous mutations in the CCDC88A gene (2p16.1).  Three affected children have been reported in a consanguineous family.

A somewhat similar disorder known as PEHO syndrome (260565) results from homozygous mutations in the ZNHIT3 gene. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

The PEHO syndrome

Riikonen R. The PEHO syndrome. Brain Dev. 2001 Nov;23(7):765-9. Review.

PubMed ID: 
11701291

Congenital Heart Defects, Dysmorphic Facies, and Intellectual Developmental Disorder

Clinical Characteristics
Ocular Features: 

The dysmorphic facial features primarily involve the periocular structures.  These include hypertelorism, ptosis, epicanthal folds, strabismus and upslanted palpebral fissures.

Systemic Features: 

Septal defects involving both the atrium and the ventricle are consistently present.  Pulmonary valve abnormalities are present in some patients.

Posteriorly rotated pinnae and a small mouth with a thin upper lip have been observed.  Camptodactyly and clinodactyly are common.  Some patients have mild microcephaly.

Global developmental delay is a consistent feature manifest as delays in walking and speech and eventual intellectual disability.  Feeding difficulties are common.  Hypotonia and hypermobile joints are often noted.  Imaging of the brain may reveal agenesis of the corpus callosum, incomplete formation of the inferior vermis, and leukomalacia of periventricular tissue.

Genetics

Heterozygous mutations have been identified in the CDK13 gene (7p14.1) in seven unrelated individuals.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the generalized condition.

References
Article Title: 

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T; INTERVAL Study., Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J; UK10K Consortium., Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD; Deciphering Developmental Disorders Study., Hurles ME. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016 Sep;48(9):1060-5.

PubMed ID: 
27479907

Spastic Paraplegia, Intellectual Disability, Nystagmus, and Obesity

Clinical Characteristics
Ocular Features: 

Patients have deep-set eyes with nystagmus, reduced vision, and often an esotropia perhaps secondary to hypermetropia.  In one of 3 reported patients the optic discs were described pale.

Systemic Features: 

Prominent foreheads are present at birth along with full cheeks and a prominent forehead.  Children grow rapidly in the first year eventually reaching the 90th percentiles in weight, height, and head circumference although neurologically they are developmentally delayed.  Speech and walking may be delayed as well.  While limbs have increased tone together with hyperreflexia, the trunk exhibits hypotonia.

Brain imaging reveals delayed myelination, dilated lateral ventricles, reduced while matter, and cerebral atrophy.

Genetics

Heterozygous mutations in the KIDINS220 gene (2p25.1) have been identified in 3 unrelated patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity

Josifova DJ, Monroe GR, Tessadori F, de Graaff E, van der Zwaag B, Mehta SG; DDD Study., Harakalova M, Duran KJ, Savelberg SM, Nijman IJ, Jungbluth H, Hoogenraad CC, Bakkers J, Knoers NV, Firth HV, Beales PL, van Haaften G, van Haelst MM. Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity. Hum Mol Genet. 2016 Jun 1;25(11):2158-2167.

PubMed ID: 
27005418

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