poor speech

Baker-Gordon Syndrome

Clinical Characteristics
Ocular Features: 

Poor visual acuity described as central in origin with poor eye contact.  Periorbital anomalies of low-set eyebrows and epicanthal folds are common.  The eyes have been described as "almond-shaped".  Strabismus and nystagmus are commonly present.

Systemic Features: 

The facial features ae described as "fine" with a short nose and a thin upper lip.  The forehead is unusually high. 

There is general developmental delay with impaired intellectual development, delayed or absent walking, and behavioral psychiatric manifestations such as stereotypic and unpredictable outbursts.   There are often involuntary and hyperkinetic movements with dystonia, dyskinesia, ataxia and choreoathetosis.  The EEG is often abnormal although seizures have not been reported.

Genetics

De novo heterozygous mutations in the SYT1 gene (12q21.2) have been associated with this condition.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

SYT1-associated neurodevelopmental disorder: a case series

Baker K, Gordon SL, Melland H, Bumbak F, Scott DJ, Jiang TJ, Owen D, Turner BJ, Boyd SG, Rossi M, Al-Raqad M, Elpeleg O, Peck D, Mancini GMS, Wilke M, Zollino M, Marangi G, Weigand H, Borggraefe I, Haack T, Stark Z, Sadedin S; Broad Center for Mendelian Genomics, Tan TY, Jiang Y, Gibbs RA, Ellingwood S, Amaral M, Kelley W, Kurian MA, Cousin MA, Raymond FL. SYT1-associated neurodevelopmental disorder: a case series. Brain. 2018 Sep 1;141(9):2576-2591.

PubMed ID: 
30107533

Schurrs-Hoeijmakers Syndrome

Clinical Characteristics
Ocular Features: 

Mild structural variants are common among the periocular structures.  There is marked hypertelorism in many individuals, the eyebrows are full and highly arched, the eyelashes are long, and the lid fissures slant downward.  Ptosis is often evident.  Myopia, nystagmus, and strabismus are frequently noted.  Colobomas have been reported.

Systemic Features: 

There is general psychomotor delay in development.  Intellectual disability (with IQs in the 50s) and hypotonia are common.  Speech is poor and sometimes absent.   Behavioral anomalies such as aggression and features of autism have been reported.  The anterior hairline is low, the mouth is wide with downturned corners, the nose is bulbous, the ears are large and low-set, and the teeth are often widely-spaced.  Cryptorchidism is common among males.

Renal and cardiac defects are common.  Brain MRIs often show cerebellar hypoplasia, enlarged ventricles, and nonspecific white matter changes.

Genetics

No treatment for the general disorder has been published.  Physical and speech therapy might be helpful

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general disorder has been published.  Physical and speech therapy might be helpful.

References
Article Title: 

Clinical delineation of the PACS1-related syndrome--Report on 19 patients

Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH, Greville-Heygate S, Hanson-Kahn A, Bernstein JA, Glass J, Chitayat D, Burrow TA, Husami A, Collins K, Wusik K, van der Aa N, Kooy F, Brown KT, Gadzicki D, Kini U, Alvarez S, Fernandez-Jaen A, McGehee F, Selby K, Tarailo-Graovac M, Van Allen M, van Karnebeek CD, Stavropoulos DJ, Marshall CR, Merico D, Gregor A, Zweier C, Hopkin RJ, Chu YW, Chung BH, de Vries BB, Devriendt K, Hurles ME, Brunner HG; DDD study. Clinical delineation of the PACS1-related syndrome--Report on 19 patients. Am J Med Genet A. 2016 Mar;170(3):670-5.

PubMed ID: 
26842493

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

Encephalopathy, Early-Onset, With Brain Atrophy and Thin Corpus Callosum

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in many patients and may be present early since lack of visual tracking or eye contact may be noted at birth.  Sparse eyebrows, upslanting palpebral fissures, and hypertelorism have also been reported.

Systemic Features: 

Severe hypotonia is present at birth often causing respiratory distress in the neonate.  Spasticity can develop later.  Growth failure with progressive microcephaly is present in infants.  Brain imaging often reveals diffuse atrophy of structures including the cerebellum, brainstem, spinal cord, and cerebrum.  Tongue fasciculations have been observed.   Micrognathia and widely spaced teeth are sometimes present.  Several patients have died during infancy.

Genetics

Homozygous mutations in the TBCD (17q25.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):950-961.

PubMed ID: 
27666374

Corpus Callosum Agenesis with Facial Anomalies and Cerebellar Ataxia

Clinical Characteristics
Ocular Features: 

The thick, bushy eyebrows and long eyelashes are part of the generalized hirsutism.  The eyelids appear puffy.  Strabismus of unknown type has been reported.

Systemic Features: 

Infants are hypertonic at birth but this seems to be less evident as they grow.  Slow physical growth and psychomotor delay are common.  The skull in newborns is small.  The ears are low-set, protruding, and posteriorly rotated.  The nostrils are anteverted and the lower lip protrudes.  There are severe cognitive defects which has been called mental retardation.  Speech is poor or may never develop.  Cerebellar ataxia and uncoordinated hand movements are features.  Brain imaging reveals cerebellar hypoplasia and some degree of corpus callosum agenesis including absence.

Genetics

Homozygous mutations in the FRMD4A gene (10p13) have been found to segregate with this disorder in a large consanguineous Bedouin kindred.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Hypotonia, Infantile, with Psychomotor Retardation and Characteristic Facies 3

Clinical Characteristics
Ocular Features: 

Deep-set eyes with highly arched eyebrows have been described and poor fixation can be present.  Cortical visual impairment has been described.

Systemic Features: 

The neurologic abnormalities become evident soon after birth.  Hypotonia and decreased reflexes may be present early and often there is little psychomotor development subsequently.  Some patients have no or very little speech and may never sit, stand, or walk.  However, there is considerable variation in the clinical picture and other individuals are able to walk and may live into the third decade.  Brain imaging reveals a variety of abnormalities including cerebellar and cerebral hypoplasia.  Respiratory difficulties and poor feeding are often present.

The facial dysmorphism may include brachycephaly with a broad forehead and narrowing of the temporal regions.  The nose may be small and the mouth appears large in the presence of micrognathia and a thin upper lip.

Genetics

This is an autosomal recessive condition as the result of homozygous or compound heterozygous mutations in the TBCK gene (4q24). 

Other similar conditions include IHPRF2 (616801) (with homozygous mutations in UNC80 and IHPRF1 (615419) (with homozygous mutations in NALCN) whose ocular features may include strabismus, nystagmus, and poor visual fixation.    

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Bhoj EJ, Li D, Harr M, Edvardson S, Elpeleg O, Chisholm E, Juusola J, Douglas G, Guillen Sacoto MJ, Siquier-Pernet K, Saadi A, Bole-Feysot C, Nitschke P, Narravula A, Walke M, Horner MB, Day-Salvatore DL, Jayakar P, Vergano SA, Tarnopolsky MA, Hegde M, Colleaux L, Crino P, Hakonarson H. Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia. Am J Hum Genet. 2016 Apr 7;98(4):782-8.

PubMed ID: 
27040691

Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy

Chong JX, Caputo V, Phelps IG, Stella L, Worgan L, Dempsey JC, Nguyen A, Leuzzi V, Webster R, Pizzuti A, Marvin CT, Ishak GE, Ardern-Holmes S, Richmond Z; University of Washington Center for Mendelian Genomics, Bamshad MJ, Ortiz-Gonzalez XR, Tartaglia M, Chopra M, Doherty D. Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy. Am J Hum Genet. 2016 Apr 7;98(4):772-81.

PubMed ID: 
27040692
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