psychomotor delays

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

Mental Retardation, AD 31

Clinical Characteristics
Ocular Features: 

A variety of ocular dysmorphisms have been described in this disorder including up-slanting lid fissures, epicanthal folds, hypertelorism, and telecanthus.  Ptosis was described in 1 patient.  Strabismus, nystagmus, and disconjugate gaze have been observed.  Visual acuity has not been reported but "variable visual impairment" has been described.  One patient was considered to have cortical visual impairment.

Systemic Features: 

Neonatal hypotonia and feeding difficulties are among the first signs along with seizure-like activity (50%) including infantile spasms.  EEG anomalies are present in the majority of individuals.  Gastroscopy tubes may be required in a significant minority of patients.  Hypotonic or myopathic facies is common.  Apneic episodes may be seen in the neonatal period and most infants have respiratory difficulties in the first year of life which may improve during this period.  Learning difficulties and features of autism are common.  Some patients are unable to walk while others have an ataxic or broad-based gait.  Speech may be absent or severely limited.  The forehead is prominent while the hard palate is usually highly vaulted.

Brain MRIs may show delayed myelination but such scans have been described as normal in other individuals.  Enlarged ventricles, a thin corpus callosum, and periventricular white matter changes may also be present.   Neuropathologic studies have revealed chronic inflammatory changes around the arterioles of deep while matter.

Genetics

Heterozygous mutations in the PURA gene (5q31) have been identified in this disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Expanding the neurodevelopmental phenotype of PURA syndrome

Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, Stodgell C, Bennetto L, Kwon J, Fong CT, Gripp KW, Marsh ED, Smith WE, Huq AM, Coury SA, Tan WH, Solis O, Mehta RI, Leventer RJ, Baralle D, Hunt D, Paciorkowski AR. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 Jan;176(1):56-67.

PubMed ID: 
29150892

De novo mutations in PURA are associated with hypotonia and developmental delay

Tanaka AJ, Bai R, Cho MT, Anyane-Yeboa K, Ahimaz P, Wilson AL, Kendall F, Hay B, Moss T, Nardini M, Bauer M, Retterer K, Juusola J, Chung WK. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000356. doi: 10.1101/mcs.a000356.

PubMed ID: 
27148565

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, McGuire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet AL, Yang Y, Wang MC, Xia F. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet. 2014 Nov 6;95(5):579-83.

PubMed ID: 
25439098

Mental Retardation, X-Linked 99, Syndromic, Female-Restricted

Clinical Characteristics
Ocular Features: 

Palpebral fissures are generally shortened and may slant up or down.  Cataracts of unknown morphology have been reported and strabismus is common.

Systemic Features: 

The systemic phenotype is highly variable.  Skull and facial anomalies are common with brachycephaly, bitemporal narrowing, and a broad low nasal bridge. There is general developmental delay in both motor and cognitive abilities.  Patients are short in stature while scoliosis, hip dysplasia, and post-axial polydactyly may be present.  The teeth may be malformed and numerous (29%) of individuals have hypertrichosis.  Nearly a third of individuals have a cleft palate/bifid uvula.   Heart malformations, primarily atrial septal defects, are found in about half of affected individuals and urogenital anomalies such as renal dysplasia are relatively common.  Feeding difficulties have been reported while anal atresia is present in about half of patients.   

Brain imaging reveals hypoplasia of the corpus callosum, enlarged ventricles, Dandy-Walker malformations, cerebellar hypoplasia, and abnormal gyration patterns in the frontal lobe.  Generalized hypotonia has been diagnosed in half of reported patients and seizures occur in 24%.

Genetics

This female-restricted syndrome is caused by heterozygous mutations in the USP9X gene (Xp11.4).  X-chromosome inactivation is skewed greater than 90% in the majority of females but the degree of skewing in one study was independent of clinical severity.  The majority of cases occur de novo.

In males, hemizygous mutations in the USP9X gene (300919) cause a somewhat similar disorder (MRX99) without the majority of the congenital malformations having mainly the intellectual disabilities, hypotonia, and behavioral problems.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

There is no known treatment for the general disorder but individual anomalies or defects such as atrial septal defects, cleft palate, and anal atresia might be surgically corrected.

References
Article Title: 

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Reijnders MR, Zachariadis V, Latour B, Jolly L, Mancini GM, Pfundt R, Wu KM, van Ravenswaaij-Arts CM, Veenstra-Knol HE, Anderlid BM, Wood SA, Cheung SW, Barnicoat A, Probst F, Magoulas P, Brooks AS, Malmgren H, Harila-Saari A, Marcelis CM, Vreeburg M, Hobson E, Sutton VR, Stark Z, Vogt J, Cooper N, Lim JY, Price S, Lai AH, Domingo D, Reversade B; DDD Study, Gecz J, Gilissen C, Brunner HG, Kini U, Roepman R, Nordgren A, Kleefstra T. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb 4;98(2):373-81.

PubMed ID: 
26833328

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 can be evident at birth, requiring tube feeding and respiratory assistance.  Death may occur before 6 months of age but with intense supportive care children can 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

Infantile Cerebellar-Retinal Degeneration

Clinical Characteristics
Ocular Features: 

Visual tracking can be normal during the newborn period but lack of visual fixation and attention soon become evident.  Strabismus, nystagmus, and abnormal pursuit movements are often present.  Optic atrophy has been reported as early as 3 years of age.  VEP and ERG responses are extinguished in the first two years. The nystagmus may be multidirectional.  Acuity loss seems to be progressive.  A progressive retinal degeneration (not further characterized) has been reported.

Systemic Features: 

Infants generally appear normal at birth.  Within the first 6 months they show signs of developmental delay and neurological signs such as truncal hypotonia, seizures, athetosis and head bobbing.  Milestones of sitting, rolling over, and reactions to others are seldom achieved.  Cerebellar brain imaging shows progressive atrophy in all patients and some have cortical atrophy as well.  Some patients have evidence of hearing loss.   Severe failure to thrive and psychomotor delays are usually present.  Death may occur within several months of birth although some live for several decades.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ACO2 gene (22q13.2).  The mutation has also been associated with optic atrophy 9 (616289).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond supportive care is known.

References
Article Title: 

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8.

PubMed ID: 
25351951

Tenorio Syndrome

Clinical Characteristics
Ocular Features: 

The eyebrows appear bushy.  Inflammation of the limbus and keratoconjunctivitis sicca are often present and reported to resemble Sjogren syndrome.

Systemic Features: 

Infants appear large at birth with a large forehead and macrocephaly.  Birth weight, length, and head circumference are usually above the 97th percentile. The mandible appears large and the lips are full and ‘fleshy’.  Dentition is delayed.  Recurrent stomatitis and gastroesophageal reflux have been noted.  Closure of the fontanels is delayed.  Hypotonia and hyperflexible joints can be a feature.

Multiple brain anomalies have been described including cortical atrophy, dilated and asymmetrical ventricles, and mild hydrocephalus.  Psychomotor development and milestones are delayed.  Intellectual disabilities, syncope, hypoglycemia, seizures, apneic episodes, mood anomalies, abnormal gait, and general clumsiness may be present.  There was considerable clinical variation among the six reported patients. 

Genetics

Heterozygous mutations in RNF125 (18q12.1) are responsible for this syndrome. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

A new overgrowth syndrome is due to mutations in RNF125

Tenorio J, Mansilla A, Valencia M, Martinez-Glez V, Romanelli V, Arias P, Castrejon N, Poletta F, Guillen-Navarro E, Gordo G, Mansilla E, Garcia-Santiago F, Gonzalez-Casado I, Vallespin E, Palomares M, Mori MA, Santos-Simarro F, Garcia-Minaur S, Fernandez L, Mena R, Benito-Sanz S, del Pozo A, Silla JC, Ibanez K, Lopez-Granados E, Martin-Trujillo A, Montaner D; SOGRI Consortium, Heath KE, Campos-Barros A, Dopazo J, Nevado J, Monk D, Ruiz-Perez VL, Lapunzina P. A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 Dec;35(12):1436-41.

PubMed ID: 
25196541

CODAS Syndrome

Clinical Characteristics
Ocular Features: 

Dense nuclear cataracts can be seen by six months of age.  Some patients have ptosis. The fundi have been described as normal at one month of age in a single infant but vision was described at the 20/200 level at 2 years of age.  Cataracts noted at 4 months had been removed.

Systemic Features: 

Patients have multiple severe systemic abnormalities.  There is generalized developmental delay along with mild microcephaly and hypotonia.   The forehead is often broad while the face appears flattened with anteverted nares, a flat nasal bridge, a short philtrum, low-set and crumpled ears.  Infants may have an inadequate upper respiratory apparatus with atrophic vocal cords and some die of laryngeal obstruction in the first days of life.  Sialorrhea and difficulty swallowing have been noted.  Mild to moderate neurosensory hearing loss is often present but there may also be a conduction component to this. 

Brain imaging has revealed large ventricles, with subcortical hypomyelination, a thin corpus callosum, and prominent cortical sulci.  The vertebrae may have coronal clefts and scoliosis often develops. Generalized metaphyseal dysplasia and delayed bone age are usually present.  The anus may be imperforate and a rectovaginal fistula and cryptorchidism have been reported.  Long bones may be malformed as well and most patients are short in stature. Delayed dentition, enamel dysplasia, and abnormal cusp morphology are often present.  Cardiac septal defects may be seen.

Genetics

Homozygous mutations in LONF1 (19p13.3) segregate with the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no general treatment available and infants sometimes die from laryngeal obstruction in the first days of life.   Individual anomalies may be surgically correctable in selected individuals.  Occasional infants are stillborn but one patient died an accidental death at 14 years of age. 

References
Article Title: 

CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease

Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, Mikita N, Thilagavathi J, Lee J, Sarafianos S, Benkert A, Koehler A, Zhu A, Trovillion V, McGlincy M, Morlet T, Deardorff M, Innes AM, Prasad C, Chudley AE, Lee IN, Suzuki CK. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet. 2015 Jan 8;96(1):121-35.

PubMed ID: 
25574826

Chorioretinopathy with Microcephaly 2

Clinical Characteristics
Ocular Features: 

Microphthalmia and microcornea are seen in most individuals and one patient had unilateral clinical anophthalmia. Hyperopia and cataracts may be present. Nystagmus is common.  One patient had a corneal opacity.  The chorioretinopathy has not been described beyond evidence of the maculopathy, attenuated retinal vessels, and occasionally hyperpigmented zones.  The ERG is either not recordable or consistent with a severe rod-cone dystrophy.  Vitreous inclusions and a 'vitreoretinal dystrophy' with falciform retinal folds were noted in several patients.  A traction detachment was present in one and bilateral serous detachments were noted in another.

Systemic Features: 

Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays.  Profound intellectual disability is a consistent feature.  Physical growth is retarded and patients have shortness of stature.  Most patients are unable to sit, stand, or walk unassisted.  One patient died at 5.5 years of age while another was alive at 20 years of age.  Rare patients may have hearing loss and seizures.

Scoliosis, kyphosis, and lordosis may be seen while  other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.  

The forehead slopes markedly.  Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small.  Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.

Genetics

Homozygous mutations in the PLK4 gene (4q28.2) segregate with this condition.  Its product localizes to centrioles and plays a central role in centriole duplication.

For a somewhat similar condition but without the sloping forhead see Chorioretinoapathy with Microcephaly 1 (251270) but resulting from homozygous mutations in TUBGCP6.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is know.

References
Article Title: 

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Daire VC, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-92.

PubMed ID: 
25344692

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 34 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities to Meckel syndrome (249000) and Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Jul 25. pii: S0161-6420(18)30686-9. doi: 10.1016/j.ophtha.2018.05.026. [Epub ahead of print].

PubMed ID: 
30055837

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

Spastic Ataxia 4, mtPAP Deficiency

Clinical Characteristics
Ocular Features: 

Ocular examinations in 4 adult individuals of a single family aged 18 to 27 years were reported to have optic atrophy.  One of these had a horizontal nystagmus and another was described as having a vertical nystagmus.  No ocular evaluations were available for 2 children, aged 2 and 6 years.  Visual acuity testing was not reported but all individuals participated appropriately in family and educational activities. 

Systemic Features: 

This is a congenital disorder with cerebral ataxia (limb and truncal), spastic paraparesis (increased lower limb tone with brisk knee jerks and extensor plantar responses), cerebellar and spastic dysarthria, learning difficulties and emotional lability as prominent features.  The onset of both speech and mobility are delayed.  Older individuals have slow and spastic tongue movements with brisk jaw jerks, and increased tone in the upper limbs.  Motor function progressively declines although even older individuals in the third decade of life remain mobile albeit with an increasingly spastic and ataxic gait, and require only minimal assistance with self-care.  Children in grade school require special education accommodations but there is no obvious deterioration in intellectual function as they mature.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the MTPAP gene (10p11.22).  The mutation leads to a defect of mitochondrial mRNA maturation in which the poly(A) tails are severely truncated.

Optic atrophy is also present in some patients who have autosomal dominant spastic ataxia with miosis (SPAX7) (108650) and in another form of autosomal recessive childhood-onset spastic ataxia and mental retardation (270500).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known but special education and physical and speech therapy may be helpful.

References
Article Title: 

Defective mitochondrial mRNA maturation is associated with spastic ataxia

Crosby AH, Patel H, Chioza BA, Proukakis C, Gurtz K, Patton MA, Sharifi R, Harlalka G, Simpson MA, Dick K, Reed JA, Al-Memar A, Chrzanowska-Lightowlers ZM, Cross HE, Lightowlers RN. Defective mitochondrial mRNA maturation is associated with spastic ataxia. Am J Hum Genet. 2010 Nov 12;87(5):655-60.

PubMed ID: 
20970105

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