cerebellar hypoplasia

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

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

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

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

Hoyeraal-Hreidarsson Syndrome

Clinical Characteristics
Ocular Features: 

Little is known about the ocular signs in this rare disorder.  As many patients have systemic features of dyskeratosis congenita, however, it is possible that some of the ocular findings such as conjunctival and corneal scarring and lid margin distortion might be similar.  Hoyeraal-Hreidarsson syndrome, though, is a more severe disease and many infants may die before the mucocutaneous manifestations appear.  At least one patient has had an exudative retinopathy similar to that seen in Revesz syndrome (268130).  Epiphora and a preretinal hemorrhage have also been reported.

Systemic Features: 

Features of pancytopenia usually appear after 5 months of age while growth retardation and microcephaly are evident soon after birth.  The marrow may show progression to myelodysplasia.  Birth weight is usually low.  Truncal ataxia and axial hypotonia have been reported and MRI imaging reveals cerebellar hypoplasia.  Global developmental delay is a common feature and a few patients have seizures.  Susceptibility to infection has been noted but the basis for an immunodeficiency remains elusive.  Some patients have signs of dyskeratosis congenita such as sparse hair, nail dysplasia, and a reticular pattern of skin pigmentation.

Genetics

This is an X-linked disorder resulting from mutations in the DKC1 gene (Xq28) active in telomere maintainence.  As expected, the vast majority of affected individuals are male but at least 3 females have been reported. The same gene is also mutated in the X-linked form of dyskeratosis congenita (305000) suggesting that the two are allelic or that both are the same disease.  There are clear clinical differences, however, as severe developmental delay, immunodeficiency, cerebellar hypoplasia, and microcephaly are generally not present in the latter disorder.

There is evidence for telomere length variations in this syndrome and in dyskeratosis congenita.  Homozygous mutations in RTEL1 (regulator of telomere length helicase 1) (20q13.33) have also been found in these conditions.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Révész Syndrome

Clinical Characteristics
Ocular Features: 

This is likely a severe form of dyskeratosis congenita with an exudative retinopathy in addition to the usual lid deformities, corneal opacification, conjunctival scarring.  The exudates are often present in early childhood, and may be of sufficient volume to present as leukocoria mimicking a retrolental mass.  The exudates extend through nearly all layers of the retina and are said to resemble Coats retinopathy. Vitreous hemorrhage and opacification has also been reported.  Severe vision loss and blindness may occur depending on the degree of retinal and vitreous disease.

Systemic Features: 

Patients with Revesz syndrome have cerebral calcifications, and hypoplasia of the cerebellum in addition to mild signs of dyskeratosis congenita such as a reticulated skin pattern, nail dysplasia, and oral leukoplakia.  Ataxia is a prominent sign but is not present in all patients.  Bone marrow failure with pancytopenia and a high risk of malignancies, however, are serious problems.  Aplastic anemia and neutropenia may present in early childhood while other signs may not appear until late childhood.  Sparse hair, intrauterine growth retardation and low birth weight are also features.   

Few patients with Revesz syndrome have been reported and the clinical features have not been fully delineated.  It is important to note that there is a large amount of clinical variation among patients.

Genetics

Heterozygous mutations in the TINF2 gene (14q12) have been found in Revesz syndrome.  Mutations in the same gene have also been found in the autosomal dominant form of dyskeratosis congenita (613990) suggesting that the two disorders, if distinct, are allelic.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Bone marrow failure may respond favorably to hematopoietic stem cell transplantation, at least for some time. Lifelong medical monitoring is required for the systemic and ocular disease.

References
Article Title: 

Cataracts, Hearing Loss, and Neurodegeneration

Clinical Characteristics
Ocular Features: 

Congenital cataracts are the important ocular feature in this syndrome.

Systemic Features: 

Hearing loss is an important part of this syndrome.  Severe hypomyelination and hypoplasia are seen on MRI.  Marked developmental delay and early death are also seen.  Reduced ceruloplasmin secretion and low serum copper are present.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in SLC33A1 (3q25) encoding an acetylCoA transporter (AT-1).  The defect in hepatic cells results in reduced ceruloplasmin secretion with low serum copper.  Wilson disease (277900), Menkes disease (309400), and aceruloplasminemia (604290), other disorders of copper metabolism, have similar blood findings but due to different mechanisms.

Heterozygous mutations in SLC33A1 result in an autosomal dominant form of spastic paraplegia (SPG42) (612539). No ocular abnormalities have been reported in SPG42 though.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No information on treatment has been reported.

References
Article Title: 

Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin

Huppke P, Brendel C, Kalscheuer V, Korenke GC, Marquardt I, Freisinger P, Christodoulou J, Hillebrand M, Pitelet G, Wilson C, Gruber-Sedlmayr U, Ullmann R, Haas S, Elpeleg O, N?ornberg G, N?ornberg P, Dad S, M??ller LB, Kaler SG, G?SSrtner J. Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin. Am J Hum Genet. 2012 Jan 13;90(1):61-8.

PubMed ID: 
22243965

Incontinentia Pigmenti

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of skin, teeth, hair, and the central nervous system but 35% of patients have important ocular features.  The iris is variably atrophic and has pigmentary anomalies often with posterior synechiae.  Nystagmus, strabismus, and limited vision are often present.  The majority (up to 90%) of individuals have significant retinal disease.  The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others.  Preretinal fibrosis and retinal detachments may suggest the presence of a retinoblastoma.  Cataracts are common in patients who have a retinal detachment and some patients have microphthalmia. The retinal pigment epithelium is often abnormal with various-sized patches of sharply demarcated depigmentation.  Cases with uveitis, papillitis and chorioretinitis have been observed and it has been suggested that the observed retinal and choroidal changes result from prior inflammatory disease, perhaps even occurring in utero. There is a great deal of asymmetry in the clinical findings in the two eyes.

Systemic Features: 

Skin changes consisting of erythematous eruptions in a linear pattern are often present at birth and this may be followed by a verrucous stage.  The acute, early findings of inflammatory disease eventually subside, ultimately resulting in pigmentary changes that appear in a 'marbled pattern' in young adults.  Hypodontia and anodontia may be present.  Alopecia and CNS abnormalities are found in nearly half of patients.  Skeletal and structural deformities are common in patients with severe neurological deficits.  The only sign of this disorder in adult women may be a whorled pattern of scarring alopecia.

As many as 30% of patients have neurological features which may be present in the neonatal period.  Seizures of various types occur in 30% of patients.  MRI findings include periventricular and subcortical white matter changes, as well as corpus callosum hypoplasia, cerebral atrophy, and cerebellar hypoplasia.

 

Genetics

The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur.  The mutation occurs as a genomic rearrangement of the IKK-gamma gene, also known as NEMO (IKBKG) located at Xq28.  There is evidence from skin cultures that cells with the mutant X chromosome inactivated are preferentially viable.  It has been proposed that cells with the mutant bearing X chromosome as the active one are gradually replaced by those in which the normal X chromosome is active accounting for the post-natal course of the skin disease.

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

No treatment for the generalized disorder is available although ocular surgery might be beneficial in rare cases with cataracts and detachments.

References
Article Title: 
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