microcephaly

Cerebellar Atrophy, Visual Impairment, and Psychomotor Retardation

Clinical Characteristics
Ocular Features: 

Patients usually have deep-set eyes.  Cortical visual impairment has been described in one patient but optic atrophy has been seen in another.  The VEP and ERG are described as 'abnormal'.  Strabismus, hyperopia, and myopia are sometimes seen.

Systemic Features: 

Progressive microcephaly is often noted.  Truncal hypotonia and scoliosis may be present while muscle tone is increased in the extremities in the presence of diminished deep tendon reflexes in other patients.  Dystonic posturing occurs in some families.  Gingival hyperplasia is a common feature and retrognathia is often present.

Brain imaging reveals progressive cerebellar atrophy and a foreshortened corpus callosum in all families.  Various degrees of cerebral atrophy have been identified while intellectual disability may be marked.  Speech delay is common.

Genetics

This is an autosomal recessive condition associated with homozygous mutations in the EMC1 gene (1p36.13).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatnent has been reported.

References
Article Title: 

Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy

Harel T, Yesil G, Bayram Y, Coban-Akdemir Z, Charng WL, Karaca E, Al Asmari A, Eldomery MK, Hunter JV, Jhangiani SN, Rosenfeld JA, Pehlivan D, El-Hattab AW, Saleh MA, LeDuc CA, Muzny D, Boerwinkle E; Baylor-Hopkins Center for Mendelian Genomics, Gibbs RA, Chung WK, Yang Y, Belmont JW, Lupski JR. Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. Am J Hum Genet. 2016 Mar 3;98(3):562-70.

PubMed ID: 
26942288

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: 

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

Clinical Characteristics
Ocular Features: 

Patients have been described as having variable oculofacial features including epicanthal folds, hypertelorism, strabismus, and 'tapetoretinal degeneration'.    

Systemic Features: 

The full phenotype is variable and unknown based on the 5 reported patients from 4 families of whom 3 were consanguineous.  Recurrent infections (especially respiratory and otitis media) seem to be among the most consistent features.  Others include intrauterine growth retardation, developmental delay including psychomotor delays, a flat midface with various anomalies, low-set ears, renal dysgenesis, polydactyly, severe agammaglobulinemia, hypospadias, and cryptorchidism.  Normal T-cell function and normal B cells are present.  Conductive hearing loss, polydactyly, and scoliosis may be features as well.  Two of the 5 reported patients with ICF3 were reported to have mental retardation.  One patient died at the age of 26 years.

Genetics

Homozygosity of CDCA7 (2q31.1) mutations with centromeric instability and hypomethylation of selected juxtacentromeric heterochromatin regions is responsible for this (ICF3) autosomal recessive condition.  There is genetic heterogeneity in ICF (ICF1, ICF2, ICF3, and ICF4 [see 242860).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome

Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Gungor T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870.

PubMed ID: 
26216346

Microcephaly, Congenital Cataracts, and Psoriasiform Dermatitis

Clinical Characteristics
Ocular Features: 

Congenital cataracts are usually present.  No further description is available.  Some individuals have a chronic blepharitis.

Systemic Features: 

Small stature, microcephaly, and developmental delay are important features. The skin in early life, even in infancy, may have an psoriasiform dermatitis that waxes and wanes in some patients while others have only dry skin.  Chronic arthralgias are sometimes present leading to joint contractures especially in the lower extremities.  Skeletal maturation is delayed and there may be cognitive deficits.

Serum total cholesterol levels are generally low but triglycerides are in the normal range.  Serum levels of IgE and IgA may be elevated.  This condition results from defects in the cholesterol synthesis pathway.

Genetics

Compound heterozygosity or homozygosity of mutations in the SC4MOL gene (4q32.3) (also known as MSMO1) is responsible for this condition.  Parents with a single mutation may have mildly elevated plasma methylsterol levels.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cholesterol supplementation and the use of statins has been reported to improve symptoms.  The usual treatments for psoriasis may provide some temporary relief.  Physical therapy may prevent joint contractures.  Antibiotic drops or ointment may be helpful in the treatment of blepharitis.

References
Article Title: 

The role of sterol-C4-methyl oxidase

He M, Smith LD, Chang R, Li X, Vockley J. The role of sterol-C4-methyl oxidase
in epidermal biology. Biochim Biophys Acta. 2014 Mar;1841(3):331-5. Review.

PubMed ID: 
24144731

Vici Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts, both unilateral and bilateral are common.  The fundus appears hypopigmented. Nystagmus, optic neuropathy, and mild ptosis have been reported.  Nothing is known regarding acuity. 

Systemic Features: 

Infants at birth have striking hypotonia with a weak cry and feeding difficulties.  Dysmorphic features such as micrognathia, microcephaly, low-set ears, some degree of generalized hypopigmentation (hair and skin), and a broad nose with a long philtrum may be present. The face may appear triangular.  Cleft lip and palate may be present.  Evidence of cardiac dysfunction may also be present early with both dilated and hypertrophic cardiomyopathy reported.  Hearing loss has been reported in some individuals.  Recurrent infections are common and immunologic studies have revealed, in some patients, granulocytopenia, low T cell counts (primarily T4+ cells), thymic dysplasia, and low levels of IgG.  Seizures may occur.  Liver dysfunction has been variably reported.

Neurological and brain evaluations have reported agenesis of the corpus callosum, defects in the septum pellucidum, and hypoplasia of the cerebellar vermis along with pontocerebellar hypoplasia.  Psychomotor retardation is severe in most individuals along with general growth retardation.

Histologic studies of skeletal muscle fibers have shown considerable variation in fiber size, centralized nuclei, fucsinophilic inclusions, and enlarged abnormal mitochondria.  Other central nervous system abnormalities include in some individuals a paucity of white matter, schizencephaly, neuronal heterotopias, and enlargement of the ventricles.

The cumulative effects of these multiorgan abnormalities lead to death within the first year or two of life, generally of heart failure or sepsis. 

Genetics

Homozygous or compound heterozygous mutations in the EPG5 gene (18q12.3) have been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Vici syndrome: a

Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: a
review. Orphanet J Rare Dis. 2016 Feb 29;11(1):

PubMed ID: 
4772338

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, Simpson MA, Yau S, Bertini E, McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wijburg FA, ten Hoedt AE, Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM, Windpassinger C, Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel HH, Sewry CA, Abbs S, Mohammed S, Josifova D, Gautel M, Jungbluth H. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013 Jan;45(1):83-7.

PubMed ID: 
23222957

Pontocerebellar Hypoplasia 3

Clinical Characteristics
Ocular Features: 

Optic atrophy is an inconsistent feature (sometimes even unilateral) of patients with PCH.  Cortical blindness has also been described.  There may be dysmorphic facial features such as wide palpebral fissures, epicanthal folds, and prominent eyes. 

Systemic Features: 

Infants are generally small and hypotonic at birth.  The skull is small and often brachycephalic.  The ears are large and low-set and  facial dysmorphism (full cheeks, long philtrum) is present.  Infants have poor head control and truncal ataxia.  Later, hyperreflexia and spasticity become evident.  Seizures are common.  Developmental delays, both somatic and mental, are nearly universal and large joint contractures are often seen. Many of these signs are progressive.  

Brain imaging generally reveals cerebral and cerebellar atrophy, a hypoplastic corpus callosum, a small cerebellar vermis, and a hypoplastic brainstem.  Short stature is a feature and early death often occurs.

Genetics

PCH3 is one of at least 10 syndromes belonging to a clinically and genetically heterogeneous group of conditions known as pontocerebellar hypoplasias.  Members of this group, while individually rare, nevertheless collectively account for a significant proportion of what was once labeled cerebral palsy.

PCH3 results from homozygous mutations in the PCLO gene (7q21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general disorder.

References
Article Title: 

Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH, Mochida GH. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28;84(17):1745-50.

PubMed ID: 
25832664

3-methylglutaconic Aciduria with Cataracts, Neurologic Involvement and Neurtropenia

Clinical Characteristics
Ocular Features: 

Descriptions of ocular findings have been limited.  Congenital nuclear cataracts have been described in one patient but lens opacities have been noted in others.

Systemic Features: 

There is considerable heterogeneity in the phenotype with some patients having minimal signs and living to adulthood whereas others succumb to their disease in the first year of life.  The onset of progressive encephalopathy usually occurs in infancy as evidenced by various movement abnormalities and psychomotor delays.  Neonatal hypotonia sometimes progresses to spasticity.  However, other infants are neurologically normal.  Delayed psychomotor development, ataxia, seizures, and dystonia may be seen.  Brain imaging may reveal cerebellar and cerebral atrophy along with brain stem abnormalities.  Neuronal loss, diffuse gliosis, and microvacuolization have been seen on neuropathologic examination.  Dysphagia is common.  Severe neutropenia and recurrent infections may begin in infancy as well.

Increased amounts of 3-methylglutaconic acid are found in the urine while the bone marrow may contain evidence of arrested granulopoiesis. 

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CLPB gene (11q13.4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported for this condition.

References
Article Title: 

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015 Feb 5;96(2):245-57.

PubMed ID: 
25597510

Mental Retardation, AD 34

Clinical Characteristics
Ocular Features: 

Patients may have upslanting lid fissures, epicanthus, ptosis, synophrys, and cortical visual impairment.

Systemic Features: 

Among the three reported individuals with the COL4A3BP mutation, one had postnatal microcephaly, widely spaced teeth, synophrys, and intellectual disability. Another had trunk hypotonia, global developmental delay, wide intermamillary distance, 2-3 toe syndactyly, tonic-clonic seizures, and myopathic facies. The third had a broad-based gait, coarse and curly hair, tonic-clonic seizures, and global developmental delay. 

Genetics

In a screening study of 1133 children with severe undiagnosed developmental conditions, three males were found with heterozygous mutations in the COL4A3BP gene (5q13).  Family history data are not given for these three individuals but autosomal dominant transmission seems to be a reasonable assumption.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive care is required but no other treatment has been reported.

References
Article Title: 

Chorioretinopathy with Microcephaly 3

Clinical Characteristics
Ocular Features: 

The eyes are not notably small although several patients have been reported to have significant hyperopia.  Vision can be impaired and some individuals have early-onset nystagmus.  The ERG responses are attenuated and may be absent.  The retina is dysplastic with multiple atrophic punched-out lesions, attenuated retinal vessels, and sparse pigmentation. Large retinal folds have been described and one patient developed a retinal detachment.  Optic atrophy was noted in one individual.

Systemic Features: 

Microcephaly of 3-4 standard deviations below normal is a constant feature.  Motor and language abilities can be mildly delayed and  several patients have had mild learning difficulties.   Brain imaging has been normal in most individuals but a shortened and thin corpus callosum was present in one patient.

Genetics

Family and genetic evidence suggest autosomal recessive inheritance.  Compound heterozygous mutations in the TUBGCP4 gene (15q15.3) code for part of a protein complex involved in microtubule organization.

For a somewhat similar condition with a different mutation involving the same microtubule complex see Chorioretinopathy with Microcephaly 1 (251270).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids may be helpful in selected patients.

References
Article Title: 

Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy

Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, Plagnol V, Drunat S, Passemard S, Toutain A, Obringer C, Koob M, Geoffroy V, Marion V, Strahle U, Ostergaard P, Verloes A, Merdes A, Moore AT, Dollfus H. Mutations in TUBGCP4 Alter Microtubule Organization via the g-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy. Am J Hum Genet. 2015 Apr 2;96(4):666-74.

PubMed ID: 
25817018

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