sensorineural hearing loss

Spastic Paraplegia with Psychomotor Retardation and Seizures

Clinical Characteristics
Ocular Features: 

The eyes are usually deeply set.  Nothing is known regarding visual acuity.  Strabismus is a common feature.  Retinal dystrophy (not further described) has been reported in 4 of 8 patients described.  The ERG in one individual was read as consistent with cone-rod dystrophy.

Systemic Features: 

Newborns are hypotonic and severe psychomotor retardation is evident a few months later.  Truncal ataxia and progressive lower limb spasticity are seen later.  Mobility is significantly impaired and many individuals are confined to bed or a wheelchair and never walk.  Dysarthria is frequently present and some individuals have a neurosensory hearing loss.  Myoclonic seizures may be evident.  Kyphoscoliosis, macrocephaly, and various foot deformities have been described.

CT scans of the brain may show generalized cerebral atrophy and a hypoplastic corpus callosum.  The ventricles may be enlarged and the EEG confirms the occurrence of myoclonic as well as tonic-clonic and focal epilepsy.

Genetics

This is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the HACE1 gene (6q16).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this condition but physical therapy and assistive devices such as hearing and visual aids may be helpful.

References
Article Title: 

DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9.

PubMed ID: 
26437029

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Hollstein R, Parry DA, Nalbach L, Logan CV, Strom TM, Hartill VL, Carr IM, Korenke GC, Uppal S, Ahmed M, Wieland T, Markham AF, Bennett CP, Gillessen-Kaesbach G, Sheridan EG, Kaiser FJ, Bonthron DT. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803.

PubMed ID: 
26424145

Cataracts, Growth Hormone Deficiency, and Skeletal Dysplasia

Clinical Characteristics
Ocular Features: 

Lens opacities can be seen in infancy or childhood and may be congenital in onset.  Nystagmus has been noted in one patient. 

Systemic Features: 

There is considerable clinical heterogeneity in the phenotype.  Motor milestones may be slightly delayed.  Dysmorphic features in at least some individuals include bushy eyebrows, a prominent forehead, and a small mouth.  Thoracic scoliosis and genu valgum may be present.  Physical growth is reduced during infancy and childhood resulting in a short stature in adulthood.  Growth hormone and cortisol deficiency have been documented. Episodic hypoglycemia has been documented. The pituitary adenohypophysis appears atrophied on MRI.

Neurosensory hearing loss has been diagnosed in the first two years of life.  A distal sensory neuropathy with loss of pain, temperature and touch sensation may be present late in the first decade of life.  There are no cognitive deficits and patients can live independently.

Genetics

This is likely an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the IARS2 gene (1q41).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Appropriate hormonal replacement therapy can be beneficial.  Individual skeletal surgery for scoliosis and hip dislocation should be considered.  Visually significant lens opacities may require surgery.

References
Article Title: 

Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome

Schwartzentruber J, Buhas D, Majewski J, Sasarman F, Papillon-Cavanagh S, Thiffaut I, Sheldon KM, Massicotte C, Patry L, Simon M, Zare AS, McKernan KJ; FORGE Canada Consortium, Michaud J, Boles RG, Deal CL, Desilets V, Shoubridge EA, Samuels ME. Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome. Hum Mutat. 2014 Nov;35(11):1285-9.

PubMed ID: 
25130867

Pigmentary Retinopathy with Congenital Sideroblastic Anemia

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been fully described, but several patients with a pigmentary retinopathy resembling retinitis pigmentosa have been reported.

Systemic Features: 

Patients present at a median age of two months with typically severe microcytic sideroblastic anemia. Median hemoglobin levels are 7.1 g/dl.  Lymphopenia and panhypogammaglobulinemia are usually present and many children have periodic febrile illnesses.  The number of CD19+ B cells is reduced.  Aminoaciduria, hypercalcinuria, and nephrocalcinosis have been observed.  Cardiomyopathy has been seen in several patients and may be responsible for the early demise.  Developmental delays may be severe with variable neurodegeneration features such as seizures, cerebellar symptoms, and sensorineural hearing loss.  Achievement of milestones is generally delayed.  Median survival is 4 years although one patient has lived to the age of 19 years.

Genetics

Homozygous mutations in TRNT1 (3p25.1) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Allogeneic bone marrow transplantation in one patient reversed the hematologic and immunologic anomalies although retinitis subsequently developed.

References
Article Title: 

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)

Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D, Campagna DR, Lau A, Sendamarai AK, Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Wynn RF, Laxer RM, Minniti CP, Moppett J, Bordon V, Geraghty M, Joyce PB, Markianos K, Rudner AD, Holcik M, Fleming MD. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014 Oct 30;124(18):2867-71.

PubMed ID: 
25193871

A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Chakraborty P, Geraghty MT, Major-Cook N, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Fleming MD, Wynn RF. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood. 2013 Jul 4;122(1):112-23.

PubMed ID: 
23553769

Optic Atrophy, Areflexia, Ataxia, Hearing Loss

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is a consistent feature of all reported cases.  It may have its onset during the first year or two of life but always before the age of 10 years.  Nystagmus may be seen early during acute febrile episodes but eventually becomes permanent.

Systemic Features: 

Onset of neurological symptoms usually occurs in childhood during or following an acute febrile illness which may be recurrent.  This may consist of cerebellar ataxia, hypotonia, drowsiness, dysarthria, and lethargy.  There may be partial or full recovery following the febrile illness initially but some signs remain after subsequent episodes.  Areflexia and sensorineural deafness can be additional signs and pes cavus eventually appears.

The acute febrile episodes tend to decrease in time along with the progression of neurological signs.  Plantar responses remain normal while peripheral neuropathy and seizures are not consistent features.  MRI imaging of the brain is normal.  Cognitive function usually remains normal but some children have autism features and social adjustment problems have been noted.

Genetics

This is an autosomal dominant condition (which may be considered a form of ‘ataxia-plus’) secondary to heterozygous mutations in the ATP1A3 gene (19q13.31).  The protein product is a subunit of an ATPase enzyme primarily active in neural tissue.

Other mutations in the same gene have been found in dystonia-12 and alternating hemiplegia of childhood.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this condition but physical therapy and mobility-assistive devices may be helpful.  Low vision aids may be useful as well.

References
Article Title: 

A novel recurrent mutation in ATP1A3 causes CAPOS syndrome

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM; FORGE Canada Consortium. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014 Jan 28;9:15.

PubMed ID: 
24468074

Baraitser-Winter Syndrome 2

Clinical Characteristics
Ocular Features: 

Hypertelorism, high arched eyebrows, ptosis, and  colobomas occur in the majority of individuals.

Systemic Features: 

Short stature, postnatal microcephaly, lissencephaly, intellectual disability, seizures, and sensorineural hearing loss are common.

Genetics

This syndrome can be considered to be an autosomal dominant disorder secondary to heterozygous mutations in the ACTG1 gene (17q25.3).  However, all patients have been sporadic.

Mutations in ACTG1 are also responsible for autosomal dominant progressive nonsyndromic hearing loss.  

A similar but unique condition known as Baraitser-Winter syndrome 1 (243310) is caused by heterozygous mutations in the ACTB gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment but special education, hearing devices, and physical therapy may be helpful.

References
Article Title: 

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783

Baraitser-Winter Syndrome 1

Clinical Characteristics
Ocular Features: 

Ptosis (both unilateral and bilateral), hypertelorism, prominent epicanthal folds, and colobomata are common.  The iris stroma may be dysplastic and correctopia has been observed.  Visual acuity has not been measured.

Systemic Features: 

Postnatal growth retardation leads to short stature.  Microcephaly and morphological aberrations in the brain such as lissencephaly, agenesis of the corpus callosum and pachygyria are present.  Seizures and developmental delays are common.  Hearing loss is sensorineural in type.

The ears are low-set and the posterior hair line may be low as well.  The nasal bridge appears broad and the nose appears short. Male genitalia are often underdeveloped.  Bicuspid aortic valves, patent ductus arteriosus, and aortic stenosis have been reported.

Genetics

Heterozygous mutations in the ACTB gene (7p22.1) are responsible for this apparent autosomal dominant syndrome.  However, all patients have been sporadic.

This condition is clinically similar to Baraitser-Winter syndrome 2 (614583) which is a unique entity caused by a mutation in ACTG1. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available.

References
Article Title: 

New ocular finding in Baraitser-Winter syndrome

Rall N, Leon A, Gomez R, Daroca J, Lacassie Y. New ocular finding in Baraitser-Winter syndrome. Eur J Med Genet. 2017 Oct 9. pii: S1769-7212(17)30156-8. doi: 10.1016/j.ejmg.2017.10.006. [Epub ahead of print].

PubMed ID: 
29024830

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783

Smith-Magenis Syndrome

Clinical Characteristics
Ocular Features: 

Ocular abnormalities have been found in the majority of patients.  Microcornea, myopia, strabismus and iris dysplasia are the most common.  Rare patients have iris colobomas or correctopia.  The eyes appear deep-set and lid fissures are upward slanting.

Systemic Features: 

The facial features are considered to be distinctive, characterized by a broad, square face, prominent forehead, broad nasal bridge, and midface hypoplasia.  These and other features appear more pronounced with age as in the size of the jaw which is underdeveloped in infancy and eventually becomes prognathic.  Most patients have developmental delays, speech and motor deficits, cognitive impairments and behavioral abnormalities.  Hypotonia, hyporeflexia, failure to thrive, lethargy, and feeding difficulties are common in infants.  Older individuals have REM sleep disturbances with self-destructive behaviors, aggression, inattention, hyperactivity, and impulsivity.  Short stature, hypodontia, brachydactyly, hearing loss, laryngeal anomalies, and peripheral neuropathy are common. Seizures are uncommon.

The behavioral profile of this syndrome can resemble that of autism spectrum disorders although symptoms of compulsivity are more mild.

A related developmental disorder known as Potacki-Lupski syndrome (610883) involving the same locus on chromosome 17 has a similar behavioral profile.  Ocular and systemic malformations may be less severe though.

Genetics

Most patients (90%) with the Smith-Magenis syndrome have interstitial deletions in the short arm of chromosome 17 (17p11.2).  However, it is included here since a few have heterozygous molecular mutations in the RAI1 gene which is located in this region.  While there is considerable phenotypic overlap, individuals with chromosomal deletions have the more severe phenotype as might be expected.  For example, those with RAI1 mutations tend to be obese and are less likely to exhibit short stature, cardiac anomalies, hypotonia, hearing loss and motor delays than seen in patients with a deletion in chromosome 17.  However, the phenotype is highly variable among patients with deletions depending upon the nature and size of the deletion.

The retinoic acid induced 1 gene (RAI1) codes for a transcription factor whose activity is reduced by mutations within it.

Familial cases are rare and reproductive fitness is virtually zero.  If parental chromosomes are normal, the risk for recurrence in sibs is less than 1%.  Males and females are equally affected.

In Potocki-Lupski syndrome (610883) there is duplication of the 17p11.2 microdeletion as the reciprocal recombination product of the SMS deletion.   

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Medical monitoring, psychotropic medications and behavioral therapies are all useful.  Special education and vocational training may be helpful for those less severely affected.

References
Article Title: 

Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and

Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM,
Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C,
Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski
JR. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and
delineation of a dosage-sensitive critical interval that can convey an autism
phenotype. Am J Hum Genet. 2007 Apr;80(4):633-49.

PubMed ID: 
17357070

Peroxisome Biogenesis Disorder 1A (Zellweger)

Clinical Characteristics
Ocular Features: 

Ocular signs resemble those of other peroxisomal disorders with cataracts and retinopathy.  The lethal consequences of ZWS have hampered delineation of the full spectrum of ocular manifestations but many infants have these features plus optic atrophy and horizontal nystagmus.  Most infants do not follow light.  Pupillary responses may be normal in early stages but disappear later. Hypertelorism has been described but metrics are often normal.

Systemic Features: 

Many infants have hepatomegaly at birth and may develop splenomegaly as well.  Jaundice often occurs with intrahepatic biliary dysgenesis.   Severe hypotonia is present at birth but improves in those patients who survive for several years.  Psychomotor retardation can be profound and seizures may occur but sensory examinations are normal.  Most infants have a peculiar craniofacial dysmorphology with frontal bossing, large fontanels, and wide set eyes.  Pipecolic acid levels are low in serum and absent in the CSF.  Most infants do not survive beyond 6 months of age.

 

Genetics

This is a peroxisome biogenesis disorder with a complex biochemical profile resulting from a large number of mutations in at least 13 PEX genes.  It is inherited in an autosomal recessive pattern.

What was formerly called Zellweger Syndrome is now more properly called Zellweger Spectrum Disorder, or sometimes a peroxisomal biogenesis disorder in the Zellweger spectrum of disorders.  The spectrum also includes neonatal adrenoleukodystrophy (601539) and Infantile Refsum disease (601539). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Waardenburg Syndrome, Type 4

Clinical Characteristics
Ocular Features: 

The skin and ocular pigmentary changes and the sensorineural hearing loss in type 4 Waardenburg syndrome resembles that of other types.  Patients, however, usually lack synophrys and dystopia canthorum.

Systemic Features: 

Type 4 Waardenburg syndrome is largely similar to other types except that many patients also have Hirschsprung disease.

Genetics

Both autosomal dominant and recessive inheritance have been reported for type 4 Waardenburg syndrome.  Both heterozygous and homozygous mutations in the EDNRB (endothelin-B receptor) gene (13q22) occur in patients.  The aganglionic megacolon feature may be dose sensitive since homozygotes have been reported to have a 74% chance of developing Hirschsprung disease while only 21% of heterozygotes do so.

Types 4A (277580) and 4B (613265) are both caused by mutations in the EDNRB gene, and type 4C (613266) results from a mutation in the SOX10 gene.  Waardenburg syndrome WS2E is allelic to type 4C.  This is an example of genetic heterogeneity both within the main types and within the subtypes.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No ocular treatment is necessary but assistive hearing devices can be beneficial.

References
Article Title: 

Waardenburg syndrome

Read AP, Newton VE. Waardenburg syndrome. J Med Genet. 1997 Aug;34(8):656-65. Review.

PubMed ID: 
9279758

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