low-set ears

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

Heart and Brain Malformation Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia is the cardinal ocular malformation.  Hypertelorism has been described.  Poor vision without further description has also been reported.   

Systemic Features: 

The ears are low-set, malformed, and posteriorly rotated.  The forehead is prominent and there is usually a wide anterior fontanel.  The nasal bridge is wide and frequently depressed while the lower lip is full and may be everted and split.  The palate is highly arched.  Physical growth is slow.  A ventricular septal defect is often present while the valves are hypoplastic and the aortic arch can be interrupted.

Microcephaly is often present and there may a profound delay in psychomotor development with truncal hypotonia and hyperreflexia in the limbs.   Brain imaging shows generalized atrophy with decreased myelination.  Cerebellar vermis hypoplasia has been reported.  Two of 5 patients were reported to have Dandy-Walker malformations, and a thin corpus callosum.  Seizures may occur.

Genetics

Homozygous mutations in the SMG9 gene (19q13.31) are responsible for this condition so far reported in 5 individuals in two unrelated consanguineous Arab families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice

Shaheen R, Anazi S, Ben-Omran T, Seidahmed MZ, Caddle LB, Palmer K, Ali R, Alshidi T, Hagos S, Goodwin L, Hashem M, Wakil SM, Abouelhoda M, Colak D, Murray SA, Alkuraya FS. Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice. Am J Hum Genet. 2016 Apr 7;98(4):643-52.

PubMed ID: 
27018474

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 1

Clinical Characteristics
Ocular Features: 

Nystagmus, strabismus and sometimes optic atrophy have been noted.  Poor fixation may be present.   

Systemic Features: 

This progressive disorder can be evident at birth based on the facial dysmorphism.  The face is triangular, the forehead is prominent, the nose is small, the ears appear large and low-set.  The mouth appears wide with a thin upper lip.  Early development may be near normal for the first 6 months but thereafter psychomotor regression and slow physical growth are evident.  Patients have microcephaly and seldom achieve normal milestones.  Spasticity in the extremities and truncal hypotonia with distal muscle atrophy are evident.  The face appears triangular, the forehead is prominent, the nose is small, and the ears appear large and low-set.  Pectus carinatum and pes varus may be present.   Males often have cryptorchidism.

Brain imaging has revealed cerebellar atrophy and "while matter abnormalities".  Sural nerve biopsies show evidence of infantile neuroaxonal dystrophy.

Some individuals are less severely affected, retain the ability to speak, and are able to walk at least into the second decade of life.

Genetics

Based on transmission patterns this condition is inherited as an autosomal recessive disorder caused by mutations in in the NALCN gene (13q32.3-q33.1.

For somewhat similar disorders caused by mutations in other genes see IHPRF2 (616801) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

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: 

Developmental Delay with Short Stature, Dysmorphic Features, and Sparse Hair

Clinical Characteristics
Ocular Features: 

Patients may have downward-slanting lid fissures, hypertelorism, epicanthal folds, and sparse eyebrows and eyelashes.

Systemic Features: 

Patients have scaphocephaly with or without craniosynostosis and facial dysmorphism with a depressed nasal bridge and micrognathia.  Short stature, sparse hair, and developmental delay are characteristic.  Hypoplastic toenails and dental anomalies are present.  Brain imaging may show Dandy-Walker malformations and cerebellar vermis hypoplasia.  The kidneys may have focal interstitial nephritis and there may be intermittent hematuria and proteinuria in the presence of otherwise normal renal function.  Cardiac septal defects have been noted.

Genetics

Homozygous mutations in the DPH1 gene (17p13.3) are responsible for this disorder.  Two families have been reported with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Matching two cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies

Loucks CM, Parboosingh JS, Shaheen R, Bernier FP, McLeod DR, Seidahmed MZ, Puffenberger EG, Ober C, Hegele RA, Boycott KM, Alkuraya FS, Innes AM. Matching two independent cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. Hum Mutat. 2015 Oct;36(10):1015-9.

PubMed ID: 
26220823

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families

Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA, Faqeih E, Alhashem A, Bashiri FA, Al-Owain M, Kentab AY, Sogaty S, Al Tala S, Temsah MH, Tulbah M, Aljelaify RF, Alshahwan SA, Seidahmed MZ, Alhadid AA, Aldhalaan H, AlQallaf F, Kurdi W, Alfadhel M, Babay Z, Alsogheer M, Kaya N, Al-Hassnan ZN, Abdel-Salam GM, Al-Sannaa N, Al Mutairi F, El Khashab HY, Bohlega S, Jia X, Nguyen HC, Hammami R, Adly N, Mohamed JY, Abdulwahab F, Ibrahim N, Naim EA, Al-Younes B, Meyer BF, Hashem M, Shaheen R, Xiong Y, Abouelhoda M, Aldeeri AA, Monies DM, Alkuraya FS. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 Jan 13;10(2):148-61.

PubMed ID: 
25558065

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

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

Spondyloocular Syndrome

Clinical Characteristics
Ocular Features: 

Cataracts have been noted in several patients in the first and second decades of life.  Nystagmus and ‘amblyopia’ have also been reported.  Several individuals have had retinal detachments.

Systemic Features: 

Only a small number of families have been reported.  Poor bone mineralization with frequent fractures in long bones and vertebral compression seem to be consistent features often noted in the first and second decades of life.  Moderate osteoporosis and advanced bone age with platyspondyly may be present.  The vertebral fractures lead to abnormal spinal curvature and may result in shortened stature. 

Some sensorineural hearing loss is sometimes detected in the first decade.  The ears have been described as low-set and posteriorly rotated.  A variety of cardiac defects have been reported including mitral valve prolapse, septal defects, and anomalies of the aortic valve. 

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in the XYLT2 gene located at 17q21.33. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pamidronate given intravenously seems to have little therapeutic value.  Hearing aids can be beneficial.  Lensectomy may be of benefit although no reports of cataract surgery have been reported.  Fractures need immediate attention.  Patient may become wheelchair-bound by the second decade.  Special education may be helpful for those with learning difficulties.

References
Article Title: 

Mandibulofacial Dysostosis with Alopecia

Clinical Characteristics
Ocular Features: 

The extensive dysplasia of the facial bones involves those of the orbital rims and zygomatic arches.  The orbital rims can be malformed and there is often a broad depression at the inferolateral region of the eyes.  Hypoplasia or even aplasia of the eyelids maybe present and some individuals have colobomas of the lower eyelids.  The lacrimal punctae may be temporally displaced.  The eyebrows and eyelashes are often sparse as part of the generalized alopecia.

Systemic Features: 

This is a disorder of craniofacial development resulting in extensive malformations of facial bones and skin.  Different rates of development among these structures leads to facial asymmetry in many patients. Maxillary, zygomatic arch, and mandibular bones are dysplastic resulting in micrognathia and a flat midface.   The temporomandibular joints are absent and the external ear canals are often incompletely formed.  Conductive hearing loss is common with hypoplastic ossicular chains while the pinnae are low-set, crumpled and abnormally cupped.  There may be preauricular tags or pits present.  Tooth eruption is often delayed and there may be agenesis of many permanent teeth.  The maxillary sinuses may be absent.  Cleft palate is often present.

Genetics

Heterozygous mutations in the EDNRA gene (4q31) are responsible for this condition.  No familial cases have been reported and it can be assumed that the mutations arise de novo. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual anomalies such as the colobomas, dental deformities and cleft palate may be surgically repaired.  Upper airway obstruction may require tracheostomy in infants.

References
Article Title: 

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia

Gordon CT, Weaver KN, Zechi-Ceide RM, Madsen EC, Tavares AL, Oufadem M, Kurihara Y, Adameyko I, Picard A, Breton S, Pierrot S, Biosse-Duplan M, Voisin N, Masson C, Bole-Feysot C, Nitschke P, Delrue MA, Lacombe D, Guion-Almeida ML, Moura PP, Garib DG, Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ, Kurihara H, Saal HM, Weaver DD, Katsanis N, Lyonnet S, Golzio C, Clouthier DE, Amiel J. Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am J Hum Genet. 2015 Apr 2;96(4):519-31.

PubMed ID: 
25772936

Anterior Segment, Brain, and Facial Anomalies

Clinical Characteristics
Ocular Features: 

The interpupillary distance appears abnormally wide.  VEP and ERG responses suggest abnormal retinal bipolar cells.  Specular microscopy reveals variable sizes and shapes of corneal endothelial cells with scattered vesicles and large 'holes' in the usual hexagonal array.  The iris may be malformed (no collarette, stromal hypoplasia) and there may be peripheral iridocorneal adhesions.  Elevated IOP, band keratopathy, corneal clouding, and keratoconus have been reported.  Visual acuity is impaired to some extent, from near normal (20/25) to NLP.  Progressive optic atrophy was observed in one patient.

Systemic Features: 

Four members of a 3 generation family had malformed pinnae (posterior placement and rotation).  Other features variably present were an empty sella turcica, posterior fossa cyst, and hydrocephalus. The propositus also was found to have abnormal auditory bipolar cells based on the audiogram and audio-evoked brainstem responses.

Genetics

Based on direct sequencing in one family (3 adults and 1 child), this condition seems to be caused by heterozygous variations or mutations in the VSX1 gene (20p11.21). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Monitoring for glaucoma and appropriate treatment are indicated.  Hearing tests should be performed early.  The usual treatments for keratoconus should be considered.  Excess brain fluid may need surgical drainage.

.

References
Article Title: 

Pages

Subscribe to RSS - low-set ears