ptosis

Intellectual Disability with Dysmorphic Facies and Ptosis

Clinical Characteristics
Ocular Features: 

The eyes appear widely spaced and the lid fissures slant downward.  Ptosis and blepharophimosis are present.  Strabismus is an uncommon feature.

Systemic Features: 

The characteristic facial profile (round, flat) is evident at birth. Microcephaly has been seen in some children.  Low birthweight is common.  Most infants feed poorly with general growth delay and short stature becoming evident in childhood.  Hypotonia and joint hypermobility are constant features.  Gross and fine motor movements appear uncoordinated.  Expressive language is delayed and impaired.  Intellectual disability is mild and achievement of developmental milestones may be delayed.  Seizures are seen in about half of affected individuals.  Brain MRIs may reveal mild white matter anomalies.  Spinal fusion among cervical vertebrae is common.

Individuals may live to adulthood.

Genetics

Heterozygous mutations in the BRPF1 gene (3p25) are responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Mattioli F, Schaefer E, Magee A, Mark P, Mancini GM, Dieterich K, Von Allmen G, Alders M, Coutton C, van Slegtenhorst M, Vieville G, Engelen M, Cobben JM, Juusola J, Pujol A, Mandel JL, Piton A. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis. Am J Hum Genet. 2017 Jan 5;100(1):105-116.

PubMed ID: 
27939639

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Yan K, Rousseau J, Littlejohn RO, Kiss C, Lehman A, Rosenfeld JA, Stumpel CT, Stegmann AP, Robak L, Scaglia F, Nguyen TT, Fu H, Ajeawung NF, Camurri MV, Li L, Gardham A, Panis B, Almannai M, Sacoto MJ, Baskin B, Ruivenkamp C, Xia F, Bi W; DDD Study.; CAUSES Study., Cho MT, Potjer TP, Santen GW, Parker MJ, Canham N, McKinnon M, Potocki L, MacKenzie JJ, Roeder ER, Campeau PM, Yang XJ. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. Am J Hum Genet. 2017 Jan 5;100(1):91-104.

PubMed ID: 
27939640

Mitochondrial DNA Depletion Syndrome 1

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia has an adult onset, usually in the late second or early third decade of life.  Ptosis is commonly present as well.

Systemic Features: 

This condition has been called a mitochondrial neurogastrointestinal encephalopathy (MNGIE).  Gastrointestinal problems are among the most disabling with poor absorption of foodstuffs leading to weight loss, marked cachexia, and chronic malnutrition.  Added to this are gastroparesis, constipation, vomiting, and intermittent diarrhea with abdominal pain.  Many individuals develop diverticulosis and diverticulitis that may lead to intestinal perforations.  The combined intestinal dysfunctions can lead to signs of intestinal pseudoobstruction.

Many patients have a progressive sensorineural hearing loss.  Leukoencephalopathy, sensorimotor peripheral neuropathy, and sometimes mild proximal limb weakness may be present.

Genetics

Homozygous and compound heterozygous mutations in the TYMP gene (22q13.33) are responsible for this autosomal recessive disorder.  This nuclear gene is active in the maintainence of mitochondrial DNA.  When the gene is dysfunctional, the mitochondria can be depleted to a variable extent and they may contain multiple deletions and point mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment for the overall condition.  Nutritionists can provide important advice on diet to maintain good nutrition.  Regular monitoring by gastroenterologists is important.  Perforations of the bowels require prompt surgical repair.  

References
Article Title: 

Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations

Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, Connolly AM, Verloes A, Guimaraes J, Maillard I, Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL, Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I, Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol. 2000 Jun;47(6):792-800.

PubMed ID: 
10852545

Takenouchi-Kosaki Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype consists of mild ptosis, synophrys, exotropia, and eversion of the lower eyelids.  One of two reported patients was described as having bilateral retinal dysplasia and a falciform retinal detachment in one eye.  Visual acuity is significantly impaired.

Systemic Features: 

Affected individuals may be of normal birth weight but skeletal growth is subnormal and there is general developmental delay.  Congenial cardiac anomalies such as persistent ductus arteriosus may be present.  Lymphedema has been noted at one year of age and probably persists throughout life.  Protein-losing enteropathy secondary to intestinal lymphangiectasia was present in one individual.  The same patient had pericardial effusion, hydrothorax, and ascites.  Intellectual disability may be severe although there is no evidence of progression.  Neurosensory hearing loss has been described in one patient.

Thrombocytopenia is a consistent finding and has been described as early as one year of age.  Platelet numbers as low as 52,000/microL have been recorded and appear larger than normal. 

Genetics

Both unrelated female patients reported have heterozygous missense mutations in the CDC42 gene (1p36). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Cleft Palate, Psychomotor Retardation, and Distinctive Facial Features

Clinical Characteristics
Ocular Features: 

The facial dysmorphism is present at birth together with the cleft palate.  Downslanting lid fissures, widely spaced eyes, and ptosis may be present.  Eyebrows have been described as sparse in one patient.  Strabismus and ocular apraxia are present in some children. 

Systemic Features: 

Three patients have been reported, one of whom also had a second deletion in a gene implicated in the Kabuki syndrome.  This individual had hypertrichosis and synophyrys whereas the others had sparse eyebrow and temporal hair.  The teeth are malformed with some conically shaped and widely spaced.  The forehead is prominent and the fingers are tapered and brachydactylous with 5th finger clinodactyly.

There are significant delays in achieving developmental milestones.  Hypotonia has been described.  Speech and walking in particular may be delayed for several years.   Physical growth may be delayed as well.  A variety of brain anomalies have been seen in some but not all individuals.  Hypospadius and cryptorchidism have been described.  All children reported have palatal anomalies.

Genetics

Heterozygous mutations in the KDM1A gene have been identified in two patients.  In another report a single patient had an out-of-frame 3-nucleotide deletion in the ANKRD11 gene (as sometimes found in Kabuki syndrome) plus a mutation in the KDM1A gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, Rauch A, Saenz MS, Boltshauser E, Patterson KE, Nickerson DA, Bamshad MJ. Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet Med. 2015 Dec 10. doi: 10.1038/gim.2015.161. [Epub ahead of print].

PubMed ID: 
26656649

Basel-Vanagaite-Smirin-Yosef Syndrome

Clinical Characteristics
Ocular Features: 

The eyes appear abnormally far apart.  Ptosis, microcornea, congenital cataracts, sparse eyebrows, and strabismus are usually present.  Epicanthal folds are often seen.

Systemic Features: 

Psychomotor development is severely delayed and with delay or absence of milestones.  DTRs are often hyperactive but some infants are described as hypotonic.  Some individuals have seizures.  There may be a nevus flammeus simplex lesion on the forehead and body hair is sparse.  Cleft palate, cardiac septal defects, hypospadius, thin corpus callosum and cerebral ventricular dilation have been observed.  The upper lip may have a tented morphology with everted lower lip vermilion. A short philtrum is common. 

Genetics

A homozygous missense mutation in the MED25 gene (19q13.33) has been reported and the transmission pattern is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No known treatment has been reported.

References
Article Title: 

Homozygous MED25 mutation implicated in eye-intellectual disability syndrome

Basel-Vanagaite L, Smirin-Yosef P, Essakow JL, Tzur S, Lagovsky I, Maya I, Pasmanik-Chor M, Yeheskel A, Konen O, Orenstein N, Weisz Hubshman M, Drasinover V, Magal N, Peretz Amit G, Zalzstein Y, Zeharia A, Shohat M, Straussberg R, Monte D, Salmon-Divon M, Behar DM. Homozygous MED25 mutation implicated in eye-intellectual disability syndrome. Hum Genet. 2015 Jun;134(6):577-87.

PubMed ID: 
25792360

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: 

Cataracts, Congenital, Deafness, Short Stature, Developmental Delay

Clinical Characteristics
Ocular Features: 

The facial features superficially resemble those often seen in Down syndrome patients with slanting (up or down) lid fissures and epicanthal folds. The amount of ptosis is variable.  Lens opacities are usually congenital in origin.  Hypopigmentation of the macula has been noted in two individuals.

Systemic Features: 

The characteristic facies may be evident at birth and requires karyotyping to rule out the trisomy of Down syndrome. Brachycephaly and a flat face may be present.  The mouth is often small and the nasal tip is shortened while the philtrum is long and smooth.  Some degree of intellectual disability and neurosensory hearing loss soon become evident.  There is postnatal growth delay and most individuals are short in stature.  The ears are low-set and rotated posteriorly.

The skeletal anomalies are not fully delineated but one patient had bilateral radioulnar synostosis while hip chondrolysis requiring hip replacement has been seen in two adult individuals.  Limited motion may be present in some joints, both large and small.  Seizures have been reported in a few individuals. Nails may appear dystrophic and there are variable tooth anomalies present. 

Genetics

The responsible heterozygous mutations are in the MAF gene (16q22-q23).  Type 4 (CCA4) (610202) autosomal dominant cerulean cataracts with multiple morphologies may also result from mutations in this transcription factor gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment for this condition is known.  Congenital cataracts can be removed.  Some patients may benefit from special education.   Seizure medications may be indicated and some patients can benefit from hearing aids.  Severe joint disease may require replacement.

References
Article Title: 

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies

Niceta M, Stellacci E, Gripp KW, Zampino G, Kousi M, Anselmi M, Traversa A, Ciolfi A, Stabley D, Bruselles A, Caputo V, Cecchetti S, Prudente S, Fiorenza MT, Boitani C, Philip N, Niyazov D, Leoni C, Nakane T, Keppler-Noreuil K, Braddock SR, Gillessen-Kaesbach G, Palleschi A, Campeau PM, Lee BH, Pouponnot C, Stella L, Bocchinfuso G, Katsanis N, Sol-Church K, Tartaglia M. Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies. Am J Hum Genet. 2015 May 7;96(5):816-25.

PubMed ID: 
25865493

Kabuki Syndrome 1

Clinical Characteristics
Ocular Features: 

The facial features and specifically the periocular anomalies are diagnostic and responsible for the eponymic designation (resembling the make-up of actors of a Japanese theatrical form known as Kabuki). The lid fissures are long and narrow and the lateral third of the lower lids are often everted.  The eyebrows are highly-arched and broad with some sparsity especially in the lateral portion.  The eyelashes are thick and ptosis is often noted. Strabismus may be present.  Blue sclerae have been reported.

Some patients may have extreme microphthalmia.

Systemic Features: 

Post-natal growth delay and short stature are present as a result of anomalies in the vertebrae often with secondary scoliosis.  Persistence of the fetal fingertip pads is common. Hypotonia and joint hypermobility have been noted and some degree of intellectual disability is common.  Seizures have been reported but these are not common. Cleft lip and palate are seen in about a third of patients and the palate is highly arched in about 75%.  The teeth are small, frequently malformed and widely spaced.  Feeding difficulties are common.  Anal anomalies such as imperforate anus, anovestibular fistulas, and an anteriorly placed opening may be present, especially in females.  A small penis, hypospadias, and cryptorchidism are common in males.

An ill-defined immune deficit seems to be a common feature as evident by susceptibility to infections, primarily otitis media in infants and later recurrent sinopulmonary infections.   The majority of patients have hypogammaglobulinemia with a variable pattern of antibody abnormalities resembling common variable immune deficiency and especially low levels of serum IgA.  

Hearing loss is seen in nearly half of patients, some of which is no doubt due to recurrent otitis media but CT radiography has demonstrated dysplastic morphology of inner ear structures and the petrous bone.  The ears are large and cupped and preauricular pits may be present as well.

Biliary atresia and a variety of morphological anomalies of the kidney have been reported.  Renal failure can occur.  Perhaps as many as 58% of patients have congenital heart defects, mostly septal in location. 

Genetics

Heterozygous mutations in KMT2D (12q13.12) (also called MLL2) are responsible for Kabuki syndrome 1 but parental transmission to offspring is rare and the majority of patients occur sporadically.  There is also an X-linked form (Kabuki 2) caused by mutations in KDM5A (Xp11.3).  Insufficient clinical data regarding the X-linked phenotype so far has precluded the ability to distinguish the two disorders without genotyping.

Residual genetic heterogeneity remains, however, as a substantial proportion of patients do not have mutations in the two mutant genes known.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this condition.  Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

MLL2 and KDM6A mutations in patients with Kabuki syndrome

Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A. 2013 Sep;161A(9):2234-43. 

PubMed ID: 
23913813

Kaufman Oculocerebrofacial Syndrome

Clinical Characteristics
Ocular Features: 

Alterations in the morphology of periocular structures is the most consistent ocular feature.  These include epicanthal folds, upward-slanting lid fissures, ptosis, blepharophimosis, sparse eyebrows, and telecanthus.  However, pale optic discs, iris colobomas, microcornea, strabismus, nystagmus, and hypertelorism are variably present. 

Systemic Features: 

There is both intrauterine and postnatal growth retardation.  Hypotonia is often noted along with general psychomotor delays.  Neonatal respiratory distress and laryngeal stridor may be present.  The intellectual disability can be severe.  Corpus callosum aplasia and hypoplasia have been reported.  Microcephaly and brachycephaly with delayed suture closure are features.  The face is long and narrow and the mouth is disproportionally large.  A high arched palate can be present and the pinnae are often deformed, posteriorly rotated and may be accompanied by preauricular skin tags. The teeth appear widely spaced (diastema) and the lower jaw is underdeveloped.

Genetics

Kaufman BPIDS syndrome results from homozygous or compound heterozygous mutations in the UBE3B gene (12q23).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment is available although repair of some specific malformations is possible.

References
Article Title: 

Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome

Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miro X, White JK, Desir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmuller J, Nurnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nurnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet. 2012 Dec 7;91(6):998-1010.

PubMed ID: 
23200864

An oculocerebrofacial syndrome

Kaufman RL, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Artic Ser. 1971 Feb;7(1):135-8.

PubMed ID: 
5006210

Beare-Stevenson Syndrome

Clinical Characteristics
Ocular Features: 

The midface hypoplasia and shallow orbits result in the appearance of prominent eyes.  Ptosis and hypertelorism have been reported while the palpebral fissures are downslanting. One patient has been reported to have optic atrophy.  Another patient was described with cloudy corneas, irregular irides and nonreactive pupils.

Systemic Features: 

Pregnancies may be complicated by polyhydramnios.  Infants are born with craniosynostosis with a cloverleaf pattern usually.  The skull is often shortened in the anteroposterior axis with flattening of the occipital region.  The skin is deeply furrowed with the cutis gyrata patterns most prominent in the posterior scalp but also present on the palms, soles, pinnae, and elsewhere.  Acanthosis nigricans is often present.

There is midface hypoplasia and nearly all individuals have intellectual disability.

The external ear canals can be atretic, the nares are often anteverted, and the mouth may be small.  An excess number of neonatal teeth and hypoplastic nails have been noted.  Hydrocephalus is common.  The umbilical stump is often unusually prominent.  Anogenital anomalies such as an anteriorly placed anus, cryptorchidism, and bifid scrotum may be present.  Pyloric stenosis is sometimes present.

Upper airway obstruction with respiratory distress may necessitate a tracheotomy. A cartilaginous tracheal sleeve replacing the normal C rings of cartilage has been found in several infants. These can be difficult to detect and their presence may have been responsible for breathing restrictions that has led to the demise of some children before two years of age.

Genetics

Reported cases have occurred sporadically.  Increased paternal age has been suggested as a factor in the occurrence of heterozygous mutations in the FGFR2 gene (10q26.13) which have been identified in some individuals.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Crouzon Syndrome (123500), Pfeiffer Syndrome (101600), Apert Syndrome (101200), Jackson-Weiss Syndrome (123150), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this syndrome.  Several infants have had tracheotomies and CNS shunts.

References
Article Title: 

Beare-Stevenson cutis gyrata syndrome

Hall BD, Cadle RG, Golabi M, Morris CA, Cohen MM Jr. Beare-Stevenson cutis gyrata syndrome. Am J Med Genet. 1992 Sep 1;44(1):82-9. PubMed PMID: 1519658.

PubMed ID: 
1519658

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