growth retardation

Al Kaissi Syndrome

Clinical Characteristics
Ocular Features: 

Reported facial dysmorphism features include periocular anomalies of ptosis, hypertelorism, down-slanting lid fissures, and epicanthal folds.  

Systemic Features: 

The phenotype is somewhat variable.  Intrauterine and postnatal growth retardation with hypotonia are common.   Moderate to severe intellectual disability is usually present and speech may be severely delayed.  The forehead is narrow, the nasal tip is broad, the nasal bridge is depressed, and the ears are low-set and posteriorly rotated.   Small hands and sometimes joint laxity are commonly present.  Cervical spine abnormalities including clefting, improper fusion, and segmentation anomalies are common.

Brain MRI may be normal but a small corpus callosum was present in some patients.

Genetics

Homozygous mutations in the CDK10 gene (16q24.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Windpassinger C, Piard J, Bonnard C, Alfadhel M, Lim S, Bisteau X, Blouin S, Ali NB, Ng AYJ, Lu H, Tohari S, Talib SZA, van Hul N, Caldez MJ, Van Maldergem L, Yigit G, Kayserili H, Youssef SA, Coppola V, de Bruin A, Tessarollo L, Choi H, Rupp V, Roetzer K, Roschger P, Klaushofer K, Altmuller J, Roy S, Venkatesh B, Ganger R, Grill F, Ben Chehida F, Wollnik B, Altunoglu U, Al Kaissi A, Reversade B, Kaldis P. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am J Hum Genet. 2017 Sep 7;101(3):391-403.

PubMed ID: 
28886341

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

Cataracts, Congenital, Intellectual Disability, Abnormal Striatum, and ADHD

Clinical Characteristics
Ocular Features: 

Cataracts (not further described) were described as congenital although the diagnosis was usually made early in the first decade of life.  One patient was diagnosed at the age of 8 years with glaucoma and a cloudy cornea of the left eye.  Another patient had cataract surgery.  Visual acuities have not been reported.

Systemic Features: 

Four members of a consanguineous Saudi family have been reported with growth and mental retardation, microcephaly, dystonia, and spasticity.  IQs in the range of 77-89 were reported.  Linguistic delay is common.  Dysarthria and decreased cognitive function are present.  MRIs revealed thinning of the lentiform nucleus and swelling of the caudate heads.  

Genetics

Homozygous mutations in the KCNA4 (11p14.1) (176266) gene are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general condition.  Cataract surgery may be considered.

References
Article Title: 

KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

Kaya N, Alsagob M, D'Adamo MC, Al-Bakheet A, Hasan S, Muccioli M, Almutairi FB, Almass R, Aldosary M, Monies D, Mustafa OM, Alyounes B, Kenana R, Al-Zahrani J, Naim E, Binhumaid FS, Qari A, Almutairi F, Meyer B, Plageman TF, Pessia M, Colak D, Al-Owain M. KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability. J Med Genet. 2016 Aug 31. pii: jmedgenet-2015-103637. doi: 10.1136/jmedgenet-2015-103637. [Epub ahead of print].

PubMed ID: 
27582084

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: 

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: 

Barber-Say Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features consist mainly of skin changes in the lids including hyperlaxity and redundancy.  There may be ectropion of the lower eyelids and sparsity of the eyebrows.  Some evidence of micro- or ablepharon is often present.  Hypertelorism and exophthalmia have been described.

Systemic Features: 

Multiple external congenital anomalies are present at birth including skin laxity, hypertrichosis (especially of the forehead, neck and back), and low-set and malformed pinnae.  Macrostomia and thin lips with redundant facial skin are often evident.  The nose appears bulbous.  The thoracic skin can be atrophic and the nipples may be hypoplastic.  Hypospadias has been reported.  A highly arched or cleft palate may be present and some individuals have a conductive hearing loss.  The teeth are small and eruption may be delayed.  Cognitive deficits may be present and mental retardation has been reported. 

Genetics

Based on genotyping and the limited number of reported pedigrees, inheritance most likely follows an autosomal dominant pattern.  Direct parent to child transmission has been reported.  Detailed examination of parents sometimes reveals mild features that are easily missed.  Mutations in the TWIST2 gene have been found in 10 unrelated individuals with Barber-Say syndrome.

TWIST2 mutations have also been found in Setleis syndrome (227260) and in ablepharon-macrostomia syndrome (200110).  These conditions have some clinical features in common with Barber-Say syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for this disorder but correction of selected anomalies such as ectropion and cleft palate may be indicated.

References
Article Title: 

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, Markello TC. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110.

PubMed ID: 
26119818

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

Perrault Syndrome

Clinical Characteristics
Ocular Features: 

Nystagmus and limited extraocular movements are usually present in PRLTS1.  Optic atrophy and poor visual acuity have been reported. Ptosis may be present.  The clinical manifestations are variable among and within the types.  Rod dysfunction and ‘retinal atrophy’ were reported in one patient.  The majority of patients have had only limited ocular evaluations.

Systemic Features: 

This is a sex-influenced condition in which both sexes have a sensorineural hearing deficit and neurodegenerative disease (both central and peripheral) but only the females have gonadal dysgenesis.  Motor development is often delayed and ataxia along with a peripheral sensory neuropathy and a variable degree of limb weakness can be present.  Learning difficulties, cognitive decline, and frank mental retardation are frequently described.  The cerebellum may be atrophic.

There is considerable variability in the clinical signs.

Genetics

The combination of hearing loss in males and females, ovarian dysgenesis in females, and variable neurologic signs including external ophthalmoplegia and sometimes optic atrophy is known as Perrault syndrome.  The ocular movement abnormalities are seen primarily in PRLTS1. 

At least 5 unique mutations have been found accounting for types PRLTS1-5.  PRLTS1 (233400) results from mutations in HSD17B4 (5q23.1), type PRLTS2 (614926) is caused by mutations in the HARS2 gene, PPRLTS3 (614129) by mutations in the CLPP gene, PRLTS4 (615300) by mutations in the LARS2 gene, and PRLTS5 (616138) by mutations in C10orf2 (listed in this database as External Ophthalmoplegia, C10orf2, and mtDNA mutations,.

The inheritance pattern among different types may be autosomal recessive or autosomal dominant.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Perrault syndrome: further evidence for genetic heterogeneity

Jenkinson EM, Clayton-Smith J, Mehta S, Bennett C, Reardon W, Green A, Pearce SH, De Michele G, Conway GS, Cilliers D, Moreton N, Davis JR, Trump D, Newman WG. Perrault syndrome: further evidence for genetic heterogeneity. J Neurol. 2012 May;259(5):974-6.

PubMed ID: 
22037954

Perrault syndrome in sisters

McCarthy DJ, Opitz JM. Perrault syndrome in sisters. Am J Med Genet. 1985 Nov;22(3):629-31.

PubMed ID: 
4061497

Chorioretinopathy with Microcephaly 2

Clinical Characteristics
Ocular Features: 

Microphthalmia and microcornea are seen in most individuals and one patient had unilateral clinical anophthalmia. Hyperopia and cataracts may be present. Nystagmus is common.  One patient had a corneal opacity.  The chorioretinopathy has not been described beyond evidence of the maculopathy, attenuated retinal vessels, and occasionally hyperpigmented zones.  The ERG is either not recordable or consistent with a severe rod-cone dystrophy.  Vitreous inclusions and a 'vitreoretinal dystrophy' with falciform retinal folds were noted in several patients.  A traction detachment was present in one and bilateral serous detachments were noted in another.

Systemic Features: 

Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays.  Profound intellectual disability is a consistent feature.  Physical growth is retarded and patients have shortness of stature.  Most patients are unable to sit, stand, or walk unassisted.  One patient died at 5.5 years of age while another was alive at 20 years of age.  Rare patients may have hearing loss and seizures.

Scoliosis, kyphosis, and lordosis may be seen while  other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.  

The forehead slopes markedly.  Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small.  Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.

Genetics

Homozygous mutations in the PLK4 gene (4q28.2) segregate with this condition.  Its product localizes to centrioles and plays a central role in centriole duplication.

For a somewhat similar condition but without the sloping forhead see Chorioretinoapathy with Microcephaly 1 (251270) but resulting from homozygous mutations in TUBGCP6.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is know.

References
Article Title: 

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Daire VC, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-92.

PubMed ID: 
25344692

Spinocerebellar Ataxia 18

Clinical Characteristics
Ocular Features: 

Ocular signs in SCAR18 include nystagmus, oculomotor apraxia, and optic atrophy.  The nystagmus may be rotatory or horizontal and can be gaze-evoked.  Some patients have intermittent and tonic upgaze.  Visual acuity has not been reported.

Systemic Features: 

Patients are developmentally delayed and have intellectual disability.  These features do not seem to be progressive.  Ataxia, both truncal and cerebellar, is present.  Mobility is impaired from early childhood and eventually requires assistance.   Joint contractures sometimes develop and patients can be wheelchair-bound by the second decade.  Dysarthric speech is common.  No dysmorphic facial features are present.

Brain imaging shows progressive cerebellar and sometimes cerebral atrophy.

Genetics

This autosomal recessive disorder results from homozygous deletions in the GRID2 gene (4q22).  This gene codes for a subunit of the glutamate receptor channel and is thought to be selectively expressed in the Purkinje cells of the cerebellum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.  However, physical therapy, assistive devices for mobility, and low vision aids may be helpful.

References
Article Title: 

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