short stature

SHORT Syndrome

Clinical Characteristics
Ocular Features: 

Deeply set eyes are frequently noted and perhaps are a result of the lipodystrophy.  Anterior segment abnormalities resembling Rieger anomalies are often associated with congenital glaucoma. 

Systemic Features: 

There is considerable clinical heterogeneity.  The facial gestalt, however, is said to be characteristic.  These are: triangular progeroid facies with a prominent forehead, absence of facial fat, midface hypoplasia, and hypoplastic nasal alae.  Insulin resistance seems to be a consistent feature as well and nephrocalcinosis is common.  Serum and urinary calcium may be elevated even in infancy.

Teeth are late to erupt and bone age is delayed with shortness of stature the final result in many cases.  Joints are often hyperextensible.  A neurosensory hear loss has been found in some individuals.  Notably, developmental milestones are usually timely although mild cognitive delays are rarely seen and speech may be delayed.  Inguinal hernias are part of the syndrome. 

Genetics

Heterozygous mutations in the PIK3R1 gene (5q31.1) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serum and urinary calcium should be monitored.  The risk of glaucoma is high and patients should be monitored and treated appropriately.  Blood sugar and insulin levels may require treatment.  Inguinal hernias may require surgical repair.

References
Article Title: 

Mutations in PIK3R1 cause SHORT syndrome

Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL; FORGE Canada Consortium., Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. 

PubMed ID: 
23810382

Muscular Dystrophy, Congenital, with Cataracts and Intellectual Disability

Clinical Characteristics
Ocular Features: 

Cataracts have been diagnosed by 6 months of age and may be congenital in origin. Several patients have had strabismus.

Systemic Features: 

Progressive muscle weakness begins in early childhood.  Hypotonia is usually present at birth followed by atrophy of the proximal muscles (especially in the lower limbs).  Muscle weakness progresses for several years and may stabilize but not before severe gait difficulties occur.  Most adult patients are confined to a wheelchair.  No cardiac involvement occurs although respiratory weakness is often present.  Serum creatine kinase is usually elevated and biopsied muscle fibers show dystrophic changes and increased variability in fiber size with vacuolization.

Other signs in some individuals are contractures, scoliosis, seizures, short stature, cognitive deficits (usually mild), and spinal rigidity.  Paradoxically, some patients have limb spasticity and hyperreflexia with pyramidal signs.  No cerebellar signs are present.

Genetics

This condition results from homozygous or compound heterozygous mutations in the INPP5K gene (17p13).  

See Marinesco-Sjogren Syndrome for a disorder with a somewhat similar clinical presentation plus cerebellar signs.  It is caused by a different mutation, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts have been surgically removed in several patients by the age of two years.  Physical therapy may be beneficial.  Selected individuals could benefit from release of contractures.

References
Article Title: 

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment

Wiessner M, Roos A, Munn CJ, Viswanathan R, Whyte T, Cox D, Schoser B, Sewry C, Roper H, Phadke R, Marini Bettolo C, Barresi R, Charlton R, Bonnemann CG, Abath Neto O, Reed UC, Zanoteli E, Araujo Martins Moreno C, Ertl-Wagner B, Stucka R, De Goede C, Borges da Silva T, Hathazi D, Dell'Aica M, Zahedi RP, Thiele S, Muller J, Kingston H, Muller S, Curtis E, Walter MC, Strom TM, Straub V, Bushby K, Muntoni F, Swan LE, Lochmuller H, Senderek J. Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am J Hum Genet. 2017 Mar 2;100(3):523-536.

PubMed ID: 
28190456

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Osborn DP, Pond HL, Mazaheri N, Dejardin J, Munn CJ, Mushref K, Cauley ES, Moroni I, Pasanisi MB, Sellars EA, Hill RS, Partlow JN, Willaert RK, Bharj J, Malamiri RA, Galehdari H, Shariati G, Maroofian R, Mora M, Swan LE, Voit T, Conti FJ, Jamshidi Y, Manzini MC. Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjogren Syndrome and Dystroglycanopathy. Am J Hum Genet. 2017 Mar 2;100(3):537-545.

PubMed ID: 
28190459

Cataracts, Congenital, With Short Stature and Minor Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Early-onset cataracts are the main ocular feature of this syndrome.  A nonconsanguineous Korean family with 4 affected individuals has been reported.  Cataracts were diagnosed at various ages, including one adult, one juvenile, and one infant.  All had horizontal nystagmus and reduced vision even after surgical removal of the lenses.  

Systemic Features: 

Macrocephaly and short stature are consistent features.  Brachydactyly of the fingers is usually present.  The feet are described as "flat" and contain accessory navicular bones.

Genetics

A 3 generation Korean family with 4 affected members has been reported.  Three living members and a deceased grandfather had cataracts in an autosomal dominant pattern.  A mutation in the BRD4 gene (19p12.12) mutation segregated with the cataract phenotype.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical removal of the cataractous lenses may be helpful in selected individuals but amblyopia is likely present as postoperative vision may remain below normal.

References
Article Title: 

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

Optic Atrophy 11

Clinical Characteristics
Ocular Features: 

Optic atrophy is seen as early as 5 years of age but may be congenital in origin as hypoplasia of the optic nerve was present in all patients.  Three of 4 affected children also were myopic.

Systemic Features: 

This is a form of mitochondriopathy with considerable clinical heterogeneity.  A single consanguineous family with 4 affected children of ages 5-16 years of age has been reported.

Common features include short stature, microcephaly (1 had macrocephaly), hearing impairment. Ataxia, dysmetria, and athetotic movements may be present.  Motor and mental development are delayed as is expressive speech.  Intellectual disability is present in all 4 patients.  Leukoencephalopathy was seen in all patients and one had brain atrophy.  Cerebellar hypoplasia was present in 2 of four patients.

Muscle mitochondria in one patient had morphologic changes.  Lactate levels and lactate/pyruvate ratios were elevated in the blood and CSF fluid of three patients.

Genetics

Homozygous mutations in the YME1L1 gene (10p12.1) were responsible for this condition in 4 offspring of a consanguineous Saudi Arabian family.   This is a nuclear encoded mitochondrial gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.Hom

References
Article Title: 

ZTTK Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are deep-set and the palpebral fissures slant downward.  Optic atrophy is often present.  The majority of individuals have poor visual responses which may also be attributed to central or cortical impairment.  Strabismus and nystagmus are frequently present.

Systemic Features: 

ZTTK syndrome is multisystem malformation and developmental disorder with a heterogeneous clinical presentation.  The facial features might suggest the diagnosis at birth but most of the signs are nonspecific including frontal bossing, underdevelopment of the midface, facial asymmetry, low-set ears, broad and/or depressed nasal bridge, and a short philtrum.  Poor feeding and hypotonia in the neonatal period are usually present and physical growth is subnormal resulting in short stature.

Brain imaging may show abnormal gyral patterns, ventriculomegaly, hypoplasia of the corpus callosum, cerebellar hypoplasia, arachnoid cysts, and loss of periventricular white matter.  About half of patients develop seizures and many have intellectual disabilities.  Spinal anomalies include hemivertebrae with scoliosis and/or kyphosis.  Other skeletal features include joint laxity in some patients and contractures in others.  Arachnodactyly, craniosynostosis, and rib anomalies have been reported.  There may be malformations in the GI, GU, and cardiac systems while immune and coagulation abnormalities have also been reported.

Genetics

Heterozygous mutations in the SON gene (21q22.11) have been identified in patients with this condition.  They may cause truncation of the gene product with haploinsufficiency or, in other patients, a frameshift in the reading.  The SON gene is a master RNA splicing regulator that impacts neurodevelopment.

Virtually all cases are the result of de novo mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.  Physical therapy and assistive devices may be helpful.

References
Article Title: 

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive

Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Kury S, Besnard T, Isidor B, Latypova X, Bezieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, Walkiewicz MA. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive. Am J Hum Genet. 2016 Sep 1;99(3):720-7.

PubMed ID: 
27545676

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Kim JH, Shinde DN, Reijnders MR, Hauser NS, Belmonte RL, Wilson GR, Bosch DG, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CT, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BB, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortum F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Behunova J, Rehder H, Gordon CT, Rio M, Romana S, Tang S, El-Khechen D, Cho MT, McWalter K, Douglas G, Baskin B, Begtrup A, Funari T, Schoch K, Stegmann AP, Stevens SJ, Zhang DE, Traver D, Yao X, MacArthur DG, Brunner HG, Mancini GM, Myers RM, Owen LB, Lim ST, Stachura DL, Vissers LE, Ahn EY. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711-9.

PubMed ID: 
27545680

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

Progeroid Short Stature with Pigmented Nevi

Clinical Characteristics
Ocular Features: 

The presence of cataract has been reported.   One patient with keratoconus, endothelial dystrophy, and chronic conjunctivitis required a corneal transplant for a perforated ulcer.  Another individual with endothelial dystrophy, keratoconus, dry eye syndrome, and conjunctivitis developed OCT evidence of progressive retinal thickening and folding of inner retinal layers.  Retinal electrodiagnostic tests were normal.   Few patients have had complete ocular examinations, however.

Systemic Features: 

Short stature beginning in utero is characteristic and general growth parameters are usually in the third percentile.  The appearance of premature aging is suggested by a pinched bird-like facies and lack of facial subcutaneous fat.  Striking cutaneous pigmented nevi are present and may increase in number throughout life.  Joint mobility is limited to about half of normal.  The voice is often characteristically high-pitched.  Hypodontia and irregular dentition are often seen.

There may be an immunodeficiency as reflected by susceptibility to recurrent infections due to subnormal numbers of B and T cells.  Cognitive abilities are subnormal and some decline in adulthood has been reported.  Some individuals have been considered mentally retarded.  Agitation, touch hypersensitivity, depression, panic attacks, and severe insomnia may be present.  Sensorineural hearing loss is common.  Males may have hypospadias while females experience premature puberty and premature menopause.

Genetics

Consanguinity among some parents suggests autosomal recessive inheritance but no locus or mutation have been identified.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatnent 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

Spondylometaphyseal Dysplasia, Axial

Clinical Characteristics
Ocular Features: 

Due to the small number of individuals reported, the ocular phenotype is variable and likely incompletely described.  Optic atrophy and pigmentary retinopathy are the most consistent findings.  The most completely studied individual had evidence of slight bilateral optic nerve atrophy on cerebral MRI imaging as well.  There may be extensive RPE atrophy but the fundus pigmentation is usually described as resembling retinitis pigmentosa.  The ERG in several patients during the second decade of life already shows severe dysfunction of the photoreceptors, with cones the most severely impacted.  In spite of this Goldmann visual fields have been reported to be normal.  The macula and OCT have been reported as normal.  Telecanthus, nystagmus, hypertelorism, proptosis, and photophobia have been reported.  Early onset and progressive visual impairment are characteristic.

Systemic Features: 

Only 5 patients with this condition have been reported most of whom were short in stature.  There may be frontal bossing and the chest is narrow and flattened.  Moderate platyspondyly has been described with enlarged but shortened ribs and an irregular iliac crest.  Rhizomelic shortening of the limbs is common.  The femoral metaphyses are abnormal with their necks shortened and enlarged.  The ribs are enlarged but shortened as well and are flared at the ends.  Mental development and function are normal.

Genetics

This is an autosomal recessive condition due to homozygous or compound heterozygous mutations in C21orf2.

Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

Wang Z, Iida A, Miyake N, Nishiguchi KM, Fujita K, Nakazawa T, Alswaid A, Albalwi MA, Kim OH, Cho TJ, Lim GY, Isidor B, David A, Rustad CF, Merckoll E, Westvik J, Stattin EL, Grigelioniene G, Kou I, Nakajima M, Ohashi H, Smithson S, Matsumoto N, Nishimura G, Ikegawa S. Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. PLoS One. 2016 Mar 14;11(13).

PubMed ID: 
26974433

Axial spondylometaphysealdysplasia

Ehara S, Kim OH, Maisawa S, Takasago Y, Nishimura G. Axial spondylometaphysealdysplasia. Eur J Pediatr. 1997 Aug;156(8):627-30.

PubMed ID: 
9266195

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