short stature

Kabuki Syndrome 2

Clinical Characteristics
Ocular Features: 

The facial features are characteristic primarily because of the appearance of the periocular features.  The eyebrows are highly arched and sparse.  The lid fissures are long with eversion of the lateral portion of the lower eyelid.  The eyelashes are bushy.  Nystagmus and strabismus have been reported.

Systemic Features: 

Only a small number of individuals with Kabuki syndrome 2 have been reported and the phenotype is incompletely described.  Most of the features in type 2 are similar to those in type 1 with defects in multiple organs.  There are often cardiac malformations including septal defects.  Otitis media and hearing loss are common.  The pinnae are large and cupped.  A highly arched or cleft palate may be present and the teeth are usually small.  The joints are highly mobile and general hypotonia is often present. The fifth finger is often short and clinodactylous.  Persistent fetal fingerpads are common.  The amount of intellectual disability varies considerably with some patients functioning normally.  Urogenital anomalies are less common than found in Kabuki syndrome 1 and anal malformations do not seem to be a feature.

Genetics

Kabuki syndrome 2 is an X-linked disorder, usually as the result of a mutation in the KDM6A gene (Xp11.3).   Patients with the X-linked form of Kabuki represent about 5-10% of cases.   

Kabuki syndrome 1 (147920) is an autosomal dominant condition caused by heterozygous mutations in the KMT2D gene but remaining heterogeneity is suggested by the fact that a substantial proportion (30%) of individuals with Kabuki syndrome features has neither of these mutations.

In a 3 generation family two males had the typical Kabuki phenotype whereas their mother and grandmother (all had the KMT2D mutation) had various attenuated features.

Treatment
Treatment Options: 

Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients

Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, De Nittis P, Pellico MT, Mandriani B, Fischetto R, Boccone L, Silengo M, Biamino E, Perria C, Sotgiu S, Serra G, Lapi E, Neri M, Ferlini A, Cavaliere ML, Chiurazzi P, Monica MD, Scarano G, Faravelli F, Ferrari P, Mazzanti L, Pilotta A, Patricelli MG, Bedeschi MF, Benedicenti F, Prontera P, Toschi B, Salviati L, Melis D, Di Battista E, Vancini A, Garavelli L, Zelante L, Merla G. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014 Jul;35(7):841-50.

PubMed ID: 
24633898

Singleton-Merten Syndrome 1

Clinical Characteristics
Ocular Features: 

Several children have been diagnosed with glaucoma in early childhood or during puberty.  Glaucoma surgery has been beneficial in some but visual damage may be severe.

Systemic Features: 

Patients have early-onset calcifications of the aorta and of the aortic and mitral valves which may be seen in childhood and can be responsible for heart failure and early death.  Osteoporosis of the limbs and widened medullary cavities have been seen.  Abnormal bone mineralization and extends to the jaws leading to tooth loss and early-onset periodontal disease.  Eruption of both primary and permanent teeth is delayed but tooth roots can be truncated as well.  The hips dislocate easily due to shallow acetabulae and patients are susceptible to tendon tears.

Hypotonia and generalized weakness may be present which is sometimes exacerbated following a febrile illness.  The skin may be dry and scaly consistent with psoriasis and there may be photosensitivity.

The forehead is broad and prominent and the hairline is high and anterior.  The philtrum is smooth and the upper vermilion is thin.

Genetics

Heterozygous mutations in the IFIH1 gene (2q24.2) are responsible for this disorder.  Another form of Singleton-Merten Syndrome (SGMRT2; 609631) is the result of mutations in the DDX58 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific problems such as fractures, glaucoma, and periodontal disease.

References
Article Title: 

A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome

Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nurnberg P, Hohne W, Crow YJ, Feigenbaum A, Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):275-82.

PubMed ID: 
25620204

Cole-Carpenter Syndrome 2

Clinical Characteristics
Ocular Features: 

Postnatally the eyes are prominent and hypertelorism has been reported.  The palpebral fissures slant downward and the root of the nose is angular. 

Systemic Features: 

This is primarily a skeletal disorder with impaired skull ossification and multiple bone fractures of prenatal origin.  It is sometimes confused with forms of osteogenesis imperfecta.  The skull is poorly ossified and frequent diaphyseal fractures of the long bones occur leading to motor delays and short stature.  Rib fractures are sometimes seen. Intelligence seems to be normal.  A receding chin has been noted and the hard palate is highly vaulted.  The midface is flat.

Genetics

This disorder results from compound heterozygous mutations in the SEC24D gene (4q26).  Only a few patients have been reported.

For a somewhat similar but autosomal dominant disorder see Cole-Carpenter Syndrome 1 (112240).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical activity should be restricted to noncontact sports and where the cranium has ossification defects a helmet should be worn.  Fractures should be appropriately treated.

References
Article Title: 

Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

Garbes L, Kim K, Riess A, Hoyer-Kuhn H, Beleggia F, Bevot A, Kim MJ, Huh YH, Kweon HS, Savarirayan R, Amor D, Kakadia PM, Lindig T, Kagan KO, Becker J, Boyadjiev SA, Wollnik B, Semler O, Bohlander SK, Kim J, Netzer C. Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta. Am J Hum Genet. 2015 Mar 5;96(3):432-9.

PubMed ID: 
25683121

CODAS Syndrome

Clinical Characteristics
Ocular Features: 

Dense nuclear cataracts can be seen by six months of age.  Some patients have ptosis. The fundi have been described as normal at one month of age in a single infant but vision was described at the 20/200 level at 2 years of age.  Cataracts noted at 4 months had been removed.

Systemic Features: 

Patients have multiple severe systemic abnormalities.  There is generalized developmental delay along with mild microcephaly and hypotonia.   The forehead is often broad while the face appears flattened with anteverted nares, a flat nasal bridge, a short philtrum, low-set and crumpled ears.  Infants may have an inadequate upper respiratory apparatus with atrophic vocal cords and some die of laryngeal obstruction in the first days of life.  Sialorrhea and difficulty swallowing have been noted.  Mild to moderate neurosensory hearing loss is often present but there may also be a conduction component to this. 

Brain imaging has revealed large ventricles, with subcortical hypomyelination, a thin corpus callosum, and prominent cortical sulci.  The vertebrae may have coronal clefts and scoliosis often develops. Generalized metaphyseal dysplasia and delayed bone age are usually present.  The anus may be imperforate and a rectovaginal fistula and cryptorchidism have been reported.  Long bones may be malformed as well and most patients are short in stature. Delayed dentition, enamel dysplasia, and abnormal cusp morphology are often present.  Cardiac septal defects may be seen.

Genetics

Homozygous mutations in LONF1 (19p13.3) segregate with the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no general treatment available and infants sometimes die from laryngeal obstruction in the first days of life.   Individual anomalies may be surgically correctable in selected individuals.  Occasional infants are stillborn but one patient died an accidental death at 14 years of age. 

References
Article Title: 

CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease

Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, Mikita N, Thilagavathi J, Lee J, Sarafianos S, Benkert A, Koehler A, Zhu A, Trovillion V, McGlincy M, Morlet T, Deardorff M, Innes AM, Prasad C, Chudley AE, Lee IN, Suzuki CK. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet. 2015 Jan 8;96(1):121-35.

PubMed ID: 
25574826

Filippi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features have not been fully described.  The most consistent features are long eyelashes, thick (bushy) eyebrows, and 'visual disturbance'.  Most individuals have a facial dysmorphism which includes a broad nasal base suggestive of hypertelorism.  Optic atrophy and proptosis have been noted. 

Systemic Features: 

Intrauterine growth retardation is sometimes seen.  Microcephaly, short stature, syndactyly, intellectual disability (often labeled mental retardation), and a dysmorphic face are characteristic.  Some individuals have cryptorchidism, seizures, and ectodermal abnormalities including nail hypoplasia, hirsutism, and microdontia.  Mental and physical delays are common.  The syndactyly usually involves only soft tissue between toes 2, 3, and 4 and fingers 3 and 4 accompanied by clinodactyly of the 5th finger.  Polydactyly is sometimes present while radiologically the radial head may show evidence of hypoplasia. 

Genetics

Homozygosity or compound heterozygosity in the CKAP2L gene (2q13) segregates with this phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome

Hussain MS, Battaglia A, Szczepanski S, Kaygusuz E, Toliat MR, Sakakibara S, Altmuller J, Thiele H, Nurnberg G, Moosa S, Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nurnberg P. Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet. 2014 Nov 6;95(5):622-32.

PubMed ID: 
25439729

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

Osteogenesis Imperfecta, Type VII

Clinical Characteristics
Ocular Features: 

Shallow orbits sometimes lead to severe and even progressive proptosis.  Bluish sclerae are sometimes present.

Systemic Features: 

Infants may be born with multiple fractures and adults are often short in stature.  Hypoplasia of the midface, frontal bossing, sutural craniosynostosis, hydrocephalus, and shallow orbits are frequently present and contribute to what is sometimes considered a distinctive facial dysmorphism.  Dentinogenesis imperfecta and hearing loss are variable features.  Neurological development is normal.

Multiple fractures occur and may result in marked long bone deformities, scoliosis, and short stature.  When the ribs are involved, respiratory insufficiency may result and can be responsible for early death.  Type VII osteogenesis imperfecta is sometimes considered a lethal form of OI. 

Genetics

Homozygous mutations in the CRTAP gene (3p22.3) are responsible for this condition.  This gene codes for a cartilage-associated protein and in mice is highly expressed in chondrocytes at growth plates and around the chondroosseous junction.  

This condition has been confused with Cole-Carpenter 1 syndrome (112240) but the latter is due to heterozygous mutations in P4HB (17q25.3) (PDI gene family).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Fractures require stabilization and hydrocephalus, if present, needs to be treated promptly.  Extreme proptosis can lead to inadequate hydration of the eye (especially the cornea) that may require lid surgery or orbital reconstruction.

References
Article Title: 

CRTAP mutation in a patient with Cole-Carpenter syndrome

Balasubramanian M, Pollitt RC, Chandler KE, Mughal MZ, Parker MJ, Dalton A, Arundel P, Offiah AC, Bishop NJ. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A. 2015 Jan 21. doi: 10.1002/ajmg.a.36916. [Epub ahead of print].

PubMed ID: 
25604815

New case of Cole-Carpenter syndrome

Amor DJ, Savarirayan R, Schneider AS, Bankier A. New case of Cole-Carpenter syndrome. Am J Med Genet. 2000 Jun 5;92(4):273-7. Review.

PubMed ID: 
10842295

Retinal Dystrophy, Cataracts, and Short Stature

Clinical Characteristics
Ocular Features: 

Patients develop progressive night vision problems in the first decade of life.  However, central acuity remains in the 20/20 to 20/30 range at least through the second decade.  Cataracts are noted during this time period as well.  Visual field constriction is present.

Pigmentary retinopathy is present, especially in the posterior poles.  Macular mottling is evident at an early age with attenuation and narrowing of the retinal arterioles.  The pigmentary changes are salt-and-pepper in appearance but there are also areas of RPE atrophy with relative sparing of the fovea.  Pigment clumping in the shape of bone spicules has been observed in the periphery.  Full field ERGs show generalized rod-cone dysfunction with scotopic function more affected.  OCT examination reveals a disruption of the outer retinal layers from the parafoveal region into the periphery.

Systemic Features: 

Early childhood psychomotor delays are evident in early childhood by the lack of fine motor and coordination skills along with learning difficulties.  Patients have facial dysmorphism with hypoplasia of the ala nasae, upslanting palpebral fissures, and malar hypoplasia.  The teeth are widely spaced and there is malocclusion.  Short stature is characteristic (fifth percentile).

Genetics

This disorder results from homozygosity of mutations in the RDH11 gene (14q24) encoding retinol dehydrogenase 11.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition but patients may benefit from correction of the malocclusion, special education classes, cataract removal, and low vision aids.  Physical therapy may also be helpful.

References
Article Title: 

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

Cranial Dysinnervation Disorders with Strabismus and Arthrogryposis

Clinical Characteristics
Ocular Features: 

Strabismus and/or ophthalmoplegia are important features of a group of conditions known as cranial dysinnervation disorders.  Ptosis, Duane syndrome, V pattern exotropia and various degrees of ophthalmoplegia may be seen.  There may be considerable asymmetry in the manifestations in the two eyes.  Epicanthal folds, blepharophimosis, and hypermetropia are sometimes present.  Some patients have corneal leukomas, keratoglobus, high corneal astigmatism, and dysplastic optic disks. 

A pigmentary retinopathy and folds in the macula with an abnormal ERG has been reported.  Subnormal vision has been reported in some patients.

Systemic Features: 

Patients are often short in stature with pectus excavatum, spine stiffness, highly arched palate, and club feet.  Limited forearm rotation and wrist extension may be present.  The fingers appear long and often have contractures while the palmar and phalangeal creases may be absent.  Camptodactyly and clinodactyly are common.  Deep tendon reflexes are often hyporeactive and decreased muscle mass has been noted.  The muscles seem "firm" to palpation.  Restrictive lung disease has been reported.  Hearing loss is experienced by some individuals.

Genetics

Distal arthrogryposis type 5D is caused by homozygous or compound heterozygous mutations in the ECEL1 gene located at 2q36.  However, a similar phenotype (albeit with more severe ocular manifestations) results from heterozygous mutations in PIEZO2 (18p11).  Heterozygous mutations in the PIEZO2 gene have also been reported to cause distal arthrogryposis type 3 (Gordon syndrome [114300]) and Marden-Walker syndrome (248700) and all of these may be simply phenotypical variations of the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this condition.  Patients with subnormal vision may benefit from low vision aids and selective surgery may be helpful in reducing the physical restrictions from physical deformities.

References
Article Title: 

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44.

PubMed ID: 
24726473

Pages

Subscribe to RSS - short stature