short stature

Roberts Syndrome

Clinical Characteristics
Ocular Features: 

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features: 

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References
Article Title: 

Baraitser-Winter Syndrome 2

Clinical Characteristics
Ocular Features: 

Hypertelorism, high arched eyebrows, ptosis, and  colobomas occur in the majority of individuals.

Systemic Features: 

Short stature, postnatal microcephaly, lissencephaly, intellectual disability, seizures, and sensorineural hearing loss are common.

Genetics

This syndrome can be considered to be an autosomal dominant disorder secondary to heterozygous mutations in the ACTG1 gene (17q25.3).  However, all patients have been sporadic.

Mutations in ACTG1 are also responsible for autosomal dominant progressive nonsyndromic hearing loss.  

A similar but unique condition known as Baraitser-Winter syndrome 1 (243310) is caused by heterozygous mutations in the ACTB gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment but special education, hearing devices, and physical therapy may be helpful.

References
Article Title: 

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783

Baraitser-Winter Syndrome 1

Clinical Characteristics
Ocular Features: 

Ptosis (both unilateral and bilateral), hypertelorism, prominent epicanthal folds, and colobomata are common.  The iris stroma may be dysplastic and correctopia has been observed.  Visual acuity has not been measured.

Systemic Features: 

Postnatal growth retardation leads to short stature.  Microcephaly and morphological aberrations in the brain such as lissencephaly, agenesis of the corpus callosum and pachygyria are present.  Seizures and developmental delays are common.  Hearing loss is sensorineural in type.

The ears are low-set and the posterior hair line may be low as well.  The nasal bridge appears broad and the nose appears short. Male genitalia are often underdeveloped.  Bicuspid aortic valves, patent ductus arteriosus, and aortic stenosis have been reported.

Genetics

Heterozygous mutations in the ACTB gene (7p22.1) are responsible for this apparent autosomal dominant syndrome.  However, all patients have been sporadic.

This condition is clinically similar to Baraitser-Winter syndrome 2 (614583) which is a unique entity caused by a mutation in ACTG1. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available.

References
Article Title: 

New ocular finding in Baraitser-Winter syndrome

Rall N, Leon A, Gomez R, Daroca J, Lacassie Y. New ocular finding in Baraitser-Winter syndrome. Eur J Med Genet. 2017 Oct 9. pii: S1769-7212(17)30156-8. doi: 10.1016/j.ejmg.2017.10.006. [Epub ahead of print].

PubMed ID: 
29024830

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783

Retinitis Pigmentosa, RDH11 Syndrome

Clinical Characteristics
Ocular Features: 

Night vision problems and cataracts may be noted late in the first decade of life.  The fundus has changes typical of retinitis pigmentosa such as a salt-and-pepper retinopathy and narrowing of the arterioles with relative sparing of the fovea.  Confluent bone-spicule pigmentation is present in the periphery.  The optic nerve may have a pinkish waxy appearance.  Best-corrected visual acuity early is in the 20/25-20/30 range early in life with progressive deterioration.  Full field ERGs and visual fields are consistent with retinitis pigmentosa with the scotopic system more severely affected than the photopic.

Systemic Features: 

Developmental delays and cognitive deficits are apparent in early childhood.  Diastema and malocclusion may be present.  Short stature (5th percentile) is characteristic along with facial dysmorphology consisting of hypoplasia of the alae nasae, malar hypoplasia and slight up slanting of the palpebral fissures.

Genetics

A single family with three affected sibs (2 boys and one girl) has been reported.  The parents were phenotypically normal consistent with autosomal recessive inheritance.  Two variants in the RDH11 (14q24.1) gene were identified in the (compound heterozygous) siblings as responsible for a truncated, inactive enzyme.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment information is available.  Patients may benefit from special education, low vision aids, and physical therapy.Cataract surgery may be indicated.

References
Article Title: 

Microphthalmia, Syndromic 5

Clinical Characteristics
Ocular Features: 

One or both eyes may be small, sometimes resembling clinical anophthalmia. Other ocular anomalies such as coloboma, microcornea, cataracts, and hypoplasia or agenesis of the optic nerve have been reported.

A pigmentary retinopathy has been described.  The retinal vessels are often attenuated and sometimes sparse.  The optic nerves and chiasm are frequently absent or hypoplastic as seen on the MRI.  ERG and VEP responses are inconsistent but are generally abnormal indicating photoreceptor malfunction.  

Systemic Features: 

Patients have a variety of systemic abnormalities including pituitary dysfunction, joint laxity, hypotonia, agenesis of the corpus callosum, and seizures.  Hypothyroidism and deficiencies of growth hormone, gonadotropins, and cortisol are present in some patients.  Developmental delay and cognitive impairment are frequently present but mental functioning is normal in some patients.  The genitalia of males are often underdeveloped.  Patients are often short in stature.

Genetics

This is an autosomal dominant condition secondary to heterozygous mutations in the OTX2 gene (14q22.3).  A variety of point mutations as well as microdeletions involving the OTX2 gene have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the syndrome but surgical and/or endocrinological treatment may be used to correct individual features.  Special education and low vision aids may be helpful in selected patients.

References
Article Title: 

Heterozygous mutations of OTX2 cause severe ocular malformations

Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet. 2005 Jun;76(6):1008-22. Apr 21. Erratum in: Am J Hum Genet. 2005 Aug;77(2):334..

PubMed ID: 
15846561

Retinopathy with Neutropenia

Clinical Characteristics
Ocular Features: 

Pigmentary retinopathy was reported in a 25 year old female with moderately reduced visual acuity. Rare bone spicules pigment deposits were present in the periphery and macular edema was noted. Severely reduced scotopic and photopic responses were recorded.

Systemic Features: 

The single reported individual had congenital neutropenia and microcephaly. She had evident growth retardation and microcephaly at birth with subsequent recurrent upper respiratory infections and gingivitis. Speech and motor development were normal. Short stature was noted as well. The limbs were described as slender as in Cohen syndrome (216550) but no truncal obesity or joint hypermobility was present. The facial dysmorphism only vaguely resembled that found in Cohen syndrome (216550).

Genetics

This is a newly described condition whose unique identity remains to be established since only a single patient has been reported. This patient carried two heterozygous splicing mutations in the same VPS13B gene, the same gene in which more than 100 homozygous mutations have been found in individuals with Cohen syndrome (216550). Each parent carried a different splicing mutation in VPS13B.

Cohen syndrome (216550) however, has additional phenotypic features such as truncal obesity, intellectual disabilities, intermittent neutropenia, microcephaly, facial dysmorphism, myopia, and progressive chorioretinal dystrophy. Variable amounts of neutropenia were observed from age 5 years but the marrow was normocellular in appearance.

Isolated retinopathy with neutropenia may or may not be an autosomal recessive variant of Cohen syndrome (216550).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Orofaciodigital Syndrome, Type VI

Clinical Characteristics
Ocular Features: 

Hypertelorism and epicanthal folds have been described.  Some patients have nystagmus and strabismus. Ocular apraxia and difficulties in smooth visual pursuit may be present.   

Systemic Features: 

Polydactyly of the hands is a common feature.  The central metacarpal is often Y-shaped leading to ‘central polydactyly’.  The large toes may be bifid.  Cognitive deficits are common and some patients have been considered mentally retarded.  The ears are low-set and rotated posteriorly.  Some patients have a conductive hearing loss.  Oral anomalies may include a lobed tongue, lingual and sublingual hemartomas, micrognathia, clefting, and multiple buccoalveolar frenula.  Congenital heart anomalies, micropenis, and cryptorchidism have been reported.  Tachypnea and tachycardia have been noted.  Some patients have some degree of skeletal dysplasia and many individuals are short in stature.

The presence of cerebellar abnormalities such as hypoplasia (including absence) of the vermis may help to distinguish type VI from other forms of OFDS.  Hypothalamic dysfunction may be responsible for poor temperature regulation (hyperthermia). The ‘molar tooth sign’ seen on brain MRIs in Joubert syndrome (213300) is also present in OFDS VI. 

Genetics

This is a rare condition with limited family information.  Parents in one family were consanguineous, and multiple affected sibs in other families suggest this may be an autosomal recessive condition.  Homozygous mutations in TMEM216 have been found. Other patients have mutations in C5orf42.

Many of the clinical features in OFDS VI are also found among individuals with Joubert (213300) and Meckel (249000) syndromes that also sometimes have mutations in the TMEM216 and C5orf42 genes.  Some consider all of these conditions to be members of a group of overlapping disorders called ciliopathies or ciliary dyskinesias.   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this syndrome but individual signs and symptoms may need treatment.

References
Article Title: 

C5orf42 is the major gene responsible for OFD syndrome type VI

Lopez E, Thauvin-Robinet C, Reversade B, Khartoufi NE, Devisme L, Holder M, Ansart-Franquet H, Avila M, Lacombe D, Kleinfinger P, Kaori I, Takanashi JI, Le Merrer M, Martinovic J, No?'l C, Shboul M, Ho L, G?oven Y, Razavi F, Burglen L, Gigot N, Darmency-Stamboul V, Thevenon J, Aral B, Kayserili H, Huet F, Lyonnet S, Le Caignec C, Franco B, Rivi?(r)re JB, Faivre L, Atti?(c)-Bitach T. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet. 2013 Nov 1. [Epub ahead of print].

PubMed ID: 
24178751

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, Lev D, Sagie TL, Michelson M, Yaron Y, Krause A, Boltshauser E, Elkhartoufi N, Roume J, Shalev S, Munnich A, Saunier S, Inglehearn C, Saad A, Alkindy A, Thomas S, Vekemans M, Dallapiccola B, Katsanis N, Johnson CA, Atti?(c)-Bitach T, Gleeson JG. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet. 2010 Jul;42(7):619-25.

PubMed ID: 
20512146

Trichomegaly Plus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelashes are described as ‘long’, and the eyebrows are bushy.  The majority of individuals have poor vision secondary to severe receptor dysfunction.  Night blindness and severe photophobia are features in some cases.  Both retinal and choroidal atrophy have been diagnosed in the first 5 years of life and most patients have a progressive and extensive pigmentary retinopathy.

Systemic Features: 

Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes.  Frontal bossing has been noted in some patients.  Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.

Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded.  There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life.  The peripheral neuropathy includes both sensory and motor components.  Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period.  Several patients have had evidence of progressive cerebellar ataxia.

Genetics

Compund heterozygous mutations in PNPLA6 (19p13.2), coding for neuropathy target esterase, have been found in several patients presumed to have this condition.  Autosomal recessive inheritance has been proposed on the basis of a single family in which an affected brother and sister were born to first cousin parents.   

The relationship of this disorder to that found in two cousins, offspring of consanguineous matings, described as ‘cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition’ (204110 ) is unknown.  They were described as having visual impairment from birth and profound photophobia.  Fundus changes were minimal with a bull’s eye pattern of pigment changes in the macula described as indicative of a rod-cone congenital amaurosis.  ERG responses were unrecordable.  These individuals apparently did not have other somatic, psychomotor or neurologic deficits.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition although growth hormone and testosterone supplementation have been reported to have the appropriate selective effects.

References
Article Title: 

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Watson Syndrome

Clinical Characteristics
Ocular Features: 

Iris nodules similar to those seen in neurofibromatosis are found in some but not all patients with Watson syndrome.

Systemic Features: 

Short stature and low normal intelligence are the most consistent features.  Pulmonic stenosis and cafe-au-lait spots are also common.   The macrocephaly is relative and not striking.  Neurofibromas have been seen in a minority of patients.

Genetics

Mutations in the NF1(17q11.2) gene have been identified in members of several large pedigrees with an apparent autosomal dominant pattern.

It remains uncertain if this condition is allelic to neurofibromatosis I(162200) or if Watson syndrome is the result of mutations in contiguous genes.

The LEOPARD syndrome(151100) shares some clinical similarities such as short stature, pulmonic stenosis, cognitive deficits and cafe-au-lait spots but is caused by mutations in PTPN11.   The phenotype also resembles Noonan syndrome in some aspects.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for this condition but multidisciplinary management is recommended for isolated problems.

References
Article Title: 

Watson syndrome: is it a subtype of type 1 neurofibromatosis

Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991 Nov;28(11):752-6.

PubMed ID: 
1770531

LEOPARD Syndrome

Clinical Characteristics
Ocular Features: 

Ocular hypertelorism is a characteristic of all forms of the LEOPARD syndrome.  The lid fissures may be downward slanting.  Combined with the inverted triangle facies, the appearance is similar to that of the Noonan syndrome (163950).

Systemic Features: 

This is a multisystem disorder manifest in skin, heart, skeletal, genital, neurologic and auditory systems.  Generalized lentiginosis is characteristic but they may not be present until age 4 or 5 years following the appearance of cafe-au-lait spots.  Some patients have patchy scalp hair loss.  The facies bears some resemblance to the Noonan syndrome but usually without the short, webbed neck.  Sensorineural hearing loss is found in 20% of individuals.  Cardiac conduction defects, pulmonic stenosis, and hypertrophic cardiomyopathy are often (85%) present.  Cognitive defects are present in 30% of patients and some individuals have been described as mentally retarded.  Juvenile behavior may be evident in the presence of normal intelligence.  Hypospadias, cryptorchidism, and gonadal infantilism have been seen in some patients.  The ears are often malformed (87%).  Thoracic skeletal anomalies have been described in 75% of patients.  Although somatic growth is described as slow, short stature is present in less than half of patients.

Rare patients without lentigines are said to resemble the Noonan syndrome (163950) in appearance.

Genetics

Heterozygous mutations in the PTPN11 gene (12q24) are most frequently responsible for this autosomal dominant disorder.  The same gene is mutated in more than half of patients with the Noonan syndrome (NS1)(163950) with which it is allelic.  Other mutations that cause what is called LEOPARD syndrome are RAF1 and BRAF.

Other types of LEOPARD syndrome such as LEOPARD syndrome 2 (611554) are far more rare but also share mutations with Noonan syndrome (RAF1 mutations in Noonan syndrome 5) (611553) and LEOPARD syndrome 3 (613707) with mutations in BRAF similar to that seen in NS7 (613706).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Assistive hearing devices, especially cochlear implants, may be helpful.  Special education can be of value in more mildly affected individuals.Treatment of cryptorchidism is similar to that of other children.

References
Article Title: 

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