osteopenia

Coats Plus Syndrome

Clinical Characteristics
Ocular Features: 

Retinal telangiectasia and exudates (Coats disease) occur in association with intracranial cysts, calcifications and extraneurologic manifestations in this condition.  Coats disease lesions may also occur in Labrune syndrome (614561) and, of course, in isolation.

Whereas simple Coats disease almost exclusively occurs unilaterally and in males, both sexes and both eyes may have Coats retinal lesions in this syndrome.

Systemic Features: 

As a result of intracranial calcifications, leukodystrophy and brain cysts, patients have a variety of neurologic signs including spasticity, ataxia, dystonia, cognitive decline, and seizures.  Vascular ectasias may also occur throughout the body such as the intestines, stomach, and in the liver increasing the risk of GI bleeding and portal hypertension with anemia and thrombocytopenia.  Some individuals have sparse hair, abnormal pigmentation of the skin, and dysplastic nails as well. 

Some extraretinal features are also found in patients with dyskeratosis congenita (127550), and in Labrune syndrome (614561).

Genetics

This autosomal recessive pleotropic disorder results from compound heterozygous mutations in the CTC1 gene (17p13.1).  Several patients with mutations in STN1 have also been reported.

Most cases of simple Coats disease occur sporadically.  No associated locus or mutation has been found.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general condition has been reported.  Specific treatment for the retinal vascular and brain lesions might be of benefit.  Physical therapy and special education should be considered in selected patients.

References
Article Title: 

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016 Jul 25;213(8):1429-40

Simon AJ, Lev A, Zhang Y, Weiss B, Rylova A, Eyal E, Kol N, Barel O, Cesarkas K, Soudack M, Greenberg-Kushnir N, Rhodes M, Wiest DL, Schiby G, Barshack I, Katz S, Pras E, Poran H, Reznik-Wolf H, Ribakovsky E, Simon C, Hazou W, Sidi Y, Lahad A, Katzir H, Sagie S, Aqeilan HA, Glousker G, Amariglio N, Tzfati Y, Selig S, Rechavi G, Somech R. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016 Jul 25;213(8):1429-40.

PubMed ID: 
27432940

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafe L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenco CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, Crow YJ. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 2012 Jan 22;44(3):338-42.

PubMed ID: 
22267198

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

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

Iridogoniodysgenesis and Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Megalocornea, congenital glaucoma, a concave iris with stromal atrophy and corectopia, and deep anterior chambers are typical ocular features.  High myopia has been reported and retinal detachments have been observed.  Glaucoma control can be difficult to achieve and there is a significant risk of cataracts and phthisis bulbi following surgery.  Posterior embryotoxon has not been observed.

Systemic Features: 

Facial features seem to be consistent.  The forehead is wide, the nose appears broad with a large nasal tip and broad nares although the bridge appears narrow.  The philtrum is long and wide.  The ears may appear large and the neck is short.  The thorax is abnormally wide and the nipples are widely spaced and umbilicated.  The long bones are slender with thin cortices and wide metaphyses.  There is generalized osteopenia.  Vertebral bodies are cuboid-shaped with narrow vertebral canals and enlarged apophyses

Genetics

Two non-consanguineous families each with 3 sibs have been reported suggesting autosomal recessive inheritance.  Nothing is known about the mutation or its locus.

The ocular features may resemble Rieger or Axenfeld anomaly but these are inherited in autosomal dominant patterns and the skeletal features are dissimilar.       

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Vigorous treatment of glaucoma is indicated but successful control, even with surgery, is difficult to achieve.

References
Article Title: 

Glaucoma, Congenital Primary D

Clinical Characteristics
Ocular Features: 

Evidence of glaucoma can appear in early childhood but may appear much later.  However, typical signs such as enlarged corneas or frank buphthalmos, cloudiness of the corneas, tearing and photophobia are present only when the pressure is elevated due to pupillary block or when the lens migrates into the anterior chamber.  Most patients have additional signs such as ectopia lentis and spherophakia.

Systemic Features: 

Some patients have osteopenia, a high arched palate, and a marfanoid habitus.

Genetics

This form of congenital glaucoma has been described primarily in Middle Eastern and Asian as well as Roma/Gypsy families and is inherited in an autosomal recessive pattern.  The mutations occur in the LTBP2 gene (14q24) which is in close proximity to GLC3C, another putative gene with mutations causing congenital glaucoma. 

Mutations in other genes are also associated with primary congenital glaucoma such as in CYP1B1 causing type A (231300) and in GLC3B causing type B (600975).

THIS IS NOT A PRIMARY GLAUCOMA DISORDER.  Microspherophakia and ectopia lentis are not features of primary congenital glaucoma.  Elevated pressures in these patients are found only when there is a pupillary block or when the lens dislocates into the anterior chamber.  The enlarged cornea is clear and has no breaks in the Descemet membrane.  THIS CONDITION IS THEREFORE RECLASSIFIED AS "MEGALOCORNEA, ECTOPIA LENTIS, AND SPHEROPHAKIA".     

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The usual surgical and pharmacological treatments for glaucoma apply but vision preservation is a challenge.  The spherophakic or dislocated lenses may need to be removed.

References
Article Title: 

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Azmanov DN, Dimitrova S, Florez L, Cherninkova S, Draganov D, Morar B, Saat R, Juan M, Arostegui JI, Ganguly S, Soodyall H, Chakrabarti S, Padh H, L??pez-Nevot MA, Chernodrinska V, Anguelov B, Majumder P, Angelova L, Kaneva R, Mackey DA, Tournev I, Kalaydjieva L. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet. 2011 Mar;19(3):326-33.

PubMed ID: 
21081970

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Organoid Nevus Syndrome

Clinical Characteristics
Ocular Features: 

The sebaceous nevi often involve the eyelids, cornea, and conjunctiva.  Dermoids and lipodermoids are also seen.  Iris and choroidal colobomas are often present.  The sclerae may contain cartilage and bone which can be visible on CAT scans.  Depending upon the structures involved, patients may have strabismus, nystagmus, ptosis, exposure keratitis, and nerve palsies.

 

Systemic Features: 

Phakomatous lesions on the skin seem to preferentially occur on the upper part of the body including the face, neck and scalp but they may occur anywhere on the body including the oral cavity.  Initially they appear as papules but become verrucous around puberty.  Malignant transformation is seen in 15-20 per cent of patients.

Mental retardation and seizures are often seen in the first year of life.  Milestones achieved during that time are often lost subsequently.  Generalized weakness, osteopenia, and intracranial aneurysms are features in some patients.  Bone involvement may be highly asymmetrical.

Biopsies of conjunctival lesions show choristomas containing hyperplastic sebaceous and apocrine glands along with hair follicles.

Genetics

No clear genetic basis exists for this disease.  However, several families with multigenerational involvement have been reported in an autosomal dominant pattern.  It has been suggested that the disorder may result from a dominant lethal gene that allows some patients to survive by chance mosaicism.

Treatment
Treatment Options: 

No treatment is available for the generalized disease but therapy for specific symptoms such as epilepsy may be helpful.

References
Article Title: 

Ophthalmic features of the organoid nevus syndrome

Shields JA, Shields CL, Eagle RC Jr, Arevalo F, De Potter P. Ophthalmic features of the organoid nevus syndrome. Trans Am Ophthalmol Soc. 1996;94:65-86; discussion 86-7. Review.

PubMed ID: 
8981690

Gaucher Disease

Clinical Characteristics
Ocular Features: 

Gaucher disease is often divided into three clinical types, I, II, and III although all are caused by mutations in the same gene.  Type I, sometimes called nonneuronopathic type I, has ocular features including white deposits in anterior chamber structures such as the corneal endothelium, pupillary margin, and the angle, as well as in the ciliary body.  Pingueculae can be prominent.  The perimacular retina often appears grayish and also can show some white spots.  These may also be seen in the posterior vitreous in at least some patients with type III  There may be pigmentary changes in the macula and uveitis occurs rarely.  Macular atrophy has been reported and the retinal vasculature may be abnormally permeable. Corneal opacities have been seen in some patients.  Oculomotor apraxia and abnormal opticokinetic responses are common in types II and III.  Visual acuity may be in the range of 20/200.

Other conditions with ataxia and oculomotor apraxia are: ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600), ataxia-telangiectasia (208900) and Cogan-type oculomotor apraxia (257550) which lacks other neurologic signs.

Systemic Features: 

This is a severe systemic disease with perinatal lethality in some patients.  The range of clinical heterogeneity is wide, however, and minimally affected adult patients have also been described.  Individuals with nonneuropathic type I lack central nervous system involvement.  They often do have hepatosplenomegaly and pancytopenia with bone marrow involvement which are common to all types.  The latter may be responsible for frequent bone fractures and other orthopedic complications such as vertebral compression.  Thrombocytopenia with bleeding complications contributes to the primary anemia which is also present.  Interstitial lung disease can be seen in type I disease but occurs in less than 5% of patients. This is the most common of the three types. 

Patients with type I Gaucher disease have an increased risk of cancer, especially those of the hematological system.  For example, the risk for multiple myeloma has been estimated to be 37 times higher than in the general population.  There is also evidence of an increased incidence of multiple consecutive cancers in this condition.  Enzyme replacement therapy may reduce the risk of malignancies.

Patient with types II (acute neuronopathic [230900]) and III (subacute neuronopathic [231000]) are more likely to have neurologic disease with bulbar and pyramidal signs and sometimes seizures.  In type II, onset is in infancy and lifespan is about 2 years.   They have hepatosplenomegaly with growth arrest and developmental delays after a few months.  The clinical signs in type III or subacute neuronopathic type the onset is later (2.5 years to adulthood) than in type II and progression of neurologic disease is slower.  Early childhood development may appear normal for several years until abnormal extraocular movements or seizures are observed.  Type III is sometimes called Norrbottnian type.

Genetics

All three types of Gaucher disease are caused by mutations in the GBA (glucocerebrosidase) gene (1q21) and are inherited in an autosomal recessive pattern.

Evidence indicates that SCARB2, which codes for lysosomal integral membrane protein type 2 (LIMP-2), is a modifier of the phenotype in Gaucher disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Supportive care is required for all patients.  Splenectomy may be required for thrombocytopenia and blood transfusion can be helpful in severe anemia and excessive bleeding.  The course of disease is highly variable in all types, ranging from neonatal mortality to mild disease into adulthood, especially for individuals with type III.  Testing for deficiency in glucosylceramidase enzyme activity in leukocytes can be diagnostic.   Enzyme replacement or substrate reduction therapies can reduce the severity of clinical disease especially in type I disease but less so in types II and III.

References
Article Title: 

The clinical management of type 2 Gaucher disease

Weiss K, Gonzalez AN, Lopez G, Pedoeim L, Groden C, Sidransky E. The clinical management of type 2 Gaucher disease. Mol Genet Metab. 2014 Nov 14.  [Epub ahead of print] Review.

PubMed ID: 
25435509

A Mutation in SCARB2 is a Modifier in Gaucher Disease

Velayati A, Depaolo J, Gupta N, Choi JH, Moaven N, Westbroek W, Goker-Alpan O, Goldin E, Stubblefield BK, Kolodny E, Tayebi N, Sidransky E. A Mutation in SCARB2 is a Modifier in Gaucher Disease. Hum Mutat. 2011 Jul 27. doi: 10.1002/humu.21566. [Epub ahead of print]

PubMed ID: 
21796727
Subscribe to RSS - osteopenia