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Microcephaly Chorioretinopathy Syndrome

Also referred to as:  MLCRD Syndrome

Synonyms:

Heredity: 

Diagnosis: 

Symptoms:

Complications:

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Pat O'Connor

June 8, 2008

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LYMPHEDEMA, MICROCEPHALY, CHORIORETINOPATHY SYNDROME
 
%152950 GeneTests, Links
LYMPHEDEMA, MICROCEPHALY, CHORIORETINOPATHY SYNDROME
Alternative titles; symbols MICROCEPHALY, LYMPHEDEMA, CHORIORETINAL DYSPLASIA SYNDROME
MLCRD SYNDROME
LYMPHEDEMA AND RETINAL FOLDS WITH MICROCEPHALY AND MICROPHTHALMOS

TEXT

In 5 members of 4 generations of a Chinese family, Leung (1985) described the combination of microcephaly and lymphedema. The lymphedema was present at birth or began soon after birth. Intelligence was normal. Male-to-male transmission was observed. Crowe and Dickerman (1986) described congenital lymphedema in association with microcephaly in a young boy and his maternal uncle. The mother, maternal grandmother and a sister of the grandmother had microcephaly. The pattern was consistent with X-linkage but may have been indicative of autosomal recessive inheritance with reduced expression in females; the proband's mother, grandmother, and great aunt were microcephalic. In an accompanying editorial, Opitz (1986) made many useful comments. Congenital lymphedema is frequent and represents delay in the maturation of the lymphatics and delay in clearing of the lymphedema regularly present in the fetus. 'Lymphedema nails,' i.e., white nails, especially in the toes, is a persisting sign. Coarseness of the hair follicles over the dorsum of the hands and feet and first phalanges where edema was present earlier is another sign. Unusual persistence of fetal lymphedema is usually associated with congenital hypotonia which clears faster than the lymphedema. Lymphedema in the hands causes thick volar tissues and later numerous white lines seen on palm prints and with a magnifying glass. Change in the pattern of hair may be seen in other areas of the body in addition to the nape of the neck, e.g., in the forearms. Leung (1987) emphasized the intellectual normality in these cases. 

Jarmas et al. (1981) described 2 brothers with severe microcephaly, microphthalmos, retinal folds, and visual deficit. Their mother was also microcephalic and showed mild mental retardation. Young et al. (1987) reported a retarded boy with microcephaly, microphthalmos, and retinal folds. His mother and sister showed microphthalmos and the sister was also microcephalic. Angle et al. (1994) pointed out that the patients of Jarmas et al. (1981) and Young et al. (1987) had lymphedema in addition to microcephaly and chorioretinal dysplasia. 

Feingold and Bartoshesky (1992) described 2 unrelated boys with microcephaly, lymphedema, and chorioretinal dysplasia. They concluded that their patients had the same entity as the patients reported by Leung (1985), who had an autosomal dominant disorder, and those reported by McKusick et al. (1966), who had an autosomal recessive disorder (see 251270). 

Angle et al. (1994) presented 2 unrelated boys with microcephaly, lymphedema, and chorioretinal dysplasia. Kozma et al. (1996) described a sister and brother from a nonconsanguineous Saudi family who, in addition to severe microcephaly (without mental retardation) and lymphedema, had attention deficit disorder. One brother was more severely affected, and X-linked dominant inheritance could not be excluded. 

Strenge and Froster (1998) described a boy with congenital microcephaly and lymphedema. He also had short stature, a feature that had not been described as part of this syndrome, even though it was present in 1 patient reported by Fryns et al. (1995). Bilateral limb lymphedema with lymphedema toenails was still present at age 2 years. At the age of 4 years, the lymphedema began decreasing. At the age of 8 years, lymphedema was restricted to the surface of the toes and the distal part of both feet. His height was at the 3rd centile; the occipital-frontal circumference was 48 cm (less than 3rd centile). Psychomotor development was normal. 

Limwongse et al. (1999) provided follow-up on the family reported by Crowe and Dickerman (1986) which was considered to have the microcephaly-lymphedema syndrome. They found chorioretinal dysplasia with variable visual deficit in multiple relatives, supporting the concept that the combination of microcephaly, lymphedema, and chorioretinopathy constitutes a single autosomal dominant genetic entity with variable expression. In an editorial comment on the report by Crowe and Dickerman (1986), Opitz (1986) had suggested that the facial characteristics of their proband at birth and during childhood resembled those of other patients with disorders associated with congenital lymphedema, i.e., what Opitz (1986) called the 'congenital lymphedema facies' (thick tissues, full cheeks, underdeveloped bridge of nose and supraorbital ridges, thick epicanthal folds, bilateral ptosis with thick lids, and micrognathia). Limwongse et al. (1999) noted a striking similarity between the facial characteristics of their proband at age 14 years and those of the 11-year-old patient of Sadler and Robinson (1993) with microcephaly and chorioretinopathy (see 156590). Both patients had prominent ears, broad nasal bridge, broad and large nasal tip with anteverted nares, prominent full lips, and pointed chin. 

Abdel-Salam et al. (2000) stated that 40 cases of microcephaly with chorioretinopathy, some with additional features such as lymphedema, had been reported. They noted that the facial features in their 2 patients, who had the additional features of severe mental retardation, epilepsy, and spasticity (see 251270), were similar to those described by Limwongse et al. (1999)

Vasudevan et al. (2005) reported 3 unrelated male patients with all of the major features of the microcephaly, lymphedema, chorioretinal dysplasia syndrome. All had a distinct facial appearance involving upslanting palpebral fissures, broad nose with rounded tip, anteverted nares, long philtrum with thin upper lip, pointed chin, and prominent ears. Vasudevan et al. (2005) stated that these cases support the hypothesis of a characteristic facial phenotype in MLCRD syndrome. 

REFERENCES

1. Abdel-Salam, G. M. H.; Czeizel, A. E.; Vogt, G.; Imre, L. :
Microcephaly with chorioretinal dysplasia: characteristic facial features. (Letter) Am. J. Med. Genet. 95: 513-515, 2000.
PubMed ID : 11146476
2. Angle, B.; Holgado, S.; Burton, B. K.; Miller, M. T.; Shapiro, M. J.; Opitz, J. M. :
Microcephaly, lymphoedema, and chorioretinal dysplasia: report of two additional cases. Am. J. Med. Genet. 53: 99-101, 1994.
PubMed ID : 7856652
3. Crowe, C. A.; Dickerman, L. H. :
A genetic association between microcephaly and lymphedema. Am. J. Med. Genet. 24: 131-135, 1986.
PubMed ID : 3706402
4. Feingold, M.; Bartoshesky, L. :
Microcephaly, lymphedema, and chorioretinal dysplasia: a distinct syndrome? Am. J. Med. Genet. 43: 1030-1031, 1992.
PubMed ID : 1415329
5. Fryns, J. P.; Smeets, E.; Van den Berghe, H. :
On the nosology of the 'primary true microcephaly, chorioretinal dysplasia, lymphoedema' association. Clin. Genet. 48: 131-133, 1995.
PubMed ID : 8556819
6. Jarmas, A. L.; Weaver, D. D.; Ellis, F. D.; Davis, A. :
Microcephaly, microphthalmia, falciform retinal folds and blindness. Am. J. Dis. Child. 135: 930-933, 1981.
PubMed ID : 7293993
7. Kozma, C.; Scribanu, N.; Gersh, E. :
The microcephaly-lymphoedema syndrome: report of an additional family. Clin. Dysmorph. 5: 49-54, 1996.
PubMed ID : 8867659
8. Leung, A. K. C. :
Dominantly inherited syndrome of microcephaly and congenital lymphedema with normal intelligence. (Letter) Am. J. Med. Genet. 26: 231 only, 1987.
PubMed ID : 3812569
. Leung, A. K. C. :
Dominantly inherited syndrome of microcephaly and congenital lymphedema. Clin. Genet. 27: 611-612, 1985.
PubMed ID : 4017282
10. Limwongse, C.; Wyszynski, R. E.; Dickerman, L. H.; Robin, N. H. :
Microcephaly-lymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance. Am. J. Med. Genet. 86: 215-218, 1999.
PubMed ID : 10482868
11. McKusick, V. A.; Stauffer, M.; Knox, D. L.; Clark, D. B. :
Chorioretinopathy with hereditary microcephaly. Arch. Ophthal. 75: 597-600, 1966.
PubMed ID : 5936364
12. Opitz, J. M. :
On congenital lymphedema. (Editorial) Am. J. Med. Genet. 24: 127-129, 1986.
PubMed ID : 3706401
13. Sadler, L. S.; Robinson, L. K. :
Chorioretinal dysplasia-microcephaly-mental retardation syndrome: report of an American family. Am. J. Med. Genet. 47: 65-68, 1993.
PubMed ID : 8368255
14. Strenge, S.; Froster, U. G. :
Microcephaly-lymphedema syndrome: report of a family with short stature as additional manifestation. Am. J. Med. Genet. 80: 506-509, 1998.
PubMed ID : 9880217
15. Vasudevan, P. C.; Garcia-Minaur, S.; Botella, M. P.; Perez-Aytes, A.; Shannon, N. L.; Quarrell, O. W. J. :
Microcephaly-lymphoedema-chorioretinal dysplasia: three cases to delineate the facial phenotype and review of the literature. Clin. Dysmorph. 14: 109-116, 2005.
PubMed ID : 15930898
16. Young, I. D.; Fielder, A. R.; Simpson, K. :
Microcephaly, microphthalmos, and retinal folds: report of a family. J. Med. Genet. 24: 172-184, 1987.
PubMed ID : 3573001

CONTRIBUTORS

Marla J. F. O'Neill - updated : 12/11/2006
Victor A. McKusick - updated : 2/10/2000
Victor A. McKusick - updated : 1/15/1999
Iosif W. Lurie - updated : 7/26/1996

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

carol : 12/14/2006

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Microcephaly-lymphedema-chorioretinal dysplasia associated with pachymicrogyria and atrophy of the cerebellar vermis: an integration of brain-ocular migration disorders.

Mar 2012
Pastora N, Peralta J, Canal-Fontcuberta I, Grabowska A, Pulido JS, Abelairas J, Armada F, Garcia-Alix A.

Source

Hospital Universitario La Paz, Pediatric Ophthalmology , Madrid , Spain.

Abstract

Background: Microcephaly-lymphedema-chorioretinal dysplasia (OMIM 152950) is a rare malformative inherited disorder that can be associated with other systemic features. Other ocular and brain anomalies rather than microcephaly and chorioretinal dysplasia have been inconstantly reported in this syndrome. Methods: We present a case of microcephaly-lymphedema-chorioretinal dysplasia with a dysmorphic facies, hypertonicity in the extremities and neuropsychomotor delay. Ophthalmological examination revealed bilateral nystagmus, microphthalmia, posterior subcapsular cataratacts, extensive chorioretinal dysplasia, optic nerve aplasia, persistent fetal vasculature, and absent retinal vessels. Results: Magnetic resonance revealed pachymicrogyria and discrete atrophy of vermis cerebelosum and confirmed optic nerve hypoplasia. Conclusions: The developmental alterations observed in the retina of this patient could be analogous to central nervous system anomalies, reflecting a reduction in neural population. Ophthalmic examination of children with microcephaly is warranted.

PubMed

http://www.ncbi.nlm.nih.gov/pubmed/22420539

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Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy. 

Jan 2012

Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A,Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G,Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S.

Source

Medical Genetics Unit, Biomedical Sciences, St. George's University of London, London SW17 0RE, UK.

Abstract


We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures. 

SciVerse

http://www.sciencedirect.com/science/article/pii/S0002929711005532
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Congenital toxoplasmosis mimicking microcephaly-lymphedema-chorioretinal dysplasia

Nov 2010

http://www.springerlink.com/content/j1k6768650826673/

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Microcephaly with chorioretinopathy in a brother-sister pair: evidence for germ line mosaicism and further delineation of the ocular phenotype.

Am J Med Genet A. 2007 Jun

Trzupek KM, Falk RE, Demer JL, Weleber RG.

Casey Eye Institute and Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon 97239, USA. trzupekk@ohsu.edu

Microcephaly with chorioretinopathy (OMIM 156590) is an autosomal dominant syndrome, characterized primarily by chorioretinal lesions and microcephaly. The phenotype is variable, and has been described in association with retinal dysplasia that can be stable or show progressive degeneration, retinal folds, lymphedema, and mental retardation. We describe two siblings with microcephaly, mental retardation, and variable retinal and choroidal abnormalities. Patient 1 has multiple atrophic and dysplastic-appearing lesions of the retina and choroid in each eye. An ERG at 5 months of age disclosed markedly subnormal scotopic and photopic responses with delayed flicker timing. Patient 2 has bilateral macular folds with vitreoretinopathy, serous retinal detachments, glaucoma, and cataracts OU. Both have mental retardation with hypotonia and severe microcephaly. Chorioretinopathy and retinal folds have been described independently in microcephaly with chorioretinopathy. The present sibs are the first in whom these features are observed while the parents are normal. Our findings support an expansion of the ocular phenotype and suggest the existence of germ line mosaicism.

Wiley InterScience

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External Links:

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LYMPHEDEMA, MICROCEPHALY, CHORIORETINOPATHY SYNDROME

http://bjo.bmjjournals.com/cgi/content/full/85/4/496d

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Microcephaly with chorioretinopathy in a brother-sister pair: evidence for germ line mosaicism and further delineation of the ocular phenotype. Jun 2007

http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.31717/abstract

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