absent corpus callosum

Microcephaly 20, Primary, Autosomal Recessive

Clinical Characteristics

Ocular Features:

Microphthalmia and optic nerve hypoplasia with "blindness" seem to be common.

Systemic Features:

Short stature and global developmental delay are usually present. Poor or absent speech is characteristic and intellectual disability may be severe. Few individuals can walk. Foot deformities and hypotonia are often present. Behavior problems are common having features of ADHD, autism, and aggression. Foot deformities have been noted.

Imaging of the brain may reveal cerebellar hypoplasia, a simplified gyral pattern, and absence of the corpus callosum.

Genetics

Homozygous or compound heterozygous mutations in the KIF14 gene (1q32.1) are responsible for this disorder.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment has been reported.

References

Article Title:

Biallelic variants in KIF14 cause intellectual disability with microcephaly

Makrythanasis P, Maroofian R, Stray-Pedersen A, Musaev D, Zaki MS, Mahmoud IG, Selim L, Elbadawy A, Jhangiani SN, Coban Akdemir ZH, Gambin T, Sorte HS, Heiberg A, McEvoy-Venneri J, James KN, Stanley V, Belandres D, Guipponi M, Santoni FA, Ahangari N, Tara F, Doosti M, Iwaszkiewicz J, Zoete V, Backe PH, Hamamy H, Gleeson JG, Lupski JR, Karimiani EG, Antonarakis SE. Biallelic variants in KIF14 cause intellectual disability with microcephaly. Eur J Hum Genet. 2018 Mar;26(3):330-339.

PubMed ID:

29343805

Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Hohne W, Noegel AA, Al-Owain M, Hortnagel K, Stobe P, Baig SM, Nurnberg P, Alkuraya FS, Hahn A, Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 2017 Oct;82(4):562-577.

PubMed ID:

28892560

Corpus Callosum Agenesis with Facial Anomalies and Cerebellar Ataxia

Clinical Characteristics

Ocular Features:

The thick, bushy eyebrows and long eyelashes are part of the generalized hirsutism. The eyelids appear puffy. Strabismus of unknown type has been reported.

Systemic Features:

Infants are hypertonic at birth but this seems to be less evident as they grow. Slow physical growth and psychomotor delay are common. The skull in newborns is small. The ears are low-set, protruding, and posteriorly rotated. The nostrils are anteverted and the lower lip protrudes. There are severe cognitive defects which has been called mental retardation. Speech is poor or may never develop. Cerebellar ataxia and uncoordinated hand movements are features. Brain imaging reveals cerebellar hypoplasia and some degree of corpus callosum agenesis including absence.

Genetics

Homozygous mutations in the FRMD4A gene (10p13) have been found to segregate with this disorder in a large consanguineous Bedouin kindred.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment has been reported.

References

Article Title:

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

Fine D, Flusser H, Markus B, Shorer Z, Gradstein L, Khateeb S, Langer Y, Narkis G, Birk R, Galil A, Shelef I, Birk OS. A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A. Eur J Hum Genet. 2015 Dec;23(12):1729-34.

PubMed ID:

25388005

Microphthalmia, Syndromic 7

Clinical Characteristics

Ocular Features:

Microphthalmia and rarely clinical anophthalmia are the ocular hallmarks of this disorder. Corneal leukomas and some degree of sclerocornea are usually present as well. Orbital cysts have been observed. Other less consistent findings include iridocorneal adhesions, glaucoma, microcornea, cataracts, aniridia, persistence of the anterior hyaloid artery and other vitreous opacities, and patchy hypopigmentation of the RPE.

Systemic Features:

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions. Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia. There may be some healing of the skin defects. The corpus callosum is sometimes absent. Diaphragmatic hernias are often present. Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects. Preauricular pits and hearing loss have been found in some patients. Patients may be short in stature and some have nail dysplasia. GU and GI anomalies may be present.

Genetics

This is an X-linked dominant disorder with lethality in the hemizygous male. Many patients (79%) have interstitial deletions of the Xp22.2 region of the X chromosome. Sequence analysis of this region has revealed heterozygous point mutations in the HCCS gene (Xp22.2) in numerous other patients. In several additional cases deleterious mutations have been found in the X-linked COX7B gene. However, familial occurrence is uncommon. X chromosome inactivation may be skewed with the abnormal X being inactive in virtually all cases. Several 46 XX males with this syndrome have been described.

Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here. Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.

Other X-linked dominant disorders with lethality in hemizygous males and abnormalities in skin and the eye are Incontinentia pigmenti (308300) and Aicardi syndrome (304050). The skin lesions and ocular anomalies are dissimilar to those in MLS and they often have far more severe CNS abnormalities. Further, the mutation causing Aicardi is in the NEMO (IKBKG) gene at another location on the X chromosome.

Pedigree:

X-linked dominant, mother affected

Treatment

Treatment Options:

Treatment is organ-specific with repair of septal defects and diaphragmatic hernias. Progressive orbital prosthetics should be considered in patients with blind, microphthalmic and clinically anophthalmic eyes.

References

Article Title:

Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease

Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, D'Amato I, Conte I, Maystadt I, Demuth S, Zvulunov A, Kutsche K, Zeviani M, Franco B. Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease. Am J Hum Genet. 2012 Nov 2;91(5):942-9. doi: 10.1016/j.ajhg.2012.09.016. PubMed PMID: 23122588.

PubMed ID:

23122588

HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations

Wimplinger I, Shaw GM, Kutsche K. HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations? Mol Vis. 2007 Aug 27;13:1475-82.

PubMed ID:

17893649

Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome

Wimplinger I, Morleo M, Rosenberger G, Iaconis D, Orth U, Meinecke P, Lerer I, Ballabio A, Gal A, Franco B, Kutsche K. Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2006 Nov;79(5):878-89.

PubMed ID:

17033964

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

Ogata T, Wakui K, Muroya K, Ohashi H, Matsuo N, Brown DM, Ishii T, Fukushima Y. Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. Hum Genet. 1998 Jul;103(1):51-6. Review.

PubMed ID:

9737776

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