Acromelic Frontonasal Dysostosis

Slaney, Sarah F.; Goodman, Frances R.; Eilers-Walsman, Betty L.C.; Hall, Bryan D.; Williams, Denise K.; Young, Ian; Hayward, Richard; Jones, Barry M.; Christianson, Arnold L.; Winter, R M

doi:10.1002/(sici)1096-8628(19990312)83:2<109::aid-ajmg6>3.0.co;2-8

Cited by 22 publications

(6 citation statements)

References 27 publications

(26 reference statements)

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“…To explore the phenotypic range of ALX3 mutations, we undertook DNA sequencing of ALX3 in 14 additional unrelated individuals with various FNMs. These included one individual who was reported to have possible Pai syndrome (MIM 155145) 28 , one with oculoauriculofrontonasal syndrome (MIM 601452) 29 , three with acromelic frontonasal dysostosis (MIM 603671) 30,31 , and nine with miscellaneous combinations of hypertelorism, facial tags, and facial clefting 6 ; none of these individuals exhibited ALX3 mutations. DNA sequencing of ALX3 in 93 patients with nonsyndromic cleft lip and/or palate also gave normal results.…”

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confidence: 99%

Frontorhiny, a Distinctive Presentation of Frontonasal Dysplasia Caused by Recessive Mutations in the ALX3 Homeobox Gene

Twigg

Versnel

Nürnberg

et al. 2009

The American Journal of Human Genetics

129

102

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We describe a recessively inherited frontonasal malformation characterized by a distinctive facial appearance, with hypertelorism, wide nasal bridge, short nasal ridge, bifid nasal tip, broad columella, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. Additional recurrent features present in a minority of individuals have been upper eyelid ptosis and midline dermoid cysts of craniofacial structures. Assuming recessive inheritance, we mapped the locus in three families to chromosome 1 and identified mutations in ALX3, which is located at band 1p13.3 and encodes the aristaless-related ALX homeobox 3 transcription factor. In total, we identified seven different homozygous pathogenic mutations in seven families. These mutations comprise missense substitutions at critical positions within the conserved homeodomain as well as nonsense, frameshift, and splice-site mutations, all predicting severe or complete loss of function. Our findings contrast with previous studies of the orthologous murine gene, which showed no phenotype in Alx3(-/-) homozygotes, apparently as a result of functional redundancy with the paralogous Alx4 gene. We conclude that ALX3 is essential for normal facial development in humans and that deficiency causes a clinically recognizable phenotype, which we term frontorhiny.

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confidence: 99%

Frontorhiny, a Distinctive Presentation of Frontonasal Dysplasia Caused by Recessive Mutations in the ALX3 Homeobox Gene

Twigg

Versnel

Nürnberg

et al. 2009

The American Journal of Human Genetics

129

102

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“…AFND is an extremely rare FNM with fewer than 20 recognizable cases described in the literature . The most consistent clinical features are FNM accompanied by preaxial polydactyly of the lower limbs.…”

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confidence: 99%

“…Acromelic frontonasal dysotosis (AFND; MIM 603671) is characterized by a combination of characteristic frontonasal malformation (FNM) with limb defects and anomalies of the brain and usually occurs as a sporadic disorder. Following initial description in a review of the diverse presentations of FNM (1), Verloes et al proposed AFND as a distinct entity (2); subsequent reports have highlighted characteristic features of severe hypertelorism, ptosis, median cleft face with distinctive nasal bifurcation and widely separated nasal alae, parietal foramina, variable brain abnormalities including dysgenesis of the corpus callosum, hydrocephalus and interhemispheric lipoma, limb anomalies with preaxial polydactyly of the feet, tibial aplasia or hypoplasia, and talipes equinovarus (3)(4)(5). Although mainly arising sporadically, possible vertical transmission (5) suggested a dominant mechanism, subsequently confirmed by identification of the underlying heterozygous mutation in four AFND cases (6).…”

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Acromelic frontonasal dysostosis andZSWIM6mutation: phenotypic spectrum and mosaicism

et al. 2016

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Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling.

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“…The wide spectrum of abnormalities possibly associated with FND has led to the definition of a number of FND-related syndromes whose features are summarized in Table 1 (Toriello et al, 1986;Verloes, 1994;Jones, 1997;Slaney et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Prenatal ultrasound diagnosis of frontonasal dysplasia

et al. 2002

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We report a case of prenatal ultrasound diagnosis of frontonasal dysplasia. This represents a very rare disorder involving the face (hypertelorism, median cleft lip, absence of the nasal tip) and often the central nervous system (CNS) (cranium bifidum occultum, ethmoidal cephalocele, agenesis of the corpus callosum). Although several of the typical anomalies are diagnosable by ultrasound in utero (hypertelorism, median cleft lip, anterior cephalocele), very few cases have been reported prenatally, the present being only the third. In the present case, hemimegalencephaly is first reported among the anomalies possibly associated with frontonasal dysplasia. The diagnosis was made at 22 weeks' gestation and was confirmed by necropsy following termination of pregnancy.

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Acromelic Frontonasal Dysostosis

Cited by 22 publications

References 27 publications

Frontorhiny, a Distinctive Presentation of Frontonasal Dysplasia Caused by Recessive Mutations in the ALX3 Homeobox Gene

Frontorhiny, a Distinctive Presentation of Frontonasal Dysplasia Caused by Recessive Mutations in the ALX3 Homeobox Gene

Acromelic frontonasal dysostosis andZSWIM6mutation: phenotypic spectrum and mosaicism

Prenatal ultrasound diagnosis of frontonasal dysplasia

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