Phenotypic and molecular variability of the holoprosencephalic spectrum

Lazaro, Leïla; Dubourg, Christèle; Pasquier, Laurent; Duff, F. Le; Blayau, Martine; Durou, Marie-Renée; Pintière, Armelle Thomas de la; Aguilella, Céline; David, Véronique; Odent, Sylvie

doi:10.1002/ajmg.a.30110

Cited by 68 publications

(82 citation statements)

References 21 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As SMMCI, CNPAS has long been reported as a mild form of holoprosencephaly (5-9). The association of holoprosencephaly with a wide variety of craniofacial and extracranial anomalies is well recognized and individuals with holoprosencephaly have been ascribed to a variety of syndromes with multiple congenital anomaly (27,28). Our study showed that extracranial anomalies also frequently occurred in patients with CNPAS.…”

Section: Discussionsupporting

confidence: 54%

See 1 more Smart Citation

High Proportion of Pituitary Abnormalities and Other Congenital Defects in Children with Congenital Nasal Pyriform Aperture Stenosis

et al. 2006

View full text Add to dashboard Cite

ABSTRACT:We aimed to determine the occurrence of pituitary dysfunction and additional malformations in patients with congenital nasal pyriform aperture stenosis (CNPAS) and to predict which patients are at risk of pituitary dysfunction. Among the 40 studied patients, hypothalamo-pituitary (HP) axis abnormalities were found in 16 patients (40%), with endocrine dysfunction (n ϭ 9) and/or abnormal HP MRI findings (n ϭ 15). A normal HP axis on MRI was highly predictive of normal endocrine function. Of the 40 patients, 31 had additional abnormalities in the cranio-facial area (n ϭ 26), the brain (n ϭ 12), the vertebrae (n ϭ 5), the limbs (n ϭ 4), the heart (n ϭ 7) and the kidney (n ϭ 3). Six patients had syndromic associations: VACTERL (n ϭ 4), CHARGE (n ϭ 1) and RHYNS (n ϭ 1) syndromes. Craniofacial and brain malformations were more common in patients with HP axis abnormalities than in patients with normal HP axis. Familial history of midline defects and/or consanguinity were found in 30% of patients.In conclusion, HP axis abnormalities are frequent in patients with CNPAS and justify MRI of the brain early in life and clinical evaluation to screen for patients with pituitary insufficiency. CNPAS may be a genetically heterogeneous condition with a large phenotypic variability that shares common etiological mechanisms with the various forms of the holoprosencephaly phenotype. C ongenital nasal pyriform aperture stenosis (CNPAS) is a rare condition that causes airway obstruction in newborn children, which was first described in 1989 (1). It is caused by an overgrowth of the nasal process of the maxillar, reducing the anterior part of the nasal cavity. It can be diagnosed by physical examination and computed tomography scan. Surgical intervention early in life is usually needed (2-4). CNPAS must be distinguished to choanal atresia, which causes a reduction of the posterior part of the nasal cavity (1,3).There is limited clinical data concerning this syndrome and the disorder is considered as a mild form of holoprosencephaly (5-9). In patients with CNPAS, familial history of holoprosencephaly, cleft palate and ocular coloboma and/or consanguinity have occasionally been reported. An autosomal recessive inheritance of the disorder has been suspected (3,8,10,11). CNPAS occurs as an isolated condition or in association with other midline defects (3-7,9 -14). Solitary median maxillary central incisor (SMMCI) (3)(4)(5)(6)(12)(13)(14) and/or pituitary deficiencies (3,7,10,12,15) have been reported. The clinical symptoms of pituitary dysfunction are not always obvious in early childhood and can be potentially severe. Without early diagnosis and appropriate hormonal treatment, morbidity and mortality is high (3,10,11,16). Therefore, the study of additional congenital abnormalities is important for the management and prognosis of the patients. A systematic analysis of the whole phenotypic spectrum associated with CNPAS has not been carried out in previous studies. Therefore, we aimed to investigate the occurrence of pituitary abno...

show abstract

Section: Discussionsupporting

confidence: 54%

“…Half of the mutations have been found in the SHH gene, which is known to play a critical role in early forebrain and CNS development. However, as no anomaly to these genes were found in 80% of holoprosencephaly cases, other genes are likely to be involved (27,31). As reported in …”

Section: Discussionmentioning

confidence: 66%

High Proportion of Pituitary Abnormalities and Other Congenital Defects in Children with Congenital Nasal Pyriform Aperture Stenosis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…15 In a retrospective survey of 104 living children with HPE, Stashinko et al 16 found that 51% were microcephalic at birth. Mutations in SHH have been found in some patients with microcephaly but without HPE.…”

Section: Discussionmentioning

confidence: 99%

PTCH1 duplication in a family with microcephaly and mild developmental delay

et al. 2008

View full text Add to dashboard Cite

With the exception of the X chromosome, genomic deletions appear to be more prevalent than duplications. Because of a lack of accurate diagnostic methods, submicroscopic duplications have been under-ascertained for a long period. The development of array CGH has enabled the detection of chromosomal microduplications with nearly the same sensitivity as deletions, leading to the discovery of previously unrecognized syndromes. Using a clinical targeted oligonucleotide array (CMA-V6.3 OLIGO), we identified an B360-kb duplication in 9q22.32 in a 21-month-old boy with developmental delay, failure to thrive, and microcephaly. The same duplication was identified in the patient's mother who is also microcephalic and mildly delayed. We have sequenced the chromosomal breakpoints and determined the duplication as tandem in orientation and 363 599 bp in size. The duplicated segment harbors the entire PTCH1 gene. Deletions or loss-of-function mutations of PTCH1 result in basal cell nevus syndrome (Gorlin syndrome), whereas gain-of-function mutations were proposed to lead to holoprosencephaly 7. We propose that patients with microcephaly or holoprosencephaly of unknown origin should also be screened for PTCH1 duplication.

show abstract

“…Such disruptions could result in the subtle alterations in interneurons that are implicated in a variety of cortical illnesses. Indeed, although loss-of-function mutations in SHH in humans can result in severe holoprosencephalies, more subtle mutations or variable penetrance can result in a spectrum of disorders that includes abnormalities of learning and attention, and seizures (Muenke and Beachy, 2000;Heussler et al, 2002;Lazaro et al, 2004;Nieuwenhuis and Hui, 2005).…”

Section: Alterations In Shh-responsive Gene Expression Correlate Withmentioning

confidence: 99%

Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon

2005

View full text Add to dashboard Cite

Fate determination in the mammalian forebrain, where mature phenotypes are often not achieved until postnatal stages of development, has been an elusive topic of study despite its relevance to neuropsychiatric disease. In the ventral telencephalon, major subgroups of cerebral cortical interneurons originate in the medial ganglionic eminence (MGE), where the signaling molecule sonic hedgehog (Shh) continues to be expressed during the period of neuronogenesis. To examine whether Shh regulates cortical interneuron specification, we studied mice harboring conditional mutations in Shh within the neural tube. At embryonic day 12.5, NestinCre:ShhFl/Flmutants have a relatively normal index of S-phase cells in the MGE, but many of these cells do not co-express the interneuron fate-determining gene Nkx2.1. This effect is reproduced by inhibiting Shh signaling in slice cultures, and the effect can be rescued in NestinCre:ShhFl/Fl slices by the addition of exogenous Shh. By culturing MGE progenitors on a cortical feeder layer, cell fate analyses suggest that Shh signaling maintains Nkx2.1 expression and cortical interneuron fate determination by MGE progenitors. These results are corroborated by the examination of NestinCre:ShhFl/Fl cortex at postnatal day 12, in which there is a dramatic reduction in cell profiles that express somatostatin or parvalbumin. By contrast, analyses of Dlx5/6Cre:SmoothenedFl/Flmutant mice suggest that cell-autonomous hedgehog signaling is not crucial to the migration or differentiation of most cortical interneurons. These results combine in vitro and ex vivo analyses to link embryonic abnormalities in Shh signaling to postnatal alterations in cortical interneuron composition.

show abstract

Phenotypic and molecular variability of the holoprosencephalic spectrum

Cited by 68 publications

References 21 publications

High Proportion of Pituitary Abnormalities and Other Congenital Defects in Children with Congenital Nasal Pyriform Aperture Stenosis

High Proportion of Pituitary Abnormalities and Other Congenital Defects in Children with Congenital Nasal Pyriform Aperture Stenosis

PTCH1 duplication in a family with microcephaly and mild developmental delay

Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon

Contact Info

Product

Resources

About