Reassessment of holoprosencephaly–diencephalic hamartoblastoma (HDH) association

Castori, Marco; Douzgou, Sofia; Silvestri, Evelina; Encha‐Razavi, Férechté; Dallapiccola, Bruno

doi:10.1002/ajmg.a.31591

Cited by 7 publications

(11 citation statements)

References 41 publications

(80 reference statements)

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“…This work offered a detailed description of five 19‐ to 28‐week‐old fetuses with large hypothalamic/diencephalic hamartomas and other cephalic anomalies, primarily midline defects and severe facial asymmetry. The manuscript supported the concept that the hypothalamic mass caused additional brain and craniofacial malformations, particularly of the holoprosencephaly/arrhinencephaly type, in a sequential model [Iafolla et al, 1989; Verloes et al, 1992; Castori et al, 2007a]. Herein, I offer further speculations on this rare phenomenon.…”

Section: To the Editorsupporting

confidence: 63%

“…It has become clear that arrhinencephaly/holoprosencephaly is not the sole cephalic anomaly associated with HDH. In fact, hemifacial microsomia variably combined with an ipsilateral malformed ear and cervical and/or upper thoracic costo‐vertebral anomalies was observed in the five patients reported by Guimiot et al 2009 and six additional, previously reported cases [reviewed in Castori et al, 2007a]. This is similar to Goldenhar syndrome, which is a causally heterogeneous malformation apparently reflecting perturbed migration and/or differentiation of the cephalic neural crest [Cohen et al, 1989].…”

Section: To the Editormentioning

confidence: 91%

“…In fact, in molecularly confirmed patients, PHS is characterized by a relatively small HH, mesoaxial polydactyly and variable additional anomalies, mainly bifid epiglottis, postaxial polydactyly, nail and tooth hypoplasia [Johnston et al, 2005]. However, none of these cases show the further cephalic anomalies reported by Guimiot et al 2009 and others [reviewed by Castori et al, 2007a]. Therefore, it has been postulated that this subset of patients may belong to a different condition, recently defined with the appellation of “holoprosencephaly‐diencephalic hamartoma” (HDH) [Winter and Baraitser, 2005; Castori et al, 2007a,b].…”

Section: To the Editormentioning

confidence: 99%

“…This combination is reminiscent of frontonasal “dysplasia” in, at least two patients [Hennekam et al, 1986; patient 5 in Guimiot et al, 2009]. Other relatively common anomalies in HDH include asymmetric micro/anophthalmia, neuronal migration defects, and hindbrain abnormalities [Castori et al, 2007a; Guimiot et al, 2009].…”

Section: To the Editormentioning

confidence: 99%

“…In these three subjects marked invasion of the malformed structures by the teratomatous tissue was documented, while in HDH this phenomenon can be demonstrated for a few additional features only. This is, for example, the case of microphthalmia/anophthalmia, which is usually the result of direct infiltration of the optic chiasm/nerve and eye remnant [Verloes et al, 1995; Castori et al, 2007a]. In addition, nasal and facial bone anomalies may be related to perturbed induction caused by a huge hamartoma interposing between the two hemispheres and/or invading the skull base in others [Gitlin and Behar, 1960; Guimiot et al, 2009].…”

Section: To the Editormentioning

confidence: 99%

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Holoprosencephaly‐diencephalic hamartoma: Sequence or pleiotropy?

Castori

2009

American J of Med Genetics Pt A

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Section: To the Editorsupporting

confidence: 63%

Section: To the Editormentioning

confidence: 91%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

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Holoprosencephaly‐diencephalic hamartoma: Sequence or pleiotropy?

Castori

2009

American J of Med Genetics Pt A

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A triploid fetus further expands etiological heterogeneity in holoprosencephaly‐diencephalic hamartoblastoma

Castori

Silvestri

Nunnari

et al. 2007

American J of Med Genetics Pt A

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Our group recently described a 23-week fetus with the association of holoprosencephaly-diencephalic hamortoblastoma (HDH) and reviewed the literature, identifying 19 additional patients with similar features. Both clinical and etiological heterogeneity were outlined, thus suggesting that HDH could indeed represent an overlapping phenotype of separate conditions, perhaps within a common morphogenetic pathway. In pathogenetic perspective, we hypothesized that the cause(s) for HDH may act early in gestation, probably during blastogenesis [Castori et al., 2007].We had an opportunity to evaluate an additional fetus with HDH, born to a G1P0 36-year-old woman and a 33-year-old man. Family history was unremarkable. Following ultrasound detection of alobar holoprosencephaly (HPE) and severe IUGR, transabdominal amniocentesis performed at 17 weeks demonstrated a 69,XXX fetal karyotype. Pregnancy was terminated at 19 weeks. Physical examination showed a female fetus with a weight of 108 g (<3rd centile); crown-rump length, 13 cm; crown-heel length, 19 cm (<3rd centile); and head circumference, 13 cm (<3rd centile), suggestive of apparently symmetric growth restriction. Facial abnormalities included upslanting palpebral fissures, apparently low-set ears, premaxillary agenesis, ankyloglossia, retrognathia, and mild nuchal edema (Fig. 1A,B). Bilateral III-IV finger and II-V toe syndactyly, stubby great toe on the left, and sandal gap of the right foot were also evident ( Fig. 1C-E). Necropsy findings comprised ostium secundum type interatrial septal defect, ventricular septal defect, ''horseshoe'' kidneys with cystic dysplastic disease of the fused inferior poles, and hypoplastic adrenal glands. The placenta was small (29 g, <3rd centile) with multiple calcifications and had no sign of hydatiform degeneration. Brain dissection showed alobar HPE with a single ventricle and the absence of the falx cerebri, corpus callosum, septum pellucidum, and olfactory tracts and bulbs. Both thalami were substituted by a mass extending over the optic chiasm and the right optic nerve (Fig. 2A). Microscopically, this mass was composed of disorganized relatively mature neurons, glial cells, ependymal elements, and vessels, without any cytological atypia (Fig. 2B,C). These findings were consistent with hypothalamic hamartoma (HH). The eyes were normally formed and histologic examination showed bilateral retinal dysplasia, manifested by numerous rosettes and minimal gliosis (Fig. 2D). Neuronal migration defects and other histological abnormalities were excluded. A radiographic survey confirmed limb anomalies and

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Giant diencephalic harmartoma and related anomalies: A newly recognized entity distinct from the Pallister–Hall syndrome

Guimiot

Marcorelles

Aboura

et al. 2009

American J of Med Genetics Pt A

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An hypothalamic hamartoma is an abnormal mass of mature glio-neuronal tissue present in the hypothalamic area. It usually measures <2 cm of diameter. Most of the time, this hamartoma occurs in Pallister-Hall syndrome (PHS), due to heterozygous GLI3 mutations. We report on five fetuses with giant diencephalic hamartoma and other midline brain and facial malformations, without mutation in the GLI3 gene or genomic rearrangements in three of them. The fetuses showed facial asymmetry, unilateral ear and eye anomalies, and facial cleft. Extracephalic malformations consisted of vertebral anomalies and short nails, without polydactyly and cardiac malformation. The diencephalon was replaced by an encephaloid mass protruding into the facial cleft. Normal cerebral structures were not detectable. In one patient, holoprosencephaly of the syntelencephalic type was noted. Arhinencephaly was present in all patients. Histologically, the ill-defined, multilobulated lesion was made of neuroblastic and neurocytic cell foci, lying in a fibrillar network, elaborating sometimes perivascular pseudorosettes, with a maturation gradient in accordance with the fetal age. Owing to their location, the tumors could be described as diencephalic, rather than hypothalamic hamartomas. The striking asymmetry of the facial anomalies and the diencephalic malformations are not in the spectrum observed with PHS and related syndromes, suggesting a distinct entity involving abnormal morphogenetic developmental fields at around 5 weeks of gestation.

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Reassessment of holoprosencephaly–diencephalic hamartoblastoma (HDH) association

Cited by 7 publications

References 41 publications

Holoprosencephaly‐diencephalic hamartoma: Sequence or pleiotropy?

Holoprosencephaly‐diencephalic hamartoma: Sequence or pleiotropy?

A triploid fetus further expands etiological heterogeneity in holoprosencephaly‐diencephalic hamartoblastoma

Giant diencephalic harmartoma and related anomalies: A newly recognized entity distinct from the Pallister–Hall syndrome

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