Neuropathological findings in Wolf-Hirschhorn (4p-) syndrome

Gottfried, Marcia R.; Lavine, Leroy S.; Roessmann, Uros

doi:10.1007/bf00699242

Cited by 21 publications

(9 citation statements)

References 15 publications

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“…The brain neuroimaging findings observed in our cases extend the scant neuropathological data available in the literature on WHS [Lazjuk et al, 1980; Gottfried et al, 1981; Gonzalez et al, 1981; Righini et al, 2007]. Therefore, we would suggest consideration of neuroimaging studies in all such patients, particularly in those with frequent seizures, since malformation of the cerebral cortex may modify prognosis and management.…”

Section: Discussionsupporting

confidence: 80%

Update on the clinical features and natural history of Wolf–Hirschhorn (4p‐) syndrome: Experience with 87 patients and recommendations for routine health supervision

Battaglia

Filippi

Carey

2008

American J of Med Genetics Pt C

171

178

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Wolf-Hirschhorn syndrome (WHS) is a well-known multiple congenital anomalies/mental retardation syndrome, firstly described in 1961 by Cooper and Hirschhorn. Its frequency is estimated as 1/50,000-1/20,000 births, with a female predilection of 2:1. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3), and is considered a contiguous gene syndrome. No single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype. Since the disorder was brought to the attention of geneticists, many additional cases have been published. Only in 1999, however, were the first data on the natural history brought to the attention of the medical community. The purpose of the present study is to help delineate in more detail and over a longer period of time, the natural history of WHS, in order to establish appropriate health supervision and anticipatory guidance for individuals with this disorder. We have collected information on 87 patients diagnosed with WHS (54 females and 33 males) both in USA and Italy. Age at first observation ranged between newborn and 17 years. Twenty patients have been followed from 4 months to 23 years. The deletion proximal breakpoint varied from 4p15.32 to 4p16.3, and, by FISH, was terminal and included both WHSCR. Deletion was detected by standard cytogenetics in 44/87 (50.5%) patients, whereas FISH was necessary in the other 43 (49.5%). Array-CGH analysis at 1 Mb resolution was performed in 34/87 patients, and, in 15/34 (44%), showed an unbalanced translocation leading to both a 4p monosomy and a partial trisomy for another chromosome arm. Six more patients had been previously shown to have an unbalanced translocation by karyotype analysis or FISH with a WHS-specific probe. Sixty-five of 87 patients had an apparent pure, de novo, terminal deletion; and 1/87 a tandem duplication of 4p16.1p16.3 associated with 4p16.3pter deletion. Age at diagnosis varied between 7 months gestation and 16 years. Ninety-three percent had a seizure disorder with a good outcome; 80% had prenatal onset growth deficiency followed by short stature and slow weight gain; 60% had skeletal anomalies; 50% had heart lesions; 50% had abnormal tooth development; and 40% had hearing loss. Distinctive EEG findings were seen in 90%. Structural CNS anomalies were detected in 80%. Global developmental delay of varying degrees was present in all patients. Almost 50% was able to walk either alone or with support. Hypotonia was present in virtually all patients. A global improvement was observed in all individuals, over time. Our survey has also shown how the characteristic facial phenotype tends to be less pronounced in those patients with a smaller deletion, and microcephaly is not observed in the patients with certain cryptic unbalanced translocations.

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Section: Discussionsupporting

confidence: 80%

Update on the clinical features and natural history of Wolf–Hirschhorn (4p‐) syndrome: Experience with 87 patients and recommendations for routine health supervision

Battaglia

Filippi

Carey

2008

American J of Med Genetics Pt C

171

178

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“…This redution of the ratio value signifi cantly correlated with the subjective evaluation of the reduction of white matter volume, supporting the reliability of the multiple rater assessment. The nature of the foci of T 2 -weighted signal hyperintensity found in the white matter in half of the cases is not clear, since focal white matter lesions have not been reported in the few brain pathology studies performed in WHS [3,5] . Only in one case were some foci of malacia and glyosis detected within the white matter [5] .…”

Section: Discussionmentioning

confidence: 95%

“…On the other hand, the pathology studies support the MR imaging data on corpus callosum alterations, which seem to be the main MR imaging fi nding in WHS. The corpus callosum was found to be extremely thinned at autopsy [3] . According to histology observations, a marked disorganization of the fi bers within the corpus callosum is frequent.…”

Section: Discussionmentioning

confidence: 99%

Brain Magnetic Resonance Imaging in Wolf-Hirschhorn Syndrome

Righini¹,

Ciosci²,

Selicorni³

et al. 2007

Neuropediatrics

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Wolf-Hirschhorn syndrome (WHS) is a rare genetic disorder, which is caused by partial deletion of the short arm of one chromosome 4. Brain magnetic resonance (MR) imaging findings are lacking. We report on brain findings in 10 children with WHS. We evaluated the MR imaging films of 10 subjects affected by WHS, which had been confirmed by genetic study. The age range at MR imaging was between 1 month and 9 years. In 9/10 cases enlargement of the third lateral ventricles was present. In 9/10 cases a global reduction of cerebral hemispheres white matter was present. In 10/10 cases diffuse thinning of the corpus callosum was visible; it was severe in 7/10 cases. In 5/10 cases small foci of T (2) hyper intense signal were visible within the subcortical white matter. In three of the six cases studied within the first year of life frontal periventricular cysts were present. In three of the four cases studied after the first year of life a squared shape of the frontal horns of the lateral ventricles was visible. The MR imaging findings reported in WHS cannot be considered pathognomonic of the syndrome, however, they may suggest WHS.

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“…The ‘gain of function’ hypothesis is supported by a rare but related human genetic disorder. In Wolf–Hirschorn syndrome, where deletions of chromosome 4, including exon 1 of IT15, individuals do not display Huntington's disease‐like pathology (Gottfried et al . 1981).…”

Section: Introductionmentioning

confidence: 99%

The expression of Huntingtin‐associated protein (HAP1) mRNA in developing, adult and ageing rat CNS: implications for Huntington's disease neuropathology

Page

Potter

Aronni

et al. 1998

Eur J of Neuroscience

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Using radioactive in situ hybridization, we have mapped the expression of Huntingtin-associated protein (HAP1) mRNA in rat brain at developmental stages (E12-E19, PO-P21), in adult rats (3 months) and in 'aged' (19-21 months) rats. Using two pairs of 45mer oligonucleotide probes specific for HAP1A and a probe which recognizes regions of both the HAP1A and HAP1B mRNA sequences (panHAP1), we find that the expression of HAP1 mRNA is specific to the CNS and restricted predominantly to anatomically connected limbic structures, particularly the amygdala (medial and corticomedial nuclei), the hypothalamus (arcuate, preoptic, paraventricular and lateral hypothalamic area), bed nucleus of the stria terminalis (BNST) and the lateral septal nuclei. HAP1 mRNA was detected in embryos at E12 and displayed a prevalent distribution in the developing limbic structures by E15. In aged, 19-21-months-old, rats there is a downregulation of HAP1 mRNA expression across all CNS loci where HAP1 was previously abundant. The lowest levels of HAP1 mRNA expression corresponded with the areas of greatest pathological cell loss in Huntington's disease (HD); the caudate putamen, globus pallidus and neocortex. These observations support the suggestion that HAP1 plays an important role in the neuropathology of HD.

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Neuropathological findings in Wolf-Hirschhorn (4p-) syndrome

Cited by 21 publications

References 15 publications

Update on the clinical features and natural history of Wolf–Hirschhorn (4p‐) syndrome: Experience with 87 patients and recommendations for routine health supervision

Update on the clinical features and natural history of Wolf–Hirschhorn (4p‐) syndrome: Experience with 87 patients and recommendations for routine health supervision

Brain Magnetic Resonance Imaging in Wolf-Hirschhorn Syndrome

The expression of Huntingtin‐associated protein (HAP1) mRNA in developing, adult and ageing rat CNS: implications for Huntington's disease neuropathology

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