9q31.1q31.3 deletion in two patients with similar clinical features: a newly recognized microdeletion syndrome?

Interstitial deletions of the long arm of chromosome 9 are rare and most patients have been detected by conventional cytogenetic techniques. Disparities in size and localization are large and no consistent region of overlap has been delineated. We report two similar de novo deletions of 6.3 Mb involving the 9q31.1q31.3 region, identified in two monozygotic twins and one unrelated patient through array-CGH analysis. By cloning the deletion breakpoints, we could show that these deletions are not mediated by segmental duplications. The patients displayed a distinct clinical phenotype characterized by mild intellectual disability, short stature with high body mass index, thick hair, arched eyebrows, flat profile with broad chin and mild prognathism, broad, and slightly overhanging tip of the nose, short neck with cervical gibbus. The twin patients developed a metabolic syndrome (type 2 diabetes, hypercholesterolemia, vascular hypertension) during the third decade of life. Although long-term follow-up and collection of additional patients will be needed to obtain a better definition of the phenotype, our findings characterize a previously undescribed syndromic disorder associated with haploinsufficiency of the chromosome 9q31.1q31.3 region.

[Herpes Zoster Ophthalmicus after Pfizer BNT162b2 and Moderna mRNA-1273 vaccination in two young and immunocompetent patients]. / Zona ophtalmique après vaccination par Pfizer BNT162b2 et Moderna mRNA-1273 chez deux patients jeunes et immunocompétents.

Coronavirus disease 19 (COVID-19) was first observed in Wuhan, China. The disease is caused by a virus (SARS-CoV-2), which spread around the world within a matter of weeks, leading to a large number of deaths. While the health crisis was managed on the ground, the scientific community focused on finding a means to stop it. Vaccine candidates such as the mRNA vaccines (Pfizer BTN162b2 and Moderna mRNA-1273), started to emerge. As these treatments came on the market recently, there is still concern about potential side effects, among them, Herpes Zoster Ophthalmicus (HZO).

Interventional radiology for treatment of bone metastases.

Therapeutic advances in oncology have led to longer survival in many forms of cancer, including those complicated by bone metastases. When a bone metastasis is painful or when there is a risk of fracture, interventional radiology procedures can be carried out for pain control and/or stabilisation. All of these techniques can be performed under local anaesthesia. Cementoplasty and vertebroplasty are stabilisation procedures consisting in the percutaneous injection of acrylic cement into a lytic bone lesion. The effect on pain can be explained by the consolidation of weakened, fractured or pre-fractured bone, but also to a lesser extent by the toxic, chemical and thermal effect of the cement. Tumour ablation techniques include alcoholisation or thermal ablation (by heat with radiofrequency and microwave or cold by cryoablation). Percutaneous thermal ablation of bone tumours is most often performed as a palliative measure resulting in a significant and lasting reduction in symptoms. Radiofrequency ablation consists in placing needles through which an electrical current passes. Microwave ablation acts by causing very high frequency vibrations of water molecules. Cryoablation releases argon gas at the tip of the needle, forming an "ice ball" effectively destroying tumour cells. Any of these techniques can be combined to radiation therapy, performed before or after radiation. Finally, tumour embolisation can have a goal of pain control, or preparation of surgery to reduce the risk of peroperative haemorrhage.

Tobacco smoking in crosslinked keratoconus patients.

PURPOSE: The aim of this study was to evaluate the possibly protective link of smoking in keratoconic patients treated with accelerated cross-linking. METHODS: A telephone survey was conducted among 80 KC patients treated by accelerated cross-linking (A-CXL). The questions focused on general history, possible atopy and smoking habits. Results were compared to those of the general population by indirect standardization by age and sex according to the French national INPES survey. RESULTS: Sixty-two patients with KC were analyzed. The mean age at diagnosis was 22 years (SD 5). The mean age at which A-CXL was performed was 23 years (SD 6). Daily smokers represented 19 %, occasional smokers 8 %, ex-smokers 21 % and non-smokers 52 %. The mean age at which the patients began smoking was 17 (SD 2) years. Ex-smokers quit at a mean age of 24 (SD 4) years. The observed rates and expected rates of daily smokers were 19 % and 39 % respectively at the time of the survey (P=0.01), 24 % and 35 % at the time of the A-CXL treatment (P=0.10) and 31 % and 35 % at the time of diagnosis (P=0.58). The decrease in the rate of observed daily smokers over time was significant (P=0.02). DISCUSSION: Our data does not appear to suggest a significant protective effect of smoking on the occurrence of KC. It shows a lesser proportion of smokers in KC patients after A-CXL, but this difference did not exist at the time of KC diagnosis.

Reconstruction of exenteration socket with Integra® dermal substitute and skin graft.

The authors report their experience with the use of Integra® dermal substitute, in combination with a thin skin graft, following an orbital exenteration. The clinical case described relates to a 42-year-old gentleman with an ulcerative retractile lesion of the right lower eyelid. Histopathological examination diagnosed a moderately differentiated epidermoid carcinoma infiltrating the orbit. Total exenteration was necessary as well as secondary radiation therapy and chemotherapy. Rehabilitation of the exenterated socket was performed by inserting an Integra® patch, followed by an additional thin skin graft one month later. The authors review the various available techniques for exenterations, their indications and the various possible secondary rehabilitations. Despite being less utilized, the dermal substitute technique, which is relatively new, seems to offer quicker and easier rehabilitation compared to traditional techniques. A comparative study would be necessary to define superiority among the different techniques of exenteration, with respect to the speed of rehabilitation and resistance to radiation therapy.

Correlation between central venous oxygen saturation and oxygen delivery changes following fluid therapy.

BACKGROUND: The rationale for using central venous oxygen saturation (ScvO(2)) in various clinical scenarios is that it reflects the balance between oxygen delivery (DO(2)) and demands. In this study, we evaluated the correlation between ScvO(2) and DO(2) changes (Delta Do(2), DeltaScvO(2)) in patients receiving fluid therapy following coronary surgery. We also correlated the changes of mean arterial pressure (Delta MAP) and central venous pressure (Delta CVP), with Delta DO(2). METHODS: Sixty consecutive sedated and mechanically ventilated adult patients, with cardiac index

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). METHODS: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. RESULTS: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. CONCLUSION: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.

Anatomy of the orbit and its surgical approach.

A micro anatomical and surgical study of the orbit was conducted on cadaver specimens. First of all we reviewed the anatomy of the orbit with special emphasis on microanatomical structures. Three neurosurgical approches are then described with all structures encountered along these routes. The superior approach which provides a good access to the superior part of the orbit is the only route which can explore all parts of the optic nerve even in the optic canal. The lateral compartment of the orbit could be exposed by the lateral approach above or below the lateral rectus muscle. It is the only route that could give access to the inferior part of the orbit. The supero lateral approach is the largest route and has advantages of the two preceding routes. It gives access to the superior part of the orbit but not the optic canal and gives also a good exposition to the lateral part of the orbit but less than the lateral route in the inferior part. These approaches could be used to remove all intra orbital lesions apart from those located in the infero medial part of the orbit.

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.

Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. We review the literature on MECP2 mutations in Rett syndrome. This analysis has permitted us to produce a map of the recurrent mutations identified in this and previous studies. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, which is conserved among brain-specific regulatory factors.

Preserved speech variant is allelic of classic Rett syndrome.

Rett syndrome is a neurological disorder affecting predominantly females with regression loss of speech and purposeful hand use, after a few months of almost normal development. Postnatal microcephaly, hand dispraxia, stereotypic 'hand-washing' activities, ataxia, and abnormal breathing are among its most characteristic features. Another aspect of this disorder is growth failure. The preserved speech variant (PSV) shares with Rett syndrome the same course and the stereotypic hand-washing activities but it differs in that patients typically recover some degree of speech and hand use and usually do not show growth failure. Progressive scoliosis, epilepsy and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant. Here we explore the spectrum of mutations affecting the MECP2 gene in a group of 25 classic Rett syndrome girls and in three patients with the preserved speech variant. Among the Rett syndrome group, two novel mutational hot spots (R270X and R294X), four novel mutations, two novel small deletions, as well as the previously reported 806delG, R168X and R255X mutations, were identified in 20/25 patients. Of note, among the preserved speech variants, two patients carry deletions of 41 bp and 44 bp each, which are strikingly similar to those observed in classic Rett syndrome. Our results confirm the presence of mutational hot spots in MECP2, broaden the spectrum of mutations, pinpoint additional mutational hot spots and establish that the preserved speech variant is indeed allelic of the classic form. Phenotype variability is only partially dependent on the kind of MECP2 mutation and other mechanisms such as skewed X-inactivation, and/or modifier gene effects should be investigated to explain the variable recovery in speech and hand use.

MECP2 mutation in male patients with non-specific X-linked mental retardation.

In contrast to the preponderance of affected males in families with X-linked mental retardation, Rett syndrome (RTT) is a neurological disorder occurring almost exclusively in females. The near complete absence of affected males in RTT families has been explained by the lethal effect of an X-linked gene mutation in hemizygous affected males. We report here on a novel mutation (A140V) in the MECP2 gene detected in one female with mild mental retardation. In a family study, the A140V mutation was found to segregate in the affected daughter and in four adult sons with severe mental retardation. These results indicate that MECP2 mutations are not necessarily lethal in males and that they can be causative of non-specific X-linked mental retardation.

Autosomal recessive syndrome of growth and mental retardation, seizures, retinal abnormalities, and osteodysplasia with similarity to the Gurrieri syndrome.

We report on two sibs, brother and sister, with a multiple congenital anomaly/mental retardation syndrome consisting of severe growth and mental retardation, seizures, retinal abnormalities, osteodysplasia, brachydactyly, prognathism, and dental malocclusion. These clinical findings were present in both patients and seem to be consistent with the phenotype of the Gurrieri syndrome. The new features described in these sibs could expand the clinical spectrum of the Gurrieri syndrome and confirm the existence of this rare autosomal recessive condition.

Preserved speech variants of the Rett syndrome: molecular and clinical analysis.

Mutations in the MECP2 gene cause the severe neurodevelopmental disorder called Rett syndrome. Preliminary evidence suggests that MECP2 may be involved in a broader phenotype than classical Rett syndrome including preserved speech variants (PSV). Here we report clinical and mutation analysis of 18 PSV patients. Ten of them had a MECP2 mutation (55%). The clinical features of these girls have been characterized and two subgroups defined. All of them had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of two-to-three years, and were able to speak in sentences; four had normal weight, mental age not beyond one-to-two years, and spoke in single words and two-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand-washing was present in the first years of life but often subsequently disappeared. Significantly, all mutations found in PSV are either missense or late truncating mutations. In particular, we did not find the four early truncating hot spots: R168X, R255X, R270X, R294X. These results suggest that early truncating mutations lead to a poor prognosis (classic Rett), while late truncating and missense mutations lead either to classic Rett or PSV. We hypothesize that a missense or late truncating mutation is necessary but not sufficient to produce a PSV, based on the presence of one (or more) modifier genes whose product may interact in a epistatic manner with MeCP2 protein.

Possible case of Pitt-Hopkins syndrome in sibs.

In this article, we describe two sibs, a brother and sister, with severe mental retardation and multiple congenital anomalies including "coarse" facial features, short stature, seizures, hypertrichosis, short great toes, and overbreathing. Comparison of these patients with previous reports suggests that they could represent the first familial cases of the Pitt-Hopkins syndrome. The recurrence in sibs within the same family supports autosomal recessive inheritance for the condition. Variable expression of the respiratory symptoms, which has not been reported earlier, is underlined.

Vitamin E serum levels in Rett syndrome.

In order to study the role of vitamin E in the pathogenesis of Rett syndrome (RS), we analysed vitamin E serum levels in twenty-eight patients affected by this disorder. We found lower vitamin E serum levels in nine cases (32.1%). These results indicated that the oxidative free radical metabolism may be impaired in a significant percentage of Rett syndrome patients suggesting the need for further studies of tissue vitamin E in different brain regions.

Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.

Bromocriptine in the Rett syndrome.

Twelve typical cases of the Rett syndrome and one forme fruste were treated with bromocriptine for six months and then had a washout for two months followed by resumption of the bromocriptine treatment. During the first bromocriptine treatment there were improvements in communication and relaxation in some of the girls: a more regular sleep pattern was observed in 4 and a more varied facial expression in 8, and 4 girls began to utter a few words. The bouts of hyperpnea disappeared in 5 and grinding of the teeth in 3. There was also a reduction in stereotypic hand activities in 5 girls and signs of improved motor abilities in 3. The washout caused a general decrease in the positive effects of the previously administered bromocriptine and resumption of the treatment with this drug led to less marked improvement. Metoclopramide was tested in all the girls before the treatment, and it was noted that, while endorphins were hyporesponsive, prolactin was hyperresponsive. This test was repeated two months after the bromocriptine treatment had been performed and, while beta-lipotropin remained unchanged, beta-endorphin showed increased responsiveness.

Ultrastructural study of enteric ganglia in three patients with Rett syndrome.

In order to verify whether a pseudo-obstruction syndrome was associated with morphological changes in enteric ganglia, we performed an ultrastructural study on rectal biopsy specimens in three patients with Rett syndrome. Features of enteric neurons, detected to a different extent in all three biopsy specimens, included an abnormal dilatation of endoplasmic reticulum with a disorganization of cisternae of the Golgi apparatus, and masses of unidentified electron-dense granulo-filamentous material, probably of lipidic origin, observed in the perikaryon. Large electron-lucent membrane-bound vacuoles were found mostly within satellite glial cells. Sometimes, the axon terminals were swollen and showed intraxonal vacuolization. We conclude that the reported findings do not represent a specific sign of degeneration and do not constitute a significant morphological marker of disease.

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.