Phenotypic overlapping of trisomy 12p and Pallister–Killian syndrome

Trisomy of 12p is a rare chromosomal abnormality, which sometimes coexists with other chromosomal anomalies. We report on a patient with a supernumerary chromosome involving chromosomes 12 and 14, which was confirmed by array-comparative genomic hybridization (aCGH). He had developmental delay and dysmorphic features overlapped with those of Pallister–Killian syndrome, which is derived from an isodicentric chromosome 12. The microblepharon identified in our patient is a characteristic feature of 12p trisomy. Further patients are needed to establish the phenotypic difference between trisomy 12p and Pallister–Killian syndrome.     

Vogt–Koyanagi–Harada syndrome

Objectives

The objectives of this study are to review our current knowledge of the aetiopathogenesis of Vogt–Koyanagi–Harada syndrome, including viral infection, genetic factors and immunomediated mechanisms, and to discuss pathogenesis and its relevance to pharmacotherapy.

Systematic review methodology

Relevant publications from 1965 to 2012 on the aetiopathogenesis and pharmacotherapy of VKHS were analysed.

Results and conclusion

Vogt–Koyanagi–Harada syndrome (VKHS) is a rare multisystemic autoimmune disease that affects tissues containing melanin, including the eye, inner ear, meninges, and skin. The disease is characterised by bilateral uveitis associated with a varying constellation of auditory, neurological and cutaneous manifestations.The disease occurs more frequently among people with darker skin pigmentation. Asians, Native Americans, and Hispanics are most frequently affected. It predominates in patients aged between 20 and 50 years, and females are affected more frequently, with a female:male ratio of 2:1.The classic clinical course is characterised by bilateral panuveitis, hypoacusis, and meningitis, in addition to cutaneous involvement with poliosis, vitiligo, and alopecia.Although the exact cause of VKH disease remains unknown, it is thought to be a T-cell-mediated autoimmune process directed against melanocytes.VKHS classically begins with vague systemic symptoms suggestive of a viral infection, although a clear association between a specific viral agent and the disease has not been established.Genetic factors may play an important role in the loss of self-tolerance in VKHS. The HLA-DRB1*0405 allele is the main susceptibility allele for VKHS.Early and aggressive systemic corticosteroids are still the primary initial therapy for VKHS. Ocular complications may require an intravitreous injection of corticosteroids. Despite proper treatment with steroids, a number of patients experience recurrent attacks or steroid-associated complications. Thus, non steroid immunomodulatory therapy (IMT) has become necessary for the treatment of VKHS.     

Bardet–Biedl syndrome

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.     

Kleine–Levin syndrome

Kleine–Levin syndrome (KLS) is a rare sleep disorder. Most of the published studies have included only small numbers of patients. Therapeutic and diagnostic studies have the lowest evidence level. This study is a retrospective study including 15 KLS patients of the past 19 years. The patients had first symptoms in their early teens triggered by sleep deprivation, infections, and alcohol intake. Frequency ranged from 2–16/year, duration from 1–6 weeks. Liver enzymes, blood count, inflammatory markers, and magnetic resonance images were normal in all patients. Cerebral spinal fluid (CSF) hypocretin-1 was assessed in 6 patients. It was at the lower normal range in 2 patients and <?130 pg/ml in 2 other patients during an asymptomatic phase, while it was low in 2 patients (96–123 pg/ml) and normal in another patient during a symptomatic phase. Treatment with lithium was established in almost all patients and resulted in marked reduction or cessation of symptomatic episodes. The longest observation was 19 years with a relapse after cessation of lithium. Assessment of CSF hypocretin-1 during and outside of a symptomatic phase is recommended in the diagnostic workup of KLS; however, so far only the clinical course is helpful in establishing the diagnosis. Early treatment is recommended and has been found to be effective in the long course of the disease.     

Guillain–Barré syndrome

The term Guillain–Barré syndrome (GBS), the most frequent cause of acute paralytic neuropathy, covers a number of recognisably distinct variants. The exact cause of GBS is unknown, but 50–70% of cases appear 1–2 weeks after a respiratory or gastrointestinal infection, or another immune stimulus that induces an aberrant autoimmune response targeting peripheral nerves and their spinal roots. The interplay between the microbial and host factors that dictate whether and how the immune response shifts towards autoreactivity is still unclear, and nothing is known about the genetic and environmental factors that affect an individual's susceptibility to the disease. All patients with GBS need meticulous monitoring, and can benefit from supportive care and the early start of specific treatment. This review summarises the clinical features and diagnostic criteria of GBS and proposes an algorithm for its management. An analysis of the literature showed that, about one century after it was first described, new information concerning its etiopathogenesis has allowed the development of new treatment strategies that should be started immediately after diagnosis; however, the available therapies are not sufficient in many patients, especially in the presence of the acute inflammatory demyelinating polyneuropathy. New post-infectious forms, such as those caused by Zika virus and enterovirus D68, need to be carefully analysed and, in order to improve patient outcomes, research should continue to aim at identifying new biomarkers of disease severity and better means of avoiding axonal injury.     

Anxiety in Wiedemann–Steiner syndrome

This study examined anxiety in Wiedemann–Steiner syndrome (WSS). Eighteen caregivers and participants with WSS completed the parent- and self-report versions of the Screen for Child Anxiety Related Disorder or the adapted version of the Screen for Adult Anxiety Related Disorder. Approximately 33.33% of parents and 65% of participants with WSS rated in the clinical range for overall anxiety. Across anxiety subtypes, parents primarily indicated concerns with Separation Anxiety (72%), which was also endorsed by the majority of participants with WSS (82%). The emergent trend showed Total Anxiety increased with age based on parent-informant ratings. The behavioral phenotype of WSS includes elevated anxiety. Clinical management should include incorporating early behavioral interventions to bolster emotion regulation given the observed risk of anxiety with age.     

Retinal detachment in Loeys–Dietz syndrome

Loeys–Dietz syndrome (LDS) is an autosomal-dominant connective-tissue disorder with vascular and musculoskeletal abnormalities similar to Marfan syndrome. However, unlike Marfan, retinal detachment (RD) is rarely reported, and screening protocols do not currently feature ophthalmic assessment or RD counseling. We report a 5-generation family affected by LDS, where RD occurred in six eyes of four individuals. The proband was an 84-year-old male recently diagnosed with type-V LDS (TGFβ3 pathogenic variant c.899G>A, p.(Arg300Gln)). Further investigation was undertaken into the family's medical history. The proband experienced bilateral rhegmatogenous RD at age 60, requiring emergency surgical repair. Other notable ophthalmic features include unusual keratometry, abnormal biometry, and severe hayfever requiring long-term sodium cromoglycate treatment. The proband's sister, father, and uncle had also experienced RDs, all prior to LDS diagnosis. This series demonstrates that RD risk may be significant in LDS, and on occasion the presenting clinical feature. We suggest ophthalmic examination should be added to the initial assessment LDS patients, and patients informed of the early warning symptoms of retinal detachment. As in Marfan syndrome, LDS patients may exhibit cornea plana and abnormal corneal topography, producing atypical biometry. They may also present with allergic conjunctivitis, and awareness of these signs might facilitate earlier diagnosis.     

A diagnosis of Birt–Hogg–Dubé syndrome in individuals with Smith–Magenis syndrome: Recommendation for cancer screening

We report a series of four unrelated adults with Smith–Magenis syndrome (SMS) and concomitant features of Birt–Hogg–Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.     

Proprioceptive sensitivity in Ehlers–Danlos syndrome patients

Reaching movements are rapidly adapted following training with rotated visual feedback of the hand. Our laboratory has also found that this visuomotor adaptation results in changes in estimates of felt hand position (proprioceptive recalibration) in the direction of the visuomotor distortion (Cressman and Henriques in J Neurophysiol 102:3505–3518, 2009; Cressman et al. in Exp Brain Res 205:533–544, 2010). In the current study, we investigated proprioceptive acuity and proprioceptive recalibration in a group of individuals with Ehlers–Danlos syndrome (EDS), a degenerative condition associated with collagen malformation. Some studies have suggested that these patients may have proprioceptive impairments, but the exact nature of the impairment is unclear (Rombaut et al. in Clin Rheumatol 29:289–295, 2010a). In this study, we measured the ability of EDS patients to estimate their felt hand position and tested whether these estimates changed following visuomotor adaptation. We found EDS patients were less precise in estimating their felt hand position in the peripheral workspace compared to healthy controls. Despite this poorer sensitivity, they recalibrated hand proprioception to the same extent as healthy controls. This is consistent with other populations who experience proprioceptive deficits (e.g. the elderly, Parkinson’s disease patients), suggesting that sensory noise does not influence the extent of either motor or sensory plasticity.     

Visual depth processing in Williams–Beuren syndrome

Patients with Williams–Beuren Syndrome (WBS, also known as Williams Syndrome) show many problems in motor activities requiring visuo-motor integration, such as walking stairs. We tested to what extent these problems might be related to a deficit in the perception of visual depth or to problems in using this information in guiding movements. Monocular and binocular visual depth perception was tested in 33 patients with WBS. Furthermore, hand movements to a target were recorded in conditions with and without visual feedback of the position of the hand. The WBS group was compared to a group of control subjects. The WBS patients were able to perceive monocular depth cues that require global processing, but about 49% failed to show stereopsis. On average, patients with WBS moved their hand too far when no visual feedback on hand position was given. This was not so when they could see their hand. Patients with WBS are able to derive depth from complex spatial relationships between objects. However, they seem to be impaired in using depth information for guiding their movements when deprived of visual feedback. We conclude that the problems that WBS patients have with tasks such as descending stairs are not due to an inability to judge distance.     

KLLN epigenotype–phenotype associations in Cowden syndrome

Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis. KLLN promoter methylation was analyzed both as a continuous and a dichotomous variable in the calculation of phenotypic risks by stepwise logistic regression and Kaplan–Meier/standardized incidence ratio methods, respectively. Significantly increased KLLN promoter methylation was seen in CS individuals with and without a PTEN mutation/VUS compared with controls (P<0.001). Patients with high KLLN promoter methylation have increased risks of all CS-associated malignancies compared with the general population. Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent. KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status. Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients. Germline promoter hypermethylation of KLLN is associated with particular malignant and benign CS features, which is dependent on the PTEN mutation status.     

Hallermann–Streiff syndrome: A missing molecular link for a highly recognizable syndrome

The use of modern next-generation sequencing-based approaches for gene identification has tremendously improved our understanding of the molecular pathogenesis of the great majority of well-known syndromes, whereas only a few remain to be elucidated. Hallermann–Streiff syndrome is such a disorder for which the molecular basis is still unknown although it represents a highly recognizable phenotype. Clinically, patients with Hallermann–Streiff syndrome show typical craniofacial dysmorphism, eye malformations, a distinctive facial appearance, abnormalities of hair and skin, short stature, and, interestingly, they might also present with aspects of premature aging. The clinical diagnosis is mainly given by the very typical facial gestalt of patients. In this review, we (a) summarize the current knowledge on the phenotypic traits, focusing on described classic cases, (b) discuss the missing molecular link, and (c) present innovative future strategies for gene identification.