Giulietta Scuvera

Prevalence of diabetes and pre‐diabetes in a cohort of Italian young adults with Williams syndrome

Williams syndrome (WS) is a rare, multisystemic genomic disorder showing a high prevalence of impaired glucose metabolism in adulthood. The reason for this association is unknown, though hemizygosity for genes mapping to the WS chromosome region has been implicated. Twenty‐two Italian young adults with WS (13 females, 9 males) were studied. A 75 g oral glucose tolerance test (OGTT) was performed and β‐cell function was estimated with Homeostasis Model Assessment (HOMA)‐B%, Insulinogenic Index, and corrected insulin response whereas insulin sensitivity was assessed with HOMA‐Insulin Resistance Index, Quantitative Insulin Check Index, and composite Insulin Sensitivity Index. One patient had known diabetes mellitus (DM), whereas impaired glucose tolerance (IGT) was diagnosed in 12 patients and DM in one (63.6% prevalence of impaired glucose metabolism). IGT patients were more insulin resistant than those with normal glucose tolerance (NGT), whereas β‐cell function was unchanged or increased. Islet autoimmunity was absent. Logistic regression showed that impaired glucose metabolism was not associated with age, body mass index (BMI), or family history of DM. β‐cell function, insulin sensitivity, and post‐load insulin levels did not differ between WS patients with NGT and healthy controls comparable for gender, age, and BMI, though WS–NGT patients had higher post‐load glucose values. These data confirm the high prevalence of impaired glucose metabolism in WS young adults, thus suggesting the need for screening these patients with OGTT. IGT is associated with reduced insulin sensitivity, but not with impaired β‐cell function, islet autoimmunity, and traditional risk factors for type 2 DM.

Autoimmunity and cytokine imbalance in inherited epidermolysis bullosa

In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease.

Response to “characteristics of 2p15‐p16.1 microdeletion syndrome: review and description of two additional patients”

Dear Editor, We read with great interest the recently published paper by Shimojima et al. (2015), who described two patients with 2p15 microdeletion and reviewed the clinical features of 2p15-p16.1 microdeletion syndrome. They also identified the shortest region of overlap (SRO) as 114 kb containing the USP34 and XPO1 genes, and speculated that these may be responsible for the syndrome’s neurological symptoms, although reports of additional patients with 2p15-p16.1 microdeletion are needed to support this hypothesis. We have a patient with an even smaller 2p15-p16.1 microdeletion than those reported by Shimojima et al. (2015): a 14-year-old male (the second child of a healthy non-consanguineous couple) who weighed 3250 g (25 centile) when he was born at a gestational age of 41 weeks after an uneventful pregnancy. He was hypotonic at birth and experienced developmental delay from early infancy (he started walking at the age of 18 months and spoke his first word at the age of >2 years); when he was 13 years old, he scored 55 on the Wechsler Intelligence Scale for Children-IV (WISC-IV), which is consistent with moderate intellectual disability (ID). Brain magnetic resonance imaging (MRI) revealed a type I Arnold-Chiari malformation. At present, his weight is 84 kg (>97th centile), height 166 cm (50 centile), and OFC 57 cm (90th centile). His facial features include deep-set eyes, partial synophrys, hypoplastic tragi and earlobes, a thin nasal tip, a columella below the alae nasi, and retrognathia (Fig. 1), and he is affected by moderate ID, obstructive respiratory disorder, enuresis and scoliosis. An aCGH analysis made using an Agilent array 180K (Agilent Technologies, Santa Clara, CA, USA), detected a 103 kb microdeletion in 2p15 from 61659957 to 61762873 (the genomic positions refer to build19); the deletion was not detected in either parent, thus indicating a de novo origin. Since the first description of two patients with 2p15-p16.1 microdeletion in 2007 (Rajcan-Separovic et al. 2007), more than 10 patients have been described (Felix et al. 2010; Liu et al. 2011; Fannemel et al. 2014). They all share similar clinical manifestations, including mild to severe developmental delay, growth retardation, microcephaly, distinctive facial features primarily affecting the oral region, and brain anomalies. The symptoms of our patient are compatible with the phenotypic spectrum of 2p15 microdeletion syndrome, whose core traits are a distinctive cranio-facial appearance and ID. He also presents a type I Arnold-Chiari malformation, a structural brain abnormality that has not previously been reported in association with the syndrome. The SRO in patients with 2p15-p16.1 microdeletion syndrome has been identified as a 114 kb region of chr2 that includes the USP34 and XPO1 genes (Shimojima et al. 2015); our patient has the shortest deletion region reported so far: 103 kb completely overlapping the SRO (Fig. 2). In conclusion, this report confirms that the SRO is the critical region for the 2p15-p16.1 microdeletion syndrome, and underlines the role of USP34 and XPO1 as the genes responsible for the syndrome’s clinical features. It also expands the spectrum of brain abnormalities associated with the syndrome.

Identification of an atypical microdeletion generating the RNF135-SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth

Neurofibromatosis type I (NF1) microdeletion syndrome, which is present in 4–11% of NF1 patients, is associated with a severe phenotype as it is caused by the deletion of NF1 and other genes in the 17q11.2 region. The variable expressivity of the disease makes it challenging to establish genotype–phenotype correlations, which also affects prognosis and counselling. We here describe a 3-year-old NF1 patient with an atypical deletion and a complex phenotype. The patient showed overgrowth, café au lait spots, inguinal freckling, and neurological abnormalities. The extent of the deletion was determined by means of array comparative genomic hybridisation, and its breakpoints were isolated by means of long-range polymerase chain reaction. Sequence analysis of the deletion junction fragment revealed the occurrence of an Alu-mediated recombination that led to the generation of a chimeric gene consisting of three exons of RNF135 and eleven exons of SUZ12. Interestingly, the deletion shares a common RNF135-centred region with another deletion described in a non-NF1 patient with overgrowth. In comparison with the normal RNF135 allele, the chimeric transcript was 350-fold over-expressed in peripheral blood, and the ADAP2 gene located upstream of RNF135 was also up-regulated. In line with this, the deletion causes the loss of a chromatin TD boundary, which entails the aberrant adoption of distal cis-acting regulatory elements. These findings suggest that RNF135 haploinsufficiency is related to overgrowth in patients with NF1 microdeletion syndrome and, for the first time, strongly indicate a position effect that warrants further genotype–phenotype correlation studies to investigate the possible existence of previously unknown pathogenic mechanisms.

The absence that makes the difference: choroidal abnormalities in Legius syndrome

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

Is cutis verticis gyrata-intellectual disability syndrome an underdiagnosed condition? A case report and review of 62 cases

Cutis Verticis Gyrata‐Intellectual Disability (CVG‐ID) syndrome is a rare neurocutaneous syndrome characterized by intellectual disability and scalp folds and furrows that are typically absent at birth and are first noticed after puberty. First reported in 1893, the syndrome was mainly identified in subjects living in psychiatric institutions, where it was found to have a prevalence of up to 11.4%. Most patients were reported in the literature during the first half of the 20th century. CVG‐ID is now a less reported and possibly under‐recognized syndrome. Here, we report a patient with CVG‐ID that was diagnosed using the novel approach of magnetic resonance imaging and we conduct a systematic review of all patients reported in the last 60 years, discussing the core clinical features of this syndrome.

Correction: The absence that makes the difference: choroidal abnormalities in Legius syndrome

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78

A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome

Gillespie syndrome (GLSP) is a rare congenital disorder characterized by partial aniridia, hypotonia, progressive cerebellar hypoplasia, nonprogressive ataxia, and intellectual disability. All causative variants to date affect the central or the 3ʹ‐terminal domains of ITPR1 gene and exhibit autosomal recessive or dominant inheritance pattern. We investigated by exome sequencing the molecular cause of GLSP in a family composed by consanguineous healthy parents, two affected siblings and one healthy son. We found the novel splice site variant c.278_279 + 2delACGT located at the 5ʹ‐end of ITPR1. The affected siblings were homozygotes, their parents heterozygous carriers and the variant was absent in the healthy son, indicating a recessive inheritance pattern. The deletion abolished the splice‐donor site at exon 5/intron 5 junction, causing the skipping of exon 5 and the generation of a premature STOP codon. The mutation is predicted to result in the synthesis of a 64‐amino acids nonfunctional protein. The mutant transcript comprised >96% of ITPR1 mRNA in the affected siblings, indicating that a small amount of wild‐type transcript was still present. The novel autosomal recessive mutation here reported is the first variant affecting the ITPR1 N‐terminal suppressor domain, thus extending the spectrum of the pathogenetic variants in GLSP and the range of the associated clinical manifestations.

Perthes disease: A new finding in Floating-Harbor syndrome

Floating‐Harbor Syndrome (FHS; OMIM #136140) is an ultra‐rare autosomal dominant genetic condition characterized by expressive language delay, short stature with delayed bone mineralization, a triangular face with a prominent nose, and deep‐set eyes, and hand anomalies. First reported in 1973, FHS is associated with mutations in the SRCAP gene, which encodes SNF2‐related CREBBP activator protein. Mutations in the CREBBP gene cause Rubinstein‐Taybi Syndrome (RSTS; OMIM #180849, #613684), another rare disease characterized by broad thumbs and halluces, facial dysmorphisms, short stature, and intellectual disability, which has a phenotypic overlap with FHS. We describe a case of FHS associated with a novel SRCAP mutation and characterized by Perthes disease, a skeletal anomaly described in approximately 3% of patients with RSTS. Thus Perthes disease can be added to the list of clinical features that overlap between FHS and RSTS.

16p13 microduplication without CREBBP involvement: Moving toward a phenotype delineation

The short arm of chromosome 16 is one of the less stable regions of our genome, as over 10% of the euchromatic region of 16p is composed of highly complex low copy repeats that are known to be predisposed to rearrangements mediated by non-allelic homologous recombination. The 16p13.3p13.13 molecular region has been defined as the 16p duplication hotspot, and duplications of chromosome 16p13 have recently been confirmed to cause a recognizable syndrome, with CREBBP being the main phenotype-causing gene. To date, only one case report is present in the literature with a 16p13 duplication without CREBBP involvement; we describe here a second analogous case with a not previously reported 16p13.2p13.13 microduplication. This paper allows us to better delineate the clinical features of 16p13 microduplications that do not encompass CREBBP and, concurrently, to narrow the molecular region responsible for congenital heart defects in 16p duplications as well as to propose GRIN2A as a candidate gene for epilepsy.