Marina Macchiaiolo

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype–phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms’ tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype–phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.

Homozygous familial hypercholesterolaemia

A 5-year-old boy aff ected with homozygous familial hypercholesterolaemia, diagnosed aged 1 year, was referred to us after having an acute ischaemic cardiac event. He presented with an LDL-cholesterol concentration of 26 mmol/L, and tendon xanthomas at the wrists, knees, and achilles (fi gure A–C). He had been treated with colestyramine. Coronary angio graphy showed a complete obstruction of the left coronary artery (fi gure D; see also webvideo) and a partial obstruction of the right coronary artery, which required stent placement. After the

Severe form of Freeman-Sheldon syndrome associated with brain anomalies and hearing loss

We describe a child with whistling face and multiple contractures, including ulnar deviation of fingers, compatible with a diagnosis of Freeman-Sheldon syndrome (FSS). This patient also presented severe hypertonicity, multiple episodes of pneumonia, difficulty in swallowing, and poor weight gain, which are characteristic of the most severe cases of FSS. A brain CT scan showed cerebellar and brainstem atrophy. Auditory brainstem responses were absent. The child died at 5 months of respiratory failure. This case suggests the possibility that, especially in the most severe forms, brain abnormalities may be responsible for some of the clinical manifestations of this syndrome, i.e., respiratory problems, difficulty in swallowing and severe hypertonicity. We assume that there is more than one pathogenetic mechanism (muscular, skeletal, and neurological) underlying FSS, which, together with the genetic heterogeneity and the wide range of clinical symptoms leads us to suggest that it is more appropriate to speak of a Freeman-Sheldon spectrum rather than syndrome and that thorough investigation for CNS and auditory abnormalities should be part of the initial work-up of these patients.

Fetal growth patterns in Beckwith-Wiedemann syndrome.

We provide data on fetal growth pattern on the molecular subtypes of Beckwith–Wiedemann syndrome (BWS): IC1 gain of methylation (IC1‐GoM), IC2 loss of methylation (IC2‐LoM), 11p15.5 paternal uniparental disomy (UPD), and CDKN1C mutation. In this observational study, gestational ages and neonatal growth parameters of 247 BWS patients were compared by calculating gestational age‐corrected standard deviation scores (SDS) and proportionality indexes to search for differences among IC1‐GoM (n = 21), UPD (n = 87), IC2‐LoM (n = 147), and CDKN1C mutation (n = 11) patients. In IC1‐GoM subgroup, weight and length are higher than in other subgroups. Body proportionality indexes display the following pattern: highest in IC1‐GoM patients, lowest in IC2‐LoM/CDKN1C patients, intermediate in UPD ones. Prematurity was significantly more prevalent in the CDKN1C (64%) and IC2‐LoM subgroups (37%). Fetal growth patterns are different in the four molecular subtypes of BWS and remarkably consistent with altered gene expression primed by the respective molecular mechanisms. IC1‐GoM cases show extreme macrosomia and severe disproportion between weight and length excess. In IC2‐LoM/CDKN1C patients, macrosomia is less common and associated with more proportionate weight/length ratios with excess of preterm birth. UPD patients show growth patterns closer to those of IC2‐LoM, but manifest a body mass disproportion rather similar to that seen in IC1‐GoM cases.

Corneal arcus as first sign of familial hypercholesterolemia

Figure 2. Corneal arcus is separated from the limbus by a thin ring of clear cornea (named “lucid interval of Vogt”). A 4-year-old boy was referred for investigation after his parents noticed the presence of a grayish ring parallel to the limbus of both eyes. His past medical history was unremarkable. His father was affected by familial hypercholesterolemia, which was responsive to statin therapy. The ophthalmologic evaluation described a corneal arcus separated by a 1-mm lucid interval (Figures 1 and 2). Blood exams revealed marked low-density lipoprotein hypercholesterolemia (530 mg/dL), suggesting a diagnosis of familial hypercholesterolemia. Corneal arcus, also named “arcus lipoides” or “arcus corneae,” is a white discoloration of the peripheral cornea near the corneoscleral limbus. There is a thin clear section separating the arcus from the limbus known as the lucid interval of Vogt. Arcus deposits tend to start at 6 and 12 o’clock and fill in until becoming completely circumferential. It develops in association with hyperlipidemia as a result of lipid deposition in the deep corneal stroma and the limbal sclera. Its prevalence increases with age. Corneal arcus should be differentiated from other lipid metabolisms affecting the cornea, such as lecithin-cholesterol acyltransferase deficiency deficiency, “fish eye” disease, or Tangier disease. n

An unusual case of anisocoria by vegetal intoxication: a case report

A 12 year old boy presented with an acute onset of anisocoria and blurred vision. Ocular motility was normal but his right pupil was dilated, round but sluggishly reactive to light. There was no history of trauma, eye drops instillation, nebulised drugs or local ointments. His past medical history was negative.A third nerve palsy was considered but the performed cerebral MRI was normal.On further anamnestic investigation the boy revealed that he had spent the morning doing gardening, and especially working on a trumpet plant. Datura and Brugmansia are well known toxic plant; all Datura and Brugmasia plants contain, primarily in their seeds and flowers, tropane alkaloids such as scopolamine, hyoscyamine and atropine. Systemic and local intoxications have already been described.The day after anisocoria was much less evident and completely resolved in three days.We present this case of an unusual cause of mydriasis to underline once more the importance of a well and deeply conducted medical history.

Nomenclature and definition in asymmetric regional body overgrowth

We designate a novel term “isolated lateralized overgrowth” (ILO) for the findings previously described as “isolated hemihypertrophy” and “isolated hemihyperplasia.” ILO is defined as lateralized overgrowth in the absence of a recognized pattern of malformations, dysplasia, or morphologic variants. ILO is likely genetically heterogeneous. Further study is required to determine more of the underlying genetic etiologies and potential associations with currently unrecognized patterns of malformation.

Growth hormone excess in children with neurofibromatosis type-1 and optic glioma

In children with neurofibromatosis type 1 (NF1) and optic pathways glioma (OPG), growth hormone (GH) excess has been rarely reported and mainly associated to central precocious puberty. The aim of our study is to evaluate the prevalence of GH excess, the association with central precocious puberty, the relation with tumor site and the evolution over time in a large cohort of children with NF1 and OPG. Sixty‐four NF1 children with OPG were evaluated. Patients with stature and/or height velocityu2009>2 SD for age were studied for GH secretion. Seven out of 64 children (10.9%) with NF1 and optic pathways glioma showed GH excess, isolated in 5 cases and associated to central precocious puberty in 2. All the children with GH excess had a tumor involving the chiasma. Children with GH excess underwent medical treatment with lanreotide and a minimum clinical/biochemical follow up of 2 years is reported. The present study demonstrates that GH excess should be considered as a relative frequent endocrine manifestation in NF1 patients, similarly to central precocious puberty. Therefore, these patients should undergo frequent accurate auxologic evaluations. On the other hand, an increase in height velocity in children with NF1, even despite normal ophthalmological exams, can suggest the presence of OPG and therefore represents an indication to perform brain MRI.

Incidental finding of severe hypertriglyceridemia in children. Role of multiple rare variants in genes affecting plasma triglyceride

BACKGROUNDnThe incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL).nnnOBJECTIVEnMolecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood.nnnMETHODSnWe performed the parallel sequencing of 20 plasma TG-related genes.nnnRESULTSnThree children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant.nnnCONCLUSIONSnTargeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG.

Borderline cognitive level in a family with Bazex-Dupré-Christol syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) [OMIM 301845] is an X‐linked dominant disorder of the hair follicle characterized by multiple basal cell carcinomas, follicular atrophoderma, congenital hypotrichosis, and hypohidrosis. Additional features include multiple milia, trichoepitheliomas, and axillary hidradenitis suppurativa as well as a variety of other symptoms. Some patients with a diagnosis of BDCS have had poor school performance. But no other associated psychopathological disorders have been described in the literature. We describe the neuropsychological characteristics and the co‐occurring psychopathological disorders in an Italian family (brother and sister, and their mother) affected by BDCS. The BDCS phenotype in this family was characterized by hypotrichosis, atrophoderma follicularis, milia, and trichoepitheliomas. No basal cell carcinomas were documented. At neuropsychological assessment the three affected family members all had a borderline cognitive level. Other identified psychopathological disorders included attention deficit hyperactivity disorder, executive deficits, academic difficulties, deficits in lexical skills, and internalizing problems. The presence of cognitive impairment in the three family members affected by BDCS suggests that cognitive impairment may be associated with the syndrome. It may be useful to assess neuropsychological performance in patients with BDCS to identify possible associated neuropsychological disorders.