Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

Two-year-old girl with metabolic acidosis and hyperkalaemia.

Hyperkalaemia hypertension and metabolic acidosis in children can pose a challenge of both diagnosis and management. This case chronicles the diagnostic journey of a 2-year-old girl with hyperkalaemia associated with hypertension and metabolic acidosis accidentally detected during a viruses.

Multimodal phenotyping of foveal hypoplasia in albinism and albino-like conditions: a pediatric case series with adaptive optics insights.

Aim of the present study is to evaluate the relationship between genetic and phenotypic data in a series of patients affected by grade I and II of foveal hypoplasia with stable fixation and good visual acuity using multimodal imaging techniques. All patients underwent complete clinical and instrumental assessment including structural Optical Coherence Tomography (OCT), OCT Angiography and Adaptive Optics (AO) imaging. Central macular thickness (CMT), inner nuclear layer (INL), vessel density in superficial capillary plexus were the main variables evaluated with OCT technology. Cone density, cone spacing, cone regularity, cone dispersion and angular density were the parameters evaluated with AO. Genetic evaluation and trio exome sequencing were performed in all affected individuals. Eight patients (3 males and 5 females) with a mean age of 12.62 years (range 8-18) were enrolled. The mean best corrected visual acuity (BCVA) was 0.18 ± 0.13 logMAR, mean CMT was 291.9 ± 16.6 µm and INL was 26.2 ± 4.6 µm. The absence of a foveal avascular zone (FAZ) was documented by examination of OCT-A in seven patients in the superficial capillary plexus. However, there was a partial FAZ in the deep plexus in patients P5 and P8. Of note, all the patients presented with major retinal vessels clearly crossing the foveal center. All individuals exhibited a grade I or II of foveal hypoplasia. In 5 patients molecular analyses showed an extremely mild form of albinism caused by compound heterozygosity of a TYR pathogenic variant and the hypomorphic p.[Ser192Tyr;Arg402Gln] haplotype. One patient had Waardenburg syndrome type 2A caused by a de novo variant in MITF. Two patients had inconclusive molecular analyses. All the patients displayed abnormalities on OCT-A. Photoreceptor count did not differ from normal subjects according to the current literature, but qualitative analysis of AO imaging showed distinctive features likely related to an abnormal pigment distribution in this subset of individuals. In patients with foveal hypoplasia, genetic and multimodal imaging data, including AO findings, can help understand the physiopathology of the foveal hypoplasia phenotype. This study confirms that cone density and visual function can both be preserved despite the absence of a pit.

Cell-free DNA for the detection of kidney allograft rejection.

Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .

Cutis marmorata telangiectatica congenita being caused by postzygotic GNA11 mutations.

Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of "nevus vascularis mixtus". Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype.

PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term referring to various clinical entities, which share the same pathogenetic mechanism. These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic α subunit of PI3K (p110α). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. If present at the germinal level, these gain-of-function mutations would be lethal to the embryo, therefore we only see them in the mosaic state. The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution. However, the severity of PROS is highly variable, ranging from localized and apparently isolate overgrowth to progressive and extensive lipomatous overgrowth associated with life-threatening vascular malformations, as seen in CLOVES syndrome. Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. Specific attention has been recently paid to molecules that are used and studied in the oncogenic setting and that are targeted on specific alterations of the pathway PI3K/AKT/mTOR. In June 2018, Venot et al. showed the effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. In these cases, dramatic anatomical and functional improvements occurred in all patients across many types of affected organ. Molecular testing in PROS patients is a crucial step in providing the conclusive diagnosis and then the opportunity for tailored therapy. The somatic nature of this group of diseases makes challenging to reach a molecular diagnosis, requiring deep sequencing methods that have to be performed on DNA extracted from affected tissue. Moreover, even analyzing the DNA extracted from affected tissue there is no guarantee to succeed in detection of the casual somatic mutation, since the affected tissue itself is highly heterogeneous and biopsy approaches can be burdened by incorrect sampling or inadequate tissue sample. We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status. She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. A high-coverage Whole Exome Sequencing analysis performed on DNA extracted from a skin sample showed a mosaic gain-of-function variant in the PIK3CA gene (p.H1047R, 11% of variant allele frequency). Once molecular confirmation of our clinical suspicion was obtained, after a multidisciplinary evaluation, we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. The treatment is still ongoing.

Genetic counseling during COVID-19 pandemic: Tuscany experience.

BACKGROUND: COVID-19 outbreak prompted health centres to reorganize their clinical and surgical activity. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to pandemic. METHODS: We stratified all our scheduled visits, from March 9th through April 30th, and assessed case-by-case which genetic consultations should be maintained as face-to-face visit, or postponed/switched to telemedicine. RESULTS: Out of 288 scheduled appointments, 60 were prenatal consultations and 228 were postnatal visits. We performed most of prenatal consultations as face-to-face visits, as women would have been present in the hospital to perform other procedures in addition to our consult. As for postnatal care, we suspended all outpatient first visits and opted for telemedicine for selected follow-up consultations: interestingly, 75% of our patients' parents revealed that they would have cancelled the appointment themselves for the fear to contract an infection. CONCLUSIONS: Spread of COVID-19 in Italy forced us to change our working habits. Given the necessity to optimize healthcare resources and minimize the risk of in-hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics.