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Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions (90%), encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), or by pathogenic variants in RAI1 itself (10%). RAI1 is a dosage-sensitive gene expressed in many tissues and acting as transcriptional regulator. The majority of individuals exhibit a mild-to-moderate range of intellectual disability. The behavioral phenotype includes significant sleep disturbance, stereotypes, maladaptive and self-injurious behaviors. In this review, we summarize current clinical knowledge and therapeutic approaches. We further discuss the common biological background shared with other conditions commonly retained in differential diagnosis.

The authors report that a gain of function in the catalytic subunit beta of the cyclic AMP–dependent protein kinase (protein kinase A), resulting from the presence of four copies of PRKACB (instead of the normal two), may lead to a Carney complex phenotype. To the Editor: Beuschlein et al. report a gain of function in PRKACA, the catalytic subunit alpha (Cα) of the cyclic AMP (cAMP)–dependent protein kinase (protein kinase A [PKA]) in cortisol-producing adenomas and micronodular adrenocortical hyperplasia. 1 Micronodular adrenocortical hyperplasia is also associated with Carney complex and inactivating mutations of the PKA regulatory subunit RIα (encoded by PRKAR1A ). 2 , 3 We report the case of a young woman with Carney complex who presented at 19 years of age with acromegaly, pigmented spots, and myxomas (Figure 1A); she did not have Cushing's syndrome (see the Supplementary Appendix, available with the full text of . . .

TDP2 encodes a 5′-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients’ fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.

Background Thousand and one amino-acid kinase 1 ( TAOK1 ) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility. Case presentation We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia. Conclusions To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1 -related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.

Background Pompe disease, also known as glycogenosis type II or acid maltase deficiency, is an autosomal recessive disease caused by a deficiency of alpha-glucosidase. The severity depends mainly on the type of mutation, which in turn determines early or late onset; therapy modifies the outcome but does not alter the severity of the disease at presentation. Case presentation We present a case report of a male infant, inborn and delivered at a gestational age of 39 weeks. Medical history reveals consanguineous parents with no invasive screening tests performed during pregnancy. They chose not to undergo prenatal screening even though they were aware of the risks associated with their consanguinity. At birth, the newborn was atonic and pale, with a heart rate of 70 bpm. During resuscitation, an umbilical venous catheter was placed, and three doses of adrenaline and one dose of bicarbonate were administered. At the Neonatal Intensive Care Unit, he underwent therapeutic hypothermia. Echocardiography, performed a few hours later, revealed severe biventricular and septal hypertrophy consistent with non-obstructive hypertrophic cardiomyopathy. During recovery, even after the discontinuation of hypothermia, the newborn exhibited abnormal neurological signs, including axial hypotonia and a tendency to keep his mouth open with tongue protrusion. Given the clinical picture and the early detection of septal and biventricular hypertrophy, genetic testing was performed, revealing a homozygous c.2560 C > T variant in the acid alpha-glucosidase gene (both parents were carriers), described in scientific literature as a class 5 pathogenic variant associated with glycogenosis type II (Pompe disease). Conclusion Pompe disease is a rare genetic disorder and may be difficult to diagnose at birth. Suspicion should arise in the presence of hypertrophic cardiomyopathy, especially when associated with a history of neonatal asphyxia and abnormal neurological signs. An accurate diagnosis and early treatment are essential to improving the patient’s survival and quality of life.

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.

Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive inherited skeletal dysplasia characterized by progressive non-inflammatory arthropathy affecting primarily the articular cartilage. Currently, little is known about the functional musculoskeletal aspects of these patients. In particular, an abnormal gait pattern has been described, without a clear hypothesis of the underlying causes in terms of muscular activity. This study presents the case of two siblings, 4 and 9 years old, a boy and a girl, respectively, suffering from PPRD at different stages of the disease. In addition to the clinical assessment, an instrumental gait analysis was performed. Swelling of the interphalangeal finger joints and fatigue were present in both cases. Gait abnormalities consisted of a relevant reduction in the ankle plantarflexion in the terminal phase of the gait cycle, associated with reduced gastrocnemius EMG activity and increased activity of the tibialis anterior, resulting in overloading at the initial peak of ground reaction forces. Gait anomalies observed were similar in both siblings with PPRD, although at different ages, and confirm walking patterns previously described in the literature. The calf muscle strength deficit and reduced activity during the stance phase of gait present in these two siblings indicate the typical absence of the propulsive phase. A stomping gait pattern, with the foot striking the ground hard on each step, was originally described. Further neurophysiological investigations are required to determine the origin of muscle weakness.

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.

MEDNIK syndrome (Mental Retardation, Enteropathy, Deafness, Neuropathy, Ichthyosis and Keratodermia) is a severe hyper-rare condition resulting from the biallelic variants in the AP1S1 gene, implicated in intracellular trafficking and copper homeostasis. Only 18 affected individuals (seven AP1S1 pathogenic variants overall) have been reported to date, with a high early lethality due to life-threatening congenital enteropathy. Seven patients have been empirically treated with zinc. Due to the paucity of literature data, little is known about the clinical course of individuals affected by MEDNIK syndrome, and the possible early association with epilepsy needs to be investigated. We present the first case of Italian origin affected by MEDNIK syndrome carrying a new homozygous AP1S1 stop variant, presenting with congenital severe enteropathy and feeding-related seizures, thus representing an early, singular manifestation of the disease. We describe her clinical course and the zinc acetate therapeutic experience. We also reviewed the literature focusing on clinical manifestations (especially neurological), brain neuroimaging and the symptom evolution of patients with AP1S1-related MEDNIK syndrome and discuss possible future therapeutic attempts.

Hearing loss is the most frequent sensorineural disorder, affecting approximately 1:1000 newborns. Hereditary forms (HHL) represent 50–60% of cases, highlighting the relevance of genetic testing in deaf patients. HHL is classified as non-syndromic (NSHL—70% of cases) or syndromic (SHL—30% of cases). In this study, a multistep and integrative approach aimed at identifying the molecular cause of HHL in 102 patients, whose GJB2 analysis already showed a negative result, is described. In NSHL patients, multiplex ligation probe amplification and long-range PCR analyses of the STRC gene solved 13 cases, while whole exome sequencing (WES) identified the genetic diagnosis in 26 additional ones, with a total detection rate of 47.6%. Concerning SHL, WES detected the molecular cause in 55% of cases. Peculiar findings are represented by the identification of four subjects displaying a dual molecular diagnosis and eight affected by non-syndromic mimics, five of them presenting Usher syndrome type 2. Overall, this study provides a detailed characterisation of the genetic causes of HHL in the Italian population. Furthermore, we highlighted the frequency of Usher syndrome type 2 carriers in the Italian population to pave the way for a more effective implementation of diagnostic and follow-up strategies for this disease.