Elastography as a non-invasive method of screening non-alcoholic fatty liver disease in the adult phenotype of paediatric obstructive sleep apnoea.

PURPOSE: The high prevalence of non-alcoholic fatty liver disease (NAFLD) in obese children with obstructive sleep apnoea (OSA) calls for early non-invasive screening. The aim of this study was to use ultrasonographic liver echogenicity and elasticity to evaluate the early stages of liver injury in obese children with OSA. METHODS: Fifty-five obese children with OSA aged 12 to 15 years were included. The control group (n = 56) consisted of healthy, non-obese children. All children underwent ultrasound examination to assess liver echogenicity using the hepatorenal index (HRI) and real-time elastography to determine the liver fibrosis index (LFI). Polysomnographic parameters, sonographic values, and clinical-biochemical assessment were statistically analysed according to OSA and its severity. Subgroup 1 was obese children with OSA and AHI < 5 and subgroup 2 was obese children with OSA and AHI ≥ 5. RESULTS: Higher average values of HRI and LFI were recorded in the group of obese paediatric patients with OSA (mean age ± SD, 14.1 ± 2.2 year; 53% male; BMI z-score, 2.6 ± 0.35) compared to the control group (1.37 ± 0.19 vs. 1.12 ± 0.07, p < 0.001 and 1.82 ± 0.31 vs. 1.02 ± 0.27, p < 0.001). A significantly higher LFI was recorded in subgroup 2 compared to subgroup 1 (2.0 ± 0.3 vs. 1.6 ± 0.2, p < 0.001) while laboratory parameters and HRI (1.4 ± 0.2 vs. 1.4 ± 0.2, p = 0.630) did not change significantly. A strong positive correlation was found between the severity of OSA and the LFI (r = 0.454; p < 0.01). CONCLUSIONS: These findings suggest that ultrasound elastography is a useful non-invasive screening test for OSA-related steatohepatitis in obese adolescents, but other clinical studies are needed to confirm this result.

Koolen-de Vries syndrome in a 63-year-old woman: Report of the oldest patient and a review of the adult phenotype.

Koolen-de Vries syndrome (KdVS) is a rare genetic disorder caused by a de novo microdeletion in chromosomal region 17q21.31 encompassing KANSL1 or by a de novo intragenic pathogenic variant of KANSL1. KdVS is typically characterized by intellectual disability (ID), variable from mild to severe, developmental psychomotor delay, especially of expressive language development, friendly disposition, and multiple systemic abnormalities. So far, most of the individuals affected by KdVS are diagnosed in infancy or in adolescence; to the best of our knowledge, only 34 (including ours) adults have been reported in literature. Here we present the adult phenotype of a 63-year-old Italian woman affected by KdVS, caused by a 17q21.31 microdeletion. She is, to our knowledge, the oldest affected individual reported so far. We collected her clinical history and photographs, as well as those of other 26 adult patients described so far and compared her to them. We propose that the cardinal features of KdVS in adulthood are ID (ranging from mild to severe, usually moderate), friendly behavior, musculoskeletal abnormalities (especially scoliosis), and facial dysmorphism (a long face and a pronounced pear-shape nose with bulbous overhanging nasal tip). Therefore, we suggest considering KdVS in differential diagnosis in adult patients characterized by these features.

Motor and behavioral phenotype of Dravet syndrome in adulthood.

In a comparative cross-sectional study, 26 adult individuals with clinically typical, genetically confirmed Dravet syndrome (DS) and an equal number of individuals with early onset, problematic epilepsy, and intellectual disability (ID) of comparable severity were included. The aim of the study was to find out whether patients with DS could be clearly distinguished from the comparison group with regard to neurological and behavioral symptoms. Significant differences were found in that individuals with DS clearly more frequently exhibited a symptom cluster characterized by bradykinesia, hypomimia, hypophonia, (spastic) increased muscle tone, ataxia, sthenic perseveration, and a special interest in colors. To these symptoms must be added, according to the findings of previous examinations, mastication, camptocormia/antecollis on the one hand, and the tendency to visual hallucinations on the other hand, in order to define one neuropsychiatric phenotype of DS in adulthood. To these symptoms must be added, according to the findings of previous investigations, crouch gait with camptocormia/antecollis on the one hand, and the tendency to visual hallucinations on the other hand, in order to define one outlined neuropsychiatric phenotype of DS in adulthood.

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.

Phenotype evolution and health issues of adults with Beckwith-Wiedemann syndrome.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) phenotype usually mitigates with age and data on adulthood are limited. Our study aims at reporting phenotype evolution and health issues in adulthood. METHODS: 34 patients (16 males), aged 18-58 years (mean 28.5) with BWS were enrolled. RESULTS: 26 patients were molecularly confirmed, 5 tested negative, and 3 were not tested. Final tall stature was present in 44%. Four patients developed Wilms' Tumor (2, 3, 5, and 10 years, respectively); one hepatoblastoma (22 years); one acute lymphoblastic leukemia (21 years); one adrenal adenoma and testicular Sertoli cell tumor (22 and 24 years, respectively); and three benign tumors (hepatic haemangioma, uterine myoma, and mammary fibroepithelioma). Surgery for BWS-related features was required in 85%. Despite surgical correction several patients presented morbidity and sequelae of BWS pediatric issues: pronunciation/swallow difficulties (n = 9) due to macroglossia, painful scoliosis (n = 4) consistent with lateralized overgrowth, recurrent urolithiasis (n = 4), azoospermia (n = 4) likely consequent to cryptorchidism, severe intellectual disability (n = 2) likely related to neonatal asphyxia and diabetes mellitus (n = 1) due to subtotal pancreatectomy for intractable hyperinsulinism. Four patients (two males) had healthy children (three physiologically conceived and one through assisted reproductive technology). CONCLUSIONS: Adult health conditions in BWS are mostly consequent to pediatric issues, underlying the preventive role of follow-up strategies in childhood. Malignancy rate observed in early adulthood in this small cohort matches that observed in the first decade of life, cumulatively raising tumor rate in BWS to 20% during the observation period. Further studies are warranted in this direction.

Natural history in Malan syndrome: survey of 28 adults and literature review.

BACKGROUND: Malan syndrome (MALNS), previously referred to as "Sotos syndrome 2" due to its resemblance to Sotos syndrome (SS), is an ultra-rare neurodevelopmental disorder characterized by overgrowth, typical craniofacial features, intellectual disability (ID), and a range of psychobehavioral, musculoskeletal, vision and neurological signs. As MALNS and SS partly overlap, it is essential to more accurately profile their clinical presentations and highlight their differences in order to improve syndrome specific management. An increasing number of individuals with MALNS reach adult-age though the natural history of the disorder is poorly characterized due to the small number of adult individuals described so far. As a consequence, current guidelines are limited to the pediatric population. Further delineation of MALNS is essential to optimize care in adulthood. RESULTS: A mixed approach based on cross-sectional data collection with a survey disseminated to caregivers of adults with molecularly confirmed MALNS and literature review was conducted. Twenty-eight caregivers completed the survey. Clinical presentation in adulthood is multisystemic and defined by psychobehavioral comorbidities (96%), musculoskeletal involvement (96%), vision impairment (96%) and neurological complications (86%). The most common signs were anxiety (79%), hypotonia (75%), movement difficulty (75%), scoliosis (64%), problems with coordination (61%), strabismus (57%), constipation (54%), breastbone abnormalities (54%) and advanced bone age during childhood (54%). Impaired vision was complicated by vision decline (36%) and optic atrophy (32%). We report some previously unidentified features, including high pain threshold (46%), incontinence (25%), tremors (21%), muscle hypoplasia (18%) and tics (18%). CONCLUSIONS: This survey in the adult population has allowed a more complete description of the natural history of MALNS. Our findings will contribute to the development and improvement of standards of care for adults with MALNS to assure optimal health monitoring and treatment of evolutive complications. We propose additional recommendations to the previous dataset of clinical evaluations specifically applied to adults. The comparison of MALNS and SS adult presentation highlights significant differences in terms of prevalence and severity of ID, behavioral issues, and vision problems, confirming that a proper differential diagnosis between the two conditions is indispensable to guide physicians and mental health professionals to syndrome specific management.

Adult Height, 22q11.2 Deletion Extent, and Short Stature in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) manifests as a wide range of medical conditions across a number of systems. Pediatric growth deficiency with some catch-up growth is reported, but there are few studies of final adult height. We aimed to investigate how final adult height in 22q11.2DS compared with general population norms, and to examine predictors of short stature in in a cohort of 397 adults with 22q11.2DS (aged 17.6-76.3 years) with confirmed typical 22q11.2 microdeletion (overlapping the LCR22A to LCR22B region). We defined short stature as <3rd percentile using population norms. For the subset (n = 314, 79.1%) with 22q11.2 deletion extent, we used a binomial logistic regression model to predict short stature in 22q11.2DS, accounting for effects of sex, age, ancestry, major congenital heart disease (CHD), moderate-to-severe intellectual disability (ID), and 22q11.2 deletion extent. Adult height in 22q11.2DS showed a normal distribution but with a shift to the left, compared with population norms. Those with short stature represented 22.7% of the 22q11.2DS sample, 7.6-fold greater than population expectations (p < 0.0001). In the regression model, moderate-to-severe ID, major CHD, and the common LCR22A-LCR22D (A-D) deletion were significant independent risk factors for short stature while accounting for other factors (model p = 0.0004). The results suggest that the 22q11.2 microdeletion has a significant effect on final adult height distribution, and on short stature with effects appearing to arise from reduced gene dosage involving both the proximal and distal sub-regions of the A-D region. Future studies involving larger sample sizes with proximal nested 22q11.2 deletions, longitudinal lifetime data, parental heights, and genotype data will be valuable.

The adult phenotype of Schaaf-Yang syndrome.

BACKGROUND: MAGEL2-associated Schaaf-Yang syndrome (SHFYNG, OMIM #615547, ORPHA: 398069), which was identified in 2013, is a rare disorder caused by truncating variants of the paternal copy of MAGEL2, which is localized in the imprinted region on 15q11.2q13. The phenotype of SHFYNG in childhood partially overlaps with that of the well-established Prader-Willi syndrome (PWS, OMIM #176270). While larger numbers of younger individuals with SHFYNG have been recently published, the phenotype in adulthood is not well established. We recruited 7 adult individuals (aged 18 to 36) with molecularly confirmed SHFYNG and collected data regarding the clinical profile including eating habits, sleep, behavior, personal autonomy, psychiatric abnormalities and other medical conditions, as well as information about the respective phenotypes in childhood. RESULTS: Within our small cohort, we identified a range of common features, such as disturbed sleep, hypoactivity, social withdrawal and anxiety, but also noted considerable differences at the level of personal autonomy and skills. Behavioral problems were frequent, and a majority of individuals displayed weight gain and food-seeking behavior, along with mild intellectual disability or borderline intellectual function. Classical symptoms of SHFYNG in childhood were reported for most individuals. CONCLUSION: Our findings indicate a high variability of the functional abilities and social participation of adults with SHFYNG. A high prevalence of obesity within our cohort was notable, and uncontrollable food intake was a major concern for some caregivers. The phenotypes of PWS and SHFYNG in adulthood might be more difficult to discern than the phenotypes in childhood. Molecular genetic testing for SHFYNG should therefore be considered in adults with the suspected diagnosis of PWS, if testing for PWS has been negative.

Hypocalcaemia in an adult: the importance of not overlooking the cause.

A 58-year-old male patient was admitted at the São Bernardos's Hospital (Setúbal, Portugal) with generalised muscle spasms, dyspnoea, laryngospasm and bronchospasm in the context of severe hypocalcaemia. Despite efforts to correct serum calcium, it remained below average, leading to question the true cause of hypocalcaemia. Low parathyroid hormone and 25-hydroxyvitamin D, along with facial anomalies, palate defect and cognitive impairment with concomitant psychiatric disorder led to a suspicion of a DiGeorge/velocardiofacial/22q11.2 deletion syndrome (DS), which was confirmed through genetic testing. The 22q11.2 DS has a wide phenotypic expression and there are growing reports of diagnosis being made in adulthood. This case report highlights the importance of understanding the cause of refractory hypocalcaemia and alerts medical community to carefully access these patients, for this metabolic disorder may only present in later stages of life.

Using Zebrafish to Test the Genetic Basis of Human Craniofacial Diseases.

Genome-wide association studies (GWASs) opened an innovative and productive avenue to investigate the molecular basis of human craniofacial disease. However, GWASs identify candidate genes only; they do not prove that any particular one is the functional villain underlying disease or just an unlucky genomic bystander. Genetic manipulation of animal models is the best approach to reveal which genetic loci identified from human GWASs are functionally related to specific diseases. The purpose of this review is to discuss the potential of zebrafish to resolve which candidate genetic loci are mechanistic drivers of craniofacial diseases. Many anatomic, embryonic, and genetic features of craniofacial development are conserved among zebrafish and mammals, making zebrafish a good model of craniofacial diseases. Also, the ability to manipulate gene function in zebrafish was greatly expanded over the past 20 y, enabling systems such as Gateway Tol2 and CRISPR-Cas9 to test gain- and loss-of-function alleles identified from human GWASs in coding and noncoding regions of DNA. With the optimization of genetic editing methods, large numbers of candidate genes can be efficiently interrogated. Finding the functional villains that underlie diseases will permit new treatments and prevention strategies and will increase understanding of how gene pathways operate during normal development.