Townes-Brocks syndrome with craniosynostosis in two siblings.

This report describes a novel truncating c.709C > T p.(Gln237*) SALL1 variant in two siblings exhibiting sagittal craniosynostosis as a unique feature of Townes-Brocks syndrome (TBS, OMIM #107480). TBS is a rare autosomal dominant syndrome with variable phenotypes, including anorectal, renal, limb, and ear abnormalities, which results from heterozygous variants in the SALL1 gene, predominantly located in the 802 bp "hot spot region" within exon 2. Recent studies have suggested that aberrations in primary cilia and sonic hedgehog signalling contribute to the TBS phenotypes. The presence of the novel c.709C > T p.(Gln237*) SALL1 variant was confirmed in both the siblings and their father, whereas no mutations currently associated with craniosynostosis were detected. We hypothesise that the truncating c.709C > T p.(Gln237*) SALL1 variant, which occurs outside the "hot spot region" and inside the glutamine-rich domain coding region, could interfere with ciliary signalling and mechanotransduction, contributing to premature fusion of calvarial sutures. This report broadens the genetic and phenotypic spectrum of TBS and provides the first clinical evidence of craniosynostosis as a novel feature of the syndrome.

Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients.

In the last few years, trio-Whole Exome Sequencing (WES) analysis has revolutionized the diagnostic process for patients with rare genetic syndromes, demonstrating its potential even in non-specific clinical pictures and in atypical presentations of known diseases. Multiple disorders in a single patient have been estimated to occur in approximately 2-7.5% of diagnosed cases, with higher frequency in consanguineous families. Here, we report the clinical and molecular characterisation of eight illustrative patients for whom trio-WES allowed for identifing more than one genetic condition. Double homozygosity represented the causal mechanism in only half of them, whereas the other half showed peculiar multilocus combinations. The paper takes into consideration difficulties and learned lessons from our experience and therefore supports the powerful role of wide analyses for ascertaining multiple genetic diseases in complex patients, especially when a clinical suspicion could account for the majority of clinical signs. It finally makes clear how a patient's "deep phenotyping" might not be sufficient to suggest the presence of multiple genetic diagnoses but remains essential to validate an unexpected multilocus result from genetic tests.

Copy Number Variation Analysis Increases the Number of Candidate Loci Associated with Pediatric Obesity.

BACKGROUND/AIMS: Obesity is a multifactorial disease caused by the interaction of genetic, environmental, and behavioral factors. Currently, only a small number of obese children undergo genetic analysis, usually when obesity is associated with dysmorphic features. The aim of this study was to identify genomic rearrangement causing obesity. METHODS: We analyzed the DNA of children and adolescents by single-nucleotide polymorphism-array (platform CytoScan HD, Affymetrix). Patients included in this study were obese with dysmorphic features and/or intellectual disabilities and/or neuropsychomotor signs. RESULTS: Ninety-four children and adolescents with obesity (9.25 ± 4.04 years old, 60 males) were enrolled in the study. Dysmorphic features were found in 64 out of 94 subjects (68.1%), intellectual disability was found in 23 subjects (24.5%), and other neuropsychomotor signs in 31 (32.9%). Copy number variations (CNVs) were identified in 43 out of 94 patients (45.7%): among these 14 subjects showed at least 1 deletion, 22 duplication, whereas 7 patients showed both deletion and duplication. In 20 subjects (13 males), CNVs were linked or possibly related with obesity; in 23 subjects, this correlation cannot be inferred. CONCLUSION: A genetic origin of obesity was detected in about half of our obese children and adolescents with associated dysmorphic features and/or intellectual disability and/or neuropsychomotor signs. In these children, array-CGH analysis can be useful to identify causative genetic mutations, with consequent advantage in therapeutic management and follow-up of these patients.

Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants.

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.

Homozygous n.64C>T mutation in mitochondrial RNA-processing endoribonuclease gene causes cartilage hair hypoplasia syndrome in two siblings.

Cartilage hair hypoplasia syndrome (OMIM # 250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hair hypoplasia and variable extra-skeletal manifestations, including immunodeficiency, anemia, intestinal diseases and predisposition to cancers. Cartilage hair hypoplasia syndrome has a broad phenotype and it is caused by homozygous or compound heterozygous mutation in the mitochondrial RNA-processing endoribonuclease on chromosome 9p13. Although it is well known as a primordial dwarfism, descriptions of the prenatal growth are missing. To add further details to the knowledge of the phenotypic spectrum of the disease, we report on two siblings with cartilage hair hypoplasia syndrome, presenting n.64C > T homozygous mutation in the mitochondrial RNA-processing endoribonuclease gene. We describe the prenatal and postnatal growth pattern of the two affected patients, showing severe pre- and post-natal growth deficiency.

Consensus based recommendations for diagnosis and medical management of Poland syndrome (sequence).

BACKGROUND: Poland syndrome (OMIM: 173800) is a disorder in which affected individuals are born with missing or underdeveloped muscles on one side of the body, resulting in abnormalities that can affect the chest, breast, shoulder, arm, and hand. The extent and severity of the abnormalities vary among affected individuals. MAIN BODY: The aim of this work is to provide recommendations for the diagnosis and management of people affected by Poland syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years affected subjects. The literature search was performed in the second half of 2019. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. CONCLUSION: Being Poland syndrome a rare syndrome most recommendations here presented are good clinical practice based on the consensus of the participant experts.

Cannonball-Like Lung Nodules in a Patient With a Colorectal Tumor.

CASE PRESENTATION: A 72-year-old man underwent endoscopic resection of a 10-mm polypoid sessile lesion of the rectum. Histologic examination found a well-differentiated, low-grade (G1), neuroendocrine tumor. A thoracoabdominal CT scan was performed for staging purposes. The chest CT scan revealed a so-called cannonball-like distribution of multiple rounded nodules, with well-defined margins, ranging from 0.5 to 5 cm, scattered in both lungs (Figs 1A, 1B). The abdominal CT scan showed no abnormalities. A recent colonoscopy showed no evidence of malignancy. No prior chest imaging was available and the patient had never complained of respiratory symptoms. The patient was a former smoker, with a smoking history of 20 pack-years. He had a history of hypertension, mild stenosis of both carotid arteries, and benign prostatic hypertrophy. He reported the presence of long-standing multiple cutaneous hemangiomas on the trunk and face and a larger hemangiomatous lesion on his left lower limb, which was previously investigated by color Doppler ultrasound imaging. All these lesions were reported as unaltered and unchanged since early infancy.

Novel pathogenic TGFBR1 and SMAD3 variants identified after cerebrovascular events in adult patients with Loeys-dietz syndrome.

INTRODUCTION: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder due to heterozygous pathogenic variants in transforming growth factor beta (TGFß) signaling-related genes. LDS types 1-6 are distinguished depending on the involved gene. LDS is characterized by multiple arterial aneurysms and dissections in addition to variable neurological and systemic manifestations. Patient 1: a 68-year-old man was admitted due to an aphasic transient ischemic attack (TIA). Brain CT-scan and CT angiography revealed a chronic and asymptomatic right vertebral artery dissection. Stroke diagnostic panel was unremarkable. His history showed mild stroke familiarity. At age of 49, he was treated for dissecting-aneurysm of the ascending aorta and started anticoagulation therapy. Seven years later, he underwent surgery for dissecting aneurysm involving aortic arch, descending-thoracic aorta, left subclavian artery, and both iliac arteries. Patient 2: a 47-year-old man presented a left hemiparesis due to right middle cerebral artery (MCA) and anterior cerebral artery (ACA) occlusion caused by right internal carotid artery (ICA) dissection after sport activity. Despite i.v. thrombolysis and mechanical thrombectomy, he developed malignant cerebral infarction and underwent decompressive hemicraniectomy. Digital subtraction angiography showed bilateral carotid and vertebral kinking, aneurysmatic dilatation on both common iliac arteries and proximal ectasia of the descending aorta. His father and his uncle died because of an ischemic stroke and a cerebral aneurysm rupture with a subarachnoid hemorrhage (SAH), respectively. DISCUSSION: in both cases, considering the family history and the multiple dissections and aneurysms, LDS molecular analysis was performed. In patient 1, the novel NM_005902.3 (SMAD3): c.840T > G; p.(Asn280Lys) likely pathogenic variant was identified, thus leading to a diagnosis of LDS type 3. In patient 2, the novel NM_004612.2 (TGFBR1): c.1225T > G; p.(Trp409Gly) likely pathogenic variant was found, allowing for a diagnosis of LDS type 1. CONCLUSION: LDS is characterized by genetic and clinical variability. Our report suggests that this genetically-determined connective tissue disorder is probably underestimated, as it might firstly show up with cerebrovascular events, although mild systemic manifestations. These findings could lead to identify people at risk of severe vascular complications (i.e., through genetic consult on asymptomatic relatives), in order to perform adequate vascular assessments and follow-up to prevent complications such as stroke.

Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients.

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.

Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations.

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by developmental defects of midline structures. The most relevant clinical signs are ocular hypertelorism, hypospadias, cleft lip and palate, laryngo-tracheo-esophageal abnormalities, imperforate anus, and cardiac defects. Developmental delay, intellectual disability and brain abnormalities are also present. The X-linked form of this disorder is caused by mutations in the MID1 gene coding for a member of the tripartite motif family of E3 ubiquitin ligases. Here, we describe 12 novel patients that carry MID1 mutations emphasizing that laryngo-tracheo-esophageal defects are very common in OS patients and, together with hypertelorism and hypospadias, are the most frequent findings among the full spectrum of OS clinical manifestations. Besides missense and nonsense mutations, small insertions and deletions scattered along the entire length of the gene, we found that a consistent number of MID1 alterations are represented by the deletion of single coding exons. Deep characterization of one of these deletions reveals, for the first time within the MID1 gene, a complex rearrangement composed of two deletions, an inversion and a small insertion that may suggest the involvement of concurrent non-homologous mechanisms in the generation of the observed structural variant.

Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases.

UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. RESULTS: Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. CONCLUSIONS: The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant.

Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy.

OBJECTIVE: Homozygous recessive germline mutations of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene, encoding 15-hydroxyprostaglandin dehydrogenase, result in persistent elevation of circulating PGE(2) levels, causing the syndrome of primary hypertrophic osteoarthropathy (PHO). Homozygous HPGD mutations have so far been reported in 10 families, all but one displaying parental consanguinity. Only two of these families were of European origin. We wished to determine the role of HPGD in causing PHO in non-consanguineous European families. METHODS: Five previously unreported families of Caucasian European origin, with one or more individuals affected with typical PHO, were characterized clinically and by complete sequencing of the HPGD coding exons. RESULTS: Biallelic HPGD mutations were identified in affected individuals in all the five families, confirming a very specific association of this phenotype with HPGD mutations. The previously described c.175_176delCT frameshift mutation was observed in association with two different alleles of an adjacent single nucleotide polymorphism. CONCLUSIONS: Biallelic HPGD mutations are found in the majority of patients with typical PHO, and sequencing of the HPGD gene is a highly specific first-line investigation for patients presenting in this way, particularly during childhood. The c.175_176delCT frameshift mutation appears to be recurrent and to be the commonest HPGD mutation in Caucasian families.

Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.