A diagnosis of Birt–Hogg–Dubé syndrome in individuals with Smith–Magenis syndrome: Recommendation for cancer screening

We report a series of four unrelated adults with Smith–Magenis syndrome (SMS) and concomitant features of Birt–Hogg–Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.     

Genetic testing in the evaluation of individuals with clinical diagnosis of atypical Sturge–Weber syndrome

Sturge–Weber Syndrome (SWS) is a rare vascular malformation disorder characterized by abnormal blood vessels in the brain, skin, and eye. SWS is most commonly caused by a somatic mosaic GNAQ-p.Arg183Gln variant. In this series, 12 patients presented for clinical evaluation of SWS but were noted to have atypical features, and therefore germline and/or somatic genetic testing was performed. Atypical features included extensive capillary malformation on the body as well as the face, frontal bossing, macrocephaly, telangiectasia, overgrowth of extremities, absence of neurologic signs and symptoms, and family history of vascular malformations. Five patients had a somatic GNAQ or GNA11 pathogenic variant, one patient had a somatic mosaic likely-pathogenic variant in PIK3CA, and another one had a somatic mosaic deletion that disrupted PTPRD. The other five patients had germline variants in RASA1, EPHB4, or KIT. Our findings suggest that patients presenting for SWS evaluation who have atypical clinical characteristics may have pathogenic germline or somatic variants in genes other than GNAQ or GNA11. Broad germline and somatic genetic testing in these patients with atypical findings may have implications for medical care, prognosis, and trial eligibility.     

PCSK2 expression in neuroendocrine tumors points to a midgut,pulmonary, or pheochromocytoma–paraganglioma origin

Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor-metastasis pairs, for PCSK2 expression with polymer-based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so-called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re-evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki-67 in well-differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.     

Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair–deficient tumors

PurposeMismatch repair-deficient (MMRD) colorectal cancer (CRC) and endometrial cancer (EC) may be suggestive of Lynch syndrome (LS). LS can be confirmed only by positive germ-line testing. It is unclear if individuals with MMRD tumors but no identifiable cause (MMRD+/germ-line−) have LS. Because LS is hereditary, individuals with LS are expected to have family histories of LS-related tumors. Our study compared the family histories of MMRD+/germ-line− CRC and/or EC patients with LS CRC and/or EC patients.MethodsA total of 253 individuals with an MMRD CRC or EC from one institution were included for analysis in one of four groups: LS; MMRD+/germ-line−; MMRD tumor with variant of uncertain significance (MMRD+/VUS); and sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation or BRAF mutation). Family histories were analyzed utilizing MMRpro and PREMM_1,2,6. Kruskal–Wallis tests were used to compare family history scores.ResultsMMRD+/germ-line− individuals had significantly lower median family history scores (MMRpro = 8.1, PREMM_1,2,6 = 7.3) than did LS individuals (MMRpro = 89.8, PREMM_1,2,6 = 26.1, P < 0.0001).ConclusionMMRD+/germ-line− individuals have less suggestive family histories of LS than individuals with LS. These results imply that MMRD+/germ-line− individuals may not all have LS. This finding highlights the need to determine other causes of MMRD tumors so that these patients and their families can be accurately counseled regarding screening and management.Genet Med 17 6, 476–484.     

Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants

Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (K_ATP) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K⁺ channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.     

Classical-like Ehlers–Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility

PurposeCurrently, 31 patients with classical-like EDS (clEDS) due to tenascin-X deficiency have been reported in the literature. We report on the clinical and molecular characteristics of 20 additional patients with clEDS to expand knowledge and to enable improved management of this rare genetic disorder.MethodsPatients diagnosed with clEDS by the national EDS service in the UK (n = 21) and abroad (n = 1) were asked for consent for publication of their clinical and molecular data.ResultsOf 22 patients, 20 consented. All patients had typical features of clEDS: joint hypermobility, easy bruising, and skin hyperextensibility without atrophic scars. Importantly, 3/20 patients experienced gastrointestinal complications consisting of small or large bowel ruptures and one esophageal rupture. Other notable observations included two separate occurrences of spontaneous compartment syndrome, suspicion of nonaccidental injury due to significant bruising, and significant clinical variability regarding the debilitating effect of joint dislocations.ConclusionsWe propose a predisposition to tissue fragility, particularly of the gastrointestinal tract in patients with clEDS. As such, clinical and molecular confirmation of this diagnosis is essential. It is recommended to follow up these patients closely to understand the natural history to develop better recommendations for management.     

The role of screening expectations in modifying short–term psychological responses to low-dose computed tomography lung cancer screening among high-risk individuals

ObjectiveThis study aimed to examine the relationship between pre-screening expectations and psychological responses to low-dose computerised tomography (LDCT) screening among high-risk individuals in the United Kingdom Lung Cancer Screening (UKLS) pilot trial.MethodsPrior to screening, high-risk individuals randomised into the intervention arm of the UKLS were asked about their expected screening test result. Their actual LDCT scan result was compared with their baseline screening expectation to determine the level of congruence. Levels of concern about and perceived accuracy of the result were assessed in a questionnaire two weeks following receipt of their test result.ResultsThe sample included 1589 participants. Regardless of their expected results, patients who required follow-up investigations after their initial LDCT scan were the most concerned about their result (p < 0.001). Participants who expected to require follow-up, but did not need it, perceived the test to be least accurate (p = 0.006).ConclusionsLung cancer screening participants who require follow-up or who have unexpected negative results can be identified for supportive interventions.Practical Implications: These findings can be used to ensure that any future LDCT lung cancer screening programme is tailored to identify and support those high-risk individuals who may benefit from additional help.     

Dementia in a woman with Prader–Willi syndrome

We report on a 58-year-old woman with Prader–Willi syndrome (PWS) and dementia.This case report illustrates a new research area in older adults with PWS. Dementia might be associated with PWS. In the case of dementia, more clinical studies are warranted to observe whether premature Alzheimer changes or indications of other dementia forms indeed occur more prevalent in people with PWS.     

Clinical findings in 39 individuals with Bohring–Opitz syndrome from a global patient-driven registry with implications for tumor surveillance and recurrence risk

Bohring–Opitz syndrome (BOS) is a rare genetic condition caused by pathogenic variants in ASXL1, which is a gene involved in chromatin regulation. BOS is characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, facial nevus simplex, severe myopia, a typical posture in infancy, variable anomalies, and feeding issues. Wilms tumor has also been reported in two individuals. We report survey data from the largest known cohort of individuals with BOS with 34 participants from the ASXL Patient-Driven Registry and data on five additional individuals with notable findings. Important or novel findings include hepatoblastoma (n = 1), an additional individual with Wilms tumor, two families with a parent who is mosaic including a pair of siblings, birth weights within the normal range for the majority of participants, as well as presence of craniosynostosis and hernias. Data also include characterization of communication, motor skills, and care level including hospitalization frequency and surgical interventions. No phenotype–genotype correlation could be identified. The ASXL Registry is also presented as a crucial tool for furthering ASXL research and to support the ASXL community.     

Newborn screening for severe T and B cell lymphopenia identifies a fraction of patients with Wiskott–Aldrich syndrome

The lack or marked reduction of recently formed T and B cells provides a basis for neonatal screening for severe combined immunodeficiencies (SCID) and X-linked agammaglobulinemia (XLA). Newborns with other conditions are also identified if a severe T or B cell lymphopenia is present at birth. We retrospectively analyzed Guthrie card samples from 11 children with Wiskott–Aldrich syndrome (WAS), a rare disease that requires early diagnosis and treatment, to determine whether combined T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) screening could identify these patients. 4 of 11 patients showed markedly reduced TREC or KREC copy numbers in their DBS as compared to storage-time matched controls and prospectively screened Swedish and German newborns. No correlation was observed between the WAS gene mutations, the clinical severity/course and the result of the screening assay. A diagnosis of WAS should thus be considered in newborns with positive TREC or KREC screening results.     

BCG Vaccine–Associated Complications in Patients with PTEN Hamartoma Tumor Syndrome

Journal of Clinical Immunology -     

Early detection of idiopathic scoliosis – analysis of three screening models

Introduction

The prevalence of lateral curvatures of the spine ranges from 0.3% to 15.3% in the general population. The aim of the study was to develop and compare three different screening tests for idiopathic scoliosis (IS) with respect to their effectiveness and costs.

Material and methods

The Delphi method was used to assess the efficacy of each screening algorithm in detecting IS in the population. An economic analysis was also performed.

Results

Diagnostic Algorithm 1 for IS comprised a screening examination performed by nurses and a general practitioner (GP) with verification by specialists. The unit cost of carrying out diagnostic work-up for IS in Algorithm 1 was €94 per child. The second algorithm involved the use of the moiré computer method, followed by verification by a specialist. The lower unit cost of €86 per child of diagnostic work-up according to Algorithm 2 was due to fewer stages compared to Algorithm 1. The highest effectiveness with the highest costs were found for the third algorithm, with only one stage, a specialist''s consultation (cost €153 per child).

Conclusions

The number of stages in an algorithm does not correlate positively with its efficacy or cost. The recommended scheme is Algorithm 3, where children are examined by rehabilitation specialists or a physiotherapist using a scoliometer and an inclinometer. The use of the apparently most expensive scheme (Algorithm 3) should result in lowering the costs of treatment of established idiopathic scoliosis and, in the long term, prove to be the most cost-effective solution for the health care system.     

Exome sequencing in Crisponi/cold-induced sweating syndrome–like individuals reveals unpredicted alternative diagnoses

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.     

Cerebro-fronto-facial syndrome type 3 with polymicrogyria: A clinical presentation of Baraitser–Winter syndrome

Baraitser–Winter syndrome (BRWS) is a rare condition affecting the development of the brain and the face. The most common characteristics are unusual facial appearance including hypertelorism and ptosis, ocular colobomas, hearing loss, impaired neuronal migration and intellectual disability. BRWS is caused by mutations in the ACTB and ACTG1 genes. Cerebro-fronto-facial syndrome (CFFS) is a clinically heterogeneous condition with distinct facial dysmorphism, and brain abnormalities. Three subtypes are identified. We report a female infant with striking facial features and brain anomalies (included polymicrogyria) that fit into the spectrum of the CFFS type 3 (CFFS3). She also had minor anomalies on her hands and feet, heart and kidney malformations, and recurrent infections. DNA investigations revealed c.586C>T mutation (p.Arg196Cys) in ACTB. This mutation places this patient in the spectrum of BRWS. The same mutation has been detected in a polymicrogyric patient reported previously in literature. We expand the malformation spectrum of BRWS/CFFS3, and present preliminary findings for phenotype–genotype correlation in this spectrum.