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Persistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC. Evaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings. Prospective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings. In both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake. 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI.

Background To improve the precision of molecular diagnosis by means of a comprehensive bidirectional phenotypic and genotypic reanalysis in cases of unresolved monogenic diabetes previously investigated using a targeted next-generation sequencing (tNGS) panel. Methods Molecular and clinical data from 128 unresolved cases referred between 2011 and 2019 were analyzed. These included 92 cases of suspected maturity-onset diabetes of the young (MODY), 12 of neonatal diabetes, 16 of familial partial lipodystrophy (FPLD), 7 of mitochondrial diabetes, and 1 of Wolfram syndrome. All cases were initially investigated using a tNGS panel consisting of 51 nuclear genes and the complete mitochondrial genome. Results This extensive reanalysis process increases molecular diagnosis from 9 to 22%. Phenotypic reevaluation, entailing in-depth phenotyping, is instrumental in excluding 62 atypical cases (48.4%). Genotypic reanalysis identifies 5 previously overlooked molecular defects: two mutations in regulatory regions (one in the HNF1A promoter and another in the PTF1A enhancer); one in the MTTK mitochondrial gene; one in the MFN2 gene; and one in the GCK gene. Conclusions Our findings indicate that a combined approach of genotypic and, mainly, phenotypic reanalysis is an effective strategy for improving the accuracy of molecular diagnosis in individuals with suspected monogenic diabetes. Plain language summary Some people develop diabetes early in life due to inherited genetic conditions. However, identifying the exact cause can be difficult, and many people remain without a diagnosis after initial testing. In this study, researchers revisited the medical and genetic data of 128 individuals who were previously suspected to have a genetic form of diabetes but remained undiagnosed. By combining updated genetic tools with detailed clinical review, they were able to provide new diagnoses for some and rule out inherited diabetes in others. Because knowledge in genetics evolves rapidly, this study highlights the importance of reanalyzing past test results over time. Doing so can lead to more accurate diagnoses and better care for individuals and families affected by early-onset diabetes. Franco et al. perform a combined phenotypic and genotypic reanalysis of unresolved 128 monogenic diabetes cases. Their approach increases diagnostic yield and highlights the key role of deep phenotyping in previously overlooked cases, and provides a diagnosis for suspected cases.

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A , BBC3 , CNTN6 , and NAA15 . In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci , comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment.

Background: Syndromic obesity (SO) refers to obesity with additional phenotypes, including intellectual disability (ID)/developmental delay (DD), dysmorphic features, or organ-specific abnormalities. SO is rare, has high phenotypic variability, and frequently follows a monogenic pattern of inheritance. However, the genetic etiology of most cases of SO has not been elucidated. Subjects and methods: In this study, we investigated 20 SO patients by whole-exome sequencing (WES) trios to identify causal genetic variants. Results: 4/20 patients had negative results for array comparative genomic hybridization (aCGH) analyses. In the remaining 15 patients, in addition to SNVs and indels, CNVs were also evaluated. Pathogenic/likely pathogenic (P/LP) SNVs/indels were detected in 6/20 patients (involving MED13L, AHDC1, EHMT1, MYT1L, GRIA3, and SETD1A), while two patients carried an inherited VUS. In addition, P/LP CNVs were observed in 3/15 patients (involving SATG2, KIAA0442, and MEIS2). Conclusions: All nine detected P/LP variants involved genes already known to lead to syndromic ID/DD; however, for only two genes (EHMT1 and MYT1L) is the link with obesity well established. This is the first study applying a comprehensive genomic investigation of an SO cohort, showing a high diagnostic yield (~47%). Additionally, our findings suggested that several known ID/DD genes may also predispose individuals to SO.

Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia. To date, only four variants have been reported; one nonsense, one splice-site, and two frameshifts in five AMDP families. Here, we report the first missense variant and a second splice-site variant in PRKG2 in two patients with clinical and radiological features of acromesomelic dysplasia. Furthermore, functional studies of the novel missense variant, p.Val470Gly, revealed that it was unable to down-regulate FGF2-induced MAPK signaling and, thus, would be predicted to cause growth delay. Hence, this report expands the mutational spectrum in skeletal dysplasias associated with PRKG2 variants. In addition, we propose recognizable facial features with acromesomelic dysplasia, PRKG2 type.

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.

BACKGROUND CSHS refers to the association of epidermal nevus syndrome (ENS), skeletal dysplasia, and hypophosphatemic osteomalacia (OM) mediated by FGF23 resulting from post zygotic mutations in RAS signaling pathway, with known by relationship with human cancers. CLINICAL CASE Patient 1 presented ENS since birth at right hemibody. At 1.6-yr-old, she underwent treatment for a left inguinal rhabdomyosarcoma. At 3-yr-old, she had an atraumatic right femur fracture associated with muscle weakness, and laboratory data and X-rays suggesting OM. Phosphate and calcitriol were initiated, but with poor adherence, and no improvement; skeletal deformities got worse and the girl became wheelchair user at 13-yr-old. Skeletal CT scan at age 17 showed dysplastic lesions with lytic changes at right dimidium (skull, jaw, ribs, pelvis and femur) with systemic OM signs confirmed by bone biopsy. The progressive enlargement of the jaw lesion required surgical removal after 2 years; histopathology revealed giant cell tumor. Patient 2 also had congenital ENS on the right dimidium with complaint of bone pain and muscle weakness since 2-yr-old. She evolved with bone fractures and deformities at 4-yr-old, becoming wheelchair user after 2 years. Iliac crest biopsy confirmed OM, already suspected based on laboratorial and X-rays findings at age 7. She had few improvements with phosphate and calcitriol treatment also due to low compliance. During follow-up, symptomatic nephrolithiasis occurred and, in regions affected by EN, multiple basal cell carcinomas (BCCs) emerged requiring excisions. Skeletal CT scan at age 36 showed dysplastic lesions at right hemibody (skull, ribs, pelvis, and limbs) with diffuse bone rarefaction and signs of OM. Sanger sequencing of DNA from EN and jaw tumor samples of patient 1 and from EN and BCC samples of patient 2 disclosed heterozygous HRAS p.G13R mutation, and this mutation was absent in leukocytes DNA from both patients confirming CSHS mosaicism. Owing to the CSHS associated increase risk of cancer, screening with thyroid and breast ultrasound, mammography, CT of skull, chest, abdomen, and pelvis ruled out presence of tumors in patient 1. Patient 2 is waiting for similar screening. Nowadays, patient 1 is 25-yr-old and patient 2 is 36-yr-old; both women have maintenance of OM, characterized by persistent hypophosphatemia with elevated bone formation makers despite treatment with phosphate and calcitriol. CONCLUSION CHSC is a very rare syndrome with less than 10 cases with molecular characterization in literature. Although Collins et al suggest an age-dependent improvement in mineral abnormalities, we reported two women without OM recovery probably because of extensive bone dysplasia. These cases also reinforce association of CSHS with neoplasms, including first descriptions of patients with rhabdomyosarcoma and giant cell tumor of jaw and the longest follow-ups described until.