Altered White Matter Organization in the TUBB3 E410K Syndrome.

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.

Clinical Consultation Guide on Imaging in Male Infertility and Sexual dysfunction.

Imaging can benefit clinicians in evaluating men with infertility or sexual dysfunction by giving an overview of a patient's overall clinical condition before undertaking an invasive procedure. An understanding of the limitations and advantages of image modalities used in clinical practice will ensure that clinicians can optimize patient care with imaging when necessary. PATIENT SUMMARY: The objective of this article was to review the current literature on imaging modalities used for the diagnosis and management of male infertility and sexual dysfunction. An understanding of the advantages and limitations of these imaging modalities will ensure that clinicians can optimize patient care with imaging when necessary.

De novo SOX10 Nonsense Mutation in a Patient with Kallmann Syndrome, Deafness, Iris Hypopigmentation, and Hyperthyroidism.

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder characterized by hypogonadotropic hypogonadism and olfactory dysfunction. Recently, mutations in SOX10, a well-known causative gene of Waardenburg syndrome (WS), have been identified in a few KS patients with additional developmental defects including hearing loss. However, the understanding of SOX10 mutation associates with KS and other clinical consequences remains fragmentary. A 30-year-old Chinese male patient presented with no pubertal sex development when he was at the age of twelve years. Additionally, he showed anosmia, sensory deafness, and blue irises. Last year, he developed clinical symptoms of hyperthyroidism with a fast heartbeat, heat intolerance and weight loss. Blood examinations revealed low levels of FSH, LH, and testosterone. Thyroid function showed high levels of FT3, FT4 and extremely low level of TSH. Molecular analysis detected a de novo (c.565G>T/p.E189X) mutation in SOX10, which has previously been reported in a patient with WS4 (WS with Hirschsprung). The mutation was predicted to be probably damaging. These results highlight the significance of SOX10 haploinsufficiency as a genetic cause of KS. Importantly, our result implies that the same SOX10 mutation can underlie both typical KS and WS, while the correlation between SOX10 and hyperthyroidism still needs to be clarified in the future.

Spectral signatures of mirror movements in the sensori-motor connectivity in kallmann syndrome.

Mirror movements (MM) might be observed in congenital and acquired neurodegenerative conditions but their anatomic-functional underpinnings are still largely elusive. This study investigated the spectral changes of resting-state functional connectivity in Kallmann Syndrome (hypogonadotropic hypogonadism with hypo/anosmia with or without congenital MM) searching for insights into the phenomenon of MM. Forty-four Kallmann syndrome patients (21 with MM) and 24 healthy control subjects underwent task (finger tapping) and resting-state functional MRI. The spatial pattern of task-related activations was used to mask regions and select putative motor networks in a spatially independent component analysis of resting-state signals. For each resting-state independent component time-course power spectrum, we extracted the relative contribution of four separate bands: slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), slow-3 (0.073-0.198 Hz), slow-2 (0.198-0.25 Hz), and analyzed the variance between groups. For the sensorimotor network, the analysis revealed a significant group by frequency interaction (P = 0.002) pointing to a frequency shift in the spectral content among subgroups with lower slow-5 band and higher slow-3 band contribution in Kallmann patients with MM versus controls (P = 0.028) and with lower slow-5 band contribution between patients with and without MM (P = 0.057). In specific regions, as obtained from hand motor activation task analysis, spectral analyses demonstrated a lower slow-5 band contribution in Kallmann patients with MM versus both controls and patients without MM (P < 0.05). In Kallmann syndrome, the peculiar phenomenon of bimanual synkinesis is associated at rest with regionally and spectrally selective functional connectivity changes pointing to a distinctive cortical and subcortical functional reorganization. Hum Brain Mapp 39:42-53, 2018. © 2017 Wiley Periodicals, Inc.

Reconsidering olfactory bulb magnetic resonance patterns in Kallmann syndrome.

OBJECTIVE: The aim of this retrospective study was to perform magnetic resonance imaging assessment of olfactory pathway and skull base abnormalities in Kallmann syndrome (KS) patients with hypogonadotropic hypogonadism and olfaction disorder. METHODS: Magnetic resonance brain patterns were retrospectively studied in 19 patients clinically classified as KS. Qualitative assessment of olfactory bulb region comprised bulb atrophy and rectus and medial orbital gyrus ptosis; quantitative assessment measured olfactory fossa depth and width, sulcus depth and ethmoid angle. Results were compared to an age- and sex-matched control population (n=19) with no impairment in the region of interest. Sixteen of the 19 KS patients were genetically screened for mutations associated with KS. RESULTS: On the above qualitative criteria, 15 of the 19 patients presented either unilateral (n=2) or bilateral (n=13) olfactory bulb agenesis; 16 showed tract agenesis and 16 showed gyrus malformation (ptosis or absence). On the quantitative criteria, 18 of the 19 patients showed abnormal sulcus depth and/or olfactory fossa malformation and/or abnormal ethmoid angle. CONCLUSION: The presence of malformation abnormalities in the olfactory fossae of 18 of the 19 patients appears to be a key factor for etiological diagnosis of hypogonadotropic hypogonadism, and should enable targeted study of genes involved in KS.

Arachnoid cyst: a further anomaly associated with Kallmann syndrome?

BACKGROUND: Kallmann syndrome (KS) is defined by the association of hypogonadotropic hypogonadism and anosmia. It is characterized by a significant clinical and genetic heterogeneity; actually, it may present several non-reproductive non-olfactory anomalies, and all the ways of genetic transmission can be involved in the inheritance of the disease. Although six pathogenesis-related genes have been identified so far, KS remains sporadic in 70 % of the cases, and the genetic diagnosis is not available for all of them. The purpose of this paper is to present a further disease that can enrich the wide spectrum of KS variability, that is cerebral arachnoid cyst. CASE DESCRIPTION: This 11-year-old boy presented with the typical characteristics of KS together with those related to a sylvian arachnoid cyst. He was admitted because of worsening headache. At the admission, the physical examination revealed eunuchoid aspect, micropenis, previous cryptorchidism, and anosmia. MRI pointed out a large, left sylvian arachnoid cyst, agenesia of the olfactory bulbs/tracts complex, and hypoplasia of the left olfactory sulcus. The child was operated on by endoscopic fenestration of the cyst, followed by transient external drainage for subdural hygroma and microscopic fenestration for recurrence of the cyst. His statural growth is normal but the sexual development still delayed in spite of hormone replacement therapy. CONCLUSION: According to the present and the other four cases in the literature, arachnoid cyst should be included among the anomalies possibly accompanying KS date although this association seems to be occasional as far as embryogenesis and physiopathology are concerned.

Computed tomography of the anterior skull base in Kallmann syndrome reveals specific ethmoid bone abnormalities associated with olfactory bulb defects.

CONTEXT: Kallmann syndrome (KS) is characterized by congenital hypogonadotropic hypogonadism (CHH) and an impaired sense of smell related to defective development of the olfactory system. OBJECTIVE: The aim of the study was to use high-resolution computed tomography (CT) to detect specific abnormalities in the ethmoid bone region surrounding the olfactory bulbs in patients with KS. PATIENTS: Thirty-seven KS patients were compared to normosmic CHH (nCHH) patients (n = 15) and controls (n = 30) of similar age. DESIGN AND METHODS: We conducted a prospective study in a single referral center. Subjects underwent CT in bone windows with axial, coronal, and sagittal reconstructions centered on the olfactory fossa (OF) and cribriform plate (CP). We characterized the OF structure by measuring OF height, width, and surface area and a series of angles. The CP foramina were counted bilaterally. Olfactory bulb magnetic resonance imaging, performed in parallel, was compared with CT findings. RESULTS: OF height, width, and surface area were all significantly lower in KS patients than in nCHH patients and controls (P < .0001). KS patients also had wider angles than nCHH patients and controls (P < .0001). KS subjects with olfactory bulb agenesis on magnetic resonance imaging or who harbored KAL1 mutations had the most marked changes in OF measurements and angles. Coronal OF height distinguished KS patients from controls with the best sensitivity and specificity. The mean number of CP foramina was similar in KS, nCHH, and control subjects. CONCLUSIONS: KS is associated with specific ethmoid bone abnormalities. The preserved number of CP foramina in KS patients suggests that the integrity of olfactory structures is not mandatory for their formation during fetal development or their maintenance in adult life.

Quantitative magnetic resonance imaging evaluation of the olfactory system in Kallmann syndrome: correlation with a clinical smell test.

OBJECTIVES: To measure olfactory bulbs and sulci using dedicated magnetic resonance imaging (MRI) sequences and specific measurement tools in Kallmann syndrome (KS) patients with a well-established genotype and phenotype, as well as correlate MRI findings with a clinical smell test. METHODS: MRI was performed in 21 patients with KS and 16 healthy volunteers; olfactory dysfunction was assessed using the Smell Identification Test (UPSIT), a qualitative suprathreshold olfaction test. Coronal turbo spin echo T2-weighted and volumetric T1-weighted gradient echo sequences were acquired in a 1.5T system. ImageJ software was used to obtain olfactory bulb volumes and olfactory sulcus depths and lengths. Data were analyzed with SPSS 15.0 and the Kappa index was used to evaluate the agreement between the UPSIT and MRI. RESULTS: The UPSIT showed 14 patients with anosmia and 6 with moderate hyposmia. Eighteen patients (85%) presented altered rhinencephalon structures in the MRI. Sixteen patients (76%) presented olfactory bulb aplasia (14/16 bilaterally), and these patients presented a total of 16 aplastic sulci. There was moderate agreement between the MRI quantitative evaluation and the UPSIT (overall Kappa = 0.55), but when considering the presence of aplastic bulbs and anosmia, we found almost perfect agreement (Kappa = 0.87). Three patients had normal rhinencephalon structures, including one with a KAL1 gene mutation. CONCLUSION: Olfactory bulb and sulcus aplasia were the most common findings in KS patients. We objectively demonstrated agreement between MRI findings and the smell test, especially the presence of bulb aplasia and anosmia. Therefore, our findings help ascertain MRI accuracy in the diagnosis of KS, differentiating patients with hypogonadotropic hypogonadism with an apparently normal or difficult to evaluate sense of smell.

Identification of two novel missense mutations in the KAL1 gene in Han Chinese subjects with Kallmann Syndrome.

OBJECTIVES: To identify mutations in the KAL1, the KAL2, and PROKR2/PROK2 genes and to characterize phenotypic features in 5 Chinese subjects with Kallmann Syndrome (KS) and 6 subjects with normosmic hypogonadotrophic hypogonadism (NHH) in Taiwan. DESIGN AND PATIENTS: Five unrelated males (age range 22-52 yr) with clinical manifestations of KS and 6 unrelated males (age range 24-47 yr) with NHH were analyzed. In addition, 5 relatives of KS subjects were also evaluated. Genomic DNA extraction, PCR, and DNA sequence analyses were performed using standard procedures. RESULTS: The 1st patient had a single missense mutation in his copy of the KAL1 gene, a T→G transversion in codon 134 that results in replacement of cysteine by gly cine. The 2nd affected subject had a single missense mutation in the KAL1 gene, a T→C transition in codon 163 that results in replacement of cysteine by arginine. The 3rd case was hemizygous for a nonsense mutation in codon 424 of exon 9 (c.CGA→TGA) of the KAL1 gene. This mutation predicts a markedly truncated protein. Two of the mutations (p.C134G and p.C163R) we identified in the KAL1 gene are novel. CONCLUSIONS: We identified 3 mutations, including 2 novel mutations, in the KAL1 gene in patients with KS in Taiwan. These data extend the variety of KAL1 gene mutations in KS and further define the role of the KAL1 protein in olfactory bulb development.

Follicle-stimulating hormone does not directly regulate bone mass in human beings: evidence from nature.

OBJECTIVE: To evaluate the effect of FSH levels in the development of human osteoporosis. DESIGN: Case-series study. SETTING: Gynecology department in a teaching hospital. PATIENT(S): A total of 8 women diagnosed with Kallman syndrome (KS) were compared with 11 with Turner syndrome and 11 with pure gonadal dysgenesia (GD, karyotype 46,XX). INTERVENTION(S): We assessed the pituitary-gonadal axis, bone turnover markers, bone mass, and patient characteristics. MAIN OUTCOME MEASURE(S): Bone mineral density as assessed by dual-energy X-ray absorptiometry, plasma FSH, LH, E(2), osteocalcin (BGP), and urinary type I collagen cross-linked N-telopeptide. Other biochemical markers included 25-hydroxyvitamin D, as well as parathyroid hormone and urine concentration of calcium and creatinine. RESULT(S): In girls with Turner syndrome and GD, FSH (64.03 +/- 29.2 and 90.08 +/- 22.41 mIU/mL, respectively) and LH (45.29 +/- 11.90 and 48.83 +/- 12.44 mIU/mL, respectively) levels were significantly higher compared with those observed in girls with KS (FSH: 1.87 +/- 0.64 and LH: 1.02 +/- 0.57), whereas no differences were detected in E(2) or bone marker levels. Bone mineral density correlated positively with FSH levels but not with E(2); however, after adjusting for previous growth-hormone therapy, these differences were not found. In addition, bone mineral density in spine and total hip was significantly lower in patients with KS. CONCLUSION(S): Follicle-stimulating hormone does not appear to have a major role in the development of bone loss in young women with primary amenorrhea.

Coincidental visualization of an atypical bronchial carcinoid on Tc-99m-sestamibi scan in Kallmann's syndrome.

We report a case of an atypical bronchial carcinoid showing sestamibi uptake. A 27-year-old man with Kallmann's syndrome and hyperparathyroidism had parathyroid scintigraphy with 99mTc-sestamibi. A focal uptake was observed on the right perihilar region, and this right perihilar mass was demonstrated on computed tomography and proved histologically to be an atypical bronchial carcinoid tumor. Factors which may explain the tumoral avidity for sestamibi are increased blood flow, transmembrane potentials of plasma and mitochondrial membranes and the relative number of mitochondria present in the cells of this carcinoid tumor. The importance of this case is the coincidence of an atypical carcinoid in a patient with significant failure of secondary sexual characteristics, right renal agenesis and bilateral anosmia associated with Kallmann's syndrome.

Kallmann's syndrome: clues to clinical diagnosis.

Five cases of Kallmann's syndrome are presented, out-patients with microtestes, hypogonadotropic hypogonadism and complete anosmia. The final diagnosis was made only when they were aged between 17 and 26 (mean 21 years), although they had been seen by several physicians before: 3 for cryptorchidism and 3 for absence of spontaneous puberty; 2 had a positive family history, and 4 of the 5 patients or their parents admitted that they were aware of the fact that their sense of smell was completely absent, but they did not mention it spontaneously.

Kallmann syndrome in a boy with a t(1;10) translocation detected by reverse chromosome painting.

Prometaphase chromosomes from a 16 year old boy with hypogonadotrophic hypogonadism and anosmia (Kallmann syndrome) showed a tiny chromosome fragment attached to the long arm of one chromosome 1 without a visible reciprocal translocation chromosome. Chromosome painting with libraries from chromosomes 1 and X excluded a t(X;1) translocation, but failed to detect a second translocation chromosome. Through reverse chromosome painting, an unbalanced der(1), t(1;10) (q44;q26) translocation could be detected. This is the third case of Kallmann syndrome with a de novo rearrangement between two autosomes. The distal long arm of chromosome 1 may contain a candidate locus for a gene, mutations of which may cause the Kallmann phenotype; a 10q location seems less likely.