KAL1 Research Articles

A case of novel mutation in ANOS1 (KAL1) gene and review of Kallmann syndrome.

Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism with coexisting anosmia or hyposmia along with potential other phenotypic abnormalities depending on the specific genetic mutation involved. Several genetic mutations have been described to cause KS. The ANOS1 (KAL1) gene is responsible for 8% of mutations causing KS. A 17-year-old male presented to our clinic with delayed puberty and hyposmia, along with a family history suggestive of hypogonadism in his maternal uncle. Genetic testing for KS revealed complete exon 3 deletion in the ANOS1 gene. To the best of our knowledge, this specific mutation has not been previously described in the literature. Missense and frameshift mutations in the KAL1 or ANOS1 gene located in the X chromosome are responsible for 8% of all known genetic mutations of Kallmann syndrome. Exon 3 deletion is one of the ANOS1 gene is a novel mutation, not reported before. Targeted gene sequencing for hypogonadotropic hypogonadism can be employed based on the phenotypic presentation.

Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis

Disorders of sexual development (DSD) are a heterogeneous group of genital defects affecting chromosomal, gonadal and anatomical sex. 46,XY DSD is a subset of DSD which covers a wide range of phenotypes in which 46,XY gonadal dysgenesis (GD) is the most severe form. In this study, we report on the clinical and molecular cytogenetic findings of a study on a Tunisian girl with the syndromic form of 46,XY DSD. This case was a phenotypic female patient having several congenital anomalies including growth retardation. Karyotype, fluorescence in situ hybridization and array Comparative Genome Hybridization (array CGH) were performed. The proband exhibited a de-novo 46,X,der(Y) karyotype. Array CGH revealed a pathogenic 27.5Mb gain of an Xp21.2 chromosome segment leading to Xp functional disomy. No deletion was observed in the Y-chromosome. The duplicated region encompassed the NR0B1 (DAX1) and MAGEB genes, located within the dosage sensitive sex (DSS) reversal locus, known as promote genes responsible for human sex reversal and testis repression. The extra-dosage and interactions of these genes with different specific genes could result in the impairment of the male sex pathway. Over-dosage of KAL1 and IL1RAPL1 genes fall within the somatic features observed in the patient. To the best of our knowledge, we report on the fourth case of Xp21.2-pter duplication within Xp;Yp translocation associated with XY GD. Our findings suggest that when duplicated, the NR0B1 and MAGEB genes could be a major cause of XY GD. Therefore, we emphasize the usefulness of a combined cytogenetic approach in order to provide an accurate genetic diagnosis for those patients having syndromic XY DSD in a clinical setting.

Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism

BackgroundIdiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder.MethodsWe retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children’s Hospital from 2015 to 2021. We analysed the patients’ clinical data, including their hormone levels and gene sequences.ResultsAll male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene.ConclusionIHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.

Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis

Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress. The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients. Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL. These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA.

Genetic Study of X-Linked Recessive Ichthyosis in Eastern Ukraine

X-linked recessive ichthyosis (OMIM 308100) is a form of ichthyosis caused by abnormal keratinization and can result in disability, social maladaptation, and decreased quality of life for patients and their families. In most cases the disease is caused by a complete or partial deletion of the steroid sulfatase (STS) gene. This study estimated the prevalence of X-linked recessive ichthyosis, the inbreeding coefficient (or fixation index) FST, and the selection coefficient in individuals of eastern Ukraine (namely, Kharkiv oblast). The genealogical method was used to assess the genetic structure of families with a history of this disease. Fluorescent in situ hybridization (FISH) was carried out to detect the deletion of the STS gene in patients and their relatives. The prevalence of the disease in eastern Ukraine was 1.5 × 10–4 males, it ranged from 4.9 × 10–5 to 4.9 × 10–4 males in the districts, and from 2.2 × 10–4 males in the town of Krasnograd to 3.7 × 10–3 males in a village of Balakliia district. The burden of X-linked recessive ichthyosis was found to be positively correlated with the inbreeding coefficient FST in all the studied districts (r = 0.976). Over the past 10 years, the inbreeding coefficient FST increased 1.8 times and the prevalence of X-linked recessive ichthyosis increased 1.4–4.3 times in most districts of the region. The clinical genealogical analysis of nine large families revealed no females with X-linked recessive ichthyosis among relatives of probands, while 21.4% (n = 14) of the first-degree male relatives and 12.0% (n = 25) of the second-degree male relatives had ichthyosis. In most patients and their mothers from eastern Ukraine, FISH detected an interstitial deletion of the STS gene, ish del(X)(p22.31p22.31)(STS-), but no KAL1 gene deletions. In men with X-linked recessive ichthyosis, the average number of children per person was 2.5 times lower than in healthy relatives, and their offspring was characterized by the prevalence of females over males in a 3 : 1 ratio. In obligate heterozygous females, the average number of children per person was 2.2, and the sex ratio in the offspring approached 1 : 1.

Exploring the Genetic Diversity of Isolated Hypogonadotropic Hypogonadism and Its Phenotypic Spectrum: A Case Series.

Background:Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder being classified as Kallmann syndrome (KS). The present study was conducted to study the genotype and relative proportion of different genetic mutations in IHH and to assess its correlation with phenotype.Methods:Eleven consecutive subjects presenting to the Department of Endocrinology were retrospectively analyzed during May 2017 to December 2018 with IHH. Phenotypic features and hormonal studies were analyzed along with clinical exome by targeted gene sequencing (Next generation sequencing). Thirty-nine relevant genes were tested in the analysis.Results:Of the 11 patients studied, five had KS and six had nIHH. At diagnosis, mean chronological age was 25 years. There were associated anomalies in KS group including bimanual synkinesia (n=2), unilateral renal agenesis (n=1) and submucosal cleft palate (n=1). Absence or hypoplasia of the olfactory bulb/sulci was found in 4/5 patients with KS. Genetic mutations in KAL1, CHD7, FGFR1, GNRHR, PROKR2, HS6ST1 genes were found in nine of the eleven subjects. Of the five subjects with KS, two had mutations in KAL1 gene. Two siblings who had bimanual synkinesia had CHD7 mutation. The genotype of nIHH subjects (n=6) was more heterogeneous.Conclusion:This study analyzed the clinical, endocrinological, and genetic features in IHH patients. Detectable genetic mutations were seen in a large proportion of cases. A considerable heterogeneity was seen in the genotype with new variants detected. A definite correlation of phenotype-genotype was not possible, and significant overlap was seen between CHD7 and KAl1, and FGFR1 phenotypes.

Kallmann syndrome in a 17-year-old boy

Aim. To describe a rare hereditary disease — Kallmann syndrome — in a 17-year-old boy.Materials and methods. A retrospective analysis of anamnestic information, the course of the disease, laboratory and instrumental data and treatment of a 17-year-old patient with Kallmann syndrome was carried out. The patient underwent treatment in a gastroenterological department of the Children’s Regional Clinical Hospital in Krasnodar in March 2019.Results. Patient K., 17 years old, was admitted to the gastroenterological department of the Children’s Regional Clinical Hospital in March 2019 with complaints of weakness, nausea, “hungry” abdominal pain and decreased appetite. Upon examination, the child revealed duodenal ulcer. However, an in-depth examination found that the boy was lagging behind in physical and sexual development. In this connection, an endocrinological examination was performed, which discovered: a decrease in the concentration of sex hormones relative to the age norm (luteinizing hormone, follicle-stimulating hormone, testosterone), delayed bone age as compared to the passport age, discrepancy between the testicular size and the patient’s age, olfactory bulb hypoplasia according to brain MRI, 1st degree smell disorder, the presence of a mutation in the KAL1 gene. The boy was diagnosed with: Kallmann syndrome, X-linked recessive inheritance. Complications: hypogonadotropic hypogonadism. The chosen treatment included prolonged testosterone esters for parenteral administration of 250 mg once per 3–4 weeks. Following 6 months of therapy, positive signs were observed: an increase in height by 2 cm, an increase in testicular volume by 3 ml, the appearance of single hairs at the base of the penis.Conclusion. Kallmann syndrome is a rare pathology, whose main manifestations include delayed sexual development and hypo- or anosmia. For a timely diagnosis and treatment, it is of great importance to identify symptoms and conduct a comprehensive examination. Timely initiation of hormonal treatment allows puberty to occur in all cases, thus facilitating social and psychological adaptation of such patients.

Unbalanced X;9 translocation in an infertile male with de novo duplication Xp22.31p22.33.

Male carriers of an X-autosome translocation are generally infertile, regardless of the position of the breakpoint on the X chromosome while the pathogenicity of Xp22.3 subtelomeric duplications is under debate. To shed light into this controversy, we present a rare case, of an azoospermic male with no other significant clinical findings, in whom classical cytogenetics revealed additional unbalanced chromosomal material, at the telomere of the long arm of one homolog of chromosome 9. In peripheral blood specimens of the index case and his parents, we performed GBanding, Inverted-DAPI Banding, AgNOR staining, Telomere specific Fluorescence in Situ Hybridization (FISH), Molecular karyotyping by Multi-color FISH, whole genome SNP microarrays, sub-telomeric MLPA, and transcription analysis of the expression of KAL1 gene by RT-PCR. Multi-color FISH revealed an unbalanced translocation involving the short arm of chromosome X. SNP microarray analysis combined to classical cytogenetics and MLPA demonstrated a de novo 8.796Mb duplication of Xp22.31-p22.33. Compared to three control specimens, the patient presented significantly elevated expression levels of KAL1 mRNA in peripheral blood, suggesting transcriptional functionality of the duplicated segment. The duplicated segment contains the pseudo-autosomal region PAR1 and more than 30 genes including SHOX, ARSE, STS, KAL1, and FAM9A and is not listed as polymorphic. Our data advocate that duplications of the Xp22.3 region may not be associated with a clinical consequence.

ANOS1: a unified nomenclature for Kallmann syndrome 1 gene (KAL1) and anosmin-1.

It is accepted that confusion regarding the description of genetic variants occurs when researchers do not use standard nomenclature. The Human Genome Organization Gene Nomenclature Committee contacted a panel of consultants, all working on the KAL1 gene, to propose an update of the nomenclature of the gene, as there was a convention in the literature of using the ‘KAL1’ symbol, when referring to the gene, but using the name ‘anosmin-1’ when referring to the protein. The new name, ANOS1, reflects protein name and is more transferrable across species.

Clinical characteristics and follow-up of 5 young Chinese males with gonadotropin-releasing hormone deficiency caused by mutations in the KAL1 gene

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) pertains to a group of genetic disorders consisting of anosmic hypogonadotropic hypogonadism (Kallmann syndrome, KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). KS is genetically heterogeneous. We hereby present 5 young male patients with GnRH deficiency caused by mutations in the KAL1 gene. Their ages ranged from 9months to 16years. They were referred to our department for an endocrine consultation for micropenis. Hormone assays showed low circulating gonadotropins and testosterone. Molecular studies revealed KAL1 mutations in all cases, three reported nonsense sequence variants in the KAL1 gene were detected in 4 patients, respectively (c.784C>T (p.Arg 262*), c.1267C>T (p.Arg423*), and c.1270C>T (p.Arg424*)), and one patient harbored a novel hemizygous sequence variant [c.227G>A (p.Trp76*)]. Only one patient presented short stature without growth hormone deficiency and anosmia. Another patient had bilateral eyelid ptosis, trichiasis, and refractive error. This is the first report on the co-occurrence of a KAL1 gene mutation and tent-like upper lip in four patients. All of our cases had normal olfactory bulbs and showed no renal agenesis, cleft lip/palate, and hearing impairment. These cases expand our knowledge of the phenotype associated with KAL1 sequence variations, although the precise mechanism by which KAL1 gene influences the development of this phenotype is still unknown.

Novel homozygous deletion of segmental KAL1 and entire STS cause Kallmann syndrome and X-linked ichthyosis in a Chinese family.

Kallmann syndrome (KS) is a genetically heterogeneous disease characterised by hypogonadotrophic hypogonadism in association with anosmia or hyposmia. This condition affects 1 in 10 000 men and 1 in 50,000 women. Defects in seventeen genes including KAL1 gene contribute to the molecular basis of KS. We report the clinical characteristics, molecular causes and treatment outcome of two Chinese brothers with KS and X-linked ichthyosis. The phenotypes of the patients were characterised by bilateral cryptorchidism, unilateral renal agenesis in one patient but normal kidney development in another. The patients had low serum testosterone, follicle-stimulating hormone and luteinising hormone levels and a blunt response to the gonadotrophin-releasing hormone stimulation test. After human chorionic gonadotrophin treatment, the serum testosterone levels were normalized, and the pubic hair, penis length and testicular volumes were greatly improved in both of the patients. The two affected siblings had the same novel deletion at Xp22.3 including exons 9-14 of KAL1 gene and entire STS gene. Our study broadens the mutation spectrum in the KAL1 gene associated with KS and facilitates the genetic diagnosis and counselling for KS.

Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience.

PurposeIsolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified as Kallmann syndrome (KS) with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This study was undertaken to investigate the clinical, endocrinological, and molecular characteristics in Korean patients with KS and nIHH.MethodsTwenty-six patients from 25 unrelated families were included. Their clinical, endocrinological, and radiological findings were analyzed retrospectively. Mutation analysis of the GNRH1, GNRHR, KISS1, KISS1R, PROK2, PROKR2, TAC3, TACR3, FGF8, FGFR1, and KAL1 genes was performed in all patients. CHD7 and SOX10 were analyzed in patients with CHARGE (Coloboma, Heart defects, choanae Atresia, Growth retardation, Genitourinary abnormality, Ear abnormality) features or deafness.ResultsOf the 26 patients, 16 had KS and 10 had nIHH. At diagnosis, mean chronologic age was 18.1 years in males and 18.0 years in females; height SDS were -0.67±1.35 in males, -1.12±1.86 in females; testis volume was 2.0±1.3 mL; and Tanner stage was 1.5. There were associated anomalies in some of the KS patients: hearing loss (n=6) and congenital heart disease (n=4). Absence or hypoplasia of the olfactory bulb/sulci was found in 84.62% of patients with KS. Molecular defects in KAL1, SOX10, and CHD7 were identified in 5 patients from 4 families (16.0%, 4/25 pedigrees). After sex hormone replacement therapy, there were improvement in sexual characteristics and the sexual function.ConclusionThis study described the clinical, endocrinological, and molecular genetic features in IGD patients in Korea. Although the mutation screening was performed in 10 genes that cause IGD, molecular defects were identified in relatively small proportions of the cohort.

On the nose: genetic and evolutionary aspects of smell.

On the nose: genetic and evolutionary aspects of smell.

Renal Agenesis in Kallmann Syndrome: A Network Approach

Kallmann syndrome (KS) is defined by the combination of isolated hypogonadotrophic hypogonadism (IHH) and anosmia, with renal agenesis occurring in 30% of KS cases with KAL1 gene mutations. Unlike other KS-related disorders, renal agenesis cannot be directly associated with mutations in the KAL1 gene. We hypothesized that protein interaction networks may suggest a link between genes currently known to be associated with KS on the one hand and those associated with renal agenesis on the other hand. We created a STRING protein interaction network from KS-related genes and renal-agenesis-associated genes and analyzed it with Cytoscape 3.0.1 network software. The STRING protein interaction network provided a conceptual framework for current knowledge on the subject of renal morphogenesis in Kallmann syndrome. In addition, STRING and Cytoscape 3.0.1 software identified new potential KS renal-aplasia-associated genes (PAX2, BMP4, and SOX10). The use of protein-protein interaction networks and network analysis tools provided interesting insights and possible directions for future studies on the subject of renal aplasia in Kallmann syndrome.

A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome

ObjectiveTo describe a novel KAL1 mutation in patients affected by Kallmann syndrome.SettingEndocrinology Clinic of the João de Barros Barreto University Hospital – Federal University of Pará, Brazil.MethodsClinical examination, hormone assays and sequencing of exons 5, 6 and 9 of the KAL1 gene in four Brazilian brothers with Kallmann syndrome.ResultsDetected a novel KAL1 mutation, c.612G.A/p.Trp204*, in four hemizygous brothers with Kallmann syndrome, and five heterozygous female family members.ConclusionThe novel p.Trp204* mutation of the KAL1 gene results in the production of a truncated anosmin-1 enzyme in patients with Kallmann syndrome. This finding broadens the spectrum of pathogenic mutations for this disease.

Decreased expression of Kallmann syndrome 1 sequence gene (KAL1) contributes to oral squamous cell carcinoma progression and significantly correlates with poorly differentiated grade.

Kallmann syndrome 1 sequence gene (KAL1) protein is an extracellular matrix associated protein which plays vital roles in neurons development and cell migration. However, its biological functions and clinical implications have yet not been revealed in oral carcinogenesis. The objective of the study was to evaluate the role of KAL1 in oral cancer and determine clinical significance of KAL1 in oral squamous cell carcinomas (OSCCs). The expression pattern of KAL1 was examined in a testing cohort including OSCCs (n = 42) and paired adjacent tissues (PATs) (n = 14) by real-time PCR. The result was further validated in a validating cohort of OSCCs (n = 32). Correlation between clinicopathological parameters and KAL1 mRNA levels was analyzed by Kruskal-Wallis test. In vitro, the effects of KAL1 ablation through siRNA-mediated knockdown on the proliferation of OSCC cells were determined by CCK-8, BrdU, and colonies formation assays, respectively. In addition, cell cycle distribution was further evaluated by cytometry. We observed that remarkably decreased expression of KAL1 mRNA in two independent cohorts (P = 0.0002 and P = 0.033, respectively). Furthermore, downregulated KAL1 mRNA was significantly associated with worse pathological grade (P = 0.013 and P = 0.035, respectively). Upon KAL1 silencing, the proliferation and colonies formation potentials of OSCC cells were notably promoted by accelerating G1 to M phase transition. These data indicated that KAL1 plays a potential suppressive role on OSCC initiation and progression, and KAL1 gene may serve as an adjuvant biomarker for the identification of pathological grade.

Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.

Children with idiopathic hypogonadotropic hypogonadism: clinical data analysis and mutations analysis of KAL1 and FGFR1 gene

To summarize the clinical features of idiopathic hypogonadotropic hypogonadism (IHH) diagnosed during childhood, and detect mutations in KAL1 and FGFR1, acting as key clues for diagnoses. We collected and analyzed clinical data of 21 cases (including demographic data, chief complaint, history of present illness, family history, physical examination, laboratory tests and imaging studies, etc.) diagnosed with IHH from December 2008 to February 2013. Polymerase chain reaction and gene sequencing was applied to detect mutations on KAL1 and FGFR1. Fifty healthy unrelated individuals were choosen as controls. Of 21 patients with IHH, 19 were males and 2 females, they visited us initially from 8-17 years old, with an average of (13.58 ± 2.38) years old. Sixteen cases were KS patients (76%). One boy reported abnormal sense of smelling but having olfactory perfect picture on MRI; 2/19 male cases had no puberty when they were over 13-14 years old without abnormal external genitalia. 8/19 cases only had small penis, 8/19 had both of cryptorchidism and small penis, and the Case 2 also had hypospadias. One boy had cryptorchidism combined with a normal penis. Only 2 girls diagnosed as IHH who visited us because of no puberty signs when they were 13 and 16 years old, respectively. Other clinical manifestations included: one with gynecomastia, 2 had mental retardation, and one was deaf; one with high palatal arch; one with mirror-movement and one with left renal agenesis but normal renal function respectively. Laboratory tests showed that the basic testosterone (T) is low and with inappropriately low or normal gonadotropin hormones. The results of cases of standard human chorionic gonadotropin (HCG) test of 7 cases out of 19 male children's were normal (testosterone>1 100 ng/L), and another nine cases continued to complete the extended HCG test, and the testosterone levels of two of them (cases 6, 8) were still lower than 1 000 ng/L. Family history: the parents in 9/21 family had delayed puberty, involving only one parent in 6 families, involving both in 2 families and the other one was an uncle having micropenis with a child. Among these 21 cases, only one boy's father had hyposmia and his first emission age was 14-15 years. Eleven patients accompanied abnormal sense of smelling and the olfactory organ abnormalities on MRI, 4 had olfactory organ abnormalities on MRI while they had good smelling function self-reportedly. We got 15 samples (12 KS and 3 nIHH cases) to screen the mutation of KAL1 (14 exons) and FGFR1 (18 exons). A splicing mutation c.1062+1G>A in KAL1 is identified in case 17 with IHH. One novel heterozygous FGFR1 mutation, a single base deletion mutation on the exon 1 c.27delC is identified in case 14. This mutation causes the premature termination codons. This pilot research showed that IHH/KS diagnosis in children depends on clinical manifestation rather than gene analysis. Small penis or cryptorchidism, smelling abnormality and positive familial history may contribute to the KS/HH diagnosis. MRI of olfactory bulb acts as important proof for diagnosis of KS. Mutations in KAL1 and FGFR1 gene are not main causes of Kallmann syndrome.

Pyramidal tract abnormalities in the human fetus and infant with trisomy 18 syndrome

Trisomy 18 or Edwards syndrome is known to exhibit various developmental abnormalities in the central nervous system. We report dominant uncrossed pyramidal tract in trisomy 18 syndrome, based on the postmortem neuropathologic study of eight consecutive autopsied fetuses and infants with trisomy 18 ranging in age from 16 to 39 weeks of gestation, including six males and two females, along with autopsy cases of a stillborn triploid infant with 69XXX and two stillborn infants without chromosomal or neurodevelopmental abnormalities. Five out of eight cases with trisomy 18 showed a larger proportion of uncrossed than crossed pyramidal tract. All of these cases were male, and the anterior corticospinal tract on one side was constantly larger than the contralateral lateral corticospinal tract in the spinal cord on both sides, while the pyramidal tract was hypoplastic in female cases with trisomy 18 and a case with 69XXX. Abnormal pyramidal decussation has been found in cases with posterior fossa malformations such as occipital encephaloceles, Dandy-Walker malformation, Joubert syndrome and Möbius syndrome, but has not been described in cases with trisomy 18. Our data, together with the previous reports describing uncrossed aberrant ipsilateral pyramidal tract in patients with congenital mirror movements caused by DCC gene mutation in chromosome 18, and hypolasia and hyperplasia of the pyramidal tract in X-linked recessive disorders caused by L1CAM and Kal1 gene mutations, respectively, suggest a role of trisomy 18 in association with X-chromosome in the abnormal development of the pyramidal tract.

Congenital Hypogonadotropic Hypogonadism during Childhood: Presentation and Genetic Analyses in 46 Boys

BackgroundThe majority of the patients reported with mutations in isolated hypogonadotropic hypogonadism (HH) are adults. We analysed the presentation and the plasma inhibin B and anti-müllerian hormone (AMH) concentrations during childhood and adolescence, and compared them to the genetic results.MethodsThis was a retrospective, single-center study of 46 boys with HH.ResultsFourteen (30.4%) had Kallmann syndrome (KS), 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had HH without olfaction deficit nor olfactive bulb hypoplasia. Eighteen (39%) had an associated malformation or syndromes. At diagnosis, 22 (47.8%) boys were aged <one year, 9 (19%) 1–11 and 15 (32.6%) 11–17.6 years. They presented with micropenis (n = 32, 69.6%, including all those <one year), cryptorchidism (n = 32, 69.6%, unilateral in 8, bilateral in 24), and/or pubertal delay (n = 11). The plasma inhibin B concentrations were normal in 8 (3 KS including one CHARGE and 5 other HH), at the lower limit of the normal in 6 and decreased in 13 (48%) boys. The AMH concentrations were normal in 15 (6 KS including one CHARGE and 9 other HH) and decreased in 12 (44%) boys. In addition to the CHD7 gene mutations in 4 patients with CHARGE, mutations were found in 5/26 other boys analysed including one in KAL1 gene with STS, 2 in FGFR1 gene, one in PROKR2 gene and one in GnRHR gene.ConclusionsThe presence of micropenis in neonate, particularly if associated with cryptorchidism, is an indication to look for gonadotropin deficiency isolated or associated with other hypothalamic-pituitary deficiencies. Inhibin B and AMH concentrations are suggestive if low, but they may be normal. Despite the high frequency of the associated malformations and excluding the patients with CHARGE or ichtyosis, the 4 patients with mutations had no family history or malformation. This suggests that many other genes are involved.