Epiphysiolysis in a 22-year-old Patient with Congenital Hypogonadotropic Hypogonadism: Case Report / Epifisiólise em paciente de 22 anos de idade com hipogonadismo hipogonadotrópico congênito: Relato de caso

Abstract Epiphysiolysis is a relatively common disease in the adolescent population (9-16 years); however, it is rare in the adult population. It is characterized by non-traumatic proximal femur slipping. When it occurs in this population it is associated with some disease that slows sexual development and physis closure, such as endocrine diseases or brain tumors. The aim of the present study is to report a case of epiphysiolysis in a 22-year-old patient with hypogonadotropic hypogonadism. There are only 63 cases reported in the world literature on epiphysiolysis in the adult population.

Resumo A epifisiólise é uma doença relativamente comum na população adolescente (de 9-16 anos), entretanto rara na população adulta. Se caracteriza pelo escorregamento metáfiso-epifisário do fêmur proximal não-traumático. Quando ocorre nessa população, está associada a alguma doença que retarda o desenvolvimento sexual e fechamento fisário, como doenças endocrinológicas ou tumores cerebrais. O objetivo do presente estudo é relatar um caso de epifisiólise numa paciente com 22 anos de idade e hipogonadismo hipogonadotrófico. Existem apenas 63 casos relatados na literatura mundial sobre epifisiólise na população adulta.

ANOS1 variants in a large cohort of Chinese patients with congenital hypogonadotropic hypogonadism / 中南大学学报(医学版)

Objective: Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). ANOS1, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of ANOS1 in CHH and the relationship between clinical phenotype and genotype. Methods: In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of ANOS1 in a Chinese cohort of 165 male CHH patients. Four commonly used in silico tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The ANOS1 genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data. Results:Through WES analysis for 165 CHH patients, ANOS1 RSVs were detected in 17 of them, with the frequency of 10.3％. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p. T76X, p. R191X, p. W257X, p. R262X, and p. W589X), 2 splicing site variants (c. 318+3A>C, c. 1063-1G>C), and 6 missense variants (p. N402S, p. N155D, p. P504L, p. C157R, p. Q635P, and p. V560I). In these 17 CHH probands with ANOS1 RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p. T76X, p. R191X, p. W257X, p. R262X, p. W589X, c. 318+3A>C, c. 1063-1G>C, and p. C157R, were predicted to be pathogenic or likely pathogenic ANOS1 RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic ANOS1 variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) ANOS1 variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs. Conclusion: The ANOS1 genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic ANOS1 RSVs tend to exhibit additional phenotypes. Although non-pathogenic ANOS1 variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.

Digenic inheritance of PROKR2 and WDR11 mutations in Kallmann syndrome—A case report and literature review / 中华内分泌代谢杂志

Kallmann syndrome(KS) is a subtype of idiopathic hypogonadotropic hypogonadism(IHH), characterized by delayed puberty, undeveloped secondary sexual characters, accompanied by anosmia, or hyposmia. At present, more than 40 genes are related to the pathogenesis of IHH, and new gene loci have been found continuously. At the same time, digenic gene mutation or oligogenic mutation is considered to be an important pathogenic mechanism of IHH. The clinical phenotype of KS/IHH caused by different gene mutations is complex and diverse, and the response to treatment is also variable. This paper presents the clinical data and treatment of a case of KS caused by a compound double heterozygous mutation of WDR11 and PROKR2 genes. PROKR2 gene is a classic KS pathogenic gene, while the WDR11 gene is a relatively new type of KS pathogenic gene. Included with this case report is a literature review of characteristics of cases with WDR11 gene mutation.

Study on genetic etiology of three cases of Kallmann syndrome using whole-exome sequencing / 中华内分泌代谢杂志

Objective:Kallmann syndrome(KS) is a complex genetic disease characterized by congenital hypogonadotropic hypogonadism and anosmia. More than 20 genes have been reported to be associated with KS. Herein, we explore potential genetic aberration in 3 KS patients using the whole-exome sequencing. The potentially pathogenic variants filtered were validated by Sanger sequencing.Methods:Genomic DNA was extracted from the peripheral blood of 3 patients with KS and their family members. Sanger sequencing and pedigree verification were performed on the pathogenic variants identified using whole-exome sequencing. The function of the mutation sites were analyzed with bioinformatics software.Results:The proband 1 was a 25 years old male, characterized by lower gonadotropin gonad hypofunction, early grey hair and bilateral sensorineural hearing loss. A heterozygous mutation c. 475C>T(p.R159W) of SOX10 gene was detected in the proband 1. His mother, sister and cousin who had KS phenotype were also found carrying this mutation, showing an autosomal dominant inheritance. The proband 2 was a 15-year-old male with hypogonadotropic hypogonadism and unilateral renal agenesis. The proband was hemizygous for c. 844delC(p.R282Vfs*28) of ANOS1 gene, his mother was heterozygous for the mutation, which was consistent with the X-linked recessive inheritance. The proband 3 was a 21 years old female, characterized by hypogonadotropic hypogonadism and anosmia. A heterozygous missense mutation c. 149G>A(p.R50Q) was detected in FGF17 gene. The mutation p. R50Q was predicted to be pathogenic by the SIFT and PolyPhen2 programs, and has not been reported in HGDM database yet, which considered to be a novel mutation.Conclusion:KS is a clinically and genetically heterogeneous disease. In this study, ANOS1 c. 844delC, SOX10 c. 475C>T and FGF17 c. 149G>A mutations were found in 3 patients with KS by whole exome sequencing, which would expand the genotypic and phenotype spectrum of KS.

Genotype-phenotype and genetic analysis in five patients with Kallmann syndrome / 中华内分泌代谢杂志

To study the genotype-phenotype and genetic characteristics of Kallmann syndrome. Five patients with Kallmann syndrome were enrolled. Clinical data collection, chromosome karyotyping, whole exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA) were used. All the five patients were males, aging from 2 months to 45 years old. Three of the five patients complained cryptorchidism, one complained gonadal dysgenesis, and one complained fasting hyperglycemia. The clinical feature was hypogonadotropic hypogonadism with anosmia, and all karyotype was 46 XY. Magnetic resonance imaging (MRI) showed undeveloped olfactory bulbs and tracts. Kallmann syndrome related gene novel variants were found in all the 5 patients. The hypoplasia of right kidney was found in a patient with c. 1795_1799del (p.Asn599Profs*66) of anosmin 1 (ANOS1) variant. Clinical heterogeneity and incomplete penetrance were seen in a patient with c. 2824A>G (p.Thr942Ala) of chromodomain helicase DNA binding protein 7 (CHD7). Besides, WES indicated a 109 bp-deletion on Xp22.31 (chrX: 8507699-8507804), which was the deletion of exon 10 on ANOS1 gene verified by MLPA. The deletion variant was inherited form his mother, and conformed to X-linked recessive inheritance. Kallmann syndrome is genetic and clinical heterogeneous. WES is helpful for early diagnosis. MLPA and genome copy number variation analysis (CNV) are also recommend if necessary.

Kallman’s Syndrome in a Nigerian Boy: A Case Report

Background: Kallmann syndrome is a rare genetic hormonal condition of hypogonadotropic hypogonadism with a prevalence of 1 in 4000-10000 live born. It is often associated with anosmia or hyposmia. To the best of the author’s knowledge, it has not been reported in Nigerian literature. Methodology: The patient had been presented at the Endocrine and Metabolic Unit of our hospital, and was thus managed. The patient’s hospital records were reviewed and relevant data were extracted, with investigation results and clinical pictures presented. Ethical approval was obtained from the Institution Ethics review board. Results: We report the case of a 15-year-old boy who was presented with a small sized penis since birth, with only a slight increment since then. His developmental milestones were reportedly normal but he had the inability to smell. Examination revealed a well grown apparently healthy looking male, weighing 40 kg; with a normal height of 151.5 cm and BMI of 17.5 kg/m2. The testes were 1 ml each in volume with a stretched penile length of 3.5 cm. Laboratory investigation revealed low testosterone, luteinizing hormone, and follicular stimulating hormone. His karyotype was 46XY. He was commenced on 200 mg monthly injection of testosterone to which he made significant improvement as his penile length increased to 8.5 cm over 8 months of therapy, pubic hair also developed to Tanner 3 but his testicular volume remained pre-pubertal. He also reported that he could now smell. Conclusion: Kallmann syndrome though a rarely reported condition in the Nigerian population, could be treatable, though attainment of reproductive capability might require further intervention. A high index of suspicion and early treatment may yield a better outcome.

Approach to the patient with Kallmann syndrome / 中华内分泌代谢杂志

Kallmann syndrome ( KS) is a rare disease and characteristic of an absence of puberty, infertility, and a defective sensation of smell (anosmia or hyposmia). Here, we analyze the features of a case of KS diagnosed clinically. In addition, the etiology, genetic features, clinical manifestations, diagnosis, and treatment of KS were reviewed.

Delayed puberty versus hypogonadism: a challenge for the pediatrician

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty (DP), is mainly found in males, and is characterized by short stature and delayed skeletal maturation. A family history of the subject comprising the timing of puberty in the parents and physical examination may provide clues regarding the cause of DP. Delayed onset of puberty is rarely considered a disease in either sex. In fact, DP usually represents a common normal variant in pubertal timing, with favorable outcomes for final height and future reproductive capacity. In adolescents with CDGP, a linear growth delay occurs until immediately before the start of puberty, then the growth rate rapidly increases. Bone age is often delayed. CDGP is a diagnosis of exclusion; therefore, alternative causes of DP should be considered. Functional hypogonadotropic hypogonadism may be observed in patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions including celiac disease, inflammatory bowel diseases, kidney insufficiency, and anorexia nervosa. Permanent hypogonadotropic hypogonadism (pHH) showing low serum value of testosterone or estradiol and blunted follicle-stimulating hormones (FSH) and luteinizing hormones (LH) levels may be due to abnormalities in the central nervous system. Therefore, magnetic resonance imaging is necessary to exclude morphological abnormalities and neoplasia. Moreover, pHH may be isolated, as observed in Kallmann syndrome, or associated with other hormone deficiencies, as found in panhypopituitarism. Baseline or gonadotropin-releasing hormone pituitary stimulated gonadotropin level is not sufficient to easily differentiate CDGP from pHH. Low serum testosterone in male patients and low estradiol values in female patients, associated with high serum FSH and LH levels, suggest a diagnosis of hypergonadotropic hypogonadism. A genetic analysis can reveal a chromosomal abnormality (e.g., Turner syndrome or Klinefelter syndrome). In cases where the adolescent with CDGP is experiencing psychological difficulties, treatment should be recommended.

Kallmann syndrome with deafness caused by SOX10 mutation: Advances in research / 中华男科学杂志

The transcription factor SOX10, as a major actor in the development of the neural crest, plays a key role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation. Abnormalities of neural crest development in humans lead to a number of genetic diseases known as neurocristopathies or neural crest disorders. The mutation of SOX10 can cause Kallmann syndrome (KS), which is a clinically and genetically heterogeneous condition and defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Since then, there have been a number of related reports that mutation of SOX10 will lead to KS with deafness. This review focuses on the SOX10 gene and the advances in the diagnosis and genetic studies of KS with deafness caused by the mutatuin of SOX10.

Update of diagnosis and treatment for congenital hypogonadotropic hypogonadism / 国际儿科学杂志

Congenital hypogonadotropic hypogonadism,mainly characterized by absence of puberty and infertility,is a disorder due to deficient production,secretion or activity of gonadotropin-releasing hormone or gonadotropins.Multiple causative genes have been found till now,and other factors like environmental endocrine disruptors also participate in promoting the disease at the same time.Common diseases in this category are Kall-mann syndrome,Prader-Willi syndrome and multiple pituitary hormone deficiency.Neonatal period and early in-fancy are golden time for diagnosis of the disorder.Constitutional growth delay of puberty should be considered in the differential diagnosis for adolescent patients.Therapeutic schedule should be selected according to age, gender and demand for fertility.The treatment can be sexual hormone replacement,gonadotropin therapy and pul-satile pump gonadotropin-releasing hormone.A timely diagnosis and treatment can induce and maintain second sexual characteristics,enhance the male spermatogenesis and female ovulation and reduce psychological problems caused by the disorder.This article is to review the update in diagnosis and treatment of the disorder.

Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime.

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

PURPOSE: Isolated 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. METHODS: Twenty-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. RESULTS: Of 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. CONCLUSION: This 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.

Imaging features in children with Kallmann syndrome / 中华放射学杂志

Objective To summarize imaging features of Kallmann syndrome (KS) in children and to improve diagnostic level of the disease.Methods The imaging manifestations of 13 patients with clinically proved KS were retrospectively studied.MRI of rhinencephalon and left wrist X-ray examinations were performed in all the 13 children.Ultrasound of abdomen and pelvis was implemented in the 8 of 13 patients.Results All the patients had abnormalities of olfactory system.Bilateral olfactory bulbs and tracts were absent in 9 patients.Unilateral olfactory bulbs and tracts were absent in 4 patients,in which contralateral olfactory bulbs and tracts were hypoplastic.These patients presented 2 aplastic,17 hypoplastic and 7 normal olfactory sulci.Anterior pituitary was hypoplastic in 3 patients.Bone age showed retardation in 6 of 13 patients.Bilateral testicles were small in all the 8 cases by ultrasound.Conclusions Aplastic or hypoplastic olfactory bulbs and tracts and sulci are seen in children with KS.Anterior pituitary dysplasia is present in part of patients and bone age backward happens in approximate half of the children.

A Case of 9.7 Mb Terminal Xp Deletion Including OA1 Locus Associated with Contiguous Gene Syndrome

Terminal or interstitial deletions of Xp (Xp22.2-->Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea.

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito / Clinical and molecular aspects of congenital isolated hypogonadotropic hypogonadism

O hipogonadismo hipogonadotrófico isolado (HHI) congênito caracteriza-se pela falta completa ou parcial de desenvolvimento puberal em decorrência de defeitos na migração, síntese, secreção ou ação do hormônio liberador de gonadotrofinas (GnRH). Baixas concentrações de esteroides sexuais e valores reduzidos ou inapropriadamente normais de gonadotrofinas hipofisárias (LH e FSH) definem, do ponto de vista laboratorial, essa condição clínica. A secreção dos demais hormônios hipofisários encontra-se normal, bem como a ressonância magnética de região hipotalâmica-hipofisária, demonstrando a ausência de uma causa anatômica. Alterações olfatórias, como anosmia ou hiposmia, podem estar associadas ao HHI, caracterizando a síndrome de Kallmann. Uma lista crescente de genes está envolvida na etiologia do HHI, sugerindo a heterogeneidade e a complexidade da base genética dessa condição. Distúrbios na rota de migração dos neurônios secretores de GnRH e dos neurônios olfatórios formam a base clínico-patológica da síndrome de Kallmann. Mutações nos genes KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 e WDR11 foram associadas a defeitos de migração neuronal, causando a síndrome de Kallmann. É notável que defeitos nos genes FGFR1, FGF8, PROKR2, CHD7 e WDR11 foram também associados ao HHI sem alterações olfatórias (HHI normósmico), porém em menor frequência. Adicionalmente, defeitos nos KISS1R, TAC3/TACR3 e GNRH1/GNRHR foram descritos exclusivamente em pacientes com HHI normósmico. Neste trabalho, revisaremos as características clínicas, hormonais e genéticas do HHI.

Congenital isolated hypogonadotropic hypogonadism (IHH) is characterized by partial or complete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anatomical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11 are associated with defects in neuronal migration, leading to Kallmann syndrome. Notably, defects in FGFR1, FGF8, PROKR2, CHD7 and WDR11 are also associated with IHH, without olfactory abnormalities (normosmic IHH), although in a lower frequency. Mutations in KISS1R, TAC3/TACR3 and GNRH1/GNRHR are described exclusively in patients with normosmic IHH. In this paper, we reviewed the clinical, hormonal and genetic aspects of IHH.

Alteraciones genéticas en la producción, secreción y acción de las gonadotrofinas / Genetic disorders of gonadotropin synthesis, release and function

Pulsatile secretion of Gonadotropin-Releasing Hormone (GnRH) by the hipothalamus and its action on the pituitary gland is a complex process involving many pre and post natal events. For example, migration of GnRH neurons from the olfactory placode, GnRH release and signalling, normal anterior pituitary development and function are all needed to allow GnRH to stimulate pulsaltile pituitary secretion of follicle-stimulating hormone (FSH) and liteinizing hormone (LH). Hypogonadotropic hypogonadism can be the result of absent or inadequate GnRH secretion or action. Abnormalities in gonadotropin hormone release and function can arise from mutations in a variety of genes implicated in hypogonadotropic hypogonadism is continually growing. A given genotype at a single locus cannot reliably predict the phenotypic manifestations in any given member of affected families. Thus, the identification and characterization of these mutations are providing important information about the reproductive axis in humans and may result in improved treatment and counselling for patients with infertility.

A Familial Case of Kallmann Syndrome due to KAL1 Gene Complete Deletion / 대한소아내분비학회지

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. Although the vast majority of KS cases are sporadic, some X-linked recessive (KAL1), autosomal dominant (FGFR1), and autosomal recessive (most commonly GNRHR) modes of inheritance have been described. Two boys were referred to our department because of cryptorchidism and the absence of puberty. Upon laboratory evaluation they were diagnosed with hypogonadotropic hypogonadism. Agenesis of the olfactory bulbs was detected in radiologic tests, and total deletion of the KAL1 gene was detected through multiplex ligation-dependent probe amplification (MLPA). Although cryptorchidism was diagnosed in the siblings, only the older brother suffered from sensorineural hearing loss and right renal agenesis, a feature that had been reported in X-linked KS. We describe herein the clinical heterogeneity of two affected brothers who carry a complete deletion in KAL1; this is the first case of familial Kallmann syndrome due to the complete deletion of the KAL1 gene reported in Korea.

A Familial Case of Kallmann Syndrome due to KAL1 Gene Complete Deletion / 대한소아내분비학회지

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. Although the vast majority of KS cases are sporadic, some X-linked recessive (KAL1), autosomal dominant (FGFR1), and autosomal recessive (most commonly GNRHR) modes of inheritance have been described. Two boys were referred to our department because of cryptorchidism and the absence of puberty. Upon laboratory evaluation they were diagnosed with hypogonadotropic hypogonadism. Agenesis of the olfactory bulbs was detected in radiologic tests, and total deletion of the KAL1 gene was detected through multiplex ligation-dependent probe amplification (MLPA). Although cryptorchidism was diagnosed in the siblings, only the older brother suffered from sensorineural hearing loss and right renal agenesis, a feature that had been reported in X-linked KS. We describe herein the clinical heterogeneity of two affected brothers who carry a complete deletion in KAL1; this is the first case of familial Kallmann syndrome due to the complete deletion of the KAL1 gene reported in Korea.

A Case of Kallmann's Syndrome with Frontal Lobe Atrophy and Mental Retardation

Kallmann's syndrome is a rare condition, and this is defined as hypogonadotropic hypogonadism and anosmia or hyposmia. The syndrome may be associated with cleft lip, cleft palate, color blindness, skeletal abnormalities, renal agenesis, sensory neural hearing loss, obesity, etc. About 10 cases of Kallmann's syndrome have been reported in Korea, but there are no reports on cases of Kallmann's syndrome with atrophy of the frontal lobe, severe mental retardation and unilateral renal agenesis. We experienced a case of 17-year-old boy with abnormalities of the olfactory system, as was noted on magnetic resonance imaging (MRI). He had an atrophy of the frontal lobe, mental retardation, a micropenis and unilateral renal agenesis. Hormonal assay documented low levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and thyroid-stimulating hormone (TSH). So, we report here on an unusual case of Kallmann's syndrome along with briefly reviewing the relevant medical literature.