Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy(X-ALD),an inborn error of peroxisomalβ-oxidation,is caused by defects in the ATP Binding Cassette Subfamily D Member 1(ABCD1)gene.X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild,severe cerebral adrenoleukodystrophy to mild adrenomyeloneuropathy(AMN).Although most female heterozygotes present with AMN-like symptoms after 60 years of age,occasional cases of females with the cerebral form have been reported.Phenotypic variability has been described within the same kindreds and even among monozygotic twins.There is no association between the nature of ABCD1 mutation and the clinical phenotypes,and the molecular basis of phenotypic variability in X-ALD is yet to be resolved.Various genetic,epigenetic,and environmental influences are speculated to modify the disease onset and severity.In this review,we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD,which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

Pulmonary alveolar proteinosis induced by X-linked agammaglobulinemia:A case report

BACKGROUND Pulmonary alveolar proteinosis(PAP)and X-linked agammaglobulinemia(XLA)are rare diseases in children.Many theories infer that immunodeficiency can induce PAP,but these reports are almost all review articles,and there is little clinical evidence.We report the case of a child with both PAP and XLA.CASE SUMMARY A 4-month-old boy sought medical treatment due to coughing and difficulty in breathing for>2 wk.He had been hospitalized multiple times due to respiratory infections and diarrhea.Chest computed tomography and alveolar lavage fluid showed typical PAP-related manifestations.Genetic testing confirmed that the boy also had XLA.Following total lung alveolar lavage and intravenous immunoglobulin replacement therapy,the boy recovered and was discharged.During the follow-up period,the number of respiratory infections was significantly reduced,and PAP did not recur.CONCLUSION XLA can induce PAP and improving immune function contributes to the prognosis of children with this type of PAP.

The value of the speech audiometry in diagnosis of X-linked adrenoleukodystrophy

To the editor: Sir,X-linked adrenoleukodystrophy (X-ALD) is a hereditary metabolic disease with an incidence rate of 1:16,800.1 Mutations in the ABCD1 gene in X-q28 causes the presence of high levels of very long chain fatty acids (VLCFA) in the serum and tissues.X-ALD presents with adrenal insufficiency as well as severe cognitive and neurologic disability.

Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy

Background:X-linked adrenoleukodystrophy(X-ALD)is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1(ABCD1)gene.This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees,to analyze ABCD1 gene mutations,the effect of gene novel variants on ALD protein(ALDP)structure and function,and to expand gene mutation spectrum of Chinese patients.Methods:Twenty-five male patients diagnosed with X-ALD were enrolled in this study.The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation.ABCD1 gene mutations were analyzed.The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool,polymorphism phenotyping,sorting intolerant from tolerant,Align-Grantham variation and Grantham deviation,and Swiss-Program Database Viewer 4.04 software,respectively.Results:Childhood cerebral form ALD(CCALD)is the most common phenotype(64%)in the 25 patients with X-ALD.The progressive deterioration of neurological and cognitive functions is the main clinical feature.The demyelination of the brain white matter and elevated plasma very long chain fatty acids(VLCFAs)were found in all patients.Different phenotypes were also presented within family members of the patients.Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identifi ed in the 25 patients.Of the mutations,63.6%were missense mutations and 34.8%located in exon 1.The amino acid residues of three novel missense mutations in eight species were highly conserved,and were predicted to be"probably"damaging to ALDP function.The other five novel mutations were splice,nonsense,deletion or duplication mutations.Conclusions:CCALD is the most common phenotype(64%)in our patients with X-ALD.Eight novel mutations in the ABCD1 gene identifi ed are disease-causing mutations.Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.

A novel pathogenic splicing mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa verified by minigene splicing assay

AIM:To report a novel splicing mutation in the RPGR gene(encoding retinitis pigmentosa GTPase regulator)in a three-generation Chinese family with X-linked retinitis pigmentosa(XLRP).METHODS:Comprehensive ophthalmic examinations including best corrected visual acuity,fundus photography,vision field,and pattern-visual evoked potential were performed to identify the disease phenotype of a six-yearold boy from the family(proband).Genomic DNA was extracted from peripheral blood of five available members of the pedigree.Whole-exome sequencing(WES),Sanger sequencing,and pSPL3-based exon trapping were used to investigate the aberrant splicing of RPGR.Human Splice Finder v3.1 and NNSPLICE v0.9 were used for in silico prediction of splice site variants.RESULTS:The proband was diagnosed as having retinitis pigmentosa(RP).He had severe symptoms with early onset.A novel splicing mutation,c.619+1G>C in RPGR was identified in the proband by WES and in four family members by Sanger sequencing.Minigene splicing assays verified that c.619+1G>C in RPGR would result in the formation of a damaging alternative transcript in which the last 91 bp of exon 6 were skipped,leading to the subsequent deletion of 623 correct amino acids(c.529_619del p.Val177Glnfs*16).CONCLUSION:We identify a novel splice donor site mutation causing aberrant splicing of RPGR.Our findings add to the catalog of pathological mutations of RPGR and further emphasize the functional importance of RPGR in RP pathogenesis and its complex clinical phenotypes.

X-linked Charcot-Marie-Tooth disease after SARS-CoV-2 vaccination mimicked stroke-like episodes: A case report

BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with Xlinked Charcot-Marie-Tooth disease type 1(CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging(MRI), although this is rare.CASE SUMMARY A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence.CONCLUSION SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation.

Clinical observations of vitreoretinal surgery for four different phenotypes of X-linked congenital retinoschisis

AIM： To evaluate the outcomes of vitreoretinal surgery for four different phenotypes of X-linked retinoschisis （XLRS）. METHODS： This study included thirty-one eyes of 25 patients who developed XLRS with severe complications. Among the 31 eyes, there were 7 eyes with vitreous hemorrhage, 8 eyes with retinal detachment and vitreous hemorrhage, and 16 eyes with rhegmatogenous retinal detachment. All of the patients underwent standard three-port pars plana vitrectomy. All of the eyes were divided into 4 groups before surgery according to a modified classification scheme, with the first three groups as follows： group A, with foveal cystic schisis; group B with macular lamellar schisis; and group C with foveolamellar changes. Peripheral schisis was not present in these 3 groups; however, group D was a complex group with both macular and peripheral changes. One year after surgery, we analyzed the best corrected visual acuity and postoperative anatomical and functional outcomes of these 4 groups. RESULTS： There were 7 eyes in group A （22.6%）, 1 eye in group B （3.2%）, 15 eyes in group C （48.4%） and 8 eyes in group D （25.8%）. Postoperative anatomical and functional outcomes were satisfactory at the last visit, while the mean visual acuity was increased to 0.27±0.11, with a significant difference （t=-1.049, P=0.000） compared with the results before surgery （0.1±0.08）. Visual acuity was improved in 23 eyes （74.2%）. Complications were found in three eyes： two eyes with proliferative vitreoretinopathy and traction retinal detachment 10 and 12mo after surgery, respectively; and one eye with vitreous hemorrhage 15mo after surgery. These eyes were in groups C and D. The retinas remained attached in these 3 eyes after reoperation. CONCLUSION： We should pay greater attention to XLRS with foveolamellar changes because it is the most changeable phenotype. Once complications occur, vitreoretinal surgery can significantly improve visual acuity and restore the anatomic structure of the retina.

X-linked juvenile retinoschisis： phenotypic and genetic characterization

Juvenile X-linked retinoschisis（XLRS, MIM#312700） belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography（SD-OCT） images. The mean central foveal thickness was 569.7 μm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio（〈1.0） in all patients. RS1（NM_000330.3） gene coding exons Sanger sequencing was performed. RS1 c.599 G〉T（p.R200 L） mutation was detected in one case, showing to be pathogenic in silico analysis. c.（92_97） ins C（p.W33 fs） mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422 C〉G（p.R141 H）, HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.

CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome:A case report and review of literature

The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hype-ractivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene(c.2185C >T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling.

Targeting X-linked inhibitor of apoptosis protein inhibits pancreatic cancer cell growth through p-Akt depletion

AIM: To determine whether lentivirus-mediated shRNA targeting the X-linked inhibitor of apoptosis protein (XIAP) gene could be exploited in the treatment of pancreatic cancer. METHODS: Human pancreatic cancer cells Panc-1, Mia-paca2, Bxpc-3 and SW1990, infected with lentivirus, were analyzed by real-time polymerase chain reaction (PCR). Western blotting was used to examine XIAP protein levels, survivin and p-Akt to confirm the result of real-time PCR and determine the possible mechanism. The 3-(4,5-cimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay was used to measure IC50 to determine chemosensitivity to the chemotherapeutic drugs 5-fluorouracil (5-FU) and gemcitabine. A colony assay, MTT assay and a tumorigenicity experiment were used to study cell proliferation in vitro and in vivo . Caspase-3/7 activity, 4',6-diamidino-2-phenylindole-staining and flow cytometric measurements were used to study apoptosis in SW1990 cells. RESULTS: XIAP proteins were found to be differen- tially expressed among pancreatic cancer cell lines Panc-1, Mia-paca2, Bxpc-3 and SW1990. Data of real-time PCR and Western blotting showed that XIAP was reduced persistently and markedly by lentivirus-mediated shRNA. Downregulation of XIAP by transfection with XIAP shRNA resulted in decreased p-Akt expression. XIAP shRNA also inhibited the growth of pancreatic cancer cells in vitro and in vivo , enhanced drug-induced apoptosis and increased chemosensitivity to 5-FU and gemcitabine. Results also suggest that inhibition of XIAP and subsequent p-Akt depletion may have an anti-tumor effect through attenuating the ability of cancer cells to survive. CONCLUSION: Lentivirus-mediated gene therapy is an attractive strategy in the treatment of pancreatic cancer and justifies the use of lentivirus in pancreatic cancer gene therapy studies.

Regulatory Effects of X-linked Inhibitor of Apoptosis Protein and Pro-apoptotic Protein Smac on Apoptosis Resistance to Chemotherapy in Pancreatic Cancer Cells~*

Objective： To investigate the relation of X-linked inhibitor of apoptosis （XIAP） and second mitochondria-derived activator of caspase （Smac） signaling pathway to chemoresistance in human pancreatic cancer Panc-1 and BXPC-3 cells. Methods： Apoptosis and the changes of XIAP expression in permeabilized cells induced by cisplatin and 5-fluorouracil （FU） were measured by flow cytometry. The cytosolic expression of XIAP, Smac and caspase-3 was detected by Western blot. A recombinant plasmid vector pEGFP-N1/Smac was constructed and transfected into of Pancol cells. The effect of cytosolic overexpression of Smac on apoptosis of Panc-1 cells was evaluated by flow cytometry. Results： Panc-1 was more resistant to cisplatin or 5-FU induced apoptosis than BXPC-3. Western blot revealed that chemoresistant Panc-1 highly expressed XIAP, and increased cytosolic expression of Smac might be responsible for the marked down-regulation of XIAP in chemo-sensitive BXPC-3 cells after exposure to cisplatin or 5-FU. Furthermore, cytosolic overexpression of Smac could significantly down-regulate the levels of XIAP and promote the activity of caspase-3, as well as sensitize Panc-1 cells to anticancer drug-induced apoptosis. Conclusion： Anticancer drug-induced apoptosis requires mitochondrial release of Smac and downregulation of XIAP, which may be an important determinant of chemo-sensitivity in pancreatic cancer cells. Up-regulation of cytosolic expression of Smac may act as an effective modifying signal to overcome apoptosis resistance to chemotherapy in pancreatic cancer cells.

Expression of second mitochondria-derived activator of caspases, X-linked inhibitor of apoptosis protein, and caspase-3 in pituitary adenomas

Studies concerning correlations between pituitary adenomas and cell apoptosis have mainly focused on upstream apoptosis signaling, but seldom on downstream mediators. In the present study, second mitochondria-derived activator of caspases （Smac）, X-linked inhibitor of apoptosis protein （XIAP）, and caspase-3 protein were qualitatively analyzed using immunohistochemistry, and quantified by western blot. Smac, XIAP, and caspase-3 mRNA expressions were detected by reverse transcription-PCR. Results showed that XIAP protein and mRNA expressions were greater in the invasive pituitary adenoma group compared with the noninvasive pituitary adenoma group. However, Smac and caspase-3 protein and mRNA expressions were lower in the invasive pituitary adenoma group compared with the noninvasive pituitary adenoma group. In the invasive pituitary adenomas, Smac expression was positively correlated with caspase-3 protein and mRNA expression （Protein： r = 0.55, P 0.01; mRNA： r = 0.50, P 0.01）. Smac and caspase-3 expressions were negatively correlated with XIAP protein and mRNA expression （Protein： r = -0.56, -0.64, P 0.01; mRNA： r = -0.69, -0.67, P 0.01）. However, no significant differences in correlation among Smac, XIAP, and caspase-3 were detectable in noninvasive pituitary adenomas. These data indicated that high expression of XIAP and low expression of Smac and caspase-3 suppressed cell apoptosis and led to enhanced invasiveness of pituitary adenomas. Thus, Smac, XIAP, and caspase-3 may be useful markers in determining the invasive behavior of pituitary adenomas.

A novel nonsense mutation of GPR143 gene in a Korean kindred with X-linked congenital nystagmus

Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.

Adult Onset Cerebral X-Linked Adrenoleuokodystrophy in 18 Cases

Adrenoleukodystrophy (ALD) is an X-linked inherited metabolic disease associated with the accumulation of very long chain fatty acids (VLCFA) in the nervous system, adrenal cortex, and testes. At least seven phenotypes can be distinguished, which are Addison only, childhood, adolescent and adult cerebral ALD, adrenomyeloneuropathy (AMN), and symptomatic or asymptomatic carriers. Children most often develop rapidly a progressive cerebral disease, whereas adults rarely develop a cerebral disease. The majority of adult-onset ALD patients are AMN. The prognosis of ALD remains unpredictable in individual patients. Family history can be very informative. The plasma VLCFA assay permits precise diagnosis. Specific changes on brain Magnetic Resonance Imaging (MRI) can have diagnostic utility. However, there is considerable overlap among adult-onset leukodystrophies. Adult onset form of cerebral X-linked ALD (AOCALD) is a rare disease. The disease progresses rapidly with widespread demyelination of the cerebral hemispheres. AOCALD is an important differential diagnosis for adults with psychiatric symptoms and progressive cognitive changes. In this article, we review on case reports of AOCALD.

Multimodal imaging of the carriers of choroideremia and X-linked retinitis pigmentosa

Dear Editor,We are Dr. Zhi-Qing Li and Dr. Jin Yang, from the Neuro-ophthalmology and Medical Retinal Department of Tianjin Medical University Eye Hospital, Tianjin, China. We here present two cases of X-linked inheritable retinal diseases with genetic confirmation of the multimodal imaging findings of the patients, especially the female carriers. This study was approved by the institutional review board of Tianjin Medical University Eye Hospital, and the protocols adhered to the tenets of the Declaration of Helsinki. This letter mainly describes a novel imaging modality, multispectral imaging （MSI）, which appeared to be sensitive in detecting the pattern of chorioretinal degeneration and the tapetal-like reflex.

STS Gene in a Pedigree with X-linked Ichthyosis

To investigate the gene mutation in a pedigree with X-linked iehthyosis （XLI） and to explore the relationship between the mutation and its clinical manifestations, genomic DNA of affected members, the normal member of the pedigree and 50 unrelated normal members was extracted with a whole blood genomie DNA extraction kit and the DNA was used as a template for the polymerase chain reaction （PCR） mediated amplification of exon 1 and exon 10 of the STS gene. hHb6 （human hair basic keratin） gene was used as the internal control. Our results showed that the STS gene was deleted in affected members in the pedigree with X-linked ichthyosis. The normal member of the pedigree and 50 unrelated normal members had no such deletion. The proband and his mother had products in the internal control after PCR amplification. The blank control had no product. It is concluded that deletion of the STS gene existed in this pedigree with X-linked iehthyosis, and it is responsible for the unique skin lesions of X-linked ichthyosis.

A novel mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa

·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was collected that consisted of 20 individuals.Genomic DNA was extracted from peripheral blood,and then the target fragments were amplified by PCR and sequenced directly.In addition,all affected patients and female carriers underwent comprehensively ophthalmic evaluation.·RESULTS:A novel mutation c.2865 G>A p.W955 X in RPGR gene was identified of this family,including four affected individuals and eight carriers.All male patients,aging from 7 to 31 y,tended to have more various,even potentially deleterious clinical features of RP.At the same time,individuals with heterozygous mutations(carriers)manifested a wide spectrum of clinical features.Herein,only two male patients and three female carriers manifested pathological myopia(PM).Among the female carriers,half of subjects who harbor poor visual acuity suffered esotropia or exotropia.Additionally,16.7%and 66.7%of carriers had abnormal electroretinogram(ERG)and fundus,respectively.·CONCLUSION:In this study,a novel mutation of the RPGR gene is identified,which broadens the spectrum of RPGR mutations,and elaborates the relationship between genotype and phenotype.

Sustained virologic response following HCV eradication in two brothers with X-linked agammaglobulinaemia

X-linked agammaglobulinaemia (XLA) is a humoral immunodeficiency syndrome characterized from childhood by the absence of circulating B lymphocytes, absent or reduced levels of serum immunoglobulin and recurrent bacterial infections. For many affected patients, regular treatment with immunoglobulin is life saving. Hepatitis C viral (HCV) infection acquired through contaminated blood products is widely described in this patient cohort. The natural history of HCV infection in patients with XLA tends to follow a more rapid and aggressive course compared to immunocompetent individuals. Furthermore, standard anti-viral therapy appears to be less efficacious in this patient cohort. Here we report the cases of two brothers with XLA who contracted HCV through contaminated blood products. They were treated with a six month course of Interferon alpha-2b and Ribavirin. We report a sustained virologic response five years after completing treatment.

Expression of X-linked Inhibitor of Apoptosis Protein and Its Effect on Chemotherapeutic Sensitivity of Bladder Carcinoma

The expression of X-linked inhibitor of apoptosis protein (XIAP) gene and its effect on chemotherapeutic sensitivity in bladder carcinoma was explored. By using immunohistochemistry, the expression of XIAP was detected in 47 bladder carcinomas and 5 normal bladder tissues. The XIAP gene was transfected into bladder cancer cell line T24 by liposome and the positive clone was screened by G418. Cellular XIAP mRNA level was detected by RT-PCR. Low-dose mitocycin C was administered to induce the apoptosis of T24 cells. The in vitro growth of bladder carcinoma cells was analyzed by MTT colorimetry, and the apoptosis rate was assayed by TUNEL methods. It was found XIAP was moderately expressed in bladder carcinomas with the the positive rate being 78.73% (37/47), but the positive rate was not correlated with carcinoma stages and grades (P<0.05). XIAP mRNA level in transfected T24 cells was significantly increased by 3.8 times as compared with that in the cells not transfected with XIAP. After treatment with low-dose mitomycin C (0.005 and 0.05 mg/mL), the growth rate in XIAP no-transfected control group was increased by (11.60±0.25)% and (16.51±0.87)% (P<0.05), and the apoptosis rate was decreased by (10.1±0.2)% and (11.9±0.2%) (P<0.05) respectively as compared with XIAP transfected group. It was concluded that XIAP was expressed in most of bladder carcimoma samples. Overexpression of XIAP in T24 could significantly reduce the MMC-induced apoptosis of bladder carcinoma, suggesting its effect on the chemothera- peutic sensitivity of T24 cells.

X-linked recessive Kallmann syndrome:A case report

BACKGROUND Kallmann syndrome(KS),also known as hypogonadotropic hypogonadism(HH)or olfactory-gonadal dysplasia,is a genetic condition in which the primary symptom is a failure to begin puberty or a failure to fully complete it.It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility.The condition has a low prevalence that is estimated to be 1 in 4000 for male HH cases overall and 1:50000 for KS.It is three to five times more common in males than females.Whether this is a true sex imbalance or a reflection of how difficult KS/HH is to diagnose correctly in males vs females has yet to be fully established.CASE SUMMARY This article reports a 26-year-old male presenting with delayed puberty.The synthetic decapeptide luteinizing hormone-releasing hormone stimulation test showed that the secretion levels of follicle-stimulating hormone and luteinizing hormone were delayed.The eigengenes commonly associated with idiopathic HH(IHH)were screened,and an X-linked recessive(KAL-1)mutation was found.His gonadotropin and testosterone levels increased significantly after pulsatile gonadotropin-releasing hormone(GnRH)subcutaneous therapy by pump.A relevant literature review on the recent advances in the diagnosis and treatment of KS and genetic counseling was conducted.CONCLUSION KS is caused by a KAL-1 mutation that follows an X-linked recessive inheritance pattern.Pulsatile GnRH subcutaneous therapy by pump was effective in this patient.