Phenotypic diversity in siblings with partial androgen insensitivity syndrome

The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilisation. A point mutation of the androgen receptor gene affecting two siblings with partial androgen insensitivity syndrome is described. One had cliteromegaly and labial fusion and was raised as a girl, whereas the other sibling had micropenis and penoscrotal hypospadias and was raised as a boy. Both were shown to have the arginine 840 to cysteine mutation. The phenotypic variation in this family is thus dependent on factors other than abnormalities of the androgen receptor gene alone.     

Complete androgen insensitivity syndrome caused by the R855H mutation in the androgen receptor gene

Complete androgen insensitivity syndrome (CAIS) is characterized by a completely female phenotype in a 46,XY individual and is caused by mutations in the androgen receptor (AR) gene. A 5 year-old girl presented with bilateral hernia and was noted to have bilateral testes. She had a 46,XY karyotype and was diagnosed with CAIS. To identify the underlying mutation, the exons 2 to 8 of the AR gene were amplified by PCR using sets of known primers and reaction conditions. The results of the mutational analysis for the AR showed the presence of the R855H mutation; her mother was found to be heterozygous and both her 46,XX sister and her aunt had a normal AR gene. This mutation, is the result of a guanine to adenine transition in codon 855 at position 2926 in exon 7 of the AR gene, which causes an alteration of the coding nucleotide triad from CGC to CAC, which subsequently causes the substitution from arginine to histidine in the amino acid sequence of the receptor protein molecule. The same mutation has been reported to cause variable phenotypic expression, which could be explained by the presence of additional co-activating factors modifying the biological activity of the AR. The identification of an AR mutation in a girl with CAIS provides important information, because of the syndrome's genetic heterogeneity. This report emphasizes the fact that genetic determinants outside the coding sequence of the AR can influence the function of the AR protein molecule. Phenotypic expression of the mutation may be used for the construction of maps of functional domains of the AR.     

Phenotypic variation in a family with partial androgen insensitivity syndrome

A family with partial androgen insensitivity syndrome exhibited considerable variation in phenotypic expression of their androgen resistance. One subject died at 2 1/2 years of age of a Wilms' tumor. In the two living members, one had a micropenis with otherwise normal genitalia, while the other had a small phallus, perineoscrotal hypospadias, bifid scrotum, and persistence of a vaginoutricular pouch. At puberty, plasma androgens and serum gonadotropins increased to normal or elevated values. However, despite adequate endogenous plasma testosterone levels and testosterone therapy, these patients showed poor virilization and were sterile. Studies of cultured sexual skin fibroblasts showed adequate 5 alpha-reductase activity and normal receptor affinity and capacity for dihydrotestosterone. An X-linked mode of inheritance is postulated, although autosomal dominance cannot be ruled out.     

Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome

The partial androgen insensitivity syndrome occurs in 46,XY subjects with phenotypes ranging from perineoscrotal hypospadias with cryptorchidism and micropenis (mild undervirilisation) to clitoromegaly and partial labial fusion (marked undervirilisation). Within an affected family, wide variation in the degree of genital ambiguity between individuals can be seen. Two cousins of a previously reported subject who had severe genital ambiguity and partial androgen insensitivity were investigated. Neither of the cousins had genital abnormalities as marked as the index case, who also had qualitatively abnormal androgen binding and two mutations of the androgen receptor gene. Despite marked phenotypic differences between the index case and his cousins, similar androgen binding and the same androgen receptor mutations were shown in the cousins. Furthermore, one of the androgen receptor gene mutations has been shown in the mother and sister of one of the boys indicating that they are carriers. Thus phenotypic variation in families affected by partial androgen insensitivity is dependent on factors other than abnormalities of the androgen receptor gene alone. Although carrier status in partial androgen insensitivity can be determined, the severity of genital abnormalities in an affected offspring cannot be reliably predicted.     

Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome.

The partial androgen insensitivity syndrome occurs in 46,XY subjects with phenotypes ranging from perineoscrotal hypospadias with cryptorchidism and micropenis (mild undervirilisation) to clitoromegaly and partial labial fusion (marked undervirilisation). Within an affected family, wide variation in the degree of genital ambiguity between individuals can be seen. Two cousins of a previously reported subject who had severe genital ambiguity and partial androgen insensitivity were investigated. Neither of the cousins had genital abnormalities as marked as the index case, who also had qualitatively abnormal androgen binding and two mutations of the androgen receptor gene. Despite marked phenotypic differences between the index case and his cousins, similar androgen binding and the same androgen receptor mutations were shown in the cousins. Furthermore, one of the androgen receptor gene mutations has been shown in the mother and sister of one of the boys indicating that they are carriers. Thus phenotypic variation in families affected by partial androgen insensitivity is dependent on factors other than abnormalities of the androgen receptor gene alone. Although carrier status in partial androgen insensitivity can be determined, the severity of genital abnormalities in an affected offspring cannot be reliably predicted.     

Androgen receptor genotyping in a large Australasian cohort with androgen insensitivity syndrome; identification of four novel mutations

We genotyped the androgen receptor (AR) gene in 31 Australasian patients with androgen insensitivity syndrome (AIS). The entire coding region of AR was examined including analysis of polymorphic CAG and GGN repeats in all patients. AR defects were found in 66.7% (6/9) of patients with complete AIS (CAIS) and 13.6% (3/22) of patients with partial AIS (PAIS). A novel deletion (N858delG) leading to a premature stop codon was found in CAIS patient P1. CAIS patient P2 has a novel deletion (N2676delGAGT) resulting in a stop at codon 787. These mutations would result in inactivation of AR protein. A novel insertion of a cysteine residue in the first zinc finger of the AR DNA-binding domain (N2045_2047dupCTG) was found in CAIS patient P3. PAIS patient P4 has a novel amino acid substitution (Arg760Ser) in the AR ligand binding domain, which may impair ligand binding. Five patients were found to have previously reported AR mutations and no mutations were identified in the remaining patients.     

雄激素不敏感综合征的诊断现状及治疗

雄激素不敏感综合征（AIS）是46,XY性发育异常中最常见的疾病之一。该病表型特异性差并随年龄发生变化,且诊断标准不明确,不仅临床上诊断困难,还易与5α-还原酶缺乏症、完全性性腺发育不全等疾病相混淆,极易造成漏诊误诊。明确的诊断该病并准确的分型是提供最佳的治疗与咨询的基础,对于患者性别选择、手术方式和时机、肿瘤发生、性心理健康是至关重要的。本文从AIS的发展过程、临床特征与分型、诊断及鉴别、性别选择及性腺处理的方面进行综述,为更好的诊断及鉴别该病提供参考。     

A novel mutation of the growth hormone receptor gene (GHR) in a Chinese girl with Laron syndrome

Laron syndrome, also known as growth hormone insensitivity syndrome (GHIS), is an autosomal recessive genetic disorder associated with severe postnatal growth failure, and normal and/or elevated growth hormone. This disease is frequently caused by a point mutation in the growth hormone receptor gene (GHR). Here, we identified a novel homozygous substitution mutation (E42K: GAG-->AAG at codon 42 cDNA) of the GHR gene in a Chinese girl with Laron syndrome. This mutation was predicted to impair the GHR binding affinity to human growth hormone (hGH), and was responsible for low levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, and GH binding protein (GHBP) in serum.     

Mutational analysis of Hungarian patients with androgen insensitivity syndrome

OBJECTIVE: To support the clinical diagnosis of androgen insensitivity syndrome (AIS), we performed mutational analysis of the androgen receptor gene. DESIGN: Clinical, hormonal and molecular genetic data of ten undervirilized genetic male patients living in Hungary were recorded. METHODS: PCR-based single strand conformation polymorphism (SSCP) analysis was used to study the whole coding region of the androgen receptor gene. Direct fluorescent sequencing was applied when aberrant migration was detected by SSCP. RESULTS: Five different mutations were identified in five unrelated genetic male patients with abnormal sexual differentiation. One of these mutations was novel, while the other four mutations have been described previously in the literature. One of the mutations identified earlier in individuals with sporadic AIS showed a familial inheritance pattern in our study group. No abnormality of the androgen receptor gene was identified in three patients clinically suspected to have partial AIS. CONCLUSION: Application of molecular techniques helped to clarify the diagnosis in patients with disorders of male sexual differentiation.     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome

AIM—To identify permanent sequelae after sports injuries in children and adolescents.
METHODS—In 1985, a prospective register was drawn up of all sports related injuries reported that year by the residents of Trieste, Italy aged 6-15 years. Moderate to severe injuries (scoring ⩾ 2 on the abbreviated injury scale (AIS)) were the object of a longitudinal clinical study. In 1988, 30.9% of the 220 subjects enrolled had sequelae. A further follow up was undertaken in 1997.
RESULTS—The follow up in 1997 involved 54 subjects (26 girls; average age 24.5 years). Subjective and objective sequelae, by now considered to be permanent, were found in 61.1%, corresponding to 15% of the AIS ⩾ 2 injuries recorded in 1985. The prevalence of sequelae was similar in the two sexes, in relation to the child''s age at time of injury, and in the different sports practised. It was higher in relation to the severity of the lesion (89% of AIS 3injuries examined, 56% of AIS 2 injuries) and to the type of lesion and its location. With regard to AIS ⩾ 2 injuries, permanent sequelae were found in 50% of ankle fractures, 43% of elbow fractures, 33% of leg/foot fractures, 25% of knee sprains, and 23% of ankle sprains.
CONCLUSIONS—The frequency of sequelae in sports injuries in children and adolescents is high. The risk appears to be connected to certain anatomical and functional age characteristics. Prevention strategies should include specific assessment of physical fitness and adequate follow up after the accident, particularly rehabilitation.

     

A shared decision-making tool for individuals living with complete androgen insensitivity syndrome

Reports exist regarding a gradual approach to the care of patients with differences of sexual development. Each patient and family have different values and styles of learning that have to be taken into account. The goals of care should include education about the condition, counseling of the patient and family, and a complete outlining of treatment options. Motivated by a call from the 2010 Health Reform Law for the use of shared decision-making tools and the emphasis placed on these issues by the DSD Consensus Statement, we sought to develop and implement such tools for the DSD population.^1–3 Thus, we developed an organized checklist for providers to share with a patients and families affected by CAIS, beginning with the initial visit. The development of the document enlisted input from physicians, clinical coordinator, advocacy groups and affected individuals. It allows providers to explain the process of care and develop a plan for delivery of that care over multiple visits spanning six months or more. The checklist is divided into five sections: 1) An overview addressing how much information is desired and in what manner the patient prefers to obtain information; 2) A preferred words list so that the patient can choose nomenclature that is most comfortable; 3) A list of topics to review over the course of multiple visits; 4) A list of questions to be answered by the providers or other resources over time, and; 5) A list of concerns to be addressed before surgical intervention is considered. An organized approach to long-term delivery of compassionate care and accurate information can be facilitated for patients with CAIS by the use of a shared decision-making checklist. Documentation of the care delivery process can stimulate referral to peer support and promote fully informed consent for treatment decisions. The use of the checklist should encourage trust in the provider, as well as aid in identifying and addressing stressors for the patient and family. The checklist will be updated and revised as new treatments and advanced technology emerges.     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome.

OBJECTIVE: To study the value of measuring serum luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in androgen insensitivity syndrome (AIS). DESIGN: Retrospective study of patients on a nationwide register of AIS. PATIENTS: Sixty one cases of AIS with androgen receptor (AR) dysfunction (abnormalities of the AR gene and/or abnormal AR binding) were divided into three age groups: infants, < 1 year old; children, 1-13 years old; and postpubertal, > 13 years old. MEASUREMENTS: Age, dose of human chorionic gonadotrophin (hCG) stimulation, pre-hCG and post-hCG serum testosterone values, serum DHT values, and serum LH and FSH values before and after LH releasing hormone (LHRH) stimulation. RESULTS: In 23 of 30 infants testosterone was within age related reference ranges; six were above this range. The median testosterone rise following variable dosage of hCG was 9.5 times the basal value. The increment was not related to the hCG dose, age, or basal concentration of testosterone. The median basal and stimulated testosterone:DHT ratios were 2.5 and 6.1, respectively. The median increment in DHT was 2.2-fold. Seventeen of 18 FSH and 11 of 19 LH measurements were within age related ranges in infants; in seven patients LH values were above the range. LHRH stimulation performed in 39 patients showed an exaggerated LH in all age groups. The FSH response was not exaggerated in children. CONCLUSION: Although a positive hCG test excludes biosynthetic defects of testosterone, an inadequate response does not exclude AIS. Basal LH and testosterone may not be raised during early infancy. An LHRH stimulation test might be useful for evaluating cases of suspected AIS presenting in mid-childhood.     

Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity syndrome

We recently found that postzygotic de novo mutations occur at the expected high rate of an X-linked recessive mutation in androgen insensitivity syndrome. The resulting somatic mosaicism can be an important molecular determinant of in vivo androgen action caused by expression of the wild-type androgen receptor (AR). However, the clinical relevance of this previously underestimated genetic condition in androgen insensitivity syndrome has not been investigated in detail as yet. Here, we present the clinical and molecular spectrum of somatic mosaicism considering all five patients with mosaic androgen insensitivity syndrome, whom we have identified since 1993: Patient 1 (predominantly female, clitoromegaly), 172 TTA(Leu)/TGA(Stop); patient 2 (ambiguous), 596 GCC(Ala)/ACC(Thr); patient 3 (ambiguous), 733 CAG(Gln)/ CAT(His); patient 4 (completely female), 774 CGC(Arg)/TGC (Cys); and patient 5 (ambiguous), 866 GTG(Val)/ATG(Met). Serum sex hormone binding globulin response to stanozolol, usually correlating well with in vivo AR function, was inconclusive for assessment of the phenotypes in all tested mosaic individuals. An unexpectedly strong virilization occurred in patients 1, 3, and 5 compared with phenotypes as published with corresponding inherited mutations and compared with the markedly impaired transactivation caused by the mutant ARs in cotransfection experiments. Only the prepubertal virilization of patients 2 and 4 matched appropriately with transactivation studies (patient 4) or the literature (patients 2 and 4). However, partial pubertal virilization in patient 4 caused by increasing serum androgens and subsequent activation of the wild-type AR could not be excluded. We conclude that somatic mosaicism is of particular clinical relevance in androgen insensitivity syndrome. The possibility of functionally relevant expression of the wild-type AR needs to be considered in all mosaic individuals, and treatment should be adjusted accordingly.     

A novel homozygous deletion in the calcium-sensing receptor ligand-binding domain associated with neonatal severe hyperparathyroidism

Neonatal severe hyperparathyroidism (NSHPT) is a life-threatening disorder usually caused by homozygous mutations occurring in the calcium-sensing receptor (CaR) gene. We examined an infant hospitalised with NSHPT for mutations in the CaR gene using heterozygous sequence analysis and confirmed this result by a restriction enzyme assay. Clinical management of this case, which was beset by other complications, involved control of the hypercalcemia and the effects of hyperparathyroidism by a combination of treatments prior to parathyroidectomy performed at 10 months. Mutational analysis demonstrated a homozygous 5 base-pair deletion in the CaR gene located at the 5' end of exon 4 which would result in a severely truncated, non-functional receptor with only the first 164 amino acids of the CaR followed by 23 amino acids of aberrant sequence. This is the first report of an out-of-frame deletion in the extracellular domain of the CaR associated with clinical disease.     

A case of Rabson-Mendenhall syndrome with a novel mutation in the tyrosine kinase domain of the insulin receptor gene complicated by medullary sponge kidney

Rabson-Mendenhall syndrome (RMS) is a genetic disorder characterized by severe insulin resistance and somatic characteristics. Recombinant insulin-like growth factor 1 (r-IGF-1) is used to treat RMS, as the IGF-1 and insulin receptors share homology. However, the effect of r-IGF-1 varies in patients and it is difficult to manage metabolic status appropriately in r-IGF-1 resistant cases. We report a Japanese boy with RMS who showed resistance to r-IGF-1 therapy and a novel mutation in the insulin receptor in the tyrosine kinase domain. Mutations in this region disturb tyrosine kinase catalytic activity in IGF-1 receptors as a result of dominant negative effects. We consider this mutation to be the cause of resistance to r-IGF-1. The patient also exhibited radiographical features of medullary sponge kidney and had severe nephrocalcinosis and hypokalemia, indicating Bartter syndrome. However, analysis revealed no mutations in the responsible genes and the etiology of the renal abnormalities therefore remains unknown.     

Incomplete androgen insensitivity syndrome. Difficulties of diagnosis and management

A familial form of incomplete androgen insensitivity syndrome (AIS) is reported. The index case was first seen at 9 months of age for ambiguous genitalia. Diagnosis of AIS, suspected but first discarded on the basis of an androgen sensitivity test, was finally made at puberty on the discordance between poor virilization and elevated levels of both testosterone and LH, a florid gynecomastia, and the exclusion of any enzymatic defect in testosterone biosynthesis of 5 alpha-reductase deficiency. Androgen receptors in public skin were within the limits of normal for total number, with normal affinity. Familial occurrence included 2 first cousins born 7 and 10 years later, a maternal grand-uncle with similar ambiguous genitalia, and a maternal uncle with the gynecomastia-preserved fertility syndrome. This case report illustrates the heterogeneity of AIS in a given family and the difficulty of and early positive diagnosis in a newborn presenting with sexual ambiguity.     

Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome

Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.