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X-linked Hypogonadotropic Hypogonadism without Anosmia

X-linked hypogonadotropic hypogonadism without anosmia is a hereditary disorder associated with dysfunctions of the hypothalamic-pituitary-gonadal axis. Distinct gene defects have been related to the disease, which results in absent or partial puberty and infertility. Of note, X-linked hypogonadotropic hypogonadism without anosmia may also be referred to as normosmic X-linked hypogonadotropic hypogonadism (nXHH) or isolated X-linked hypogonadotropic hypogonadism, while the term Kallmann syndrome is generally reserved form anosmic variants of the disease.


Presentation

The clinical presentation of nXHH is highly heterogeneous [1]. The majority of neonates is asymptomatic; nXHH doesn't usually affect intrauterine growth and sexual differentiation, but it may cause micropenis and/or cryptorchidism [2]. Otherwise, infantile development is undisturbed. Gonadotropin deficiency frequently manifests in puberty, when boys present with eunuchoid body proportions but normal height, a high-pitched voice, prepubertal testes, and delayed penile growth. Gynecomastia has been described. Secondary sex characteristics are weakly defined, with nXHH patients having scant facial, axillary, and pubic hair, a relatively small muscle mass, but a higher percentage of body fat. Similar observations can be made in girls, where primary amenorrhea is diagnosed in about 90% of cases [3] [4]. Female breast development varies largely [5]. Infertility may be detected in both genders, and it may be accompanied by lack of libido, weight gain, and hot flashes [1].

In its most severe form, nXHH presents as a complete absence of puberty, but delayed puberty or post-pubertal symptom onset may also occur. In males, post-pubertal nXHH is associated with loss of libido, erectile dysfunctions, infertility, low muscle mass, a high percentage of body fat, and reduced well-being, but the development of penis and testes, as well as secondary sex characteristics, is largely normal [1]. Mildest forms in females may be revealed by isolated chronic anovulation [5].

Beyond the classical presentation of hypogonadotropic hypogonadism, mutations of the NR0B1 gene have been related to adrenal hypoplasia, while KAL1 mutations may induce bimanual synkinesia and renal agenesis [6]. Such symptoms may manifest long before puberty. With regard to the prevalence of additional complaints, they are typically assumed to be rare in patients with normosmic hypogonadotropic hypogonadism [7]. However, NR0B1 mutations are more commonly related to congenital adrenal hypoplasia with hypogonadotropic hypogonadism than to isolated hypogonadotropic hypogonadism [8].

Infertility
  • Distinct gene defects have been related to the disease, which results in absent or partial puberty and infertility.[symptoma.com]
  • In: Hargreave TB (eds) Male infertility.[link.springer.com]
  • Am J Hum Genet 95:326-31 (2014) DOI: 10.1016/j.ajhg.2014.08.006 文献 PMID: 19129711 著者 Arnhold IJ, Lofrano-Porto A, Latronico AC タイトル Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility[genome.jp]
Asymptomatic
  • The majority of neonates is asymptomatic; nXHH doesn't usually affect intrauterine growth and sexual differentiation, but it may cause micropenis and/or cryptorchidism. Otherwise, infantile development is undisturbed.[symptoma.com]
Weight Gain
  • Infertility may be detected in both genders, and it may be accompanied by lack of libido, weight gain, and hot flashes.[symptoma.com]
Virilization
  • Virilization and feminization according to age alleviate the psychological burden and allow for the development of age-appropriate sexual behavior.[symptoma.com]
High Pitched Voice
  • Here, boys present with eunuchoid body proportions, a high-pitched voice, prepubertal testes, and delayed penile growth, while lack of menstrual bleeding is the clinical hallmark in girls.[symptoma.com]
Suggestibility
  • Beyond the support of the tentative diagnosis, such genealogical information may suggest an X-linked mode of inheritance.[symptoma.com]
Increased Libido
  • Androgen replacement usually suffices to stimulate the development of male secondary sex characteristics and to reach a eugonadal state; it increases libido and resolves erectile dysfunctions.[symptoma.com]
Cryptorchidism
  • While micropenis and/or cryptorchidism may suggest the disease in infancy or childhood, it is not usually diagnosed until puberty.[symptoma.com]
  • Fertil Steril 54:315–321 PubMed Google Scholar Mengel W, Zimmermann FA (1982) Immunologic aspects of cryptorchidism.[link.springer.com]
Primary Amenorrhea
  • Similar observations can be made in girls, where primary amenorrhea is diagnosed in about 90% of cases. Female breast development varies largely.[symptoma.com]

Workup

The diagnosis of nXHH based on a thorough anamnesis, clinical examination, laboratory analyses, diagnostic imaging, and genetic tests.

  • With regard to the former, patients and their parents should be asked for a possible family history of hypogonadotropic hypogonadism. Beyond the support of the tentative diagnosis, such genealogical information may suggest an X-linked mode of inheritance. Anosmia is easily diagnosed by questioning the patient, whereas olfactometry is necessary to reliably determine whether olfaction is partially defective or normal [9].
  • The clinical examination must include an assessment of primary and, according to age, secondary sex characteristics.
  • Clinical findings don't allow for the distinction of hypogonadotropic and hypergonadotropic hypogonadism, though, which requires the determination of pituitary hormone levels (FSH, LH) as well as testosterone and estradiol concentrations in men and women, respectively. The measurement of GnRH levels poses a major challenge. A prolonged stimulated intravenous GnRH test may be useful to this end and confirms whether pituitary gonadotrope cells respond to the releasing hormone [1]. If infants are suspected to suffer from nXHH, hormone levels should be assessed at the age of 2-3 months, during mini-puberty [2].
  • Hormone concentrations below the reference range cannot be explained by structural anomalies of the central nervous system, such as tumors of the pituitary gland, as can be confirmed by neuroimaging. Anomalies of the olfactory bulb, as observed in patients with Kallmann syndrome, are not to be expected either.
  • In order to locate the disease to the X-chromosome, molecular biological analyses have to be carried out. If the patient's family is known to harbor a specific mutation, a straightforward approach may be chosen to determine whether the index patient is a carrier of this mutation. Otherwise, more comprehensive studies are necessary to test for mutations of genes NR0B1, HS6ST1, KAL1 or as-of-yet undescribed anomalies of DNA sequence.

Treatment

Hormone replacement therapy is the mainstay of treatment. The regimen of choice depends on the patient's age, developmental state, and wish for fertility.

Androgen replacement usually suffices to stimulate the development of male secondary sex characteristics and to reach a eugonadal state; it increases libido and resolves erectile dysfunctions. Androgens support the preservation of muscular strength and lean body mass, and normalize bone metabolism [1]. Similarly, low-dose estradiol is used in girls to induce secondary sex characteristics and menses [3]. Neither testosterone nor estradiol restores fertility, though [1] [3].

Patients who wish to have children should be provided with GnRH or gonadotropin therapies. GnRH is administered to those with hypothalamic dysfunction, while gonadotropins should be applied to compensate for pituitary lesions. Urinary gonadotropin preparations such as human menopause gonadotropin, which contains urinary FSH and LH, and human chorionic gonadotropin, a biological equivalent of LH, are available as well as recombinant hormones [1] [3].

Psychological support may be offered to lower the risk of stress, anxiety, and depression [3].

Prognosis

Hormone replacement therapy is generally related to considerable improvements in self-confidence and quality of life. Treatment regimens described above have been shown to be effective in nXHH, although success in individual cases depends on baseline parameters and the patient's medical history. In males, a history of cryptorchidism, largely absent sexual maturation with low testicular volumes, and previous testosterone therapies are unfavorable predictors of the outcome. Most men who undergo treatment are, however, able to impregnate their partner, with spontaneous pregnancy usually being achieved within two years [1]. Similarly, the majority of women who undergoes fertility treatment is able to conceive spontaneously [3]. Couples who are unable to conceive should be informed about assisted reproductive technologies, which may be of great help to fulfill their desire to have children.

Etiology

Normosmic hypogonadotropic hypogonadism describes a clinical syndrome characterized by a series of symptoms and laboratory findings that suggest an insufficiency of the hypothalamic-pituitary-gonadal axis. Nevertheless, this term does not refer to a precise cause of the disease. There are congenital and acquired forms of isolated hypogonadotropic hypogonadism, and gene defects accounting for congenital variants have been located to different chromosomes. nXHH may be diagnosed if mutations are identified on the X-chromosome, and three such mutations have been listed in recent reviews: mutations of NR0B1 (DAX1), HS6ST1, and KAL1 (ANOS1) [6] [7].

  • NR0B1 is to be found at Xp21.2. It encodes for nuclear receptor subfamily 0 group B member 1, a protein that contains a DNA-binding domain and functions as a dominant-negative regulator of transcription. Carriers of pathogenic mutations of NR0B1 may develop nXHH. Here, isolated hypogonadotropic hypogonadism has been reported, although the disease is much more frequently associated with adrenal hypoplasia [4] [10] [11]. Classical X-linked recessive inheritance has been described for these cases of hypogonadotropic hypogonadism, irrespective of adrenal development.
  • The product of gene HS6ST1, located at Xq26.2, is heparan sulfate 6-O-sulfotransferase 1, a member of the heparan sulfate biosynthetic enzyme family. Mutations of HS6ST1 have been implicated in normosmic and anosmic hypogonadotropic hypogonadism, but they may be insufficient to trigger any disease in the absence of further genetic defects. What's more, the phenotype of patients with HS6ST1 mutations presumably depends on additional anomalies of FGF8-FGFR1 signaling, which reflects in a complex pattern of inheritance [12].
  • KAL1 is located at Xp22.31 and encodes for a protein involved in neural cell adhesion and axonal migration, which may have protease activity. KAL1 mutations typically result in Kallmann syndrome, but patients have occasionally been described to have near-to-normal detection thresholds for odorants [13]. KAL1-associated hypogonadotropic hypogonadism is inherited in an X-linked recessive manner.

Epidemiology

The incidence of hereditary hypogonadotropic hypogonadism has been estimated at 1-10 in 100,000 live births, with one-third of cases corresponding to normosmic variants of the disease [1]. Epidemiological data regarding the genetic causes of normosmic hypogonadotropic hypogonadism are scarce, but nXHH is generally assumed to be rare [6]. Case reports on isolated, non-syndromic nXHH are rare still, with only a handful of cases described to date [4] [11].

The vast majority of normosmic hypogonadotropic hypogonadism patients is male, but women may also be affected. What's more, the partial expression of X-linked disorders in heterozygous females may give rise to isolated hypogonadotropic hypogonadism, while male carriers of the same allele develop syndromic disease [11]. In sum, there is very little data to assess the gender distribution of isolated X-linked hypogonadotropic hypogonadism.

Sex distribution
Age distribution

Pathophysiology

In clinical practice, hypogonadotropic hypogonadism refers to the peripheral consequences of central nervous system disorders [7]. Gonadal development and growth, as well as reproductive cycles, are largely guided by pituitary gonadotropin. The release of gonadotropin, in turn, responds to the binding of hypothalamic GnRH to the corresponding receptor expressed on the surface of pituitary gonadotrope cells. In this context, the absent or inadequate synthesis, secretion, or action of either gonadotropin or GnRH may induce hypogonadotropic hypogonadism. There are several genes on the X-chromosome whose gene products may interfere with these processes, but their precise roles in hypothalamic-pituitary signaling are only poorly understood. While NR0B1 encodes for a transcription factor expressed in the hypothalamus, pituitary gland, gonads, and adrenal cortex, HS6ST1 is assumed to be critical for neuronal development and neuron branching. KAL1, on the other hand, is relatively well studied and has been shown to be implicated in cell adhesion, neurite/axonal elongation and fasciculation, and the migratory activity of GnRH neurons [6].

Prevention

The identification of the genetic cause of hypogonadotropic hypogonadism is a prerequisite for genetic counseling and early diagnosis in the absence of clinical symptoms [9]. Once diagnosed, a treatment plan may be formulated to favor physical development matching that of healthy subjects of the same age. Virilization and feminization according to age alleviate the psychological burden and allow for the development of age-appropriate sexual behavior. Furthermore, knowledge regarding the underlying pathology significantly shortens the time to diagnosis and treatment in infertile patients.

Summary

Congenital hypogonadotropic hypogonadism is clinically characterized by absent or partial puberty and infertility [2]. While most patients have a reduced ability to smell and detect odors, those with nXHH are normosmic. From a biochemical point of view, the disease features low levels of gonadotropins and sex steroids, which cannot be attributed to anatomical or functional abnormalities of the hypothalamic-pituitary-gonadal axis [1]. Neither clinical nor laboratory findings allow for the distinction between X-linked hypogonadotropic hypogonadism and autosomal variants. Genealogical data may support the notion of gonosomal inheritance, but this assumption should be confirmed by means of genetic studies.

Patient Information

Hypogonadism is a descriptive term referring to an underdevelopment of primary and secondary sex characteristics. Gonadal development may be disturbed by lack or excess of gonadotropins, which are controlling hormones released by the pituitary gland. In this context, hypogonadotropic hypogonadism refers to the absent or inadequate synthesis, secretion, or action of gonadotropins or gonadotropin-releasing hormone, a hypothalamic hormone that is placed one step higher even in the hypothalamic-pituitary-gonadal axis.

Hypogonadotropic hypogonadism may be congenital or acquired, and there's a myriad of factors that may disturb the aforementioned hormone axis. In some cases, the disease is caused by gene defects located on the X-chromosome, which gives rise to the designation of X-linked hypogonadotropic hypogonadism. Finally, hypogonadotropic hypogonadism may be associated with a reduced ability to smell and identify odors, but this is not the case in normosmic variants of the disease.

Accordingly, normosmic X-linked hypogonadotropic hypogonadism is characterized by absent or partial puberty and infertility in the absence of anatomical or functional abnormalities of the hypothalamus, pituitary glands, or gonads. While micropenis and/or cryptorchidism may suggest the disease in infancy or childhood, it is not usually diagnosed until puberty. Here, boys present with eunuchoid body proportions, a high-pitched voice, prepubertal testes, and delayed penile growth, while lack of menstrual bleeding is the clinical hallmark in girls. Scant facial, axillary, and pubic hair may be observed in both genders.

References

Article

  1. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics. 2013; 68(S1):81-88.
  2. Dwyer AA, Phan-Hug F, Hauschild M, Elowe-Gruau E, Pitteloud N. TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence. Eur J Endocrinol. 2015; 173(1):R15-24.
  3. Dzemaili S, Tiemensma J, Quinton R, Pitteloud N, Morin D, Dwyer AA. Beyond hormone replacement: quality of life in women with congenital hypogonadotropic hypogonadism. Endocr Connect. 2017; 6(6):404-412.
  4. Merke DP, Tajima T, Baron J, Cutler GB, Jr. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. N Engl J Med. 1999; 340(16):1248-1252.
  5. Brioude F, Bouligand J, Trabado S, et al. Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype-phenotype relationships. Eur J Endocrinol. 2010; 162(5):835-851.
  6. Lima Amato LG, Latronico AC, Gontijo Silveira LF. Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism. Endocrinol Metab Clin North Am. 2017; 46(2):283-303.
  7. Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013; 98(5):1781-1788.
  8. Muscatelli F, Strom TM, Walker AP, et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 1994; 372(6507):672-676.
  9. Young J. Approach to the male patient with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2012; 97(3):707-718.
  10. Achermann JC, Gu WX, Kotlar TJ, et al. Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay. J Clin Endocrinol Metab. 1999; 84(12):4497-4500.
  11. Seminara SB, Achermann JC, Genel M, Jameson JL, Crowley WF, Jr. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab. 1999; 84(12):4501-4509.
  12. Miraoui H, Dwyer AA, Sykiotis GP, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013; 92(5):725-743.
  13. Massin N, Pêcheux C, Eloit C, et al. X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab. 2003; 88(5):2003-2008.

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Last updated: 2019-07-11 19:54