Monogenic Disorders of Puberty

Normal puberty is associated with the onset and progressive activation of the hypothalamic-pituitary-gonadal (HPG) axis and the resultant development of secondary sexual characteristics. Puberty begins with increasing nocturnal pulsatile hypothalamic GnRH secretion, which gradually occurs throughout the 24-h day. Pulsatile GnRH stimulates pituitary FSH and LH secretion, ultimately stimulating gonadal steroid production and gametogenesis in females and males. In the ovary, FSH stimulates follicular maturation and estrogen production through aromatization of androgens, whereas LH stimulates androgen production by theca cells, triggers ovulation, and maintains progesterone production by the corpus luteum. In the testis, FSH acts on Sertoli cells to initiate spermatogenesis and LH acts on Leydig cells to stimulate testosterone production. The hypothalamic-pituitary-adrenal (HPA) axis also has some minor input into the physiological process of puberty, through the secretion of adrenal androgens. However, the major involvement of the HPA axis in puberty is in its potential pathological influence, primarily in accelerating its onset and/or progress. Traditionally, the onset of adrenal androgen secretion in childhood has been termed “adrenarche,” whereas the onset of gonadal steroid secretion has been called “gonadarche.” Delayed puberty describes the clinical condition in which the pubertal events start late or are attenuated or arrested. In contrast, precocious puberty describes the clinical condition in which the pubertal events start early. Mutations have been identified in an increasing number of genes that influence the onset and progression of puberty. These discoveries have provided new insights into the physiology and pathophysiology of this important life transition and have greatly influenced the practice of reproductive medicine. For instance, the concept of two gonadotropins acting on two separate cell types in the gonad has been the cornerstone of reproductive endocrinology, while it has been traditionally believed that both FSH and LH are required for fertility in females and males. However, studies of mutant gonadotropin receptors indicate that female reproductive capacity depends primarily on FSH, whereas male reproductive capacity depends primarily on LH. We summarize the molecular defects that influence gonadal and/or adrenal function and cause delayed (Table 1) or precocious puberty (Table 2). Here, we present genes whose alterations result in abnormal puberty in girls and boys. Genetic defects causing delayed puberty Genetic defects causing delayed puberty Genetic defects causing precocious puberty Genetic defects causing precocious puberty Kallmann syndrome is characterized by hypogonadotropic hypogonadism and anosmia/hyposmia, and is transmitted in an X-linked recessive mode of inheritance. Kallmann syndrome is the most common form of isolated gonadotropin deficiency, occurring in 1 in 10,000 males and 1 in 50,000 females (1). The KAL gene is located in the pseudoautosomal region of chromosome X, at Xp22.3, and encodes a 680-amino acid extracellular matrix protein (2, 3). The KAL protein has homologies to neural cell adhesion molecules, protease inhibitors, neurophysins, phosphatases, and kinases and appears to serve a more generalized role in development (1). A variety of nonsense, missense, and frameshift point mutations or large deletions of the KAL gene have been reported (4). In some cases, Kallmann syndrome includes multiple other anomalies, such as hypoplasia of the cerebellar vermis and other midline structures, and unilateral renal agenesis (5). The connection between anosmia/hyposmia and hypogonadism can be explained by an embryonic link: immunohistochemistry and in situ hybridization in mouse embryos have demonstrated that both GnRH and olfactory neurons originate in the olfactory placode, with the former migrating into the hypothalamus (6). Furthermore, in a fetus with Kallmann syndrome, lack of GnRH-expressing cells was noted in the brain, despite the presence of dense clusters of GnRH cells and fibers in the nose; in contrast, in normal fetuses, GnRH cells and fibers were observed in the hypothalamus and preoptic area (7). Approximately half of families with X-linked hypogonadotropic hypogonadism have KAL-1 gene mutations (5), whereas only 5% of sporadic cases have such mutations (8). Interestingly, unilateral renal agenesis occurs in 50% of all males with KAL gene mutations (5). Of note, there is a lack of genotype-phenotype correlation in this syndrome. In a set of two brothers with the same point mutation within KAL, one sibling had hypogonadism, left renal agenesis, and cryptorchidism, while his brother had hypogonadism but none of the associated findings (9). AHC is a rare X-linked disorder characterized by primary adrenal insufficiency and hypogonadotropic hypogonadism (10). The gene responsible for this disorder, DAX-1 (for dosage-sensitive sex reversal, AHC-critical region of the X-chromosome, gene 1), is located on the short arm of the X chromosome (Xp21) encoding a 470-amino acid member of the nuclear hormone receptor superfamily (11). This orphan nuclear hormone receptor has a novel DNA-binding domain that has a unique structure consisting of a 66–67 amino acid that the DNA-binding domain in this region of nuclear The region of DAX-1 has with of orphan nuclear receptors The DAX-1 gene is in the pituitary and mutations in DAX-1 have been reported in more with X-linked AHC mutations in DAX-1 have been identified in the whereas frameshift or mutations have been in the domain of mutations are frameshift or mutations in of the DAX-1 protein with DAX-1 mutations present with adrenal in or childhood as a result of a of of the of the adrenal (11). the present of and of adrenal an increasing number of with AHC hypogonadism has been as a of this syndrome in are with adrenal and of have at whereas have normal axis in the of puberty, present with hypogonadotropic onset of puberty, but with pubertal has been reported Pulsatile GnRH has been to puberty with the of DAX-1 at the of the pituitary of gonadotropin stimulates testosterone into the normal in most spermatogenesis gonadotropins is to a of DAX-1 on Sertoli cell function Interestingly, an mutation in DAX-1 was in a with adrenal and hypogonadotropic hypogonadism in his studies that this mutation a of DAX-1 function in a variety of gene mutations in DAX-1 can present with hypogonadotropic hypogonadism and adrenal in for DAX-1 gene mutations present with delayed puberty, but normal fertility However, a female for a DAX-1 mutation had isolated hypogonadotropic hypogonadism, but normal development and normal adrenal function In in genotype-phenotype the same mutation in two brothers with the syndrome, an and an with only hypogonadotropic hypogonadism The located at encodes for an orphan nuclear receptor that an role in the development of the adrenal testis, ovary, and hypothalamus cases of gene mutations have been The mutation was reported in a with female with primary adrenal the of life and The had a point mutation of the gene in the of the an area to be for of other nuclear This mutant protein to to and of a A gonadotropin to GnRH was the of puberty, but with testosterone to gonadal normal and and were this it that is for sex and The point mutation was in a female with normal and adrenal pubertal development to be in the development and/or be to A of 1 gene mutation has been reported in a with childhood at the of primary and defects in to In to the of there was of of and secondary a more generalized to of the hypogonadotropic hypogonadism, the development of secondary sexual was the of was with and A male was reported with a gene mutation The was for an gene mutation and with and and were but gonadotropins to the hypothalamic of the A receptor mutation a in a with and hypogonadotropic hypogonadism GnRH is in the hypothalamus and by the to the cells of the of GnRH to receptors on the pituitary the of both FSH and LH. with GnRH present with pubertal and gonadotropin the GnRH gene to be the most gene for mutations that cause GnRH in with hypogonadotropic hypogonadism, such mutations have been to the other mutations of other have been to that the function of hypothalamic is for physiology and GnRH receptor gene mutations result in hypogonadotropic hypogonadism of recessive The GnRH receptor to the receptor which an extracellular a domain extracellular and most this receptor an The GnRH receptor gene is located on chromosome The is present in two and families GnRH receptor defects have been to of receptors in cells GnRH defects or In cases the receptors some The reported a in which two one male and one had hypogonadotropic hypogonadism The male with hypogonadism at of puberty was noted at but was of and had testosterone and gonadotropin FSH and LH were The had a of primary and with normal at of and a at with in two normal were for two GnRH receptor gene a mutation in the extracellular and an mutation in the was observed in with GnRH receptor gene one and his two were for the same mutations The had a form of GnRH receptor deficiency, with of of LH and of to GnRH or pulsatile whereas the two had of LH but to of GnRH reported with GnRH receptor gene with female and one with delayed puberty with gonadotropin and in a GnRH female had primary The were for the GnRH receptor The GnRH receptor gene mutation was an mutation in the also and the other mutation was a in the region mutant GnRH receptors were into cells and cell were GnRH was receptor was observed and both demonstrated production of a male with delayed puberty was reported to a mutation of the GnRH receptor had and was and gonadotropins were and to to GnRH The had a point mutation for at of the GnRH receptor in a to in the studies with cells that this mutation in of the to GnRH most of the with GnRH receptor gene mutations have of the In one female a pulsatile of GnRH and has an of 1 in of are and have been as transmitted in an or X-linked recessive can be by mutations in required for pituitary such as as or of 1) is located at with mutations of present with short and delayed puberty. A variety of mutations have been but the most common mutation is a and for half of cases between with the same mutation The at is on the of between and of in all is that of and to to or present with puberty, but with of LH and FSH normal hypogonadotropic hypogonadism Normal pubertal development depends on normal of FSH and LH. These are of a common and a by a separate The is common to FSH, and whereas the is the with gene mutations have been reported a have at and lack of pubertal The LH and FSH genes are in and are located on and In the ovary, FSH through with its receptor on the of The the of the which in the aromatization of and testosterone to FSH also stimulates cell and In LH stimulates theca cell androgen triggers and cell and maintains progesterone production of the corpus luteum. In the testis, FSH acts on the Sertoli cells and cells to whereas LH acts on Leydig cells and testosterone production and male sexual The gonadotropins to the FSH receptor and the LH receptor to the receptor superfamily In the FSH has been to the cells whereas in the male it has been to the Sertoli cells The FSH gene is located at cases with FSH by mutations in the gene of the of FSH have been The female with primary and The mutation to a between and of the which was by a and lack of of amino to The protein was and to with the to form The had normal but development or the of with a for the had and The was a with delayed puberty, with primary and secondary sex had FSH and LH and an FSH to was a for two mutations in the mutation was the same as that and the other was a mutation that a to at The were normal In reported with FSH to FSH was and to be for the same reported Furthermore, two with gene mutations were The had normal puberty and but was had and was with of a to transition in to The with secondary hypogonadism associated with an isolated of FSH had a in the for the of FSH, in a the amino at the of the The had LH and testosterone and FSH or LH is to in which protein protein and in the of the Mutations of the gonadotropin receptors are into and or The genes for and are on chromosome The gene has whereas the has The of the and the of the the extracellular whereas the of gene encodes a of the extracellular and the domain of hormone to the extracellular domain of receptor the receptor to of activation of and genes and mutations of the were in with primary and were to be for a to transition at of of the gene an studies a mouse Sertoli a lack of production by the receptor on FSH The clinical of primary or secondary and with development of secondary sex the presence of The of the had normal fertility and mutations of the in primary have been reported as Interestingly, in to development and primary to normal development and secondary These findings indicate that the of follicular maturation are of FSH, but the of follicular maturation this male brothers for the same mutation were to have normal development of secondary sex but of associated with a of However, none of was and some of FSH were whereas LH were normal to These findings indicate that FSH is for male mutation of the gene was reported in a had been of a pituitary and was testosterone despite gonadotropin with secondary hypogonadism are on testosterone to However, have a in spermatogenesis to gonadotropin fertility with FSH and LH. this had normal spermatogenesis and Of note, spermatogenesis of this was testosterone was The had a mutation to at located in the studies in cells that the mutant receptor an in production of FSH This that FSH maintains spermatogenesis in The of in this the of the the of occurring with normal pituitary function are The gene is located at A male with a mutation in of the gene with delayed puberty and LH but normal FSH A spermatogenesis and Leydig and testosterone were by the of This mutation of gene was to of the LH to the of his were for the mutation were with LH and FSH whereas his and were In to the mutation other alterations have been which to be in LH function mutations result in male whereas mutations to and sporadic of male precocious puberty also as mutations to have in Genetic an and an have been to the mutations are recessive in In the are females male to males with the of Leydig cell and function cell to and and mutations and have been identified The of mutations have been in has been identified In studies or cells or and production in to or of the receptor are with or and to secondary sex at puberty. These at puberty of primary and lack of pubertal have of normal of FSH, and of which to of the of Leydig cells is a correlation between the of the clinical and the of of the The are observed in with that to the or are to the hormone are observed in with that have but as reported brothers with by a mutation in a of a for an at were with of pubertal and to in to the late of In one of the of testosterone in a in to and fertility In the of the hypogonadism and primary We have the of a with mutation in the gene This was a of male was for of at the of Normal and development at the had a and A was identified in this as as in in an at the of the only females with gene mutations have been of were of with to Leydig cell one and two and the were identified in to a of have primary or secondary and at whereas progesterone in all LH and were The presence of normal follicular in that FSH can stimulate estrogen production for normal pubertal development in male precocious puberty called is as an disorder and is by mutations of the cases also The by with of puberty, and short to males testosterone associated with LH and to the GnRH of of Leydig cells of the axis and fertility are in with male puberty. receptors a for mutations in the and and of mutations in production with mutations have been within of the gene The most common mutation is which occurs in The cells with for the production in the of Leydig cell mutations of the have on females This is to the that it is FSH that and Interestingly, this is in to an which and of androgen to testosterone and to of estrogen and of the A has been reported of a with a recessive mutation in the estrogen receptor had normal onset of puberty. The major of estrogen that demonstrated were with of delayed and was for a mutation in the estrogen receptor gene the protein was to be both the DNA-binding and The androgen receptor androgen in the cell and is for and of the male and and secondary male sex characteristics. The X-linked describes a of defects in the androgen in of in The androgen receptor to the steroid superfamily of nuclear hormone The gene encodes for a protein an a DNA-binding and domain mutations in the androgen receptor gene have been reported causing The a female with but and and to an or male Approximately of have other acid mutations in the and DNA-binding can to lack of to androgens. In mutations in the domain or androgen In the are female These females have a pubertal despite to of The of is normal but normal In the are puberty, with have sex and In of the the are but have or at of with is on the of the the testosterone to and the potential for a of with be on a identified androgen receptor gene in families is In a to be for studies is the presence of a for the androgen receptor gene which can the with steroid are males have female or at and at puberty The gene encoding is located on chromosome The is in an recessive to mutations of the mutations the whereas other mutations function by or are with female and as girls puberty, of spermatogenesis greatly to normal for are normal and have the in estrogen the of to and to the is of and is by the gene on chromosome is in an recessive The syndrome is more in mutations of the of the deficiency, large androgen are to the and in of the and of the in female are of two males and girls with In the male the clinical were in had with normal sexual were with a of a with in associated with with have and progressive at puberty with of present with primary and female secondary sex associated with hypogonadism, delayed and is of estrogen and We reported a with syndrome in an in which males had precocious puberty and/or and females had precocious puberty and/or were the of with greatly and A with had precocious puberty, with development and at with of and had and The had at the of The and and a of that most of the aromatization in which the and the adrenal The to be of adrenal to was in and the A new was present in the of this which to be in this of the short both were with an and a GnRH which delayed and pubertal development recessive mutations in gene the of testosterone in the and to with female This disorder is the result of a in the in testosterone in the of to or for mutations in gene have located in the or and are as but puberty, to of to testosterone are normal females describes a of recessive characterized by an in with in secretion and and of the adrenal (for a result a in of the to and and are associated with gonadal androgen and estrogen secretion and cause delayed puberty in both and are associated with androgen and cause of precocious puberty in both is responsible for more of cases and is one of the most common recessive The gene for deficiency, on chromosome within the of the major genes result is the and is an is by large mutations or or point mutations in the These mutations cause of of which are responsible for the of clinical of the are and the of the is by the of the with to present with precocious puberty, whereas females present with precocious puberty. maturation and resultant short in both The at in males to the of or with present at of life with and whereas males present with precocious puberty, characterized by and at of with present at with of to of in can be to cause sex at The form of is and is the same gene is in both the and at one of the mutations associated with only present with puberty and In of adrenal in the to or and present with and the clinical includes and/or male and are responsible for 5% of cases with mutations in the gene and with with or and mutations in the in and the is to adrenal in it both the and the In with of males or male whereas females have normal or of androgen in both is the the of to The is located on chromosome gene mutations were to cause adrenal were to lack mutations is believed that mutations are with is required for of which is to a fetus for a mutation at of production of progesterone the corpus A mutation was in a with male and adrenal insufficiency This the that all are adrenal is a rare disorder, characterized by of all the adrenal and sex is the most disorder of steroid hormone by mutations in the gene for as a protein in with within with have a in adrenal and gonadal adrenal to and and have normal female However, puberty with missense, nonsense, and frameshift gene mutations have been identified causing mutations are in whereas and frameshift mutations are throughout the gene to is an recessive disorder by mutations on the located on chromosome that encodes both and in adrenal and In the stimulates the of a large of and which to with or In of androgen to a female and sexual in both mutations of this gene have been females for in but the to steroid hormone is mutations of the receptor gene are causing of and with associated of adrenal and with (for a androgen to precocious puberty. The receptor gene of In with a point mutation to a amino acid to at at the domain of the In a cells, the in a In the of we a identified at the of and This a in one of the two receptor gene to of only the other receptor defects have been two of amino acid the nuclear of the receptor or its to nuclear receptor types of mutant receptors on the The of this condition is with of such as with The syndrome is a clinical condition characterized by a clinical precocious puberty, and In and have been syndrome is by a mutation at of the gene for the of the which is with and the of protein syndrome occurs and is more common in girls in puberty is in of and and of are observed as a of puberty is in of of and In all cases, gonadal is demonstrated by the of gonadal sex with of gonadotropin secretion, both and GnRH The of this condition of a of and androgen The of the and HPA are and defects in axis pubertal gene causing delayed or precocious puberty, have been The of occurring mutations have the and pathological of genes in the process of puberty. the gene to be in X-linked Kallmann syndrome, is a neural cell adhesion is required for normal of olfactory and GnRH neurons the olfactory to the hypothalamus (2, 3). that there are other of Kallmann syndrome, recessive but the responsible genes have been identified as Mutations in two and can also result in hypogonadism DAX-1 encodes a that a role in the development and function of the and adrenal DAX-1 defects result in X-linked hypogonadotropic hypogonadism associated with is an orphan nuclear receptor that a role in the development and function of the axis and the adrenal with a mutation of has been reported with structures, and primary adrenal In to the hypogonadotropic hypogonadism of DAX-1 this had hypogonadism, that DAX-1 is more important at the hypothalamic and pituitary A in has been to and to hypogonadotropic hypogonadism and Of note, the between and is also by the that defects in or its receptor result in hypogonadotropic hypogonadism and Mutations of the GnRH gene have been in with GnRH deficiency, but have been identified in the gene encoding the GnRH on the other have been identified and result in isolated hypogonadotropic hypogonadism, with the with the to which GnRH and is Mutations in a pituitary in the of pituitary cell result in pituitary hormone deficiency, short and hypogonadotropic hypogonadism of the pituitary gonadotropins and receptors are mutations of the common gene have been In the the associated with gene mutations and gene mutations is associated with primary and secondary sex and also have These findings that FSH is important for estrogen normal pubertal and the other FSH is for follicular development to but to be required for follicular gene mutations a as for gene that the former result in hypogonadotropic hypogonadism, whereas the result in In the gene mutations have been associated with Of note, the role of FSH has been in the male by the of a with an mutation of the This testosterone was despite gonadotropin This that FSH has a role in the of spermatogenesis in the of the lack of FSH are with a mutation of the have a of and none of had in have a on the male mutations in the of LH to a of Leydig cells, lack of puberty, and mutations of the result in male precocious puberty whereas mutations to male The between the of LH and mutations that the have an important role in the of testosterone production and male sexual in with LH to mutations of the gene have and primary or secondary The presence of normal follicular in that FSH can stimulate estrogen production for pubertal The of males with estrogen such as estrogen and have the role and of estrogen in the is that estrogen has a role in male development and and are characterized by with into delayed lack of and Interestingly, of with the syndrome are of the of the to adrenal to the development of the normal male through the androgen the function of androgen receptor result in a variety of to minor of In the syndrome, males present with precocious puberty and/or and females present with precocious puberty and/or have been with androgen to aromatization of and androgen the androgen are associated with and of the adrenal the of normal production adrenal in and of the adrenal The clinical of the is but the in cases of and are associated with gonadal androgen and estrogen secretion and cause delayed puberty in both Of the is rare and has been associated with a of the with gene mutations have a in adrenal and gonadal and both and are females and are associated with androgen and cause of precocious puberty in both The molecular in the syndrome, a mutation of the gene for the of the the clinical of the syndrome as activation in the function of cells in the ovary, the and the precocious puberty, and This condition to with androgen while the estrogen and with GnRH puberty has The molecular insights into pubertal physiology and pathophysiology have to for some of male sexual syndrome, syndrome, and as hypoplasia androgen adrenal pituitary hormone FSH LH