Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
Aug. 24, 2021
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This article includes discussion of Kallmann syndrome, anosmic hypogonadism, dysplasia olfactogenitalis of de Morsier, hypogonadotropic hypogonadism and anosmia, Kallmann de Morsier syndrome, Kallmann syndrome 1, Kallmann syndrome 2, Kallmann syndrome 3, and olfactogenital syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Kallmann syndrome is a genetic condition manifesting hypogonadism and decreased ability to smell. Expressivity and penetrance are variable, accounting for considerable phenotypic and genetic heterogeneity. The first gene recognized, KAL1, is responsible for the X-linked form of the disease; KAL2 is responsible for the autosomal dominant form. In this article, the author presents new information from research studies in his discussions of the clinical manifestations, pathogenesis, genetics, epidemiology, and diagnosis, and management of this syndrome.
• Kallmann syndrome is a heterogeneous genetic condition associated with mutations in KAL1 (X-linked), KAL2 (autosomal dominant), or several other genes under current investigation.
• The diagnosis may be suggested by the observation of micropenis or cryptorchidism in infancy, or delayed onset of puberty at a later stage; for this reason, diagnosis can be challenging early in the adolescent years.
• Affected individuals have variably deficient gonadal function, reduced ability to smell, and a wide variety of other changes.
Kallmann syndrome is a genetic disorder in which hypogonadism (deficient function of gonads secondary to a deficiency in gonadotropin releasing hormone, or GnRH) is associated with decreased ability to smell (hyposmia or anosmia). This is often associated with hypoplasia or aplasia of olfactory bulbs and tracts, although rare individuals may have normal olfactory structures by MRI but may still be anosmic (43). The condition was described by Kallmann and colleagues in 1944, although it was apparently recognized as early as 1856 (87; 44; 17; 69). The genetic understanding of the condition continues to evolve. A gene responsible for the X-linked form of Kallmann syndrome was first discovered in a disease involving abnormal neuronal migration in the CNS (156).
A congenital deficiency in gonadotropin secretion, caused by reduced production of hypothalamic GnRH, is responsible for hypogonadism in Kallmann syndrome. This deficiency ranges from partial to severe. In partial forms, a degree of sexual development occurs, resulting in patients known as “fertile eunuchs.” In more severe forms, levels of luteinizing and follicle-stimulating hormones are low; sexual maturation is absent.
The sense of smell is affected, either partially (hyposmia) or completely (anosmia). The phenotype is more consistent in X-linked families than autosomal ones; no patient with X-linked Kallmann syndrome has intact smell (138). The severity of hypogonadism and loss of smell are not correlated directly, and complete anosmia may be associated with partial gonadotropin deficiency (203). In one study of patients with hypogonadotropic hypogonadism, approximately one third were anosmic, one third hyposmic, and one third normosmic (108). The severity of loss of smell is also variable. Patients with mutations associated with Kallmann syndrome may sometimes exhibit normosmic idiopathic hypogonadotropic hypogonadism (18; 145). In one study, all carrier females had normal smell and sexual function (74), but in other investigations, carriers have suffered from hyposmia or anosmia. Patients may report a distorted body image, depression, and loss of libido (77). Phenotypic variability, which has been observed in families affected by the X-linked form, is thought to result from the presence of putative modifier genes or possible epigenetic factors (119).
The diagnosis is difficult to make before puberty and has traditionally been made later when delayed sexual maturation becomes evident. Progress is being made in neonatal diagnosis, however, and at either age findings include small penis, cryptorchidism, and, later, gynecomastia. The face has been described as characteristic in a mother and affected son (autosomal dominant inheritance hypothesized), with square forehead, small nose, telecanthus, and thin upper lip (78).
CNS abnormalities are not limited to hypoplastic or absent olfactory bulbs and tracts and may also include holoprosencephaly and gyral anomalies (polymicrogyria, pachygyria, and lissencephaly); Dandy-Walker malformation or variant has been diagnosed in two (unrelated) teenage males (190; 07); the eyes may exhibit microphthalmia or ocular hypotelorism; intracranial calcifications have been noted in some patients. Partial agenesis of the corpus callosum, white matter abnormalities resembling multiple sclerosis, and acoustic schwannoma have been reported in older patients (118). Neurologic symptoms include mirror movements, cerebellar ataxia, abnormal eye movement, synkinesia, gaze-evoked horizontal nystagmus, strabismus, sensorineural deafness, spatial attentional abnormalities, spastic paraplegia, and mental retardation. Some patients are color blind. It has been suggested that neurologic complications occur only in the X-linked form of Kallmann syndrome (67). The association of synkinesia with KAL1 mutations offers support for this suggestion (38).
Extracranial abnormalities include thoracic cage anomalies (pes cavum), small or otherwise dysplastic, horseshoe, or absent kidney, highly arched feet (pes cavus), and ichthyosis (202; 101; 127). The sporadic appearance of femur-fibula-ulna dysostosis has been observed in one female patient with Kallmann syndrome (61).
Prognosis depends on the number and severity of anomalies. Limited sense of smell, hypogonadism, and mental retardation are important quality-of-life issues. The effects of hypogonadism, namely delayed sexual maturation and altered sexual function and behavior, may have a profound psychological effect but are, fortunately, treatable. Pre-treatment testicular volume appears to be an important prognostic factor, as patients with larger testes exhibit better response to human chorionic gonadotropin/human menopause gonadotropin (hCG/hMG) therapy (126), a treatment that is more efficacious than testosterone alone (207). Schizophrenia in one patient with Kallmann syndrome was thought to be a rare association rather than a condition with shared pathogenesis (192). Transsexualism has been recognized in two patients and can be difficult to treat (124). Early intervention is important, as therapy can stimulate the onset of puberty. Premature fusion of bony epiphyses, with resulting short stature, may occur as part of the (untreated) natural history of the disorder or may be a complication of hormonal replacement therapy (179; 169). A complication of insufficient treatment is increased fat mass and body mass index (102). The onset of testosterone therapy can also induce painful, low flow priapism, which, in one case, required placement of a cavernous spongiosal shunt for relief (169). Neurologic deficits and bone loss are additional complications (184). Reduced lumbosacral bone density and vertebral deformity have been reported in adult males (81). Hormone replacement therapy is beneficial, but not in all cases. This may be related to the age at which diagnosis is made and therapy begun (180). Some may progress to osteoporosis despite long-term therapy (102). Careful life-long care is thus indicated. Cases of reversible Kallmann syndrome (ie, acceleration in testicular growth and function) following cessation of testosterone therapy have been reported in a 41-year-old man with a KAL1 mutation and in an 18-year-old with a KAL2 mutation (144; 152); one case of reversible Kallmann syndrome has been reported in a patient with a mutation in fibroblast growth factor receptor 1. Low testosterone levels have been associated with vasculitis (Henoch-Schönlein purpura) in one patient with Kallmann syndrome (99). Patients with X-linked Kallmann syndrome may have abnormal corticospinal tracts and display mirror movements of the upper limb (52). Focal dystonia of the lower limbs has been reported (75). Gynecomastia (169), rare instances of breast cancer (129), and conductive hearing loss (34) have been reported. Calcifications of the basal ganglia accompanied by a history of infantile epilepsy and duodenal ulcer have been documented in a 20-year-old man (206). Nerve growth is influenced in nonolfactory regions as well. Anosmin-1, the glycoprotein encoded by KAL1 and produced by keratinocytes, has a modulating effect on epidermal nerve density in atopic dermatitis (185). It may also be found in multiple sclerosis or certain cancers (41). Patients with mutations in PROK2 and PROKR2 may suffer from obesity and sleep disorders (161).
Kallmann syndrome is a genetically heterogeneous condition whose chief findings are hypogonadotropic hypogonadism and anosmia. It is currently thought to be due to a defect in neuronal interaction or migration that affects the olfactory bulbs and tracts and the GnRH-secreting region of the brain. Several genes have been identified; to date, mutations in nine genes have been identified in one third of patients (142; 195). Of these, KAL1 is responsible for X-linked Kallmann syndrome, and KAL2 is responsible for the autosomal dominant form (50; 06). In about half of the cases, the genetic cause is unknown (80), and mutations in known genes are recognized in only 35% to 45% of cases (147; 48; 198). The genetic understanding of the condition is under considerable flux, and between 30 and 60 mutations are recognized in congenital hypogonadotropic hypogonadism (209; 29).
Heritability in Kallmann syndrome may be autosomal dominant, autosomal recessive, or X-linked. The majority appear to be the latter, for the overall male-to-female ratio in Kallmann syndrome is about 3:1 to 5:1, occurring in 1 in about 5000 males (193). A variety of genetic mechanisms has been proposed to explain this heterogeneity but remain understood incompletely. Mutations in leptin (the GnRH receptor) and the leptin receptor, for example, cause autosomal recessive hypogonadotropic hypogonadism, but this only explains a tiny proportion of total cases (103). In one study, workers ruled out KAL gene mutations as a significant cause of sporadic GnRH deficiency in females and suggested the existence of unidentified genes (105). Homozygous inactivating mutations in the GNRH1 gene have been identified in male and female subjects with hypothalamic non-syndromic hypogonadotropic hypogonadism (23).
KAL1 is responsible for X-linked Kallmann syndrome. The gene encodes an extracellular matrix glycoprotein called anosmin or anosmin-1 (84). Anosmin-1 appears to be important in branching and guidance (targeting) of olfactory neurons (113; 176). KAL1 is located at Xp22.3 in humans, consists of 14 exons, and has two motifs associated with adhesion function and antiprotease activity (106; 109). The sequence analysis of the coding region and splice site junctions has been reported for three affected males (82). Several novel mutations in KAL1 have been identified, but these are rare, suggesting that other genes may exist or that polymorphisms within KAL1 may predispose to disease in some individuals (173). The issue of polymorphism continues to be studied; some suspected polymorphisms may be pseudogene products instead (174).
A second gene, KAL2, has been identified and is responsible for the autosomal dominant form of the syndrome with incomplete penetrance (06; 144; 49). It is homologous with FGFR1 and located at 8p12. Mutations in a ligand of FGFR1 (FGF8) cause varying degrees of gonadotropin-releasing deficiency and consequent change in olfactory phenotype (187; 199). The gene is important to forebrain development, as mutations have also been identified in patients with holoprosencephaly (08) and is found in patients with craniosynostosis. Some 10% of patients with Kallmann syndrome have mutations in FGFR1, so it is not surprising that skeletal anomalies (spine, limb) have also been observed in affected patients (85; 134). Overexpression of KAL1, due to partial or complete duplications of the gene, may also result in skeletal anomalies (ie, ectrodactyly) (177). In this instance, KAL1 appears to interfere with FGFR1 signaling activity, producing skeletal and genital anomalies and intellectual shortcomings. A dominant negative mutation of FGFR1 has been reported (111).
Additional genes have been identified, or suspected of playing roles, in the development of Kallmann syndrome. These include TAC3, TAC3R, GPR54, PROKR2, PROK2, CHD7, WDR11, SEMA3A, GNRHR, GLI3, ANOS1, and PTCH1 (70; 19; 30; 25; 92; 208; 14; 57; 183). It is possible that mutations in some of these genes (ie, SEMA3A and SEMA7A) modify the Kallmann phenotype but are not causative independently (88). These latter genes encode semaphorins, a family of molecules that provides cues to axonal guidance and appears to regulate embryonic migration and survival and later functioning of GnRH neurons (107). PROKR2 and PROK2 may constitute an autosomal recessive monogenic KAL3 as well as a digenic-oligogenic form (49; 198). Inheritance in these latter two genes is non-Mendelian, which highlights the genetic heterogeneity of this condition and may help explain the high number of sporadic cases (51). WDR11 is necessary for the development of cilia; mutations of this gene in Kallmann Syndrome suggest that the disorder may represent another example of a ciliopathy (94). HESX1 mutations have been reported in three of 217 male patients (132). Much is unknown about the function of many of these genes, which together account for approximately 35% to 45% of cases (48). Patients with combined pituitary hormone deficiency or septo-optic dysplasia may also exhibit such mutations, suggesting a significant genetic overlap in developmental anomalies of the forebrain (148). Contiguous gene deletions that encompass genes for Kallmann syndrome appear to be responsible for unexpected associations such as ichthyosis (115).
In the chick, KAL is expressed in a number of CNS neuronal populations (including the olfactory bulbs) and may play a role in late neuronal development. The molecular and cellular mechanisms of action of the gene product continue to be studied. The protein may be related to targeting olfactory axons to olfactory bulbs, or it may serve as an extracellular matrix component and contribute to the formation of the olfactory bulb (112). KALIG1 (Kallmann syndrome interval gene-1) also maps to the distal short arm of X in humans and shares homology with cell adhesion and axonal pathfinding molecules, providing further support for abnormal neuronal migration in Kallmann syndrome (56). The association of Kallmann syndrome with steroid sulphatase deficiency provided evidence for deletion at the tip of X-p (13; 12). Experiments in the rodent, which lacks Kal1 and manifests GnRH that is diffuse throughout the forebrain and not confined to the olfactory region, have required special genetic manipulation, but generally support findings in the human (135).
The primary mechanism responsible for Kallmann syndrome is unknown, but appears to involve defective neuronal interaction, synaptogenesis, or migration (156). Defective migration of olfactory neurons provides a ready explanation for hyposmia or anosmia in affected individuals, but the association with hypogonadism is not as readily explained. The neurons that populate the olfactory neurons and those that secrete GnRH arise from the olfactory placode. Olfactory neurons send axons through the cribriform plate to form synapses with the olfactory bulbs. Early in fetal development, GnRH-secreting neurons migrate from the nasal placode, following the olfactory neurons and tracts, to reside in the medial basal hypothalamus (72). From there, the release of GnRH activates the production and secretion of pituitary gonadotropin (168). In arhinencephaly, this does not occur, and microscopic arrests of olfactory axons can be identified between cribriform plate and forebrain (65; 167). This finding is thought to result from abnormal neuronal induction or migration and possibly from a defect in “guidance molecules” (156). Although KAL is expressed in developing olfactory bulbs, it is unclear if, or how, the gene is responsible for guiding GnRH neurons into the brain or whether other factors, including physical ones, might also be involved (155; 204). In the chick, the gene ANOS1 is involved in the VEGF pathway leading to angiogenesis of normally developing olfactory bulbs; mutations in ANOS1 are associated with Kallmann syndrome in humans (121). A novel mutation in CCDC141 has been identified in a group of patients and, additionally, studied in mice (79). The gene is expressed in olfactory tracts, reduces GnRH neuronal migration (but not olfactory receptor neurons) when knocked down, and appears to affect the corresponding hypothalamic neuronal network. Thus, patients with this mutation have normal olfactory function and anatomically normal olfactory bulbs and, therefore, idiopathic hypogonadotropic hypogonadism, but not Kallmann syndrome (189). A murine homolog to KAL1 has not been identified; therefore, much current experimentation utilizes the nematode C. elegans and the fruit fly D. melanogaster, elucidating the role of neurons in influencing migration, adhesion of epidermal cells, and neurite outgrowth (157; 46).
Several craniofacial anomalies have been identified in patients with Kallmann syndrome. Anomalies of the ethmoid bone are associated with defects of olfactory bulbs (116). Cleft lip and palate occur with increased frequency in affected patients, but these appear to be restricted to those with KAL2 mutations (06); choanal atresia has been reported in the autosomal recessive form (95). Nasal cartilage may be absent (199). Agenesis of the teeth has been reported in patients with KAL2 (FGFR1) mutations (06; 09). Those with cleft lip and palate show increased mandibular inclination and angulation, retrognathism of the maxilla and mandible, and altered sphenoid bone and anterior cranial base anatomy (128). Absent pyramidal decussation with mirror movements has been noted in Kallmann syndrome (194). Cerebellar ataxia in one case was thought to be due to a small posterior fossa (75).
A subgroup of patients suffers from congenital heart disease. Many of these patients are retarded. The cause of this association is unknown. Because most fail to exhibit a family history, they may represent the results of a teratogenic event, sporadic dominant mutation, or recessive inheritance (37). Another subgroup consisting of males with X-linked Kallmann syndrome and renal anomalies has a prevalence estimated at 27% to 40% (42; 43). Renal agenesis has been described in eight members of an Australian family (35); the KAL1 mutation was variably present in this family, and one female exhibited a pelvic kidney, suggesting to the authors that an autosomal dominant or X-linked gene may have independently or codependently contributed to the appearance of renal agenesis. In other studies, unilateral renal agenesis or dysgenesis has been identified in patients with KAL1 mutations (06; 62) and is a suggested indication for screening (178). Multicystic renal dysplasia has been diagnosed in two brothers with Kallmann syndrome (42). It remains unclear if this form of renal dysplasia is a true component of Kallmann syndrome, or if such kidneys involute, leading to a diagnosis of renal agenesis.
The incidence of Kallmann syndrome is estimated to be 1 in 5,000 males, with males affected three to five times more than females (193). In one study of 101 individuals with idiopathic hypogonadotropic hypogonadism (136), 59 manifested anosmia (true Kallmann syndrome) but 42 did not. Of the 59 with Kallmann syndrome, 38 occurred sporadically and 21 were familial. Three of the familial cases (14%) and four of the sporadic cases (11%) had mutations in KAL. One report has suggested that the prevalence of Kallmann syndrome may be increased in Brazil, but this will require verification with larger numbers of patients (188).
Sporadic cases cannot be predicted or prevented. Prevention in affected families is only possible by avoiding pregnancy. Of course, treating affected patients with hormonal supplementation improves fertility and increases the chances of transmitting gene mutations to the following generation (162).
As with any genetic disease, genetics specialists can provide information regarding risk. This will most likely involve acquiring a family pedigree, which in itself carries a risk of invasion of privacy (28).
Micropenis can be observed in a variety of other syndromes (139). Absent olfactory bulbs and tracts are observed in a number of malformation complexes, including holoprosencephaly, or may be isolated. Some affected patients have abnormal karyotypes, including dup(1q), dup(6p), dup(6q), i(12p), dup(16q), and 49,XXXXY (171). Mutations in SIX3 or GLI2 in a small number of patients with Kallmann syndrome and holoprosencephaly (and no mutation in a known Kallmann syndrome gene) suggest a genetic overlap between the two conditions (191). Monogenic forms of arhinencephaly are recognized in Perrin syndrome, Johnson syndrome, Varadi syndrome, Fitch syndrome, anosmia or radiohumeral synostosis syndrome, and campomelic dysplasia (66). Patients with CHARGE syndrome (coloboma, heart defect, atresia of choanae, retarded physical and mental development, genital hypoplasia, and ear anomalies or hearing loss) may also exhibit hypogonadotropic hypogonadism and abnormal development of the olfactory bulbs and tracts (143). Similar findings have been noted in previous anatomic studies of patients with CHARGE association (172). The genetic basis for this is becoming clear, in that CHD7 mutations (responsible for a significant number of patients with CHARGE syndrome) have been identified in patients with Kallmann syndrome and features of CHARGE syndrome (91; 86; 83; 16; 10) and has been found to influence neural crest cell development and migration (166). In fact, olfactory ensheathing cells (the glial portion of the olfactory system) have a neural crest origin and are important to olfactory development and GnRH-1 neuronal migration (55; 183). In mice, homologous mutations in Chd7 are linked to defects in olfactory neural stem cell proliferation and subsequent olfactory bulb development (104). Based on these observations, some have suggested that Kallmann syndrome represents a mild form of CHARGE syndrome (92). One-third of patients with Kallmann syndrome and hearing loss have mutations in SOX10 (142). One such mutation has also been associated with hypopigmented iris and hyperthyroidism (201). These findings raise the possibility that the Hedgehog signaling pathway plays an important role in the development of Kallmann syndrome and GnRH neuron migration (14).
Hypogonadotropic hypogonadism is also observed in combined pituitary hormone deficiency (panhypopituitarism). Patients with idiopathic hypogonadotropic hypogonadism have olfactory bulbs (apparent on MRI), although they may be hypoplastic (200; 90; 11). Microadenomas (or larger masses, measuring several millimeters) and irregularly contrasting pituitary are also observed by MRI in these patients (22; 02).
Workers have noted an overlap of findings between some schizophrenic males and those with Kallmann syndrome (39). On this basis, it has been suggested that some males with schizophrenia, abnormal olfactory ability, and decreased sex drive might have mutations affecting the KAL-X gene; however, proof of this has not been forthcoming (137). In fact, one patient with paranoid schizophrenia showed no genetic imbalance or mutation in genes recognized in Kallmann syndrome (195).
Familial anosmia without hypogonadism or arhinencephaly has also been recognized. Cases are consistent with autosomal dominant inheritance with incomplete penetrance and may result from defective olfactory epithelium or olfactory cortex (64).
Physical diagnosis and imaging. Because one of the chief findings is delayed sexual development, few infants or young children have been diagnosed with Kallmann syndrome (20; 182; 21), although this area has seen encouraging development (24). In the complete form of Kallmann syndrome, physical maturation is delayed at puberty (findings at that time include cryptorchidism, micropenis, and gynecomastia); in the partial form, sexual development is somewhat more advanced, but still retarded. Hyposmia or anosmia is also present in affected patients. Traditionally, the ability to smell has been a central diagnostic finding, but some have suggested that clinical or historical evidence of decreased pubertal development is a more reliable feature (146). MRI and computed tomography provide good delineation of olfactory anatomy, which need not be bilaterally symmetric; absent or hypoplastic bulbs are recognized, as well as absent or hypoplastic olfactory sulci and hypoplastic anterior pituitary glands (114; 32; 211). In addition to altered configuration of olfactory sulci, gray and white matter volumes may be abnormal in adjacent regions (118). MRI can be especially helpful in cases where smell is difficult to evaluate or seemingly normal (98). An empty sella turcica has been noted in two female patients by MRI (40). Olfactory thresholds are measured using the Smell Identification (156; 53) or other tests (73; 05). Taste has been normal by electrogustometry in four patients with Kallmann syndrome (71). Standard MRI as well as PET and whole-brain voxel-based morphometry have been used to study mirror movements in Kallmann syndrome, in the process identifying white matter abnormalities in corticospinal tract and contralateral motor cortex (100; 97; 96). Mirror movements can, in fact, be important to diagnosis, even beyond infancy (63). Renal ultrasound is recommended for individuals with hearing loss, especially those with microphallus, or cryptorchidism, or both (89).
History. A careful history should be elicited and should include medical and family information, possible history of substance abuse, chronic disease, and exposure to chemotherapy or radiation exposure (122).
Other morphological tests. Testicular biopsy shows no evidence of sexual maturation in the complete form of Kallmann syndrome; interstitial fibrosis and decreased (type B) Sertoli and Leydig cell populations have been described (141). Studies have shown, however, that testicular histology is varied (133). In the partial form, some germinal cell maturation is present (159). Laparoscopy has been employed to visualize hypoplastic internal female genitalia and to biopsy immature ovaries (61). Ptosis and esotropia were the presenting symptoms in two prepubertal brothers later shown to have Kallmann syndrome (151).
Endocrine studies. In the complete form of Kallmann syndrome, serum levels of testosterone, estrogen, follicle-stimulating hormone, and luteinizing hormone are low. Patients may have a poor response to luteinizing hormone-releasing hormone stimulation (47). Oligomenorrhea and synkinesia have been observed in carrier mothers (84). Hyperparathyroidism has been noted in one patient with X-linked hypophosphatemic rickets and Kallmann syndrome (130).
Biochemical tests. The search for epididymal markers of infertility (eg, measures of alpha-glucosidase, glycerophosphocholine, and L-carnitine in seminal plasma) has not been successful in differentiating patients with Kallmann syndrome from those with other forms of hypogonadism (36). Low plasma inhibin B and anti-Mullerian hormone (AMH) may serve as indicators of testicular damage (03). X-linked hypophosphatemic rickets has been observed in one teenager with Kallmann syndrome (130).
Genetics. Inheritance may occur on an X-linked, autosomal dominant, or autosomal recessive basis. Karyotypes are generally normal in Kallmann syndrome, although a few abnormalities have been reported. Two sisters, born to consanguineous parents, have exhibited normal female phenotypes (with androgen insensitivity) and XY karyotypes but no mutations in KAL1 or KAL2 (58). The finding of 8p11.2 deletion in a patient with hypogonadotropic hypogonadism, anosmia, and congenital spherocytosis (the latter of which has a locus assigned to 8p) suggests that 8p11.2 may be an autosomal locus for Kallmann syndrome (196). This viewpoint is supported by the identification of overlapping deletions at 8p11-p12 in two patients with autosomal dominant Kallmann syndrome (KAL2). Because the missing region contains the fibroblast growth factor receptor 1 gene and because mutations in fibroblast growth factor receptor 1 have been identified in a number of patients with Kallmann syndrome, it has been suggested that a loss-of-function in fibroblast growth factor receptor 1 may be the basis for this form of the disorder (50). FGFR1, now known to be KAL2, is responsible for about 10% of patients with Kallmann syndrome (163). The FGFR1/KAL2 mutations are associated with a broader but less severe phenotype than KAL1 mutations (158). Mutations in genes encoding prokineticin 2 (PROK2) and prokineticin receptor 2 (PROKR2) have also been identified in a number of patients (147; 93) and have been designated KAL3 (49). Another gene associated with Kallmann syndrome is NELF (nasal embryonic LHRH factor), which is a human homolog for the mouse gene (Nelf) that encodes a molecule important for guiding migration of olfactory axon and GnRH neurons (125). In fact, NELF mutations have been identified in a small number of patients with Kallmann syndrome (205). Other changes have been described as well. Best and colleagues described an individual with balanced de novo translocation (7; 12) (q22,q24) (17); Schinzel and colleagues reported a boy with a t(1; 10) translocation (165); Guioli and colleagues reported a patient with an X;Y translocation involving the X-linked Kallmann syndrome gene and Y homolog (68). Mutations in asymptomatic carrier mothers have been identified by comparative multiplex polymerase chain reaction (131). A somatic mutation involving a 2-base pair deletion in FGFR1 in one symptomatic mother, with passage to her son via germline mosaicism, has also been reported (164). Deletions in genes expressed only in testis have also been identified (76). Otherwise, deletions appear to be rare (140).
Certain findings may suggest avenues for genetic workup. For example, synkinesia is associated with KAL1 mutations; dental agenesis or digital anomalies with FGF9/FGFR1; and hearing loss with CHD7 mutations (38).
These many findings provide evidence that Kallmann syndrome is multigenic and the result of divergent genetic pathways (93). Undiscovered genes and epigenetic or environmental factors may be involved in pathogenesis as well (197). Because of the possibilities of non-Mendelian (eg, oligogenic) inheritance, incomplete penetrance, and variable expressivity, genetic counseling must be undertaken with great care (117).
Counseling is hindered by the wide heterogeneity of the condition, with its variable penetrance and expressivity (29). For this reason, the list of associated abnormalities that may be manifest in Kallmann syndrome is lengthy and many complicate management. High quality patient care may, therefore, require the participation of a number of specialists.
Because hypogonadism results in delayed development of secondary sex characteristics, sexual function, and behavior, hormonal treatment is often desired (154). The benefits of neonatal gonadotropin therapy have been demonstrated (24). In fact, the period extending from the third trimester to six postnatal months, which is termed “minipuberty,” is crucial to testicular maturation and must be considered when devising a treatment regimen (180). Virilization of males with primary hypogonadism can be achieved with exogenous androgens; in secondary hypogonadism, gonadotropin or GnRH therapy is used (120). Surgery may be required for undescended testes (175). Otherwise, the administration of HcG can induce the descent of testes and onset of fertility, even in adults. A history of testicular descent prior to initiation of therapy is a good prognostic indicator, although spermatogenesis has also been initiated in men with bilaterally undescended testes and can be maintained for extended periods with HcG alone (27; 45; 153). In women with idiopathic hypogonadotropic hypogonadism, levels of anti-Müllerian hormone and antral follicle counts are low but can be corrected with follicle-stimulating hormone (26). Reproductive success following HcG administration may be related to genotype, although this hypothesis awaits confirmation with additional cases (212). Recombinant human follicle-stimulating and luteinizing hormones have been used to increase testicular growth and sperm production (150; 186). In one study, reversal of hypogonadism was sustained in 10% of patients following cessation of hormonal therapy (149). In fact, reversal (activation of hypothalamic-pituitary-gonadal axis, with normal steroid production, or gamete production, or both) has been observed in some 10% to 22% of patients; such reversal may be temporary (170; 209). With early treatment and brain sexual maturation, eunuchoid behavior and appearance can be prevented (31). Testicular prostheses may also be used to reduce psychosexual problems (54). Assisted reproductive techniques (ART) have been used with success in some patients (59). Because of the obvious complexities, endocrinologic, genetic, and psychological consultations are indicated in patients with Kallmann syndrome (01; Garrido Oyarzun and Castelo-Branco 2016).
In the future, genetic rescue may be possible. The effects of mutations in PKR2, a recognized cause of Kallmann syndrome, have been reversed with treatment of 10% glycerol under experimental conditions (33).
With a positive family history and prenatal ultrasonography, the diagnosis of Kallmann syndrome can be made or at least suggested prior to birth (160). No risks are recognized for women pregnant with male fetuses with Kallmann syndrome. Females are affected infrequently, but hypogonadism in these individuals would severely limit the ability to conceive (depending on severity of disease and availability and efficacy of treatment). Hormonal stimulation, although complex and sometimes refractory, can lead to successful development of secondary sex characteristics, ovulation, and pregnancy (04; 110; 210; 123). Highly purified follicle-stimulating hormone has also been used to induce ovulation and subsequent pregnancy (15). Intracytoplasmic sperm injection has also been employed following induction of ovulation (181). Adult females are more likely carriers, a condition not known to have an adverse effect on pregnancy.
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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