NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.

Spermatogenic arrest during meiosis is a cause of infertility. The histologic picture of meiotic arrest is rather constant. Meiotic arrest is characterized by germ cells that enter meiosis and undergo the first chromosomal reduction from 4n to 2n but are then unable to proceed further. This results in tubules containing spermatocytes as the latest developmental stage of germ cells. Meiotically arrested spermatocytes accumulate in the tubules, degenerate, and are easily distinguishable from normal spermatocytes by their partially condensed chromosomes. Although the cause of infertility in patients with meiotic arrest often remains unidentified, this histologic picture can be observed in patients with nonidiopathic infertility as well, such as in the case of microdeletions of the Y chromosome, chromosomal abnormalities, and cryptorchidism, suggesting that different causal factors can result in the same effect (summary by Luetjens et al., 2004). Genetic Heterogeneity of Spermatogenic Failure See SPGF2 (108420), caused by mutation in the MSH4 gene (602105) on chromosome 1p31; SPGF3 (606766), caused by mutation in the SLC26A8 gene (608480) on chromosome 6p21; SPGF4 (270960), caused by mutation in the SYCP3 gene (604759) on chromosome 12q23; SPGF5 (243060), caused by mutation in the AURKC gene (603495) on chromosome 19q13; SPGF6 (102530), caused by mutation in the SPATA16 gene (609856) on chromosome 3q26; SPGF7 (612997), caused by mutation in the CATSPER gene (606389) on chromosome 11q13; SPGF8 (613957), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; SPGF9 (613958), caused by mutation in the DPY19L2 gene (613893) on chromosome 12q14; SPGF10 (614822), caused by mutation in the SEPT12 gene (611562) on chromosome 16p13; SPGF11 (615081), caused by mutation in the KLHL10 gene (608778) on chromosome 17p21; SPGF12 (615413), caused by mutation in the NANOS1 gene (608226) on chromosome 10q26; SPGF13 (615841), caused by mutation in the TAF4B gene (601689) on chromosome 18q11; SPGF14 (615842), caused by mutation in the ZMYND15 gene (614312) on chromosome 17p13; SPGF15 (616950), caused by mutation in the SYCE1 gene (611486) on chromosome 10q26; SPGF16 (617187), caused by mutation in the SUN5 gene (613942) on chromosome 20q11; SPGF17 (617214), caused by mutation in the PLCZ1 gene (608075) on chromosome 12p12; SPGF18 (617576), caused by mutation in the DNAH1 gene (603332) on chromosome 3p21; SPGF19 (617592), caused by mutation in the CFAP43 gene (617558) on chromosome 10q25; SPGF20 (617593), caused by mutation in the CFAP44 gene (617559) on chromosome 3q13; SPGF21 (617644), caused by mutation in the BRDT gene (602144) on chromosome 1p22; SPGF22 (617706), caused by mutation in the MEIOB gene (617670) on chromosome 16p13; SPGF23 (617707), caused by mutation in the TEX14 gene (605792) on chromosome 17q22; SPGF24 (617959), caused by mutation in the CFAP69 gene (617949) on chromosome 7q21; SPGF25 (617960), caused by mutation in the TEX15 gene (605795) on chromosome 8p12; SPGF26 (617961), caused by mutation in the TSGA10 gene (607166) on chromosome 2q11; SPGF27 (617965), caused by mutation in the AK7 gene (615364) on chromosome 14q32; SPGF28 (618086), caused by mutation in the FANCM gene (609644) on chromosome 14q21; SPGF29 (618091), caused by mutation in the SPINK2 gene (605753) on chromosome 4q12; SPGF30 (618110), caused by mutation in the TDRD9 gene (617963) on chromosome 14q32; SPGF31 (618112), caused by mutation in the PMFBP1 gene (618085) on chromosome 16q22; SPGF32 (618115), caused by mutation in the SOHLH1 gene (610224) on chromosome 9q34; SPGF33 (618152), caused by mutation in the WDR66 gene (618146) on chromosome 12q24; SPGF34 (618153), caused by mutation in the FSIP2 gene (615796) on chromosome 2q32; SPGF35, caused by mutation in the QRICH2 gene (618304) on chromosome 17q25; SPGF36 (618420), caused by mutation in the PPP2R3C gene (615902) on chromosome 14q13; SPGF37 (618429), caused by mutation in the TTC21A gene (611430) on chromosome 3p22; SPGF38 (618433), caused by mutation in the ARMC2 gene (618424) on chromosome 6q21; SPGF39 (618643), caused by mutation in the DNAH17 gene (610063) on chromosome 17q25; SPGF40 (618664), caused by mutation in the CFAP65 gene (614270) on chromosome 2q35; SPGF41 (618670), caused by mutation in the CFAP70 gene (618661) on chromosome 10q22; SPGF42 (618745), caused by mutation in the TTC29 gene (618735) on chromosome 4q31; SPGF43 (618751), caused by mutation in the SPEF2 gene (610172) on chromosome 5p13; SPGF44 (619044), caused by mutation in the CEP112 gene (618980) on chromosome 17q24; SPGF45 (619094), caused by mutation in the DNAH2 gene (603333) on chromosome 17p13; SPGF46 (619095), caused by mutation in the DNAH8 gene (603337) on chromosome 6p21; SPGF47 (619102), caused by mutation in the DZIP1 gene (608671) on chromosome 13q32; SPGF48 (619108), caused by mutation in the M1AP gene (619098) on chromosome 2p13; SPGF49 (619144), caused by mutation in the CFAP58 gene (619129) on chromosome 10q25; SPGF50 (619145), caused by mutation in the XRCC2 gene (600375) on chromosome 7q36; SPGF51 (619177), caused by mutation in the CFAP91 gene (609910) on chromosome 3q13; SPGF52 (619202), caused by mutation in the C14ORF39 gene (617307) on chromosome 14q23; SPGF53 (619258), caused by mutation in the ACTL9 gene (619251) on chromosome 19p13; SPGF54 (619379), caused by mutation in the CATIP gene (619387) on chromosome 2q35; SPGF55 (619380), caused by mutation in the SPAG17 gene (616554) on chromosome 1p12; SPGF56 (619515), caused by mutation in the DNAH10 gene (605884) on chromosome 12q24; SPGF57 (619528), caused by mutation in the PNLDC1 gene (619529) on chromosome 6q25; SPGF58 (619585), caused by mutation in the IFT74 gene (608040) on chromosome 9p21; SPGF59 (619645), caused by mutation in the TERB2 gene (617131) on chromosome 15q21; SPGF60 (619646), caused by mutation in the TERB1 gene (617332) on chromosome 16q22; SPGF61 (619672), caused by mutation in the STAG3 gene (608489) on chromosome 7q22; SPGF62 (619673), caused by mutation in the RNF212 gene (612041) on chromosome 4p16; SPGF63 (619689), caused by mutation in the RPL10L gene (619655) on chromosome 14q21; SPGF64 (619696), caused by mutation in the FBXO43 gene (609110) on chromosome 8q22; SPGF65 (619712), caused by mutation in the DNHD1 gene (617277) on chromosome 11p15; SPGF66 (619799), caused by mutation in the ZPBP gene (608498) on chromosome 7p12; SPGF67 (619803), caused by mutation in the CCDC62 gene (613481) on chromosome 12q24; SPGF68 (619805), caused by mutation in the C2CD6 gene (613481) on chromosome 2q33; SPGF69 (619826), caused by mutation in the GGN gene (609966) on chromosome 19q13; SPGF70 (619828), caused by mutation in the PDHA2 gene (179061) on chromosome 4q22; SPGF71 (619831), caused by mutation in the ZSWIM7 gene (614535) on chromosome 17p12; SPGF72 (619867), caused by mutation in the WDR19 gene (608151) on chromosome 4p14; SPGF73 (619878), caused by mutation in the MOV10L1 gene (605794) on chromosome 22q13; SPGF74 (619937), caused by mutation in the MSH5 gene (603382) on chromosome 6p21; SPGF75 (619949), caused by mutation in the SHOC1 gene (618038) on chromosome 9q31; SPGF76 (620084), caused by mutation in the CCDC34 gene (612324) on chromosome 11p14; SPGF77 (620103), caused by mutation in the FKBP6 gene (604839) on chromosome 7q11; SPGF78 (620170), caused by mutation in the IQCN gene (620160) on chromosome 19p13; SPGF79 (620196), caused by mutation in the KCNU1 gene (615215) on chromosome 8p11; SPGF80 (620222), caused by mutation in the DRC1 gene (615288) on chromosome 2p23; SPGF81 (620277), caused by mutation in the TEKT3 gene (612683) on chromosome 17p12; SPGF82 (620353), caused by mutation in the AKAP3 gene (604689) on chromosome 12p13; SPGF83 (620354), caused by mutation in the DNALI1 gene (602135) on chromosome 1p34; SPGF84 (620409), caused by mutation in the CFAP61 gene (620381) on chromosome 20p11; SPGF85 (620490), caused by mutation in

Torticollis-keloids-cryptorchidism-renal dysplasia syndrome is an extremely rare developmental defect during embryogenesis malformation syndrome characterized by congenital muscular torticollis associated with skin anomalies (such as multiple keloids, pigmented nevi, epithelioma), urogenital malformations (including cryptorchidism and hypospadias) and renal dysplasia (e.g. chronic pyelonephritis, renal atrophy). Additional reported features include varicose veins, intellectual disability and musculoskeletal anomalies.

Spermatogenic failure-2 (SPGF2) is characterized by male infertility due to azoospermia (Tang et al., 2020; Akbari et al., 2021). For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

CATSPER-related male infertility results from abnormalities in sperm and can be either CATSPER-related nonsyndromic male infertility (NSMI) or the deafness-infertility syndrome (DIS) when associated with non-progressive prelingual sensorineural hearing loss. Males with NSMI have infertility while females have no symptoms. Males with DIS have both infertility and hearing loss, while females have only hearing loss. Routine semen analysis typically identifies abnormalities in sperm number, morphology, and motility. Otologic examination and audiologic assessment can identify hearing loss.

Myotonic dystrophy type 2 (DM2) is characterized by myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects, insulin-insensitive type 2 diabetes mellitus, and other endocrine abnormalities. While myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third to fourth decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and proximal and axial weakness of the neck flexors and the hip flexors. Subsequently, weakness occurs in the elbow extensors and finger flexors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. In a subset of individuals, calf hypertrophy in combination with brisk reflexes is notable.

Any azoospermia in which the cause of the disease is a mutation in the NR5A1 gene.

SOFT syndrome is characterized by severely short long bones, peculiar facies associated with paucity of hair, and nail anomalies. Growth retardation is evident on prenatal ultrasound as early as the second trimester of pregnancy, and affected individuals reach a final stature consistent with a height age of 6 years to 8 years. Relative macrocephaly is present during early childhood but head circumference is markedly low by adulthood. Psychomotor development is normal. Facial dysmorphism includes a long, triangular face with prominent nose and small ears, and affected individuals have an unusual high-pitched voice. Clinodactyly, brachydactyly, and hypoplastic distal phalanges and fingernails are present in association with postpubertal sparse and short hair. Typical skeletal findings include short and thick long bones with mild irregular metaphyseal changes, short femoral necks, and hypoplastic pelvis and sacrum. All long bones of the hand are short, with major delay of carpal ossification and cone-shaped epiphyses. Vertebral body ossification is also delayed (summary by Sarig et al., 2012).

Spermatogenic failure-10 (SPGF10) is associated with a defective annulus, a ring structure that demarcates the midpiece and the principal piece of the sperm tail. The firm attachment of the annulus to the flagellar membrane suggests that it may supply mechanical support and prevent displacement of the caudal mitochondrial helix (summary by Kuo et al., 2012). For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Any azoospermia in which the cause of the disease is a mutation in the KLHL10 gene.

A rare, genetic form of obesity characterized by morbid obesity, hypertension, type 2 diabetes mellitus and dyslipidemia leading to early coronary disease, myocardial infarction and congestive heart failure. Intellectual disability and decreased sperm counts or azoospermia have also been reported.

Spermatogenic failure-38 (SPGF38) is characterized by primary infertility and asthenoteratozoospermia due to multiple morphologic abnormalities of the flagella (MMAF). Spermatozoa show total sperm motility below 10% and exhibit morphologic anomalies including short, absent, coiled, bent, or irregular-caliber flagella (Coutton et al., 2019). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-39 (SPGF39) is characterized by infertility due to asthenozoospermia. In some patients, spermatozoa exhibit multiple morphologic anomalies of the sperm flagellum (MMAF), including short, absent, irregularly shaped, and coiled flagella. Abnormalities of the sperm head and midpiece have also been observed, and ultrastructural analysis shows a lack of the outer dynein arms (ODAs) in sperm cells. In other patients, sperm do not exhibit MMAF, and ultrastructural analysis shows that many flagella lack 1 or more of microtubule doublets (MTDs) 4 to 7 at the principal piece or end piece; however, ODAs are present at the remaining MTDs (Whitfield et al., 2019; Zhang et al., 2020). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-40 (SPGF40) is characterized by multiple morphologic abnormalities of the flagella (MMAF), including absent, short, bent, coiled, and irregular-caliber tails, resulting in severely reduced to absent motility. Patient spermatozoa may also show morphologic defects of the sperm head, with acrosomal hypoplasia or aplasia (Wang et al., 2019; Li et al., 2020). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-41 (SPGF41) is characterized by infertility due to multiple morphologic abnormalities of the flagella (MMAF). Patient semen analysis has also shown oligozoospermia, and the flagellar abnormalities include short, absent, coiled, and irregular-caliber flagella. Some sperm show tapered heads and acrosomal abnormalities (Beurois et al., 2019). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-47 (SPGF47) is characterized by male infertility due to asthenoteratospermia. Affected individuals have reduced sperm concentrations and spermatozoa are immotile, with short or absent flagella as well as centriolar abnormalities (Lv et al., 2020). For a discussion of genetic heterogeneity of spermatogenic failure, see 258150.

Spermatogenic failure-48 (SPGF48) is characterized by male infertility due to a variable spectrum of severely impaired spermatogenesis, primarily at meiosis and resulting in azoospermia. However, sparse postmeiotic germ cell development and retrieval of sperm in some cases has been reported (Wyrwoll et al., 2020). For a discussion of genetic heterogeneity of spermatogenic failure, see 258150.

X-linked spermatogenic failure-3 (SPGFX3) is characterized by male infertility due to multiple morphologic abnormalities of the flagella (MMAF). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-51 (SPGF51) is characterized by male infertility due to severe asthenoteratozoospermia. Patients exhibit multiple morphologic abnormalities of the flagella (MMAF), including absent, short, bent, coiled, and irregular-caliber tails, resulting in severely reduced to absent motility. Abnormalities of the sperm head, base, and acrosome have also been observed (Martinez et al., 2020). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-54 (SPGF54) is characterized by male infertility due to oligoteratoasthenozoospermia, with markedly reduced sperm counts and severely reduced or absent sperm motility (Arafat et al., 2021). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-56 (SPGF56) is characterized by male infertility due to multiple morphologic abnormalities of the flagella (MMAF), resulting in severely reduced sperm motility (Tu et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-58 (SPGF58) is characterized by male infertility due to multiple morphologic abnormalities of the flagella (MMAF). Sperm are immotile or show severely reduced progressive motility due to short and irregular caliber flagella as well as bent, coiled, and absent flagella. Head abnormalities have also been observed, including acrosomal and postacrosomal defects (Lores et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-63 (SPGF63) is characterized by male infertility due to severe oligozoospermia with markedly reduced progressive motility (Tu et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-64 (SPGF64) is characterized by male infertility due to oligoasthenoteratozoospermia or nonobstructive azoospermia. Some patients have absent sperm due to meiotic arrest at the diplotene stage, whereas others show low sperm counts and reduced progressive motility, and spermatozoa have enlarged amorphous heads (Ma et al., 2019; Wu et al., 2022). Mutation in the FBXO43 gene can also cause female infertility due to early embryonic arrest (see OOMD12, 619697). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-65 (SPGF65) is characterized by male infertility due to asthenoteratozoospermia. Progressive sperm motility is severely reduced or absent, and patients exhibit multiple morphologic abnormalities of the flagella (MMAF), including coiled, irregular-caliber, short, and absent flagella. Abnormalities of the flagellar midpiece are also present (Tan et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of SPGF, see SPGF1 (258150).

Spermatogenic failure-70 (SPGF70) is characterized by male infertility due to azoospermia or sperm immotility and necrozoospermia (Yildirim et al., 2018). Hypospermatogenesis and meiotic arrest have also been observed (Kherraf et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-76 (SPGF76) is characterized by male infertility due to oligoasthenoteratozoospermia. Multiple morphologic abnormalities of the flagella (MMAF) have been observed, including short, absent, and irregular caliber flagella. Ultrastructural anomalies include disordered outer dense fibers and abnormal 9+2 microtubular structures (Cong et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-77 (SPGF77) is characterized by male infertility due to extreme oligozoospermia or azoospermia. Nearly all spermatozoa present on semen analysis are morphologically abnormal, with amorphous, enlarged, and/or fragmented heads, and some are multiflagellated. Testicular tissue shows arrest at the round spermatid stage (Wyrwoll et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-79 (SPGF79) is characterized by male infertility due to an abnormal acrosome reaction and impaired membrane potential after capacitation. Some patients exhibit asthenoteratozoospermia, with defective acrosome formation and mitochondrial sheath assembly, and reduced progressive motility (Lv et al., 2022; Liu et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-80 (SPGF80) is characterized by male infertility due to multiple morphologic abnormalities of the flagella (MMAF), including short, coiled, absent, and irregular-caliber flagella, with correspondingly reduced or absent progressive motility of sperm. Abnormalities of the sperm head have also been observed. Severe axonemal disorganization is evident on transmission electron microscopy (Zhang et al., 2021). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-81 (SPGF81) is characterized by male infertility due to oligoasthenoteratozoospermia. Patient spermatozoa exhibit acrosomal hypoplasia as well as detachment of the acrosome from the sperm head, and also show markedly reduced progressive motility (Liu et al., 2023) For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Spermatogenic failure-84 (SPGF84) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), including irregular-caliber, bent, coiled, absent, or short tails, resulting in severely reduced motility. Some patients also have a reduced sperm count (Liu et al., 2021; Hu et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of SPGF, see SPGF1 (258150).

Primary ciliary dyskinesia-51 (CILD51) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), resulting in severely reduced progressive motility. Some men also have a low sperm count. In addition, affected individuals experience chronic rhinosinusitis and bronchitis, and recurrent upper and lower respiratory infections, and some exhibit dextrocardia and/or situs inversus (Guo et al., 2021). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).