From: The evolving role of genetic tests in reproductive medicine
Main indications for genetic test | Hypogonadotropic hypogonadism (CHH) | ||||||||
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Other indications for genetic test | Genetic disorder | Frequency | Genetic test | Genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
Lack of puberty; micropenis, cryptorchidism; prepubertal testicular volume, absence of secondary sexual features, decreased muscle mass, diminished libido, erectile dysfunction, infertility, low testosterone, estradiol | Kallmann syndrome (olfactogenital syndrome with ano- or hyposmia azoospermia) | Prevalence: 1/30,000; incidence: 1/8000 | Molecular diagnosis | ANOS1 | ✓ | X-linked | ✓ | Syndromes associated with hypogonadotropic hypogonadism | |
CHD7, FGFR1, FGF8, SOX10 | AD | ||||||||
FEZF1, PROK2, PROKR2 | AR | ||||||||
Obesity, retinitis pigmentosa, postaxial polydactyly, kidney dysfunction, behavioral dysfunction; infertility | Bardet–Biedl syndrome (Laurence–Moon–Biedl syndrome) | 1:100,000 North America; 1:160,000 Switzerland; 1:17,500 Newfoundland; 1:13,500 Bedouin, Kuwait | Multigene panel | From BBS1 to BBS19 | ✓ | AR | ✓ | McKusick–Kaufman syndrome (MKS) | |
Adrenal insufficiency; cryptorchidism, delayed puberty, infertility | X-linked adrenal hypoplasia congenita | 1:12,500 | Molecular diagnosis | NR0B1 | ✓ | X-linked recessive pattern | ✓ | 21-hydroxylase deficiency; 11-hydroxylase deficiency | [26] |
Diabetes mellitus, hypothyroidism, alopecia totalis, long, triangular face, hypertelorism; dystonias, dysarthria, dysphagia; infertility | Woodhouse–Sakati syndrome (diabetes-hypogonadism-deafness-intellectual disability syndrome) | Unknown | Molecular diagnosis | DCAF17 | ✓ | AR | ✓ | Perrault syndrome; Deafness and hereditary hearing loss; Gonadotropin-releasing hormone deficiency | [27] |
Adult-onset neurodegenerative disorder; hypogonadotropic hypogonadism | Gordon Holmes syndrome (cerebellar ataxia and hypogonadotropic hypogonadism) | Unknown | Molecular diagnosis | RNF216, PNPLA6 | ✓ | AR | ✓ | Cerebellar ataxia | |
Cirrhosis, diabetes, cardiomyopathy, arthritis, skin hyperpigmentation; elevated serum transferrin-iron saturation (TS); elevated serum ferritin concentration; infertility | Hemochromatosis (Hemochromatosis Type 1, HFE-Associated Hemochromatosis, HFE-HH) | 2–5:1000 northern European ancestry; 1:200–400 non-Hispanic whites, North America | Gene-targeted or molecular diagnosis | HFE (typically p.Cys282Tyr and p.His63Asp can be performed first) | ✓ | AR | NA | Rarer primary iron overload disorders and secondary iron overload disorders | |
Azoospermia/oligozoospermia; ↑LH, normal T, hyperandrogenism; feminization of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility | Androgen insensitivity syndrome (AIS) | 2–5:100,000 | Screening for AR mutations (> 300) | AR | Donor | X-linked recessive | NA | MRKH syndrome; Hypospadias; MAIS; Undermasculinization of external genitalia and pubertal undervirilization | |
Glucocorticoid and mineralocorticoid deficiencies; hypospadias; ambiguous genitalia, infertility | 3-β-hydroxysteroid dehydrogenase (HSD) deficiency | Unknown | Molecular diagnosis | HSD3B2 | Donor | AR | NA | Ambiguous genitalia | [37] |
Deficiencies in GH,TSH, LH, FSH, PrL, and ACTH; hypothyroidism; neonatal hypoglycemia; micropenis without hypospadias, with or without cryptorchidism; short stature and delayed bone maturation; absent/delayed/incomplete secondary sexual development, infertility | PROP1-related combined pituitary hormone deficiency | 1:4000 in England and the US | Molecular diagnosis | PROP1 | ✓ | AR | ✓ | CPHD; isolated growth hormone deficiency; isolated hypogonadotropic hypogonadism | |
Ambiguous genitalia or external genitalia that appear female; micropenis and hypospadias; not much facial or body hair; infertility | 5-Alpha reductase deficiency (familial incomplete male pseudohermaphroditism, type 2) | Unknown | Molecular diagnosis | SRD5A2 | ✓ | AR | ✓ | Ambiguous genitalia |