IllnessHypospadia, differential diagnosis

NGS +

[Sanger]

In hypospadias, the meatus urethrae externus may have various malpositions. In most patients, hypospadia is an isolated malformation, but in some cases it may occur with additional genito-urinary malformations. The most common malformations associated with proximal hypospadias are cryptorchidism and inguinal hernias. Hypospadias are also associated with up to 200 different syndromes, e.g., WAGR complex, Denys-Drash, Smith-Lemli-Opitz, Wolff-Hirschhorn and CHARGE syndromes. Overall, the heritability of hypospadias appears to be approximately 67%. In general, a combination of environmental influences and genetic susceptibility causes isolated hypospadias, and only 30% of hypospadias cases have a definite genetic cause, with 10% having familial clustering. In the few monogenic cases, the inheritance patterns follow all classical schemes. The diagnostic yield by molecular genetics is unknown.

Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012964/

• Allelic: Androgen insensitivity (AR)
• Allelic: Androgen insensitivity, partial, with/-out breast cancer (AR)
• Allelic: Basal cell nevus syndrome (PTCH1)
• Allelic: Holoprosencephaly 7 (PTCH1)
• Allelic: Prostate cancer, susceptibility to (AR)
• Allelic: Spinal + bulbar muscular atrophy of Kennedy (AR)
• 17,20-lyase deficiency, isolated (CAP17A1)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• 46XX sex reversal 1 (SRY)
• 46XY gonadal dysgenesis with minifascicular neuropathy (DHH)
• 46XY sex reversal 1 (SRY)
• 46XY sex reversal 2, dosage-sensitive (NR0B1)
• 46XY sex reversal 6 (MAP3K1)
• 46XY sex reversal 7 (DHH)
• ADULT {Acro-Dermato-Ungual-Lacrimal-Tooth} syndrome (TP63)
• Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency (HSD3B2)
• Adrenal hypoplasia, congenital (NR0B1)
• Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete (CYP11A1)
• Allelic: Luteinizing hormone resistance, female (LHCGR)
• Alpha-thalassemia/mental retardation syndrome (ATRX)
• Antley-Bixler syndrome with genital anomalies + disordered steroidogenesis (POR)
• Bardet-Biedl syndrome 6 (MKKS)
• Beckwith-Wiedemann syndrome (CDKN1C)
• Cardiac-urogenital syndrome (MYRF)
• Cornelia de Lange syndrome 1 (NIPBL)
• Cornelia de Lange syndrome 3 (SMC3)
• Cornelia de Lange syndrome 4 (RAD21)
• Cornelia de Lange-like syndrome [MONDO:0016033] (BRD4)
• Developmental delay, hypotonia, musculoskeletal defects + behavioral abnormalities (SRCAP)
• Disordered steroidogenesis due to cytochrome P450 oxidoreductase (POR)
• Ectrodactyly, ectodermal dysplasia + cleft lip/palate syndrome 3 (TP63)
• Encephalitis/encephalopathy, mild, with reversible myelin vacuolization (MYRF)
• Floating-Harbor syndrome (SRCAP)
• Genitourinary and/or brain malformation syndrome (PPP1R12A)
• Glass syndrome (SATB2)
• Glutaric acidemia IIA (ETFA)
• Glutaric acidemia IIB (ETFB)
• Glutaric acidemia IIC (ETFDH)
• Guttmacher syndrome (HOXA13)
• Hand-foot-uterus syndrome (HOXA13)
• Hay-Wells syndrome (TP63)
• Hypospadias 1, XL (AR)
• Hypospadias 2, XL (MAMLD1)
• IMAGe syndrome (CDKN1C)
• Kabuki syndrome 1 (KMT2D)
• Kabuki syndrome 2 (KDM6A)
• Leydig cell hypoplasia with hypergonadotropic hypogonadism (LHCGR)
• Leydig cell hypoplasia with pseudohermaphroditism (LHCGR)
• Limb-mammary syndrome (TP63)
• McKusick-Kaufman syndrome (MKKS)
• Mental retardation-hypotonic facies syndrome, XL (ATRX)
• Mowat-Wilson syndrome (ZEB2)
• Mungan syndrome (RAD21)
• Neurodevelopmental disorder with/-out anomalies of brain, eye or heart (RERE)
• Nonsyndromic 46XY disorders of testicular development [genereviews] (DMRT1)
• Opitz GBBB syndrome, type I (MID1)
• Orofacial cleft 8 (TP63()
• Precocious puberty, male (LHCGR)
• Pseudohermaphroditism, male, with gynecomastia (HSD17B3)
• Pseudovaginal perineoscrotal hypospadias (SRD5A2)
• Rapp-Hodgkin syndrome (TP63)
• STAR syndrome (FAM58A)
• Simpson-Golabi-Behmel syndrome, type 1 (GPC3)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Split-hand/foot malformation 4 (TP63)
• Squalene synthase deficiency (FDFT1)