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| Clinical lesson learned from genetic analysis in patients prior to surgical repair of hypospadias |
| Nurin A. Listyasaria,Gorjana Robevskab,Katie L. Ayersb,c,Tiong Yang Tanc,d,Andrew H. Sinclairb,c,Sultana M. H. Faradza,e
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a Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine Diponegoro University, Semarang, Indonesia
b Murdoch Children’s Research Institute, Melbourne, Australia
c Department of Paediatrics, University of Melbourne, Melbourne, Australia
d Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia
e Diponegoro National Hospital, Semarang, Indonesia |
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Abstract In Indonesia, undervirilisation in 46,XY males is the most common form of difference of sex development (DSD). This can include hypospadias (misplacement of the urethra), micropenis, bifid scrotum, and undescended testis [1]. Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes, including Smith-Lemli-Opitz Syndrome (OMIM 602858), caused by an inborn error of cholesterol synthesis, and characterised by growth delay, intellectual disability, microcephaly, distinctive facial features, cleft palate, limb anomalies, and hypospadias [2] or Opitz syndrome (also known as Opitz G/BBB syndrome). Opitz syndrome can be caused by variants in the X-linked midline 1 (MID1) gene (Type I) or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like (SPECC1L) on chromosome 22q11.2 (Type II) [3]. Opitz syndrome is characterised by hypospadias, hypertelorism, cleft lip/palate, and heart defects [4]. The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50 000 to 1 in 100 000 males [5]. Recognition of a syndrome informs appropriate clinical management and patient care. Therefore, although these syndromes are rare, hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.
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Received: 26 June 2021
Available online: 20 April 2022
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The characteristics of the X-linked Opitz syndrome patients in this study. (A) The pedigrees of Family 1; (B and C) Hypertelorism showing in the frontal view of the proband and mother in Family 1; (D) Chromatograms of MID1 gene sequence and the affected index of the proband and mother in Family 1. Family 1 showed c.904dupT leading to p.Cys302Leufs?6 with mother is a heterozygous carrier. (E) The pedigrees of Family 2; (F and G) Hypertelorism showing in the frontal view of the proband and mother in Family 2; (H) Chromatograms of MID1 gene sequence and the affected index of the proband and mother in Family 2. Family 2 showed c.1322C>G leading to p.Pro441Arg with mother is a heterozygous carrier. Probands are hemizygous for the variant alleles. Arrow, the pathogenic variant position.
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| Reference | Exon | Nucleotide change | Protein (p.) change | Protein domain | Family history | Hypertelorism | CL/P | | Patient 1 | 5 | c.904dupT | p.Cys302Leufs?6 | Coiled-coil | Carrier mother | + | + | | Migliore et al. 2013 [10]. | 5 | c.958_959delCT | p.Leu320Glufs?4 | Coiled-coil | Carrier mother | + | + | | Patient 2 | 8 | c.1322C>G | p.Pro441Arg | FN3 | Carrier mother | + | + | | De Falco et al. 2003 [4]. | 8 | c.1387G>T | p.Val463Phe | FN3 | Foetus | + | + | | Reference | Exon | LTE defect | Hypospadias | MR/Dev delay | Anal defect | Heart defect | Brain anomaly | | Patient 1 | 5 | ND | + | ND | ND | ND | ND | | Migliore et al. 2013 [10]. | 5 | ND | + | - | - | - | ND | | Patient 2 | 8 | ND | + | ND | + | ND | ND | | De Falco et al. 2003 [4]. | 8 | + | + | Mild | - | - | ND |
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Comparison of pathogenic variants and dysmorphology of the present cases with previous reported cases.
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