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Antley-Bixler syndrome (ABS)—consisting of ABS type 1 (skeletal only) and ABS type 2, associated with cytochrome 450 mutations and P450 oxidoreductase deficiency (PORD-ABS)—is a heterogeneous syndrome with a constellation of skeletal deformation findings that classically include skull, facial, and appendicular defects. The hallmarks of ABS type 1 i...
Context in source publication
Context 1
... this time, an extensive sonographic examination of the fetus revealed bilateral femoral midshaft bowing (Figure 2A,B), clubbing with internal rotation of feet (Figure 3), and frontal bone flattening or "keel-shaped" configuration of trigonocephaly with small cisterna magna ( Figure 4A,B). Because of the presence of these anomalies, a repeat sonographic examina- tion was done one week later that confirmed the previous findings and further revealed a radiohumeral synostosis ( Figure 5) as well as micrognathia and prominent nose ( Figure 6). The differential diagnosis for these sonographic findings included trisomy 18, Jacobsen syndrome, campto- melic dysplasia, Pena-Shokeir syndrome, ABS, Apert syn- drome, Muenke syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata, Crouzon syndrome, and Pfeiffer syndrome. ...
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Background:
Prenatal diagnosis of severe bone diseases is challenging and requires complete and precise analysis of fetal anomalies to guide genetic investigation and parental counselling.
Case report:
We report a rare case of Antley-Bixler syndrome prenatally diagnosed at 26 weeks' gestation by ultrasound and computed tomography in a 28-year-ol...
Citations
... 1. In uterus, fetal skeletal malformations may be visualized on ul t r a s on og r a ph y , i n c l u di n g A B S-l i k e d i s c o ve r ie s o f craniocynostosis, protruding forehead, choanal atresia, radiohumeral synostosis, and femoral shortening and bowing, club feet, with femoral changes readily revealed (12,51). To systematically assess the severities of skeletal malformations, FIGURE 2 Simplified possible pathogenesis of ABS-like phenotype, partial adrenal insufficiency, delayed puberty, infertility, and ovarian cysts with altered HPA and HPO axis caused by POR mutations. ...
... Low E3 occurs on the presence of several other steroidogenic deficiency, such as steroidogenic acute regulatory protein deficiency, CYP17A1 deficiency, steroid sulfates deficiency, defects of placental aromatase, hypopituitarism, and Smith-Lemli-Opitz syndrome. ABS-like phenotype can be observed in multiple syndromes, including trisomy 18 syndrome, Apert, Jacobse, Jackson-Weiss, and Pfeiffer syndrome (51). Although among maternal virilization, low serum E3, and ABS-like phenotype, none of the clinical, laboratory, and sonographic findings are PORD specific, we propose that two of three otherwise unexplained features are highly indicative of PORD, which needs further investigation in clinical practice. ...
... Prenatal diagnosis may be needed in highly suspicious cases of PORD. Amniocentesis could be done to detect the underlying genetic etiology during second trimester (51). Nowadays, a noninvasive technique has been developed to obtain fetal genetic information following the discovery of fetal cell-free DNA in maternal circulation, which allows the diagnosis of single gene disorders at an early gestational age (83,84). ...
Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype–genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients’ outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.
Context:
P450 oxidoreductase deficiency (PORD) is a rare genetic disorder that is associated with significant morbidity. However there has been limited analysis of reported PORD cases.
Objective:
To determine, based on the cohort of reported PORD cases, genotype-phenotype relationships for skeletal malformations, maternal virilisation in pregnancy, adrenal insufficiency and disorders of sexual development (DSD).
Data sources:
PubMed and Web of Science from January 2004 to February 2018.
Study selection:
Published case reports/series of patients with PORD. Eligible patients were unique, had biallelic mutations and their clinical features reported.
Data extraction:
Patient data were manually extracted from the text of case reports/series. A malformation score, representing the severity of skeletal malformations, was calculated for each patient.
Data synthesis:
Of the 211 patients published in the literature, 90 patients were eligible for inclusion. Over 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modelling, as having significantly different skeletal malformation scores. Maternal virilisation in pregnancy, reported for 21% of patients, was most common for R457H mutations. Adrenal insufficiency occurred for the majority of patients (78%) and was typically mild, with homozygous R457H mutations being the least deficient. DSD affected most patients (72%) but were less common for males (46XY) with homozygous R457H mutations.
Conclusions:
PORD is a complex disorder with many possible mutations affecting a large number of enzymes. By analysing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features.
