Humeroradial synostosis (HRS) is a rare congenital limb malformation, characterised by fusion of the humeral and radial bones, leading to functional disability of the elbow joint. HRS may be reported in familial or sporadic cases and observed either isolated or as part of a syndromic condition. According to an extensive review of the literature, a dozen known conditions may comprise an HRS. The present review aims to propose an updated classification based on molecular pathways (chondrogenesis and osteogenesis; limb development and patterning; genome regulation), combined with a concise overview of the conditions associated with HRS. This knowledge could guide molecular analyses, patient management and genetic counselling. As some cases remain unexplained, further genetic and epidemiological studies are required to evaluate the contribution of genetic and environmental factors in HRS physiopathology.

How do cells precisely coordinate sterol metabolism with survival and death signals in diverse physiological and pathological contexts? This fundamental question has gained increasing attention as accumulating evidence reveals that enzymes traditionally associated with lipid biosynthesis may have unexpected regulatory functions beyond metabolism. Cytochrome P450 family 51 subfamily A member 1 (CYP51A1), a conserved sterol 14α-demethylase essential for cholesterol synthesis, exemplifies this emerging concept. Although well-characterized as an antifungal drug target in microorganisms, the roles of human CYP51A1 in development, cell death regulation, and disease pathogenesis remain underexplored. Recent studies have uncovered that CYP51A1 not only contributes to cholesterol homeostasis but also modulates multiple forms of regulated cell death-including apoptosis, ferroptosis, alkaliptosis, and pyroptosis-via sterol intermediates or cholesterol-independent mechanisms. Moreover, dysregulation of CYP51A1 has been implicated in a wide spectrum of diseases, such as cancer, cataracts, Antley-Bixler syndrome, autoimmune disorders, metabolic liver disease and neurodegeneration. In this review, we provide a comprehensive synthesis of CYP51A1's structure, regulatory networks, and non-canonical functions. We propose a unifying framework in which CYP51A1 integrates metabolic reprogramming and cell fate control, highlighting its potential as a therapeutic target across diverse human diseases.

P450 oxidoreductase deficiency (PORD) affects cytochrome enzyme activities, causing various symptoms, such as adrenal insufficiency, disorders of sex development and skeletal malformations. This study aims to elucidate the clinical manifestations, genotype characteristics, diagnosis and management of 46,XX karyotype patients with PORD in China. A retrospective study included twelve 46,XX PORD patients in a Chinese tertiary medical center from 2004 to 2024. The patients' clinical characteristics were summarized based on manifestations, hormone profiles, and responses to treatments. The age of first visit was 7-31 years. Except for one young girl presenting with ambiguous genitalia since born, 11 patients presented with either abnormal menses or multiple ovarian cysts. Six patients showed masculinization of their external genitalia, and ten patients showed varying degrees of skeletal deformity. Progesterone was elevated and ovarian reserve was poor in all patients. The most frequent POR variant, c.1370G > A, located in exon 11 occurred in 11/12 patients with an allele frequency of 87.5% (21/24). Two novel nonsense mutations, c.1684dupG and c.2040dupC, were identified and assessed as pathogenic and likely pathogenic by ACMG, respectively. The c.1370G > A might be a dominant mutation type of POR in China. Female patients with PORD have a vulnerable ovarian reserve, and their ovarian macrocysts can be managed conservatively for fertility preservation. This study specifically focuses on PORD in 46,XX Chinese individuals, which implies its genetic causes with novel genetic findings and summarizes the puzzling spectrum of clinical manifestations.

Antley-Bixler syndrome (ABS) is an extremely rare genetic disorder characterized by distinct features such as trapezoidal face craniosynostosis, midface hypoplasia with exorbitism, depressed nasal bridge, chonal atresia, radio-humeral synostosis, joint contractures and arachnodactyly. The aim of our study is to: (i) Comprehensively analyse available literature on ABS and report on the surgical management as well as treatment outcomes. (ii) Describe a case of ABS that has been successfully treated with monobloc distraction osteogenesis via virtual surgical planning. A PUBMED search was performed in June 2024. The search was based on a general search string limited to "Antley-Bixler". Inclusion criteria included systematic reviews preferably with meta-analysis, randomized controlled trials, cohort studies and case reports that were reported in English. Papers that focussed on surgical techniques were only present in the form of case reports and case series, out of which only 8 papers that fulfilled the inclusion criteria were included. Surgical techniques that were reported on included fronto-orbital advancement, midfacial advancement, distraction osteogenesis and others. The reported patients also underwent several other surgical procedures for either functional or aesthetic purposes. All the patients reported a good outcome from their surgical interventions. Monobloc distraction osteogenesis is one of the most reliable and predictable procedures that may solve various problems associated with complex craniofacial deformities such as in ABS. This can be seen from the favourable outcome reported in several studies. However, comprehensive pre-surgical virtual planning and multidisciplinary care contributes greatly to favourable functional outcomes.

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.