Inherited ichthyosis comprises a spectrum of genetic disorders related to over 50 pathogenic genes. However, there are limited data summarizing the clinical and molecular characteristics of Chinese patients. To broaden the knowledge of clinical and genetic characteristics of inherited ichthyosis and to optimize disease diagnosis and therapies, cases diagnosed with inherited ichthyosis in 1 tertiary centre from 2019 to 2023 were collected, excluding ichthyosis vulgaris and X-linked recessive ichthyosis, genomic sequencing was then performed, and clinical details of the patients were assessed. A total of 35 patients from Jiangsu and Anhui provinces of China were enrolled, 31 of whom were diagnosed with non-syndromic ichthyosis. Within this group, there were cases of autosomal recessive congenital ichthyosis (18/31), epidermolytic ichthyosis (9/31), and superficial epidermolytic ichthyosis (4/31). Additionally, 4 patients were diagnosed with syndromic ichthyosis, comprising 1 case of Chanarin-Dorfman syndrome and 3 cases of Netherton syndrome. The genetic analysis revealed a total of 47 variants across 13 genes, of which 19 were identified as novel variants. This study describes the clinical spectrum of rare inherited ichthyosis in the Jiangsu-Anhui region of China and further expands the genetic characteristics of the disease.

Male EBP disorder with neurologic defects (MEND syndrome) is an extremely rare disorder with a prevalence of less than 1/1,000,000 individuals worldwide. It is inherited as an X-linked recessive disorder caused by impaired sterol biosynthesis due to nonmosaic hypomorphic EBP variants. MEND syndrome is characterized by variable clinical manifestations including intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. The goal of this study was to investigate the disease-causing variants in a family of two patients affected with MEND syndrome. The genomic DNA of the two patients with MEND syndrome was subjected to whole exome sequencing to identify disease-causing variants. Segregation of the identified variant was tested through Sanger sequencing. Several in-silico tools were used to evaluate the pathogenicity of the variant. Protein's 3D structure analysis systems were used to predict the impact of the identified variant on the binding and function of the mutated EBP protein including AlphaFold, PyMOL, AutoDock, ChimeraX and Discovery Studio. A novel pathogenic missense EBP variant NM_006579.3:c.556T > C (Trp186Arg) was found segregating in the affected family. In-silico analysis and molecular docking results supported the pathogenicity of the identified variant. Our study expands the mutation spectrum of EBP and adds to the restricted reports of MEND patients. It strengthens the body of evidence that supports the role of EBP in the MEND syndrome phenotype. To our knowledge, this is the first report of this disorder from Pakistan.

Primary atopic disorders (PAD) are monogenic disorders caused by pathogenic gene variants encoding proteins that are key for the maintenance of a healthy skin barrier and a well-functioning immune system. Physicians face the challenge to find single, extremely rare PAD patients/families among the millions of individuals with common allergic diseases. We describe case scenarios with signature PAD. We review the literature and deduct specific clinical red flags for PAD detection. They include a positive family history and/or signs of pathological susceptibility to infections, immunodysregulation, or syndromic disease. Results of conventional laboratory and most immunological lab studies are not sufficient to make a definitive diagnosis of PAD. In the past, multistep narrowing of differential diagnoses by various immunological and other laboratory tests led to testing of single genes or gene panel analyses, which was a time-consuming and often unsuccessful approach. The implementation of whole-genomic analyses in the routine diagnostics has led to a paradigm shift. Upfront genome-wide analysis by whole genome sequencing (WGS) will shorten the time to diagnosis, save patients from unnecessary investigations, and reduce morbidity and mortality. We propose a rational, clinical landmark-based approach for deciding which cases pass the filter for carrying out early WGS. WGS result interpretation requires a great deal of caution regarding the causal relationship of variants in PAD phenotypes and absence of proof by adequate functional tests. In case of negative WGS results, a re-iteration attitude with re-analyses of the data (using the latest data base annotation)) may eventually lead to PAD diagnosis. PAD, like many other rare genetic diseases, will only be successfully managed, if physicians from different clinical specialties and geneticists interact regularly in multidisciplinary conferences.

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare autosomal recessive, X-linked, genetic disorder that involves a triad of follicular ichthyosis, atrichia of the scalp, and photophobia. We report a case of an 8-year-old boy with alopecia of the scalp, eyebrows, and eyelashes, which occurred in his first year of age. His birth was uneventful, and his developmental milestones were normal. The alopecia was non-scarring and was accompanied by mild generalized xerosis, photophobia, and recurrent angular cheilitis. Moreover, numerous non-inflammatory, follicular, keratotic tiny papules were noticed. His deciduous teeth had retention with gum hyperplasia, and his feet showed symmetrical plantar keratoderma and nail dystrophy of the right big toe. The genetic testing confirmed an X-linked recessive inheritance of IFAP syndrome without BRESHECK syndrome due to the mutation in the MBTPS2 (300294) gene located on chromosome Xp22.12. The patient was given symptomatic treatment with urea cream for plantar keratoderma and was advised to apply constant moisturizers to avoid generalized xerosis. Dermatological and ophthalmological follow-ups were recommended. This is the first case reported from Saudi Arabia. This case report throws light on the characteristics of IFAP syndrome and denotes the points of differentiation from similar conditions.

Osteogenesis imperfecta (OI) is a heritable and chronically debilitating skeletal dysplasia. Patients with OI typically present with reduced bone mass, tendency for recurrent fractures, short stature and bowing deformities of the long bones. Mutations causative of OI have been identified in over 20 genes involved in collagen folding, posttranslational modification and processing, and in bone mineralization and osteoblast development. In 2016, we described the first X-linked recessive form of OI caused by MBTPS2 missense variants in patients with moderate to severe phenotypes. MBTPS2 encodes site-2 protease, a Golgi transmembrane protein that activates membrane-tethered transcription factors. These transcription factors regulate genes involved in lipid metabolism, bone and cartilage development, and ER stress response. The interpretation of genetic variants in MBTPS2 is complicated by the gene's pleiotropic properties; MBTPS2 variants can also cause the dermatological conditions Ichthyosis Follicularis, Atrichia and Photophobia (IFAP), Keratosis Follicularis Spinulosa Decalvans (KFSD) and Olmsted syndrome (OS) without skeletal abnormalities typical of OI. Using control and patient-derived fibroblasts, we previously identified gene expression signatures that distinguish MBTPS2-OI from MBTPS2-IFAP/KFSD and observed stronger suppression of genes involved in fatty acid metabolism in MBTPS2-OI than in MBTPS2-IFAP/KFSD; this was coupled with alterations in the relative abundance of fatty acids in MBTPS2-OI. Furthermore, we observed a reduction in collagen deposition in the extracellular matrix by MBTPS2-OI fibroblasts. Here, we extrapolate our observations in the molecular signature unique to MBTPS2-OI to infer the pathogenicity of a novel MBTPS2 c.516A>C (p.Glu172Asp) variant of unknown significance in a male proband. The pregnancy was terminated at gestational week 21 after ultrasound scans showed bowing of femurs and tibiae and shortening of long bones particularly of the lower extremity; these were further confirmed by autopsy. By performing transcriptional analyses, gas chromatography-tandem mass spectrometry-based quantification of fatty acids and immunocytochemistry on fibroblasts derived from the umbilical cord of the proband, we observed perturbations in fatty acid metabolism and collagen production similar to what we previously described in MBTPS2-OI. These findings support pathogenicity of the MBTPS2 variant p.Glu172Asp as OI-causative and highlights the value of extrapolating molecular signatures identified in multiomics studies to characterize novel genetic variants. The X chromosome contains 867 identified genes; most of these genes are responsible for the development of tissues like bone, neural, blood, hepatic, renal, retina, ears, ear, cardiac,  skin, and teeth. There are at least 533 disorders due to the involvement of the genes on the X chromosome. A 'trait' or 'disorder' determined by a gene on the X  chromosome demonstrates X-linked inheritance.  In 1961, Mary Lyon proposed that in the cells of mammalian females, one X chromosome out of the two would undergo random inactivation in early embryonic life, and therefore, both males and females have a single active X. Lyon's hypothesis provided an improved understanding of the basic mechanisms responsible for X-linked diseases. Classically, the descriptions of X-linked inheritance are either  X linked recessive and X linked dominant.  X linked Recessive Inheritance Generally, it manifests only in males. A male with an affected allele on his single X chromosome is hemizygous and can not transmit the disorder to their male offsprings, but all his daughters would be obligate carriers. Healthy heterozygous carrier females pass the disorder to affected sons. So from affected males, it can be transmitted to male grandchildren through carrier daughter ('diagonal' or 'Knight's move' transmission).  RISK CALCULATION: The X chromosome from a male is transmitted to daughters, and the Y chromosome is transferred to sons. If an affected male has kids with a healthy female, none of his male offsprings will be affected, but all of his female offspring will be carriers.  If a carrier female has kids with a healthy male, each male offspring has a 50% chance of being affected, and female offspring have a 50% chance of being a carrier. VARIABLE EXPRESSION: Heterozygous female are those who are having mutant allele on one X chromosome, and normal allele on another X. Heterozygous female may have a variable expression of X linked recessive disorder due to the random process of X inactivation involving inactivation of the X chromosome with a mutant allele in some cells while inactivation of the X chromosome with a normal allele in other cells (mosaic pattern). X-LINKED DISORDERS IN FEMALES: Sometimes, females might be affected by X linked recessive disorders. This fact is explainable by one of the following possibilities. (a) Heterozygosity: X inactivation is a random phenomenon that can involve a mutant allele containing X and a normal allele X in equal proportion in the heterozygous female. It is a possibility that the active X chromosome in the majority of the cells of a heterozygous female is the one having a mutant allele (skewed X inactivation), leading to disorder expression; this has been the case in Duchenne muscular dystrophy and hemophilia A. (b) Homozygosity: When both X chromosomes of females have a mutant allele, as reported in hemophilia A and ichthyosis. (c) Translocations: If a female is having a translocation involving an autosome and one of the X chromosomes and the translocation disrupts a gene on an X chromosome, in that case, a female might be affected. This pattern has been observed in Duchenne muscular dystrophy. (d) A female having only a single X chromosome (Turner syndrome), which is bearing a mutant allele. Hemophilia has been reported in the girl infant with the turner syndrome. X linked Dominant Inheritance Male and female both are affected, but females are affected in excess and less severely. Affected males can transmit the mutant allele to female offspring but not to male offspring. Affected females can transmit the mutant allele to 50% of his male offspring and 50% of his female offspring. examples are Vitamin D resistant (hypophosphatemic) rickets, Charcot-Marie-tooth disease. Some X-like dominant disorders, such as incontinentia pigmenti (Bloch-Sulzberger syndrome), showed a mosaic pattern of involvement for heterozygous females. X-LINKED DOMINANT LETHALS: These disorders are incompatible with early embryonic survival. They are seen only in females and not in males because, in the severe form, they will cause the death of a male embryo, but as females are less severely affected female embryo will survive. Current View Many female carriers of X-linked 'recessive' disorders demonstrate abnormal phenotype. This is due to the variable expressivity of X-linked disorders and the involvement of several mechanisms (e.g. skewed X-inactivation, somatic mosaicism...etc). So, recently it has been proposed that the terms' dominant' and recessive' should be discontinued, and all disorders should categorize as X-linked. Common X-linked Disorders: Red-green color blindness is a common trait that affects at least 10% of men and only one percent of women. The red-green color blindness may be partial or complete, but the latter is much less common. Hemophilia A results from a mutation in the factor VIII gene. Hemophilia A may be inherited or may occur due to a spontaneous mutation. Acquired hemophilia A can occur if a patient develops antibodies to factor VIII. The primary cause of morbidity and mortality in hemophilia A is hemorrhage, which can range from mild to severe. Although rare, transfusions of blood can sometimes lead to transmission of HIV and hepatitis C; this was more common in the 1980s and 1990s. Duchene muscular dystrophy is associated with a mutation in the dystrophin gene and is characterized by profound muscle weakness, leading to respiratory failure and death. X-linked agammaglobulinemia results in the inability to make plasma cells and antibodies. The individual develops susceptibility to a wide range of infections, which can be fatal. Alport syndrome is an X-linked disorder that has a heterogeneous presentation. The pathology involves the basement membrane, and chiefly affects the basement membrane of the kidney in addition to the eyes and cochlea. There appears to a mutation in the type IV collagen gene. Charcot-Marie-Tooth disease is the most common inherited neurologic disorder that is characterized by an inherited neuropathy in the absence of any metabolic or biochemical dysfunction. The disorder has variable penetrance, and there are also reports of spontaneous mutations. The age of presentation does vary, but the onset of the disorder is usually within the first two decades of life. Fabry disease is an X-linked disorder that involves the lysosomes. In this disorder, there is an excessive accumulation of neutral glycosphingolipids in the vascular endothelium, smooth muscle, and epithelial cells. The continued accumulation of glycosphingolipids accounts for dysfunction in almost every organ in the body. In a young person who presents with a history of skin lesions, renal failure, stroke, or a heart attack, one must think about Fabry disease. Other less common X-linked disorders include adrenoleukodystrophy, Kabuki syndrome, and Lesch-Nyhan syndrome.