X-linked adrenal hypoplasia congenita (AHC) is a rare, life-threatening disorder caused by pathogenic variants in NR0B1 (DAX1), leading to adrenal insufficiency and hypogonadotropic hypogonadism. AHC is often associated with Xp21 contiguous gene deletion syndrome, which involves the deletion of multiple genes, including NR0B1, GK, DMD, and IL1RAPL1, resulting in a spectrum of phenotypic manifestations, such as glycerol kinase deficiency (GKD), Duchenne muscular dystrophy (DMD), and neurodevelopmental disorders. We report two cases of AHC with neurodevelopmental delays due to contiguous Xp21 deletions involving NR0B1 and IL1RAPL1, each diagnosed through distinct clinical pathways. Case 1 involved a neonate with adrenal insufficiency, persistent hyperCKemia, and excessive urinary glycerol excretion, leading to a diagnosis of Xp21 deletion syndrome with DMD and GKD. The patient's sister, an asymptomatic carrier, exhibited elevated CK levels and mild developmental delays. Array comparative genomic hybridization identified a novel complex structural variation, including duplication-deletion-duplication rearrangement, which may have modified clinical manifestations. Case 2 involved a 10-year-old boy with AHC and developmental delay that was initially considered a consequence of adrenal crises. Genetic analysis confirmed an Xp21 deletion, including IL1RAPL1, implicating it in his intellectual disability. A literature review reveals that Xp21 deletions involving IL1RAPL1 are strongly associated with neurodevelopmental delays, suggesting a distinct phenotype within Xp21 deletion syndromes. Early genetic diagnosis via chromosomal microarray analysis facilitates precise delineation of deletion regions, aiding in clinical management, genetic counseling, and early intervention strategies. Further studies are needed to elucidate genotype-phenotype correlations in Xp21 deletion syndromes and optimize individualized medical care.

Contiguous gene syndromes (CGS) arise from microdeletions and other aberrations of a chromosome region containing several gene loci. One of the CGSs is Xp21 contiguous gene deletion syndrome (Xp21.3-p21.2) (Xp21 deletion syndrome). Slightly more than 100 male patients suffering from Xp21 contiguous gene deletion have been described in the world literature. This article describes a clinical case of a boy with Xp21 deletion syndrome. Chromosomal microarray analysis revealed a microdeletion of the X chromosome region from position 28085320 to position 33391678 with a size of 5306358 bp, including 11 genes in the imbalance region. The illness declared itself in the neonatal period and manifested early and rapidly as primary adrenal insufficiency (PAI) on the first and second days after birth, with severe metabolic disorders. At 2 years and 7 months, an increase in transaminases was detected for the first time due to metabolic disorders caused by PAI, which led to a misdiagnosis of autoimmune hepatitis. At 2 years and 10 months, the signs of myopathic syndrome were noted, and primary muscular dystrophy was diagnosed. The patient had a pronounced psychomotor development delay from an early age. The child's mother was diagnosed with the same mutation, including 11 genes in the imbalance region. The hereditary history showed the death of the first boy in the family due to PAI at the age of 6 weeks, which should have been the reason for a comprehensive assessment of the clinical situation and timely medical and genetic counseling to prevent the birth of a sick child from subsequent pregnancies. Смежные (сопряженные) генные синдромы (Contiguous gene syndromes — CGS) возникают вследствие микроделеций и других аберраций участка хромосомы, содержащего несколько генных локусов. Одним из вариантов CGS является синдром протяженной делеции генов Xp21 (Xp21.3—p21.2) (Xp21 deletion syndrome). В мировой литературе описано немногим более 100 пациентов мужского пола, страдающих синдромом протяженной делеции генов Xp21. В статье представлено описание клинического наблюдения мальчика с Xp21 deletion syndrome. Хромосомный микроматричный анализ выявил у пациента микроделецию участка X-хромосомы с позиции 28085320 до позиции 33391678 размером 5306358 п.н., включающую 11 генов в области дисбаланса. Манифестация клинических проявлений имела место в неонатальном периоде и проявилась первичной надпочечниковой недостаточностью (ПНН). Ранняя и стремительная манифестация ПНН в течение 1-х и 2-х суток после рождения с выраженными метаболическими нарушениями явилась особенностью пациента. В 2 года 7 мес впервые на фоне метаболических нарушений, обусловленных ПНН, выявлено повышение трансаминаз, что послужило поводом для постановки ошибочного диагноза аутоиммунного гепатита. В 2 года 10 мес отмечено формирование миопатического синдрома и диагностирована первичная мышечная дистрофия. С раннего возраста отмечалась выраженная задержка психомоторного развития. У матери ребенка выявлена идентичная мутация, включающая 11 генов в области дисбаланса. Наследственный анамнез свидетельствует о гибели первого мальчика в семье на фоне ПНН в возрасте 6 нед, что должно было явиться поводом для системной оценки клинической ситуации, осуществления своевременного медико-генетического консультирования для предотвращения рождения больного ребенка от последующих беременностей.

Chromosome Xp21 deletion syndrome is a rare X-linked recessive defect that occurs as a result of multiple gene deletions, including Glycerol kinase (GK) and its neighboring genes, dystrophin, which causes Duchenne muscular dystrophy (DMD), and NR0B1, which causes congenital adrenal hypoplasia (CAHhttps://www.omim.org/entry/300200). Patients usually present with glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy, hyperglycerolemia, and glyceroluria, associated with DMD and/or CAH, growth failure, myopathy, osteoporosis, mental retardation, and psychomotor retardation. Herein, we report a 3-year- old boy from Iraq who had bloody diarrhea, food intolerance and abdominal cramp, adrenal insufficiency, recurrent fevers, tuberculosis (TB) infection, cervical abscess, oral thrush, cervical and mediastinal lymphadenopathies, developmental delay, and undescended testis. His parents are non-consanguine and had no family history of diseases. Next generation sequencing demonstrated a hemizygote deletion in chromosome X. Loss of a large part of the X-chromosome most likely can explain the clinical findings of this patient. Contiguous gene deletion syndrome in Xp21 should be considered after diagnosing adrenal insufficiency to treat metabolic complications efficiently.

We report a case of Xp21 deletion syndrome, a contiguous gene syndrome associating glycerol kinase deficiency, Duchenne muscular dystrophy, and congenital adrenal hypoplasia. This results in a contraindication to the use of all halogenated agents and of propofol. We used regional anesthesia combined with dexmedetomidine and ketamine. Previously, the patient had received inadvertently a propofol-based total intravenous anesthesia (TIVA) with no clinical side effects. We were unfortunately unable to document the metabolic consequences of this glycerol load. We suggest that if propofol is deemed necessary in such cases, it should only be used as a bolus dose of a 2% solution.

We present a 6-week-old male infant with persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase levels, and transaminitis since the second week of life. When he developed hyperkalemia, clinical suspicion was raised for adrenal insufficiency despite hemodynamic stability. A full endocrine workup revealed nearly absent adrenocorticotropic hormone. Coupled with his persistent hypertriglyceridemia (peak of 811 mg/dL) and elevated creatine kinase levels (>20 000 U/L), his corticotropin level lead to a clinical diagnosis of complex glycerol kinase deficiency (GKD), also known as Xp21 deletion syndrome. This complex disorder encompasses the phenotype of Duchenne muscular dystrophy, GKD, and congenital adrenal hypoplasia due to the deletion of 3 contiguous genetic loci on the X chromosome. Our case exemplifies the presentation of this disorder and highlights the important lesson of distinguishing between adrenal hypoplasia congenita and congenital adrenal hyperplasia, as well as the sometimes subtle presentation of adrenal insufficiency. To our knowledge, it is also the first reported case of complex GKD deficiency with the additional finding of hepatic iron deposition, which may indicate a potential area for exploration regarding the pathogenesis of liver injury and cholestasis seen in cortisol-related endocrinopathies.