Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X, manifesting in female individuals due to mutations in the USP9X gene. It is characterized by developmental delays, behavioral alterations, and moderate-to-severe intellectual disability. The USP9X gene plays critical roles in protein turnover and the regulation of essential pathways during neural development. This work describes the case of a Brazilian patient with female-restricted X-linked syndromic intellectual developmental disorder-99 with a variant not found in databases such as Decipher and ClinVar. Information was obtained from the Center for Rehabilitation and Readaptation Dr. Henrique Santillo electronic medical record system, and exams were conducted by partner laboratories of the Unified Health System. Documenting cases in different populations enriches the knowledge of genetic variations, guides personalized treatments, and expands the field of medical genetics, underscoring the importance of this study. A 3-year-old female patient of Pardo admixed ethnicity from northern Brazil was referred to the Center for Rehabilitation and Readaptation Dr. Henrique Santillo for suspected genetic disorders. The child was born after an uneventful pregnancy but faced neonatal complications, including cardiopulmonary arrest and jaundice, requiring intensive care unit admission. She was diagnosed with nonprogressive encephalopathy and neuropsychomotor developmental delay. Additional tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. Various genetic tests were performed, but only whole exome sequencing revealed a pathogenic variant in the USP9X gene, associated with female-restricted X-linked syndromic intellectual developmental disorder-99. We report the case of a child with a heterozygous pathogenic variant in the USP9X gene, located at Xp11.4 and presenting a wide range of phenotypes. The cytosine-to-thymine substitution resulted in a premature stop codon, causing female-restricted X-linked syndromic intellectual developmental disorder-99. The mutation leads to protein function loss due to haploinsufficiency, resulting in a dominant X-linked disorder. Loss-of-function mutations in the USP9X gene cause intellectual disability and congenital anomalies, with several craniofacial anomalies observed in the patient. Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk. Genetic investigation confirmed the variant's pathogenicity, highlighting diagnostic challenges and the importance of genetic research in understanding and managing female-restricted X-linked syndromic intellectual developmental disorder-99.

We studied three brothers and a maternal half-brother featuring global developmental delay, mild to moderate intellectual disability, epilepsy, microcephaly, and strabismus. All had bilateral perisylvian and perirolandic polymicrogyria, while some also had malformations of the hippocampus (malrotation and dysplasia), cerebellum (heterotopias and asymmetric aplasia), corpus callosum dysgenesis, and brainstem asymmetric dysplasia. Exome sequencing showed that all four patients had a novel variant (c.1597C>T:p.Leu533Phe) on the KIF4A gene on chromosome X. We discuss how this variant is possibly pathogenic and could explain the reported phenotype.

Mediator complex subunit 12 (MED12) is required for the assembly of the kinase module of Mediator, a regulatory complex that controls the formation of the RNA polymerase II-mediated preinitiation complex. MED12-related disorders display unique gender-specific genotype-phenotype associations and include X-linked recessive Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, and nonspecific intellectual disability in males predominantly carrying missense variants, and X-linked dominant Hardikar syndrome and nonspecific intellectual disability in females known to predominantly carry de novo nonsense/frameshift and nonsense/missense variants, respectively. MED12 was previously identified as a low-penetrance candidate gene for non-isolated congenital diaphragmatic hernia (CDH+). At the time, however, there was insufficient evidence to confirm this association. In a clinical database search, we identified 18 individuals who were molecularly diagnosed with MED12-related disorders by exome or genome sequencing, including eight missense, four frameshift, two nonsense, and one splice variant. Nine of these variants have not been previously reported. Two females with nonspecific intellectual disability were found to carry a de novo frameshift variant, indicating that potentially truncating variants causing nonspecific intellectual disability are not limited to nonsense variants. Notably, CDH was reported in three out of seven females with Hardikar syndrome or nonspecific intellectual disability but was not reported in males with MED12-related disorders. These results suggest that pathogenic MED12 variants are a cause of CDH+ in females with Hardikar syndrome and nonspecific intellectual disability. L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1. X-linked complicated corpus callosum agenesis. Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family. The diagnosis of L1 syndrome is established in a male proband with suggestive findings and a hemizygous pathogenic variant in L1CAM identified by molecular genetic testing. The diagnosis of L1 syndrome in a female is unusual but not impossible (most likely in the setting of general delay and/or hydrocephalus) and is established with the identification of a heterozygous pathogenic variant in L1CAM by molecular genetic testing. Treatment of manifestations: It is best to involve a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics. Shunting of the cerebrospinal fluid should be performed as needed to reduce intracranial pressure. Individual educational programming is indicated for developmental delay and intellectual disability. Standard treatment guidelines should be followed for spasticity. A splint may help reduce the degree of thumb adduction; surgery is not generally indicated. Surveillance: Neurologic evaluation at regular intervals to monitor hydrocephalus, developmental progress, and spastic paraplegia. L1 syndrome is inherited in an X-linked manner. If the mother of the proband is heterozygous for an L1CAM pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the L1CAM pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected but may have a range of (typically mild) clinical manifestations. Once the L1CAM pathogenic variant has been identified in an affected family member, heterozygote detection, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.

Aicardi syndrome is an X-linked condition that is associated with multiple ophthalmic malformations. Here, we report the first published fluorescein angiography (FA) study of a morning glory optic nerve in a patient with Aicardi syndrome and contralateral persistent fetal vasculature (PFV). A 12-day old full-term baby girl with a normal neurological exam was referred for evaluation of microphthalmia. The posterior segment of the right eye demonstrated chorioretinal lacunae typical of Aicardi syndrome and microphthalmos with a stalk consistent with PFV. The right eye imaging could not be captured due to the severe microphthalmos and cataract, however, fluorescein angioscopy was performed. The left eye demonstrated a morning glory appearing optic disc with peripapillary chorioretinal lacunae. Fluorescein angiography of the eye showed and late staining in the areas of ellipsoid chorioretinal lacunae emanating from the optic nerve and extensive peripapillary staining and late leakage of the optic nerve. Patients with Aicardi syndrome can have morning glory optic nerve anomaly and PFV. Using FA under anesthesia to detect these abnormalities help in estimating the extend of the disease and its complications, which allows for better management of the complications.