Autoimmune diseases are multifaceted disorders, and their coexistence with other conditions can present unique challenges in diagnosis and management. Here, we report a rare case of autosomal recessive hyper-IgE syndrome (AR-HIES) in a child with beta thalassemia trait. AR-HIES is a distinct immunodeficiency disorder characterized by severe eczema and recurrent bacterial and viral infections, particularly affecting the sinopulmonary system. This case highlights the importance of recognizing and managing the co-occurrence of rare genetic conditions, as it can impact treatment strategies and familial counseling. This unique case of AR-HIES in a child with beta thalassemia trait underscores the complexity of autoimmune disorders and the need for comprehensive evaluation in patients presenting with multiple clinical manifestations.

AIMSWERNER SYNDROME IS A RARE PREMATURE AGEING AUTOSOMAL RECESSIVE DISORDER CAUSED BY PATHOGENIC VARIANTS IN THE WRN GENE. PEOPLE WITH WERNER SYNDROME MAY DEVELOP DIABETES MELLITUS. CHRONIC FOOT ULCERATION IS SEEN, WITH SOME CHARACTERISTICS OVERLAPPING WITH DIABETIC FOOT DISEASE. HOWEVER, THE CLINICAL COURSE OF THE ULCERATION IS ATYPICAL OF DIABETIC FOOT DISEASE. WE PRESENT FOUR SIBLINGS FROM AN IRISH TRAVELLER FAMILY WITH WERNER SYNDROME TO HIGHLIGHT THE COMPLEXITY OF THIS CONDITION. THE IRISH TRAVELLER POPULATION ARE AN INDIGENOUS, ENDOGAMOUS POPULATION IN WHICH CONSANGUINITY IS COMMON. AS A RESULT, RARE AUTOSOMAL RECESSIVE DISORDERS ARE PREVALENT AMONG THIS POPULATION: .
METHODS: We describe our experience managing the complex foot disease seen in all four siblings. Foot complications present in the siblings include painful peripheral neuropathy, chronic foor ulceration, underlying osteomyelitis and acral melanoma.
RESULTS: The cases are described individually, with a particular focus on the complex foot disease associated with the condition.
CONCLUSIONS: Although the siblings attend a diabetic foot clinic, we suggest that the combination of clinical features seen in these cases is unique to Werner syndrome and warrants the title \'Werner Syndrome\' (rather than \'Diabetic\') foot.

A cell\'s ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3\' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.

A rare autosomal recessive condition called infantile systemic hyalinosis (ISH) is characterized by early-onset skin lesions that progress to the formation of numerous contractures. The underlying disease is the progressive accumulation of hyaline substances in many tissues. We are presenting the case of a male infant who was referred for evaluation and management at the age of six months. The infant had a history of recurrent episodes of diarrhea and showed limited movement in all four limbs. Upon physical examination, hyperpigmented papulonodular lesions on bony prominences and perianal regions were found, coupled with contractures in the elbow and knee joints. Hyaline deposition in the mid-dermal region was confirmed by histopathological analysis of a skin biopsy sample. The baby also had acute otitis media, which needed to be treated with antibiotics. Parents were counseled regarding the disease\'s diagnosis, complications, prognosis, and inheritance pattern. This case highlights the clinical presentation, diagnostic process, and management strategies employed in the care of ISH, emphasizing the importance of early recognition and multidisciplinary management in mitigating its devastating effects.

Respiratory distress in the newborn is associated with numerous etiologies, some common and some rare. When respiratory distress is accompanied by laterality defects, namely, situs inversus (SI), the index of suspicion for comorbid primary ciliary dyskinesia (PCD) should be raised. Primary ciliary dyskinesia is characterized by ciliary dysmotility and the accumulation of thick secretions in the airways that obstruct air and gas exchange. Neonatal clinicians should know that while PCD is definitively diagnosed in infancy or early childhood, findings suspicious for PCD should be communicated to primary care providers at discharge from the hospital to facilitate timely subspecialty involvement, diagnosis, and treatment. This article will present a case report of a term newborn with SI totalis who was later diagnosed with PCD. We will discuss epidemiology, pathophysiology, clinical manifestations, and diagnostics, followed by management strategies. Additionally, we discuss the outpatient needs and lifespan implications.

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person\'s intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.

MUTYH germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue.
we used Sanger sequencing and immunohistochemistry to search for a second MUTYH variant in the tumoral DNA and to assess protein expression, respectively.
we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the MUTYH protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced.
our results fail to demonstrate that germinal monoallelic MUTYH variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the MUTYH protein in many tumors suggests its dysregulation regardless of MUTYH genetic status.

Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.

Recently, an autosomal recessive subtype of connective tissue disorder within the spectrum of Ehlers-Danlos syndrome (EDS), named classical-like EDS type 2 (clEDS2), was identified. clEDS2 is associated with biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, specifically, affecting its aortic carboxypeptidase-like protein (ACLP) isoform. We described the 15th patient (13th family) diagnosed with clEDS2. This patient presented with notable similarities in phenotype to the documented cases, along with additional characteristics such as significant prematurity and short stature. An EDS sequencing panel-based analysis revealed homozygous AEBP1: NM_001129.5:c.2923del, p.Ala975Profs*22 likely pathogenic variants, and maternally inherited heterozygous COL11A1: NM_001854.4:c.1160A>G, p.Lys387Arg variant of uncertain significance in our patient. Upon comprehensive review of all previously reported clEDS2 patients, our patient exhibited the following overlapping phenotypes, including cutaneous features: hyperextensibility, atrophic scars/delayed wound healing (100%), easy bruising (100%), excessive skin (93%); skeletal features: generalized joint hypermobility (93%), pes planus (93%), dislocation/subluxation (93%); and cardiovascular features (86%). Our patient did not display symptoms of the critical complications reported in a few individuals, including superior mesenteric artery aneurysms and ruptures, aortic root aneurysm/dissection, spontaneous pneumothoraxes, and bowel ruptures. Together, this case expands the genetic and clinical phenotypic spectrum of AEBP1-related clEDS2.

BACKGROUND: CAD (MIM*114010) encodes a large multifunctional protein with the enzymatic activity of the first three enzymes initiating and controlling the de novo pyrimidine biosynthesis pathway. Biallelic pathogenic variants in CAD cause the autosomal recessive developmental and epileptic encephalopathy 50 (MIM #616457) or CAD deficiency presenting with epilepsy, status epilepticus (SE), neurological deterioration and anemia with anisopoikilocytosis. Mortality is around 9% of patients, mainly related to the no use of its specific treatment with uridine. Majority of reported cases have an early onset during infancy, with some few starting later in childhood.
METHODS: Here we report a deceased female patient with CAD deficiency whose epilepsy started at 14 years. She showed a rapid neurologic deterioration including cognitive decline, electroencephalographic background slowing which later evolved to a fatal refractory SE and supra and infratentorial atrophy on neuroimaging. Anemia developed after SE onset.
RESULTS: her post-mortem whole exome sequencing identified biallelic missense variants in CAD (NM_004341.5): c.[2944G > A];[5366G > A] p.[(Asp982Asn)];[(Arg1789Gln)]. Our review of twenty-eight reported cases (2015-2023) revealed an epilepsy age onset from neonatal period to 7 years and the SE prevalence of 46 %.
CONCLUSIONS: With our case, we highlight the relevance of suspecting this treatable condition in older patients and in SE with no evident etiology.