Loeys-Dietz syndrome and Goldenhar syndrome unveiled together.

Haemifacial microsomia is an asymmetrical congenital tissue malformation developed from the first and second branchial arches with or without multi-system involvement. Alternatively recognised as Goldenhar syndrome or oculoauriculovertebral spectrum (OAVS), it is an aetiologically heterogeneous group of disorders showing dominant trends in inheritable form.We present a case of a boy in early childhood with concomitant craniofacial features of craniofacial microsomia with Loeys-Dietz syndrome. He had a unilateral hypoplastic face, asymmetrical ear malformations and multiple preauricular tags with epibulbar dermoid (features suggestive of Goldenhar syndrome). On detailed clinical evaluation, he met Beighton's criteria and was diagnosed with arterial tortuosity. Further molecular testing confirmed the diagnosis of Loeys-Dietz syndrome type II.Loeys-Dietz syndrome is characterised by aortic root enlargement or type A dissection with or without other vascular malformations and facial midline defects. Molecular testing is required to establish the diagnosis because of overlapping features with other connective tissue disorders.

Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.

OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSIONS: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.

Arterial tortuosity in pediatric Loeys-Dietz syndrome patients.

Loeys-Dietz syndrome (LDS) is an autosomal connective tissue disorder commonly presenting with hypertelorism, bifid uvula, aortic aneurysms, and arterial tortuosity. The aim of the present study was to investigate differences in tortuosity index (TI) between genotypes of LDS, possible progression over time and its use as an adjunctive prognostic tool alongside aortic dimensions to aid timely surgical planning in pediatric patients. A retrospective observational study of pediatric LDS patients referred to our center (November 2012-February 2021) was conducted. Using magnetic resonance angiography (MRA) with 3D maximum intensity projection volume-rendered angiogram, arterial TI was measured. Twenty three patients had genetically confirmed LDS with at least one head and neck MRA and 19 had no less than one follow-up MRA available. All patients presented arterial tortuosity. Patients with TGFBR2 variants had greater values of TI compared to patients with TGFB2 variants (p = 0.041). For patients who did not undergo surgery (n = 18), z-scores at the level of the sinus of Valsalva showed a significant correlation with vertebral TI (rs = 0.547). There was one death during follow-up. This study demonstrates that patients with LDS and TGFBR2 variants have greater values of TI than patients with TGFB2 variants and that greatest values of TI are associated with increased aortic root z-scores. Furthermore, as TI decreases over time, less frequent neuroimaging follow-up can be considered. Nevertheless, additional studies are needed to better define more accurate risk stratification and long-term surveillance in these patients.

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population.

Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. Exposures: Exome sequencing was performed. Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays. Results: In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669). Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

Acquired Perforating Osteoma Cutis: A Rare Histopathological Diagnosis.

ABSTRACT: Perforating osteoma cutis is a benign proliferation of mature bone within the dermis and subcutaneous tissue of the skin with transepidermal elimination. Transepidermal elimination of bone is the hallmark of perforating osteoma cutis and is defined by the breaching of bone through the epidermis. Perforating osteoma cutis is exceptionally rare because only 6 cases have been recorded in the literature at the time of preparation of this report. In this report, we present the case of a 65-year-old female patient with a medical history of nonmelanoma skin cancer, hypertension, hyperlipidemia, and type II diabetes mellitus presented for evaluation of a skin lesion of the posterior lower left leg, which had been present for 1 year. Clinical and histopathologic findings were consistent with the diagnosis of acquired perforating osteoma cutis. Treatment with surgical removal by tangential biopsy has thus far proven to be both diagnostic and therapeutic because no recurrence has been noted as of 6 months.

Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases.

Mutations in the human FAM111B gene are associated with a rare, hereditary multi-systemic fibrosing disease, POIKTMP. To date, there are ten POIKTMP-associated FAM111B gene mutations reported in thirty-six patients from five families globally. To investigate the clinical significance of these mutations, we summarized individual cases by clinical features and position of the reported FAM111B gene mutations as those within and outside the putative protease domain (MWPPD and MOPPD respectively). MWPPD cases had more clinical manifestations than MOPPD (25 versus 18). Although the most common clinical features of poikiloderma, alopecia and hypohidrosis overall occurred in 94%, 86% and 75% of all cases with no significant differences between the MOPPD and MWPPD group, less common features included life-threatening (pulmonary fibrosis 47% vs. 13%; liver abnormalities specifically cirrhosis 26% vs. 7%) and physically disabling conditions (myopathy 53% vs. 20%; tendon contracture 55% vs. 7%) were more common in MWPPD cases. Similarly, the only 2 cases of POIKTMP with fatal pancreatic cancers were both only in the MWPPD group. This review thus suggests that mutations within the putative protease domain of the FAM111B protein are associated with a broader range of clinical features and may predict increased POIKTMP severity and a poorer prognosis.

Chrysiasis: Gold Aggregates Around a Nevus and Osteoma Cutis.

ABSTRACT: Parenteral gold has historically been used to treat several conditions, including rheumatoid arthritis. Gold administration leads to a variety of cutaneous reactions, including chrysiasis, which is a permanent blue-grey hyperpigmentation of the skin due to dermal gold deposition. In this report, we describe the case of a patient who received parenteral gold injections 22 years before the onset of her chrysiasis for the treatment of rheumatoid arthritis. Biopsy of the macules showed dermal gold deposits aggregating around a melanocytic nevus, as well as around preexisting osteoma cutis. To the authors' knowledge, this is the first report in the literature describing a case of chrysiasis with gold deposits concentrated around a melanocytic nevus and an area of osteoma cutis.

Increased Internal Carotid Artery Tortuosity is a Risk Factor for Spontaneous Cervicocerebral Artery Dissection.

OBJECTIVE: Spontaneous cervicocerebral artery dissection (sCCD) is an important cause of ischaemic stroke that often occurs in young and middle aged patients. The purpose of this study was to investigate the correlation between tortuosity of the carotid artery and sCCD. METHODS: Patients with confirmed sCCD who underwent computed tomography angiography (CTA) were reviewed retrospectively. Age and sex matched patients having CTA were used as controls. The tortuosity indices of the cervical arteries were measured from the CTA images. The carotid siphon and the extracranial internal carotid artery (ICA) were evaluated according to morphological classification. The carotid siphons were classified into five types. The extracranial ICA was categorised as simple tortuosity, coiling or kinking. Independent risk factors for sCCD were investigated using multivariable analysis. RESULTS: The study included sixty-six patients with sCCD and 66 controls. There were no differences in vascular risk factors between the two groups. The internal carotid tortuosity index (ICTI) (25.24 ± 12.37 vs. 15.90 ± 8.55, respectively; p < .001) and vertebral tortuosity index (VTI) (median 11.28; interquartile range [IQR] 6.88, 18.80 vs. median 8.38; IQR 6.02, 12.20, respectively; p = .008) were higher in the patients with sCCD than in the controls. Type III and Type IV carotid siphons were more common in the patients with sCCD (p = .001 and p < .001, respectively). The prevalence of any vessel tortuosity, coiling and kinking of the extracranial ICA was higher in the patients with sCCD (p < .001, p = .018 and p = .006, respectively). ICTI (odds ratio [OR] 2.964; p = .026), VTI (OR 5.141; p = .009), and Type III carotid siphons (OR 4.654; p = .003) were independently associated with the risk of sCCD. CONCLUSION: Arterial tortuosity is associated with sCCD, and greater tortuosity of the cervical artery may indicate an increased risk of arterial dissection.

A comparative study of the efficacy of fractional neodymium-doped yttrium aluminum garnet (Nd:YAG) laser therapy alone and in combination with erbium:YAG laser therapy: tracing and objective measurement of melanin index in macular amyloidosis.

Macular amyloidosis (MA) is a common form of primary localized cutaneous amyloidosis, characterized by the eruption of brown pigments of the skin with a rippled pattern. MA can be of cosmetic concern for patients, and its treatment is challenging. In this study, we aimed to find new effective approaches for MA treatment. A total of 39 patients with the clinical diagnosis of MA were treated with two types of laser therapy, and the effectiveness of each approach was examined. Fractional Q-switched 10.64 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser therapy was compared with a combination of fractional Q-switched 10.64 nm Nd:YAG laser and long-pulsed fractional erbium:YAG laser therapy. Melanin biometric measurements were performed using a Mexameter, objective image-based evaluation was carried out, and the itching score and patient satisfaction were examined. Mexameter-based analysis showed that both types of laser therapy were effective in the treatment of MA, causing a significant decrease in the amount of melanin in the treated areas (P < 0.05). Also, combination of two types of laser therapy was significantly more effective than one type alone (P < 0.05). The itching score significantly decreased in patients undergoing a combination of laser therapies. Also, a positive correlation was observed between the amount of melanin and degree of itching in the treated areas. Moreover, analysis of patient satisfaction showed that more than 90% of patients had excellent satisfaction with combination laser therapy. The results confirmed the significant positive effects of both fractional Nd:YAG laser alone and in combination with fractional erbium:YAG laser therapy considering the reduction in melanin content; however, combination of two types of laser therapy was more effective than one type alone. Trial registration: IRCT20080901001159N23.

Clinical resolution of generalized lichen amyloidosis with dupilumab: a new alternative therapy.

Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis characterized by deposition of amyloid protein in the skin without visceral involvement. Although it is usually limited to localized areas of the body, it rarely can present in a generalized fashion and is severely pruritic. The limited form is treated with skin directed therapies such as topical or intralesional corticosteroids or topical tacrolimus but the generalized type is more difficult to treat. We present a patient with generalized primary cutaneous lichen amyloidosis successfully treated with dupilumab.

Brownish macules on the right temple.

A 28-year-old male presented with multiple pigmented macules on his right temple over two years. Physical examination showed multiple, discrete, brownish macules on his right temple. These lesions coalesced into reticular shape. Histology of the lesion demonstrated a deposit of eosinophilic acellular material in the dermal papillae. These features were consistent with macular amyloidosis (MA). Macular amyloidosis typically presented over the legs, the arms, and the upper back. We present this patient of MA involving the temple areas, which, to the best of our knowledge, has not previously been reported to occur in this region.

Ascending Aortic Aneurysm in a Case of Arterial Tortuosity Syndrome: A Rare Tortuous Disorder.

Aortic aneurysms are a common entity among adults but very rare in the pediatric age-group. Association with autosomal inheritance is well established. We describe the unusual clinical presentation of a large ascending aortic aneurysm in a young child who was ultimately found to have severe diffuse arterial tortuosity.

A Severe Form of Arterial Tortuosity Syndrome Presenting With Significant Airway Obstruction in an Infant.

We describe a severe form of arterial tortuosity syndrome in a newborn, in which the tortuous course of the aorta masqueraded as a pulmonary artery sling on fetal echocardiogram. The newborn presented with respiratory distress after birth. The clinical course was complicated by extrinsic airway obstruction requiring cardiopulmonary resuscitation. Timely diagnostic work-up in patients with arterial tortuosity syndrome is necessary to plan eventual intervention, and hopefully to prevent complications related to the abnormal vasculature.