Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

The differences between sinonasal respiratory epithelial adenomatoid hamartoma and nasal polyps: insights into immunopathology.

BACKGROUND: Respiratory epithelial adenomatoid hamartoma (REAH) is a benign lesion commonly occurring in the nasal cavity and sinuses. It is often accompanied by nasal polyps (NP). While the histological features of these two conditions have been studied, there is limited knowledge about their differences in the underlying immunopathology. METHODS: Nasal tissue specimens were collected from 8 patients with concurrent REAH and NP and 10 controls. The expression levels of inflammatory cytokines, tight junctions (TJ), and epithelial-mesenchymal transition (EMT)-related factors in the tissues were analyzed. The mRNA expression of the aforementioned factors was measured using qRT-PCR, while the expression of TJ and EMT-related proteins was analyzed through Western blotting and immunohistochemistry. RESULTS: Compared to the control group, levels of inflammatory cytokines (IFN-α, IL-5, IL-17A, IL-31, IL-33, and TNF-α) and EMT-related factors (α-SMA, COL1A1, MMP9, TGF-ß1, and Vimentin) were significantly increased in both REAH and NP tissues. Conversely, E-Cadherin and TJ-related factors (Claudin-4 and Occludin) significantly decreased. When comparing REAH with NP, it was observed that the expression of IL-4, IL-5, and IL-33 was lower in REAH, while TNF-ɑ; was higher. Regarding TJ-related factors, the expression of Occludin was lower in REAH. Furthermore, in terms of EMT-related factors, except for E-Cadherin, the expressions of ɑ-SMA, COL1A1, CTGF, MMP9, TGF-ß11, and Vimentin were higher in REAH. CONCLUSION: REAH and NP exhibit different immunopathological mechanisms. NP demonstrates a more severe inflammatory response, whereas REAH is characterized by a more pronounced TJ and EMT breakdown than NP.

Breast hamartoma: reassessment of an under-recognised breast lesion.

AIMS: Breast hamartomas are an under-recognised lesion because they lack a distinctive microscopic appearance. Microscopic diagnosis can often conclude 'no significant lesion' or 'normal breast tissue', leading to repeated biopsies and diagnostic delay. We describe the histological, immunohistochemical and radiological features of breast hamartomas with the aim of identifying specific signs to facilitate their diagnosis and to differentiate them from normal breast and fibroepithelial lesions. METHODS AND RESULTS: Forty-seven breast hamartomas were reassessed (histological diagnosis and imaging features). An immunohistochemical study [oestrogen receptor (ER), progesterone receptor (PR), CD34, high-mobility group A2 (HMGA2)] was performed. On breast imaging, hamartomas most often presented as probably benign solid masses with circumscribed margins and variable densities. Histologically, breast hamartomas resembled normal breast, although their stromal component was predominant, separating randomly scattered epithelial elements with areas of pure collagenous stroma. Pseudoangiomatous stromal hyperplasia (PASH) was present in 93.6% of cases and CD34 antibody highlighted intralobular, perilobular and interlobular distribution of CD34-positive fibroblasts. By comparison, CD34 was mainly expressed in the intralobular normal breast tissue stroma. Hamartoma stromal cells expressed HMGA2, ER and PR in 79%, 66% and 76.3% of our cases, respectively, compared to 7.7%, 23% and 19% in normal breast tissue, respectively (P < 0.0001; P = 0.0005; P < 0.0001). CONCLUSIONS: After ascertaining that core needle biopsy is effectively intralesional, breast hamartomas can be diagnosed with confidence by taking into account the presence of stromal changes, PASH, interlobular distribution of CD34-positive fibroblasts, HMGA2 and hormonal receptor stromal expression.

Segmental basaloid follicular hamartomas derive from a post-zygotic SMO p.L412F pathogenic variant and express hair follicle development-related proteins in a pattern that distinguish them from basal cell carcinomas.

Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.

Smooth muscle hamartoma and striated muscle hamartoma: Clinicopathologic characterization of two rare entities and literature review.

Smooth muscle hamartoma (SMH) and striated muscle hamartoma (STH) are anomalous proliferations of smooth muscle or striated muscle, respectively, in anatomic sites where these tissues are normally present. To date, only limited cases have been reported describing these lesions. In this study, we sought to characterize the clinicopathologic features of both SMH and STH. A total of 27 cases of SMH and 12 cases of STH from 1990 to 2020 were identified. SMH cases had a slight male predominance (63%) and a mean age of presentation of 20 years (range: 4 months-91 years), with a mean size of 9.3 mm (±13.3). In contrast, STH were equally distributed in gender, with a mean age of presentation of 40 years (range: 3 months-66 years) and a mean size of 5.7 mm (±3.6). SMH were more commonly located in the torso and extremities (70%) and STH in the head and neck area (92%). One case of SMH recurred after 1.1 years and in the initial diagnosis the lesion was present at the tissue edge. None of the cases of STH had a recurrence. We present the largest cohort of SMH and STH, and report the first case of a recurrent SMH, suggesting the importance of obtaining a clean margin for these lesions.

Rhabdomyomatous mesenchymal hamartoma presenting as a chin nodule in a 15-year-old male.

Rhabdomyomatous mesenchymal hamartoma (RMH), also known as congenital midline hamartoma and striated muscle hamartoma, is a rare congenital malformation presenting most commonly in midline sites of the head and neck region. Since its first description in 1986, 67 cases have been reported to date. We report a case of RMH presenting as a chin nodule in an otherwise healthy 15-year-old male. The patient presented with a dome-shaped subcutaneous lesion on his chin which had been present since birth, but had grown and was interfering with his ability to shave. He otherwise had no history of congenital anomalies or malformations. Histopathological examination of the excised lesion revealed a haphazard proliferation of striated muscle admixed with adipose tissue and adnexal structures within the dermis and subcutaneous tissue, consistent with a diagnosis of RMH. While the majority of reported cases are of newborns or children under 3 years of age, RMH may not come to clinical attention until later in life. This rare malformation should be included in the differential diagnosis of lesions containing dermal striated muscle and/or adipose tissue, to include nevus lipomatosus superficialis, fibrous hamartoma of infancy, neuromuscular choristoma, fetal rhabdomyoma, and rhabdomyosarcoma.

Eccrine angiokeratomatous hamartoma combined with solitary angiokeratoma or verrucous venous malformation: Report of two cases and comprehensive review of the literature.

First reported in 2006, eccrine angiokeratomatous hamartoma is a very rare vascular malformation of the skin, with only few described cases. It has a peculiar histopathology with features deriving from the combination of two different vascular malformations of the skin: solitary angiokeratoma and eccrine angiomatous hamartoma. In the past, other authors described similar hamartomatous lesions with features deriving from verrucous venous malformation and eccrine angiomatous hamartoma. We believe that these lesions are clearly overlapping from clinical, histopathological, and immunohistochemical points of view and the term "eccrine angiokeratomatous hamartoma" should be used to indicate the whole spectrum of these lesions as suggested by Kanitakis et al. Herein we present two cases of this rare vascular hamartoma, with clinical, histopathological and immunohistochemical characterization. In addition, for the first time we report a complete and detailed review of the literature to clarify the clinical, epidemiological, and histopathological features of this unique entity.

Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a ß-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

Sinonasal seromucinous hamartoma.

INTRODUCTION: Seromucinous hamartoma (SH) is a rare benign glandular proliferation of the sinonasal tract and nasopharynx. Only few cases have been reported in recent years. MATERIALS AND METHODS: We performed a retrospective medical record review of seven patients diagnosed with sinonasal SH who underwent endoscopic endonasal surgery. RESULTS: There were 5 males and 2 females, ranged in age from 40 to 98 years (mean 60 years, SD ± 18.9). Two lesions arise from middle turbinate, two from uncinate process, and 3 (but 4 specimens) from nasal septum. Pathological features revealed a polypoid lesion with submucosal proliferation of seromucinous glands arranged in lobular and haphazard patterns. In immunohistochemical study, the seromucinous glands of SH were reactive for cytokeratin, including CK7, CK19, HMWK, but negative for CK20. CONCLUSION: Sinonasal SH is a rare diagnosis characterized by a polypoid lesion with a haphazard proliferation of seromucinous glands. The rhinologists should consider it in the differential diagnosis of a polypoid lesion in the nasal cavity.

Pigmented apocrine hamartoma of the vulva: A case report.

We herein report a patient who clinically presented with a pigmented, flat plaque in the vulvar area. Histological examination showed a benign lesion mainly composed of tubular and cystic glands with apocrine differentiation. The most striking histological feature was the deposition of finely granular melanin pigment both in the epithelial cells and in the luminal surface of the glands. In addition, Melan-A immunostaining showed the presence of numerous melanocytes within the lesion suggesting that the pigment deposition was secondary to colonization of the lesion by melanocytes. We therefore diagnosed this lesion as "pigmented apocrine hamartoma." To the best of our knowledge only 3 cases of pigmented apocrine hamartoma have been reported in the literature so far.

The First Case of HER2+ Invasive Ductal Carcinoma Arising From a Breast Hamartoma and Literature Review.

Carcinomas arising from breast hamartomas are exceedingly rare. We present the first reported case of an African-American female presenting with a right breast lump and a subsequent mammogram suggestive of a hamartoma. She later underwent lumpectomy and was found to have HER2+ invasive ductal carcinoma (IDC) arising from a hamartoma. She was amenable to HER2-targeted trastuzumab, hormone therapy and adjuvant radiation but declined chemotherapy. In a review of the literature, IDC is the predominant neoplastic type found in hamartomas. The average hamartoma size at time of neoplasm diagnosis is 6.0 cm. Patients with hamartomas greater than 6.0 cm, with changes in calcification pattern; new nodules or asymmetry should be considered for additional evaluation with ultrasound, MRI and/or biopsy. HER2 status is under-reported among cases and should be evaluated in any malignancy found within hamartomas as HER-2 therapy has improved overall survival and recurrence free survival in HER2+breast cancer patients.

Classification of cysts with follicular germinative differentiation.

BACKGROUND: Cysts are very common in the routine of dermatopathology but follicular germinative (trichoblastic) differentiation in cysts is seen rarely. The presence of follicular germinative differentiation in a cyst alerts to consider the possibility of a basal cell carcinoma (BCC) arising in a cyst. METHODS: Five cystic lesions with zones of follicular germinative differentiation were collected. Hematoxylin and eosin sections were reassessed for architecture, types of follicular differentiation and stromal characteristics; immunohistochemical studies with Ber-EP4 were analyzed. Articles about follicular germinative differentiation in cystic lesions were reviewed. RESULTS: Cystic lesions with follicular germinative differentiation have been described in the literature under various names including trichoblastic infundibular cyst, cystic trichoblastoma, cystic panfolliculoma (CPF), dermoid cyst with basaloid proliferations, folliculosebaceous cystic hamartoma and BCC occurring in infundibular cysts. The lesions presented by us could be classified as three cystic trichoblastomas, one CPF and one cystic hamartoma with follicular germinative differentiation. CONCLUSIONS: Histopathologically, cystic trichoblastomas can be separated from CPFs. Some lesions defy classification and may be regarded as cystic follicular hamartomas. The presence of follicular papillae and bulb-like structures, advanced follicular differentiation like that of inner and outer root sheath exclude the differential diagnosis of BCC arising in a cyst.

Hypothalamic hamartoma with neurofibrillary tangles.

Hypothalamic hamartomas are rare tumors that typically present in childhood, often with gelastic seizures, precocious puberty, or as a manifestation of Pallister-Hall syndrome. Neurofibrillary tangles are cytoplasmic aggregates of hyperphosphorylated tau that are best recognized in Alzheimer disease, other tau-associated neurodegenerative diseases, or as part of aging, but occasionally may be seen in low-grade neoplasms with a ganglion cell component as gangliocytoma or ganglioglioma. Herein, we report a case of hypothalamic hamartoma with neurofibrillary tangles.

Nevus lipomatosus cutaneous superficialis with focal lipocytic pagetoid epidermal spread and secondary calcinosis cutis: a case report.

A case of nevus lipomatosus cutaneous superficialis is presented, wherein the lesion occurred as a gluteal swelling in a 6-year-old boy. On histopathology examination, it consisted of typical superficial expanses of mature adipose tissue in the papillary dermis of the polypoidal lesion. It was accompanied by 2 unusual findings, which consisted of the focal presence of lipocytes at the epidermal­dermal junction in the pagetoid manner and the prominent deposition of calcium resulting in calcinosis cutis­like lesions. Calcinosis cutis in the present case occurred as dystrophic calcification in focal fat necrosis changes of the lesion, whereas the focal pagetoid spread of fat cells is likely related to the same hamartomatous adipose tissue growth that ultimately results in the nevus lipomatosus.

Cytokeratin 20 expression in basaloid follicular hamartoma and infundibulocystic basal cell carcinoma.

BACKGROUND: Tumors with similar or identical histopathologic features have been termed basaloid follicular hamartoma (BFH) or infundibulocystic basal cell carcinoma (BCC). BCC typically lacks immunoreactivity with cytokeratin 20 (CK20) and pleckstrin homology-like domain, family A, member 1 protein (PHLDA1). AIM: A series of BFH and infundibulocystic BCC were investigated to determine the pattern of CK20 and PHLDA1 labeling in these lesions. MATERIALS AND METHODS: Thirty-six samples of BFH (n = 14) and infundibulocystic BCC (n = 22) were collected. CK20 and PHLDA1 staining was performed and evaluated. RESULTS: All the lesions were small (average of 3 mm), well circumscribed, and composed of basaloid to squamoid cells arranged in islands resembling ramifying rootlets with interspersed horn cysts. CK20-positive cells were present in all 36 cases (average, 22/mm(2)), throughout the tumor, including deeper portions, irrespective of original diagnosis. Six of thirty cases (20%; 5 infundibulocystic BCC, 1 BFH) were focally PHLDA1 positive. CONCLUSIONS: Findings on hematoxylin and eosin staining and those of CK20 staining in BFH and infundibulocystic BCC were similar, and in most cases were indistinguishable. The CK20 labeling was similar to that of trichoepithelioma. The findings add a degree of support to the argument that BFH and infundibulocystic BCC represent the same lesion and, further, a benign one.

Dysregulation of the TSC-mTOR pathway in human disease.

The mammalian target of rapamycin (mTOR) has a central role in the regulation of cell growth. mTOR receives input from multiple signaling pathways, including growth factors and nutrients, to stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase and eukaryote initiation factor 4E binding protein 1. High levels of dysregulated mTOR activity are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jeghers syndrome. These disorders are all caused by mutations in tumor-suppressor genes that negatively regulate mTOR. Here we discuss the emerging evidence for a functional relationship between the mTOR signaling pathway and several genetic diseases, and we present evidence supporting a model in which dysregulation of mTOR may be a common molecular basis, not only for hamartoma syndromes, but also for other cellular hypertrophic disorders.

Splenic hamartomas in Alagille syndrome: case report and literature review.

Alagille syndrome is a rare autosomal dominant disorder with characteristic findings of paucity of intrahepatic bile ducts, congenital heart disease, and vertebral, ocular, and renal abnormalities. We present a unique autopsy case of an 18-year-old female with Alagille syndrome and splenic hamartomas. Autopsy findings included growth restriction, Tetralogy of Fallot, paucity of intrahepatic bile ducts, end-stage renal disease with mesangiolipidosis, and splenomegaly with two well-circumscribed, splenic tumors. Histologic findings of the splenic tumors revealed disorganized vascular channels lined by cells without cytologic atypia. Immunohistochemical analysis demonstrated CD8(+)CD31(+) endothelial cells, consistent with splenic hamartomas. In summary, Alagille syndrome is a rare genetic disorder characterized by JAG1 mutations and disrupted Notch signaling. Review of the literature highlights the importance of Notch signaling in vascular development and disorders. However, to our knowledge this is the first description of splenic hamartomas in Alagille syndrome.

Benign cutaneous neural tumors.

Benign cutaneous neural neoplasms are one of the most frequent benign mesenchymal tumors in the skin. Because peripheral sheath nerve is composed of different cells, the tumors raised in these structures are varied and usually contain many of these cells. Most of these tumors are easy to diagnose, as usually present characteristic features well-recognized and express -specific immunohistochemical proteins. However, there are so many infrequent variants that many times require distinction from others spindle-cell tumors including melanoma. The tumors differ from one another by displaying a different proportion and arrangement of the various constituents of a peripheral nerve. In this article, we present the most characteristic clinical and histopathological features of many of these frequent benign cutaneous neural tumors including their uncommon variants.