Heterogeneity and high prevalence of bone manifestations, and bone mineral density in congenital generalized lipodystrophy subtypes 1 and 2.

Introduction: Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease caused by mutations in genes responsible for the formation and development of adipocytes. Bone abnormalities are described. However, there is a scarcity of data. Objective: To describe bone characteristics in a large CGL1 and 2 case series. Methods: Cross-sectional study that assessed bone radiological features of CGL patients of a reference hospital in Fortaleza (CE), Brazil. Patients underwent clinical and bone mineral metabolism evaluation, radiographs of the axial and appendicular skeleton and bone mineral density (BMD) assessment by DEXA (dual energy X-ray absorptiometry). Results: Nineteen patients were included, fourteen were CGL1 and 5, CGL2. Median age was 20 years (8-42) and 58% were women. Median BMI and percentage of body fat were, respectively, 21 Kg/m² (16-24), and 10.5% (7.6-15). The median leptin concentration was 1 ng/mL (0.1-3.3). Diabetes mellitus and dyslipidemia were present in 79% and 63% of patients, respectively. Median calcium and phosphate were normal in almost all patients (95%). Median parathyroid hormone and 25-OH-vitamin D were 23 pg/mL (7-75) and 28 ng/mL (18-43). Osteolytic lesions, osteosclerosis and pseudo-osteopoikylosis, were present in 74%, 42% and 32% of patients, respectively. Lytic lesions were found predominantly in the extremities of long bones, bilaterally and symmetrically, spine was spared. Osteosclerosis was present in axial and appendicular skeleton. Pseudo-osteopoikilosis was found symmetrically in epiphyses of femur and humerus, in addition to the pelvis. BMD Z-score greater than +2.5 SD was observed in 13 patients (68.4%). BMD was higher in CGL1 compared to CGL2 in lumbar spine and total body in adults. No associations were found between high BMD and HOMA-IR (p=0.686), DM (p=0.750), osteosclerosis (p=0.127) or pseudo-osteopoikilosis (p=0.342), and, between pain and bone lesions. Fractures were found in 3 patients. Conclusion: Bone manifestations are prevalent, heterogeneous, and silent in CGL1 and CGL2. Osteolytic lesions are the most common, followed by osteosclerosis and pseudo-osteopoikilosis. Bone mass is high in most cases. There was no pain complaint related to bone lesions. Thus, systematic assessment of bone manifestations in CGL is essential. Studies are needed to better understand its pathogenesis and clinical consequences.

Buschke-Ollendorff syndrome presenting with asymptomatic yellowish papules and leg length discrepancy: A case report.

Buschke-Ollendorff syndrome (BOS) is a rare, usually benign, autosomal dominant genetic disease affecting about 0.005% globally. BOS commonly manifests with asymptomatic connective tissue nevi, sometimes with sclerotic bone lesions like osteopoikilosis or melorheostosis. However, BOS may develop severe, symptomatic complications that require surgical intervention. Here we report a 9-year-8-month girl presenting with multiple nonpruritic, nonpainful skin plaques scattered around the trunk, buttocks, and bilateral legs. She had a history of right varus foot with inadequate plantar flexion. Upon visiting, obvious leg length discrepancy (LLD) was noted. Lesional biopsy revealed increased fibroblasts within dermal collagen bundles. Verhoeff-van Gieson stain revealed scattered foci of thickened elastic fibers between collagen fibers, especially in the mid-dermis. Radiographic examination of the lower extremities showed multiple small, round-to-oval shaped, radiopaque spots on the pelvic bones, femurs, tibiae, and both feet. Hyperostosis along the long axis with "dripping candle wax" appearance was characteristic of osteopoikilosis and melorheostosis. Genetic analysis showed heterozygous point mutation in exon 1 of LEMD3 gene (c.1323C>A, p.Y441X), confirming diagnosis of BOS. Sequential and epiphyseodesis were performed to correct LLD with a favorable outcome at 2-year follow-up. BOS associated with severe bone abnormalities is rare, but orthopedic surgical intervention can provide satisfactory outcome.

Spotted bones in an osteopoikilosis-related disease (Buschke Ollendorff Syndrome): Identifying this rare condition from the lab to the field.

OBJECTIVE: To improve the differential diagnosis of osteopoikilosis in past populations using a clinical case as an example of this rare condition. MATERIALS: A patient referred to our Genetic Service with suspected Buschke Ollendorff Syndrome after finding a connective nevus. METHODS: Radiological images from different body regions were accompanied by a genetic study using next-generation sequencing. RESULTS: Small circular-to-ellipsoid sclerotic lesions were found in the epiphysis and metaphysis of long bones, as well as in the pelvis. These lesions were bilaterally distributed and with well-defined margins, compatible with the characteristics of Buschke Ollendorff Syndrome, bone manifestation osteopoikilosis. A heterozygous mutation on LEMD3 (NM_001167614:c.1918 + 1G > C) was identified by next-generation sequencing. Based on this confirmed case, we have discussed the most probable causes of similar bone lesions found in the archaeological record. CONCLUSION: It has been demonstrated how a current case of a rare disease can provide useful tools to improve the differential diagnosis of this disease in ancient skeletons. SIGNIFICANCE: This work underlines the great need for multidisciplinary platforms that integrates clinical research into paleopathology in order to successfully address the study of rare diseases from the past. LIMITATIONS: Since OPK is only detected by X-rays, suspected cases of this bone lesion will only be identified when radiographs are taken for other purposes. SUGGESTIONS FOR FURTHER RESEARCH: Retrospective and large-scale studies of radiographs from other research in past populations.

Result of cementless total hip arthroplasty in a patient with osteopoikilosis, hip dysplasia and advanced osteoarthritis: a case report.

BACKGROUND: Osteopoikilosis (OPK) is a rare benign sclerosing bone dysplasia and is often incidentally found on plain radiography. OPK generally does not require treatment. Nevertheless, osteonecrosis or degenerative joint disease can occur in the setting of OPK, and little is known with regard to the longevity of arthroplasty prostheses implanted into OPK-bearing bones. CASE PRESENTATION: A 55-year-old male presented with progressive right hip pain in 2012. He was diagnosed with coexisting osteopoikilosis and developmental dysplasia of the right hip with advanced osteoarthritis after a series of imaging studies including radiographs, magnetic resonance imaging (MRI), and bone scan. A cementless total hip arthroplasty was performed to treat his right hip pain. Radiographs at eight-year follow-up showed the prosthetic components were well-fixed. Harris hip score of the patient's right hip was 93. The patient can walk without assistance and work as a construction worker. CONCLUSION: Cementless arthroplasty can be considered in patients with hip arthropathies and co-existing osteopoikilosis. Continued follow-up is required to establish the long-term results.

Buschke-Ollendorff syndrome with LEMD3 germline stopgain mutation p.R678* presenting as multiple subcutaneous nodules with mucin deposition.

Buschke-Ollendorff syndrome (BOS; OMIM 166700) is a rare autosomal dominant disorder characterized by the existence of connective tissue nevus and/or osteopoikilosis. The skin lesions usually present as firm, yellow, or flesh-colored papules and nodules, which may coalesce into plaques and increase in size and number over time. We present a case of a 26-year-old male with multiple subcutaneous nodules on the waist and thigh for more than 20 years. Being deeply seated, his skin lesions were not visible and could only be appreciated by palpation. Accordingly, pathology showed an increase in thick, crossed, or paralleled, elastic fibers arranged between the collagen bundles in the lower part of the reticular dermis and the subcutaneous fat with mucin deposition. Heterozygous point mutation in exon 8 of the LEMD3 gene was detected, which confirmed the diagnosis of BOS. The deeply situated nature of skin lesions noted in our case has not been reported in the literature of BOS. Our case thus expands the clinical and pathological features of the disease.

Osteopoiquilose: comparação entre a radiografia e a ressonância magnética / Osteopoiquilosis: comparison between radiography and magnetic resonance

A osteopoiquilose é uma displasia osteosclerótica rara que mostra uma transmissão autossômica dominante e tem características radiológicas específicas que não apresenta clínica específica; o diagnóstico é feito por achados radiológicos incidentais típicos em pacientes que procuram tratamento para outros problemas médicos. A osteopoiquilose pode ser confundida com metástases osteoblásticas, esclerose tuberosa e mastocitose óssea. Relatamos uma mulher de 37 anos queixando-se de dor e edema no punho há 20 dias. A paciente foi submetida a avaliação com ressonância magnética, apresentando ossos do carpo e regiões epifisárias do rádio e ulna, além de metacarpos e algumas falanges, com diversos focos escleróticos dispersos. Em seguida, para nova avaliação, a paciente realizou radiografias de joelhos, ombros e punhos, confirmando os focos escleróticos encontrados na ressonância magnética, confirmando o diagnóstico de osteopoiquilose

Osteopoikilosis is a rare osteosclerotic dysplasia that shows an autosomal dominant transmission and has characteristic radiological features, there are no specific clinical features; diagnosis is made by incidental typical radiological findings in patients seeking treatment for other medical problems. Osteopoikilosis can be confused with osteoblastic metastases, tuberous sclerosis, and bone mastocytosis. We report a 37-years-old woman, complaining of pain and swelling in the wrist 20 days ago. The patient submitted to MRI for evaluation, showing carpal bones and epiphyseal regions of radius and ulna, as well as metacarpal and some phalanges, presenting several scattered sclerotic foci. After that for further evaluation, the patient was referred for radiographs of the knees, shoulders, and wrists, confirming the sclerotic foci found in MRI, confirming the diagnosis of osteopoikilosis

Buschke-Ollendorff syndrome in a 6-year-old patient: clinical and histopathological aspects of a rare disease.

Buschke-Ollendorff syndrome (BOS) is a rare genetic hereditary genodermatosis characterized by benign skeletal and cutaneous lesions. Skeletal alterations known as osteopoikilosis (OPK) or "spotted bone disease" are asymptomatic areas of sclerosing dysplasia. Two skin lesion patterns have been described because they may be of either elastic tissue (juvenile elastoma) or collagenous composition (dermatofibrosis lenticularis disseminata). We present the case of a 6-year-old male patient with yellowish papules that coalesced to form plaques localized on both thighs and on the upper limbs consistent with a connective tissue nevus (CTN) diagnosis. X-ray examination of the skeletal system revealed the presence of multiple small areas (measuring between 1 and 7 mm) of increased bone density (OPK) bilaterally. A skin biopsy was performed and did not show striking alterations in the number or dimension of the extracellular matrix fibers, but it showed mucin deposition between them, which is compatible with a CTN. This study reports on the clinical presentation and histological examination of this unusual disease.

Osteopoikilosis With Germline LEMD3 Mutation Mimicking Bone Metastases in a Girl With a Concurrent Secreting Mixed Germ Cell Tumor.

Osteopoikilosis (OPK) is a rare, benign, asymptomatic bone disease causing dense bone lesions, which could be interpreted as bone metastasis. The symmetric distribution, lack of bone destruction, and location differentiate OPK from metastatic disease. It is essential to be aware of this benign condition to prevent diagnostic errors. We present the case of a 10-year-old female patient with the concurrent diagnosis of secreting mixed germ cell tumor with Yolk Salk Tumor compound and OPK. Physical examination disclosed an abdominal mass, and blood tests showed increased alfa-fetoprotein and human chorionic gonadotropin levels. Computed tomography revealed a pelvic tumor associated with multiple radiodense lesions distributed throughout the bone skeleton. Lesions were inactive on scintigraphy and FDG-PET. Pathology of the bone showed normal bone tissue and ruled out metastasis. The patient achieved complete remission after chemotherapy and surgery and remains in continued complete remission 28 months from diagnosis. The genetic analysis confirmed the LEMD3 germline mutation confirming OPK.

Osteopoikilosis: case series from Portuguese Rheumatology Centers.

Osteopoikilosis (OPK) is a rare, hereditary, usually asymptomatic disease characterized by the presence of multiple, well-defined sclerotic lesions distributed in peri-articular locations, frequently diagnosed as an incidental finding. Differential diagnosis with osteoblastic metastases is fundamental. This article reports six cases of OPK diagnosed in Portuguese Rheumatology Centers.

Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis.

Melorheostosis is an exceptionally rare sclerosing hyperostosis that typically affects the appendicular skeleton in a limited segmental fashion. It occasionally occurs on a background of another benign generalised sclerosing bone condition, known as osteopoikilosis caused by germline mutations in LEMD3, encoding the inner nuclear membrane protein MAN1, which modulates TGFß/bone morphogenetic protein signalling. Recent studies of melorheostosis lesional tissue indicate that most cases arise from somatic MAP2K1 mutations although a small number may arise from other genes in related pathways, such as KRAS. Those cases associated with MAP2K1 mutations are more likely to have the classic "dripping candle wax" appearance on radiographs. The relationship between these somatic mutations and those found in a variety of malignant conditions is discussed. There are also similar germline mutations involved in a group of genetic disorders known as the RASopathies (including Noonan syndrome, Costello syndrome and various cardiofaciocutaneous syndromes), successful treatments for which could be applied to melorheostosis. The diagnosis and management of melorheostosis are discussed; there are 4 distinct radiographic patterns of melorheostosis and substantial overlap with mixed sclerosing bone dysplasia. Medical treatments include bisphosphonates, but definitive guidance on their use is lacking given the small number of patients that have been studied. Surgical intervention may be required for those with large bone growths, nerve entrapments, joint impingement syndromes or major limb deformities. Bone regrowth is uncommon after surgery, but recurrent contractures represent a major issue in those with extensive associated soft tissue involvement.

A novel LEMD3 pathogenic variant in a son and mother with osteopoikilosis.

Elmaogullari S, Yildiz AE, Demir S, Gürkan H, Uçaktürk SA. A novel LEMD3 pathogenic variant in a son and mother with osteopoikilosis. Turk J Pediatr 2019; 61: 594-598. Osteopoikilosis (OPK) is a rare, benign condition characterized by osteosclerotic foci that occur in the epiphyses and metaphyses of long bones, wrists, feet, ankles, pelvis, and scapulae. We report a 16-year-old boy and his mother incidentally found to have sclerotic lesions on X-ray. Both of them were asymptomatic and the bone scan of the boy ruled out osteoblastic metastases. We have shown that the boy and his mother have a previously unknown pathogenic variant of the LEMD3 gene, supporting the diagnosis of osteopoikilosis.

Distrofia ósea esclerosante mixta / Mixed-sclerosing-bone-dystrophy

El término "distrofia ósea esclerosante mixta" describe la combinación de las características radiológicas correspondientes a melorreostosis, osteopoiquilosis y osteopatía estriada, como entidades individuales, que ocurren en un mismo paciente. El objetivo de esta comunicación es presentar el caso clínico de una paciente con diagnóstico de distrofia ósea esclerosante mixta y, a partir de este caso, realizar una revisión sobre el tema. (AU)

The term "mixed-sclerosing-bone-dystrophy" describes the combination of the radiological characteristics corresponding to melorheostosis, osteopoikilosis and osteopathia striata, as individual conditions, ocurring in the same patient. The aim of this communication is to present the clinical case of a patient diagnosed with mixed-sclerosing-bone-dystrophy and, based on this case, to undertake a review of this condition. (AU)

Human Genetics of Sclerosing Bone Disorders.

PURPOSE OF REVIEW: The group of sclerosing bone disorders encompasses a variety of disorders all marked by increased bone mass. In this review, we give an overview of the genetic causes of this heterogeneous group of disorders and briefly touch upon the value of these findings for the development of novel therapeutic agents. RECENT FINDINGS: Advances in the next-generation sequencing technologies are accelerating the molecular dissection of the pathogenic mechanisms underlying skeletal dysplasias. Throughout the years, the genetic cause of these disorders has been extensively studied which resulted in the identification of a variety of disease-causing genes and pathways that are involved in bone formation by osteoblasts, bone resorption by osteoclasts, or both processes. Due to this rapidly increasing knowledge, the insights into the regulatory mechanisms of bone metabolism are continuously improving resulting in the identification of novel therapeutic targets for disorders with reduced bone mass and increased bone fragility.

Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.