OSLAM syndrome's distinguishing features are osteosarcoma, limb anomalies, and erythroid macrocytosis with megaloblastic bone marrow.

• Familial accumulation of osteosarcoma was what caught the attention of health authorities in the original case: Within two years, three siblings aged 7, 14, and 18, presented with mass lesions of the proximal tibia or distal femur that have been identified histologically as osteosarcoma [1]. Both the age of the patients and the localization of the tumors coincide with what is generally known about this type of malignancy, whose peak incidence is in the second decade of life and which often develops in close proximity to the knee joint [2] [3]. Although not reported by Mulvihill et al., bone pain, increasing swelling, and limitation of joint movement may be expected in patients with osteosarcoma [4].
• OSLAM syndrome was also related to limb anomalies. Brachymesophalangy of the fifth digit with clinodactyly was observed in one of the patients suffering from osteosarcoma, and similar findings could be made in her father and at least three of her sisters. One of these girls also had a short fourth metatarsal and absent middle phalanges of two toes. The youngest member of the family was diagnosed with bilateral radioulnar synostosis and showed congenital limitations of wrist and elbow motion but no neurological deficits [1].
• Moreover, laboratory analyses of blood samples revealed macrocytosis in all but one of the nine siblings and their father. For the siblings diagnosed with osteosarcoma, the mean corpuscular volume was calculated to be 100-108 fl. Even though most family members were found to have iron deficiency, hematocrit and hemoglobin levels were within reference ranges [1].

A 19-year old sister of the patients described above was diagnosed with fibroadenoma of the breast. Whether this condition may be related to OSLAM syndrome can neither be confirmed nor denied at this time [1].

• Emotional Outbursts

  Without any internal stimulus to act creatively and unable to confront new challenges, the mind reacts with emotional outbursts and violence. This indeed is the tragedy of the Muslim world. How did the Muslim community get to this situation?” [medium.com]

Mulvihill and colleagues carried out a number of tests to determine the etiology of OSLAM syndrome. They worked with blood, urine, and bone marrow samples, and they realized genetic, immunological, and viral studies. Yet, they were only able to rule out certain conditions and could not find a definite cause of osteosarcoma, limb anomalies, and macrocytosis.

Macrocytes and polymorphonuclear leukocytes were identified in peripheral blood films, and megaloblastic erythrocytic and leukocytic precursors were observed in bone marrow specimens [1]. The causes of these hematological abnormalities could not be determined. In particular, they could not be related to vitamin B12 or folate deficiencies, alcoholism, or medication, which are the most common etiologies of macrocytosis [5]. There was no history of alcohol abuse or relevant drug therapy; serum levels of vitamin B12 and folate were within reference ranges, as were reticulocyte and eosinophil counts, thyroxine concentrations, serum and urine amino acid profiles, urinary orotic acid and orotidine [1].

Chromosomal abnormalities were mainly observed in one of the patients with osteosarcoma and her father. There were additional chromosomes in peripheral blood and marrow cells, and excessive chromosomal breaks in the bone marrow. Such breaks have also been noted in two other siblings, albeit to a lesser extent. Neither immunological nor viral studies yielded a satisfactory response as to possible causes of these findings: Elevated titers of Epstein-Barr virus antibodies were determined for all family members, although none of them reported having suffered from an illness resembling infectious mononucleosis. Antibodies targeting the Finkel-Biskis-Reilly murine sarcoma virus could not be detected in any of the siblings or their parents, and no studies were conducted to verify exposure to simian virus 40. No virus-like particles could be identified during electron microscopic examinations of bone marrow samples [1].

More detailed recommendations concerning the diagnosis of OSLAM syndrome require the analysis of additional cases, which might provide important clues as to the etiology of this condition. Yet, the disease has not been reported since its original description in the 1970s.

• Megaloblastic Bone Marrow

  OSLAM syndrome's distinguishing features are osteosarcoma, limb anomalies, and erythroid macrocytosis with megaloblastic bone marrow. [symptoma.com]

Lack of knowledge regarding the causes of OSLAM syndrome compels to symptomatic treatment of affected individuals, whereby the management of osteosarcoma clearly requires most of the attention.

Curative treatment for osteosarcoma consists of surgery and, in the case of high-grade neoplasms, postoperative chemotherapy. The surgical intervention should be performed so that the tumor and the biopsy tract are removed in their entirety, considering wide margins. Limb-salvage is often feasible. Doxorubicin, cisplatin, high-dose methotrexate (with leucovorin rescue), and ifosfamide are among the most active agents against osteosarcoma, although the optimum regimen remains to be defined [6]. The immune modulator muramyl tripeptide may complement combination chemotherapy and has been shown to improve overall survival [7]. It should be kept in mind that metastases may develop very late in the course of the disease, a fact that highlights the necessity for year-long follow-up schedules. In general, metastatic osteosarcoma is treated in a similar manner and includes the complete resection of all metastases [6]. Although the prognosis is poor, complete remission can be achieved if all tumors are resectable. Radiotherapy has a limited role and is generally reserved for inoperable sites.

Macrocytosis without anemia may persist in the absence of clinical symptoms, and may then be related to the presence of a gene defect [8]. This condition doesn't usually require any therapeutic intervention [9]. Similarly, limb anomalies associated with OSLAM syndrome are usually mild and don't affect the patients' quality of life. Decisions regarding surgery, the provision of orthopedic aids, and other measures to compensate for skeletal malformations should be made on a case-by-case basis [10] [11].

Mortality in OSLAM syndrome is related exclusively to the development and metastatic spread of malignant tumors; the remainder of features has low impacts on the patients' quality of life and does not reduce their life expectancy.

Two out of three patients with OSLAM syndrome-related osteosarcoma died from metastatic cancer 10 and 28 months after the initial diagnosis, respectively. Almost 50 years have passed since OSLAM syndrome has first been diagnosed, but the presence of metastases continues to be the most adverse prognostic factor in case of osteosarcoma. Five-year survival has been reported to be 76% for those with localized disease at the time of diagnosis and only 45% for patients with metastatic osteosarcoma [12]. The only patient who survived had been treated with radiotherapy over six weeks before amputation, which confirms the current recommendation of aggressive surgical resection as the only chance for cure [1] [12].

OSLAM syndrome is a complex condition whose etiology remains unknown. The authors of the original case report suspected a genetic origin with an autosomal dominant pattern of inheritance but were unable to identify a specific gene defect in any of the affected individuals. Their hypothesis is based on the fact that the father of the osteosarcoma patients showed characteristic anomalies of limb bones and macrocytosis, and that all of his children displayed at least one of these features. Male-to-male transmission argues against a gonosomal mode of inheritance.

Assuming that OSLAM syndrome is indeed a hereditary disease, both monogenic and polygenic come into question. The expression of all traits may be determined by the alleles of a single gene, with some carriers failing to express certain features of the disease due to incomplete penetrance and heterogeneous expressivity. Similar observations have been made in other genetic syndromes, e.g., the chromosomal breakage syndromes Fanconi anemia and Bloom syndrome, which are associated with cancer predisposition [13] [14]. On the other hand, independently segregating genes may account for this phenomenon.

Interestingly, all cases of osteosarcoma related to OSLAM syndrome were confirmed within two years. No other family members were known to have developed osteosarcoma at any time before or after this period, which may imply exposure to a common environmental agent as the true cause of cancerogenesis. The only established environmental cause of osteosarcoma is ionizing radiation, which has been ruled out as a trigger by Mulvihill et al. [1]. Notwithstanding, it has repeatedly been proposed that oncogenic viruses may play a role in the induction of this type of cancer [15] [16] [17].

The family described by Mulvihill and colleagues belonged to the Oneida people, a Native American tribe living in the Great Lakes region. The members of this family were residents of the Oneida reservation in the east of Wisconsin, United States. Parental consanguinity was suspected yet not confirmed. Besides the father, an adult male, there were nine children of either sex who displayed at least one of the features defining OSLAM syndrome. Osteosarcoma was diagnosed in three of them, namely in two girls and one boy [1].

Impaired regulation of bone and bone marrow development has been proposed as the mechanism behind conditions observed in OSLAM syndrome, but the common denominater remains unknown [1]. In line with the pathophysiology of better-known chromosome breakage syndromes, abnormalities of DNA metabolism, DNA repair, the regulation of cell cycle progression, survival and apoptosis may be assumed to account for OSLAM syndrome [14].

Indeed, one such chromosome breakage syndrome, namely Fanconi anemia, is characterized by predisposition to leukemia, squamous cell carcinoma, and other malignancies, as well as bone marrow failure and abnormalities of other organ systems. Fanconi anemia has been linked to distinct mutations, all of which interfere with a common signal transduction pathway, provoking cytogenetic instability, increased chromosomal breakage, and defective DNA repair.

Rothmund-Thomson syndrome is generally described as a genodermatosis, but may also be classified as a chromosome breakage syndrome and does predispose to the development of osteosarcoma and other malignancies [18]. This disease is caused by mutations of the RECQL4 gene, which encodes for a DNA helicase that belongs to the RecQ helicase family and is able to unwind double-stranded DNA into single-stranded DNAs.

Because the causes of OSLAM syndrome are unknown, preventive measures cannot be defined.

In 1977, Mulvihill and colleagues reported the unusual association of osteosarcoma, skeletal malformations, and bone marrow dysfunction in a family of Native American descent. They were able to examine nine siblings and both parents, with only scarce information being available about other family members. The authors carried out investigations in distinct directions but were unable to relate the condition to a certain type of trigger. They finally concluded OSLAM syndrome to most likely be a hereditary condition predisposing to malignancy. According to the authors' findings, OSLAM syndrom may be a chromosome breakage syndrome that is inherited in an autosomal dominant manner [1].

OSLAM syndrome is a very rare condition that has only ever been described in a single family of Native American origin. In 1977, the term "OSLAM" has been coined in reference to the symptoms presented by the father of the family and his nine children, namely osteosarcoma, limb anomalies, and macrocytosis. While some family members showed all of these features, others had developed one or two only.

• Osteosarcoma is a malignant tumor of the bone. It is most commonly diagnosed during the second decade of life and often develops in close proximity to the knee. Osteosarcoma may metastasize to other sites in the skeleton or to the lungs and requires radical surgical removal.
• Limb anomalies observed in OSLAM syndrome are generally mild and may comprise abnormally curved, shortened fingers or toes as well as radioulnar synostosis, i.e., the fusion of the radius and ulna bones in the forearm. They don't usually require any treatment, although surgery and/or orthopedic measures may be considered to improve the patient's quality of life.
• Macrocytosis is a laboratory finding referring to enlarged red blood cells. Macrocytosis is often associated with anemia, but this is not the case in patients with OSLAM syndrome. So far as is known, therapy is not needed to counteract macrocytosis in these individuals.

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