The only patient who has been diagnosed with PA-Okamoto was born at term after an uneventful pregnancy. The girl's birth weight, length, and occipito-frontal circumference were about 2 SD below average. Psychological and motor developmental delays became evident early in life, and it was not until the age of 4 that she was able to walk independently. She was diagnosed with osteosarcoma of the distal femur at the age of 10 [1], whereby her age at the time of diagnosis and the localization of the tumor coincide with what is generally known about this type of malignancy: Its peak incidence is in the second decade of life and it preferentially develops in close proximity to the knees [2] [3]. At the age of 13, the girl developed generalized epileptic seizures, and two years later, she was found to suffer from bilateral nuclear and subcapsular, senile-type cataracts.

At that time, she had the weight and height of a 6-year-old child, showed relative truncal obesity and disproportionately small limbs and had not developed secondary sexual characteristics. She was microcephalic and displayed unusual facial features with a round face, low-set ears with deformity, upslanting palpebral fissures, a flat nasal bridge, and micrognathia. Poor hair growth was reported, but premature graying was not observed. There were foot ulcers but no other skin changes reminiscent of the more common Werner syndrome. Speech development was severely delayed and the girl was unable to articulate clear words [1].

• Falling

  The pupillary light reflex performs very many important functions: (1) it regulates the vigour of light that falls on the retina, thereby assisting in adaption to various levels of daybreak and darkness; (2) it aids in retinal receptivity to light; and [chesapeakehumane.org]

  Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer's disease. J Am Med Dir Assoc, 2014; 15: 36-41. 2012年 Oikawa N, Goto M, Ikeda K, Taguchi R, and Yanagisawa K. [med.nagoya-u.ac.jp]

• Infertility

  Since then, she did not conceive and consulted for 2 year infertility. [ojrd.biomedcentral.com]

• Weakness

  In addition, nuclear blebs showed altered lamin A/C staining and were frequently devoid of lamin B, with a weak DNA staining suggesting chromatin decondensation, as shown by immunocytochemistry (Figure 6A). [ojrd.biomedcentral.com]

• Prognathism

  Primrose syndrome Prinzmetal's variant angina Procarcinoma Proconvertin deficiency congenital Progeria Progeria variant syndrome Ruvalcaba type Progeroid short stature with pigmented nevi Progeroid syndrome Petty type Progeroid syndrome Penttinen type Prognathism [personalizedcause.com]

• Ataxia

  Posterior column ataxia with retinitis pigmentosa Posterior urethral valves Posterior valve urethra Postorgasmic illness syndrome Postural orthostatic tachycardia syndrome Potassium aggravated myotonia Potato nose Potocki-Lupski syndrome Potocki-Shaffer [personalizedcause.com]

  Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2001 Mar;70(3):386-9. 4. [okiken.tokyo]

  In accordance, and in line with our results, cells from patients with ataxia-telangiectasia, another genetic disease due to DNA damage signalling defects, display a state of endogenous oxidative stress which induces lamin B1 overexpression, nuclear shape [ojrd.biomedcentral.com]

• Cerebellar Ataxia

  Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2001 Mar;70(3):386-9. 4. [okiken.tokyo]

  Posterior column ataxia with retinitis pigmentosa Posterior urethral valves Posterior valve urethra Postorgasmic illness syndrome Postural orthostatic tachycardia syndrome Potassium aggravated myotonia Potato nose Potocki-Lupski syndrome Potocki-Shaffer [personalizedcause.com]

Diagnostic imaging and laboratory studies were realized to complete the picture of PA-Okamoto in the index patient. Osteoporotic changes were observed in radiographic images, and the analysis of blood samples revealed erythroid macrocytosis with mild anemia. The mean corpuscular volume was calculated to be 104-109 fl. Hyaluronic acid levels in serum and urine samples were within reference ranges. Furthermore, insulin-resistant diabetes mellitus was diagnosed with an oral glucose tolerance test [1].

Fibroblast cultures were grown from skin biopsy specimens to characterize these cells' growth behavior, which turned out to be normal [1]. Whereas skin fibroblasts from patients with Werner syndrome are known to have a reduction in growth capacity, no abnormalities were seen with regards to cultured fibroblasts from the patient with PA-Okamoto [4].

No genetic studies were carried out to determine the presence or absence of mutations now known to cause specific variants of progeria, but the sum of clinical, imaging, and laboratory findings argues against a diagnosis of Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, or similar progeroid disorders [5].

More detailed recommendations concerning the diagnosis of PA-Okamoto 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 more than 20 years ago.

Due to lack of knowledge about the pathogenetic mechanisms behind PA-Okamoto, causal therapy is not available, and patients can only be provided symptomatic treatment. Moreover, they are most likely to benefit from a multidisciplinary approach and specialist care.

Life-threatening complications may arise from osteosarcoma, an aggressive malignancy prone to metastatic spread. The outcome largely depends on the resectability of the primary tumor and possible metastases, which is why the prognosis worsens considerably with increasing tumor stages. Surgery is the mainstay of treatment and should be supplemented by postoperative chemotherapy in the case of high-grade osteosarcoma. Limb-salvage is often feasible but loses priority over the complete removal of the tumor. The index patient underwent leg amputation and was subsequently treated with chemotherapy. There is no detailed description of the regimen applied, but doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide are generally considered to be most active against osteosarcoma [6]. Bone marrow suppression may lead to the premature termination of chemotherapy, as has been the case in the Japanese girl with PA-Okamoto, and every effort should be made to prevent severe side effects. High-dose methotrexate is well known for its hematological toxicity, which may be attenuated by leucovorin as rescue [7].

There are no indications that epilepsy arising in the setting of PA-Okamoto would require any non-standardized treatment. The patient described in the original report responded well to valproic acid [1], a drug that has been recommended by several societies and organizations as an option for epilepsy monotherapy [8]. In general, the choice of medication should be based on individual patient characteristics including, but not limited to the type of seizures.

Cataracts as observed in the PA-Okamoto patient result from the aging process, and surgery is the only effective treatment. In general, cataract surgery is a common and safe procedure that considerably improves vision. The index patient underwent surgery, and a similar proceeding is recommended for possible future cases [1].

Additional measures may be required to regulate metabolic and endocrine disorders, although little is known about the response of PA-Okamoto patients to standard treatments for diabetes mellitus, osteoporosis, and other conditions related to this type of progeria.

Relevant information concerning possible follow-ups of the index case is not available in the literature. Generally speaking, progeria reduces the life expectancy of affected individuals who often succumb to extensive cardiovascular disease. Hutchinson-Gilford syndrome is usually cited as the classical type of early-onset progeria and provokes premature death at a median age of 14-15 years, with myocardial infarction and stroke being the most common causes of mortality [9]. It should, however, be kept in mind that atherosclerosis and vascular calcification have not yet been described in PA-Okamoto, which probably has a favorable effect on the outcome. Néstor-Guillermo progeria syndrome shall be named in this context as another variant of early-onset progeria. It doesn't seem to be related to cardiovascular disease, diabetes mellitus, or hypertriglyceridemia, and patients were aged 24 and 32 years at the time of the last publication [10]. Osteosarcoma, on the other hand, is associated with mortality rates of 24-55% within five years of the initial diagnosis. The patient's individual prognosis largely depends on the presence of metastases, which continue to be the most adverse prognostic factor [11].

Given the similarities between PA-Okamoto and other hereditary disorders associated with premature aging, a genetic origin may be assumed for this condition. There is, however, little evidence to prove that hypothesis. The index patient was born to healthy, non-consanguineous parents, and there was no family history of premature aging or other features seen in PA-Okamoto. If one or several gene defects were to account for the condition, they may have arisen de novo. Indeed, de novo mutations have been shown to cause up to 90% of cases of typical Hutchinson-Gilford syndromes, whereby the precise phenotype observed in the individual patient seems to depend on common polymorphisms and haplotypes [12]. So far, non-genetic causes of progeria syndromes have not been described.

PA-Okamoto has been described in a Japanese, female teenager whose parents were unrelated [1]. Additional cases have not been reported since the original publication in 1997. There are a number of clinical similarities between PA-Okamoto and Werner syndrome, whose incidence is particularly high in Japan. Due to a founder effect, 1 in 100,000 Japanese people is affected by Werner syndrome, while the global prevalence is <1 in 1,000,000 persons [12]. An important difference between the two conditions is the patients' age at symptom onset: While PA-Okamoto is associated with developmental delays in infancy, clinical conditions related to Werner syndrome don't typically become apparent before the second decade of life [13]. In sum, it has been estimated that there are an estimated 200–250 children living with progeria worldwide at any one time [12]. Both girls and boys are affected, independent of their ethnicity and country of origin.

Little is known about the pathogenetic mechanisms leading to PA-Okamoto and its different features. It may be speculated that the underlying defect interferes with genomic instability, nuclear structure, or telomere metabolism, as has been shown for several progeria syndromes [14].

PA-Okamoto is similar to Werner syndrome in that the affected individual showed a severe growth delay, a primary bone neoplasm, and diabetes mellitus [5] [15]. Both osteosarcoma and juvenile cataracts are characteristic of Rothmund-Thomson syndrome, while predisposition to cancer has also been demonstrated for Bloom syndrome [5] [16]. These diseases could be associated with mutations in the RECQL2, RECQL4, and BLM genes, respectively, all of which encode for DNA helicases that belong to the RecQ helicase family or related proteins [14]. These enzymes are able to unwind double-strand DNA into single-stranded DNAs, contribute to the reparation of double-strand breaks, and are involved in telomere maintenance and replication. Besides DNA replication, they are also required for chromosome segregation [5].

Additionally, there is a single case report about recurrent osteosarcoma and erythroid macrocytosis in a family of Native American origin [17]. While both features have been observed in the Japanese girl with PA-Okamoto, limb anomalies were deemed characteristic of OSLAM syndrome but were not detected in the present case. Also, OSLAM syndrome is not associated with progeria but may rather be classified as a chromosome breakage syndrome possibly induced by impaired regulation of bone and bone marrow development.

Due to considerable knowledge gaps regarding the etiology of PA-Okamoto, no recommendations can be given to prevent the onset of the disease or to delay its progression.

Progeria syndromes are rare diseases which may be caused by a number of distinct gene defects. While some of them - such as Hutchinson-Gilford syndrome and Werner syndrome - are well studied, others have been described in very few cases only and could not yet be related to any mutation. PA-Okamoto is one of these conditions; it has only ever been diagnosed in one teenage girl from Japan. There were clinical overlaps with the aforementioned types of progeria and other variants, but the specific combination of signs and symptoms warrants the definition of a novel premature aging condition [1].

Premature aging may also be referred to as progeria and describes a number of clinical conditions mimicking physiological aging at an early age. The respective diseases may be associated with additional features, such as malformations and predisposition to cancer, which is why they are generally called progeria syndromes. The phenotype of the individual patient largely depends on the underlying gene defect, as all variants of progeria characterized to date have been related to mutations in determined genes. Environmental factors may possibly alter the severity of certain symptoms, but little can be done to delay the progression of the disease.

Premature aging type Okamoto is a particularly rare type of progeria. It has only been described in a single patient, namely in a Japanese teenage girl. This patient showed severe developmental and growth delays, was diagnosed with osteosarcoma at the age of 10, and subsequently developed epilepsy and senile cataracts. Further studies confirmed her to suffer from osteoporosis, insulin-resistant diabetes mellitus, and macrocytosis. Premature hair graying and alopecia, skin changes, and cardiovascular disease, which are commonly observed in other progeria syndromes, have not been noted in this case.

The authors of the original report were unable to associate premature aging type Okamoto to a specific gene defect. The girl had no family history of premature aging, and it may be assumed that one or more de novo mutations account for the disease. De novo means that the respective mutation has not been inherited from the patient's parents but rather occurred spontaneously.

There is no cure for premature aging type Okamoto. The affected girl was provided symptomatic care, i.e., she underwent surgery for osteosarcoma and cataracts and received anti-epileptical medication. Additional therapies were tailored to her individual needs and aimed at the correction of endocrine imbalances, among others.

1. Okamoto N, Satomura K, Hatsukawa Y, et al. Premature aging syndrome with osteosarcoma, cataracts, diabetes mellitus, osteoporosis, erythroid macrocytosis, severe growth and developmental deficiency. Am J Med Genet. 1997; 69(2):169-170.
2. Nie Z, Peng H. Osteosarcoma in patients below 25 years of age: An observational study of incidence, metastasis, treatment and outcomes. Oncol Lett. 2018; 16(5):6502-6514.
3. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009; 152:3-13.
4. Salk D, Bryant E, Au K, Hoehn H, Martin GM. Systematic growth studies, cocultivation, and cell hybridization studies of Werner syndrome cultured skin fibroblasts. Hum Genet. 1981; 58(3):310-316.
5. Carrero D, Soria-Valles C, López-Otín C. Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells. Dis Model Mech. 2016; 9(7):719-735.
6. Bielack S, Carrle D, Casali PG. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009; 20 Suppl 4:137-139.
7. Hegyi M, Gulácsi A, Cságoly E, et al. Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma. J Cancer Res Clin Oncol. 2012; 138(10):1697-1702.
8. Stern JM. Overview of evaluation and treatment guidelines for epilepsy. Curr Treat Options Neurol. 2009; 11(4):273-284.
9. Del Campo L, Hamczyk MR, Andrés V, Martinez-Gonzalez J, Rodriguez C. Mechanisms of vascular aging: What can we learn from Hutchinson-Gilford progeria syndrome? Clin Investig Arterioscler. 2018; 30(3):120-132.
10. Cabanillas R, Cadiñanos J, Villameytide JA, et al. Nestor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet A. 2011; 155a(11):2617-2625.
11. Smeland S, Bielack SS, Whelan J, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer. 2019; 109:36-50.
12. Coppedè F. The epidemiology of premature aging and associated comorbidities. Clin Interv Aging. 2013; 8:1023-1032.
13. Coppedè F. Premature aging syndrome. Adv Exp Med Biol. 2012; 724:317-331.
14. Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev. 2018; 173:80-83.
15. Lauper JM, Krause A, Vaughan TL, Monnat RJ, Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013; 8(4):e59709.
16. Zils K, Klingebiel T, Behnisch W, et al. Osteosarcoma in patients with Rothmund-Thomson syndrome. Pediatr Hematol Oncol. 2015; 32(1):32-40.
17. Mulvihill JJ, Gralnick HR, Whang-Peng J, Leventhal BG. Multiple childhood osteosarcomas in an American Indian family with erythroid macrocytosis and skeletal anomalies. Cancer. 1977; 40(6):3115-3122.