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Keywords:

  • accelerated aging;
  • genome sequencing;
  • nuclear lamina;
  • osteolysis;
  • osteoporosis;
  • lipodystrophy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Progeria syndromes are rare disorders that involve premature aging. Mutations in BANF1 have been recently reported to cause a new hereditary progeroid syndrome that we now propose to call the Néstor–Guillermo progeria syndrome (NGPS). We describe herein the clinical features of the first two NGPS patients, who phenocopy features of classic progerias (i.e., Hutchinson–Gilford progeria syndrome or mandibuloacral dysplasia), such as aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. However, these NGPS patients have a distinctive phenotype. In their early adulthood (32 and 24 years of age), they have no signs of cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, they suffer profound skeletal abnormalities that affect their quality of life. The observed differences are of utmost importance to patients and their families and palliation of osseous manifestations is a priority, given their relatively long lifespan. We define NGPS as a chronic progeria because of its slow clinical course and relatively long survival, despite its early onset. Understanding the differences between progeria syndromes might contribute to the development of treatment strategies for common skeletal conditions, as well as aging itself. © 2011 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Segmental aging syndromes are characterized by features of normal aging such as alopecia, skin wrinkling, osteoporosis, insulin resistance, and, usually, cardiovascular disease. These rare genetic conditions, frequently referred to as “progeroid,” offer valuable insights into the normal aging process [Ramirez et al., 2007; Burtner and Kennedy, 2010]. The most widely studied infantile premature aging syndrome is Hutchinson–Gilford progeria syndrome (HGPS) [Merideth et al., 2008]. However, numerous childhood-onset progeroid syndromes have been reported [Agarwal et al., 2003; Arboleda et al., 2007; Kraemer et al., 2007; Kivuva et al., 2008; Braddock et al., 2010; Friedrich et al., 2010; Shastry et al., 2010]. They all share a common pseudosenile appearance and due to their early manifestation and fast and fatal course, most of them can be termed as acute progerias.

We report herein on a detailed description of two patients with clinical findings consistent with a new progeroid disorder with atypical features. Both patients phenocopied characteristics of HGPS. However, their long survival relative to other progerias of the childhood (patients are alive at 24 and 32 years), their height (150 and 145 cm), the presence of eyebrows and eyelashes, the persistence of scalp hair until the second decade of their lives (it has never disappeared completely), a very severe osteolysis, and the absence of coronary dysfunction, atherosclerosis, or metabolic complications, led to the diagnosis of a novel progeria. These findings, together with the absence of mutations in LMNA and/or ZMSPTE24, the two genes most frequently mutated in previously described early-onset progerias [Agarwal et al., 2003; De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003] prompted the search for the causal gene through exome sequencing in the index case and his parents. The candidate genetic alteration responsible for this new progeroid syndrome, a homozygous mutation in BANF1, was confirmed by PCR amplification and capillary sequencing of DNA from a second patient. These findings and the functional consequences of BANF1 mutations have been reported elsewhere [Puente et al., 2011]. Now, we provide detailed information for the clinical delineation of this syndrome that confirms it as a unique progeroid disorder. Despite their dissimilar lifestyles, Néstor–Guillermo progeria syndrome (NGPS) patients (entity named after the names of both patients) look strikingly similar, underscoring the strong contribution of their common BANF1 mutation to the pathobiology of this condition. We define NGPS as a chronic progeria because of its early onset but slow clinical course, which leads to a relatively long survival.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Two patients with atypical progeroid features and mutations in BANF1 are the subjects of this study. Affected individuals are members of two unrelated Spanish families, from distant regions of the country (Gran Canaria, Patient 1, and Castilla-La Mancha, Patient 2). BANF1 mutational analysis has been previously reported [Puente et al., 2011]. The study protocol was approved by the Comité Científico de la Fundación Centro Médico de Asturias. The patients gave written informed consent and a specific consent was obtained to include clinical photographs.

CLINICAL REPORTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Index Case (Patient 1)

A 32-year-old man was referred because of an unusual appearance and small stature (weight 23 kg, height 145 cm—underestimated as a result of his scoliosis). The patient was the second child born to consanguineous third cousins. Both parents and his four brothers were healthy and there was no significant clinical family history. After an uneventful pregnancy, he was delivered at term. At birth, he was phenotypically normal with weight of 2,950 g. The patient exhibited normal development until 2 years of age. From that age onwards, he experienced failure to thrive, progressively started to lose the subcutaneous fat pad, and developed an unusual face with “progeroid” features. At about 3 years of age, his parents noted stiffness at his fingers and the distal phalanges of fingers and toes started to become abnormal. Progressively, the restricted motility extended to other joints. Tooth eruption and shedding of primary teeth were within normal ranges. By age 10, he started to lose his hair. He entered puberty at 12 years of age, experiencing a growth spurt. At about 17 years, he started to notice the resorption of his clavicles. The cognitive development was referred as normal. He had no allergic manifestations nor frequent infections (Fig. 1A–E).

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Figure 1. Parallel life course pictures of Patient 1 (AE) and Patient 2 (FJ). Progeroid features are not apparent until 2 years of age. (A) and (F) have been previously reported in Puente et al. [2011]. [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

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On examination, the patient's skull has widely open cranial sutures, sparse hair on scalp, and marked subcutaneous veins (Fig. 2A–C). Although light, he has eyebrows and eyelashes. He has prominent eyes, a convex nasal ridge, a small retrognathic chin, malocclusion, dental crowding, and thin lip vermillion. Opening of the mouth is restricted. Teeth are normal size, with usual eruption pattern. The ears lack lobules, and otoscopy only shows a mild right serous otitis (the nasal septum is deviated and occludes the right fosse). He has normal sight and no sensorineural hearing loss.

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Figure 2. Photographs (A,B,D,E) and volume rendering multidetector computed tomography reconstructions of head (C,F) illustrating progeroid features. The patients´ skull (A–C: Patient 1; D–F: Patient 2) has widely open cranial sutures. The presence of eyebrows and eyelashes (A: Patient 1; D: Patient 2) are characteristics of atypical progeria. Small chin, convex nasal ridge, prominent eyes, and notorious submaxillary glands are secondary to severe bone changes and atrophic subcutaneous fat pad, originating a characteristic pseudosenile appearance. [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

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The skin is thin, dry, and atrophic, with small light-brown spots over the thorax, scalp, and limbs, and fine wrinkles over the face. He has no photosensitivity and wound healing is normal. Over the phalanges of fingers and toes, the skin is red and swollen, with dystrophic nails (Fig. 3C,E). He has a pronounced and generalized lipoatrophy (he has very little subcutaneous fat over the limbs, abdomen, neck, and head).

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Figure 3. Radiographs of the hands and photographs of the hands and feet, showing severe diffuse osteopenia and marked acro-osteolysis of the distal phalanges, dystrophic nails, and red and swollen skin over the phalanges (A,C,E: Patient 1; B,D,F: Patient 2). [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

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Craniofacial helical CT shows marked osteolysis of the facial skeleton, mainly affecting the mandible and the alveolar processes of the maxilla. While the body of the mandible is significantly reduced, the ascending ramus and the condyle are completely absent (Fig. 4B,C). The atrophic facial subcutaneous fat pad and the marked osteolysis of the maxillary and mandible originate a typical pseudosenile facial appearance, conditioned by the prominence of the parotid gland in the cheeks and the submaxillary glands in the neck. The nose is collapsed, and the convex nasal ridge can be justified by resorption of the espina nasale of the maxilla.

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Figure 4. Radiograph of the skull of Patient 2 (A). Note the open fontanela and the relatively large neurocranium compared to the viscerocranium. Volume rendering multidetector computed tomography reconstructions of Patient´s 1 facial skeleton (B,C) and upper left limb (D). Note the severe osteolysis of the proximal left radius and of the edentulous mandible (the jaw without teeth disappeared completely) (asterisks), while on the other hand, the styloid process is long and thick, and an exostosis of the proximal humerus, can be seen in the insertion of the deltoid muscle (arrows). [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

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The shoulders are narrow, due to the absence of clavicles. Limbs are thin and the joints are stiff. The main mobility restriction is at fingers, hands, knees, and elbows. Knees and elbows protrude significantly. The absence of plantar fat causes significant foot pain. However, the patients´ main concern is his scoliosis. The scoliosis has been progressive, starting at age 18. At the age of 27 years, he developed shortness of breath with exertion. He was diagnosed with pulmonary hypertension secondary to his severe scoliosis (Fig. 5A,B). At present, he has dyspnea with minor efforts and a severe restrictive spirometry pattern. Thin ribbon ribs with partial resorption of the proximal segments on the right side allow an extra pulmonary expansion and a slight improvement of his vital capacity. On echocardiogram, a moderate tricuspid insufficiency, a severe mitral regurgitation, and pulmonary hypertension (69 mmHg) are patent.

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Figure 5. Back view pictures of Patient 1 (A) and Patient 2 (C). Scoliosis is very severe in Patient 1 (32-year old), but just incipient in Patient 2 (24-year old). Volume rendering multidetector computed tomography (MDCT) reconstructions of the thorax of Patient 1 (B) reveals very severe scoliosis and multiple costal erosions. In the thorax radiograpy of Patient 2 (D), a mild scoliosis can be seen, as well as the absence of both clavicles. [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

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ECG showed sinus tachycardia, with dilatation of both atria and right bundle branch block, without signs of ischemia. Doppler ultrasound of the carotid arteries did not show arteriosclerosis. Coronary arteries computed angiography showed no coronary calcification or stenosis. His blood pressure is normal (120/70 mmHg).

As in the facial skeleton, clavicles and ribs, pronounced osteolysis was patent on the distal phalanges of hands and feets, and in the proximal left radius (Fig. 4D). On X-rays, bone density was significantly reduced. Densitometry at the lumbar spine showed severe osteoporosis (z-score, 6 SD). X-rays and CT imaging also revealed a symmetrical exostosis at the proximal submetaphyseal regions of the humerus, coinciding with the insertion of the tendon of the deltoid muscle (Fig. 4D).

The abdomen is not prominent and he has no abdominal visceromegaly. His testicles and phallus are normal. The neurological examination is normal and his intelligence is normal. Likewise, cerebral MRI was normal except for the persistence of a cavum septum pellucidum, an anatomical variant (Fig. 6A).

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Figure 6. Axial cerebral MRI of Patient 1 (A) and Patient 2 (B). No signs of cerebral microangiopathy are depicted. On panel A an anatomic variant (cavum septum pellucidum) is revealed (arrow). Patient´s 2 cerebral MRI sagital view (C) reveals a mega cisterna magna, as an anatomic variant (arrow). [Color figure can be seen in the online version of this article, available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

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Normal laboratory tests included coagulation studies, complete blood cell count, hemoglobin, urea, uric acid, creatinine, sodium, potassium, chlorine, calcium, phosphorous, magnesium, phosphate and alkaline phosphatase, cholesterol and triglycerides, liver enzymes (SGOT, SGPT, γGT), total bilirubin, direct and indirect bilirubin, C-reactive protein, homocysteine, lactic dehydrogenase, creatine kinase, proteinogram, total protein, albumin, iron, total iron binding capacity, serum ferritin, vitamin B12, folic acid, routine urine, and sediment. Hormones and tumor markers were also normal: total PSA, free PSA, TSH, free T3, free T4, prolactin, GH, ACTH, PTH, FSH, LH, cortisol, estradiol, insulin, and IGF-BP3. Moreover, parameters with substantial impact on bone remodeling, such as somatomedin-C (also called IGF-1) and testosterone, were within the normal reference ranges (84.4 ng/ml, range: 55–358 and 5.91 ng/ml, range: 1.75–7.81, respectively). The only parameters not within normal range were a low fasting glucose (48 mg/dl), low 25-OH-vitamin D (24 ng/ml), and very low leptin (<1 mg/ml).

His parents, both heterozygous carriers of BANF1 Ala12Thr mutation, have no signs of the syndrome as assessed by performing clinical, radiological, and analytical examinations. Their high and weight are within normal ranges.

Patient 2

The patient is a 24-year-old Caucasian male, unrelated to the index case. His parents and his brother are healthy. His mother has persistent wormian bones as unique clinical finding after performing the same radiological and analytical evaluation than her son. Until age 2 the child was healthy, with normal growth and development. At about 2 years of age, the mother noted growth retardation and hair loss (Fig. 1F–J). At 3 years, mandibuloacral dysplasia (MAD) syndrome was diagnosed. From then until age 10, he was treated with growth hormone. He underwent two surgical procedures (at 12 and 14 years of age) to distract the mandible. Both attempts were unsuccessful because of premature closure of the osteotomies. In order to improve the dental crowding, the inferior molars and premolars were extracted. However, the progressive osteolysis of the edentoluous mandibule, and the subsequent retrognatia finished in dental crowding. Between the age of 20 and 23 years, the patient was treated for 18 months with subcutaneous teriparatide (recombinant human parathyroid hormone 1–34), experiencing a densitometric improvement measured at the lumbar spine (z-score, 6.2 SD at 20 years, and 5.4 SD at the end of the treatment). Despite the treatment, at age 21 he suffered a spontaneous fracture of the right femur (an impacted subcapital neck fracture), that healed successfully with conservative treatment.

The current clinical examination, performed at the age of 24, revealed a man with a phenotype almost identical to the index case (Figs. 1–4). Height and weight were 150 cm and 24 kg, respectively. He has a normal intellect. He has a mild scoliosis without impact on cardiovascular functions (Fig. 5C,D). Densitometry at the lumbar spine showed severe osteoporosis (z-score, 5.6 SD). Thorough cardiovascular examination (echocardiogram, stress test, cardiac computed tomography, and Doppler ultrasound of carotid arteries) did not show signs of ischemia or atherosclerosis. Blood pressure was normal (110/60). ECG showed sinus tachycardia and right bundle branch block. Cerebral MRI was within normal limits except for the presence of mega cisterna magna (Fig. 6B,C).

The laboratory tests performed in the index case were repeated in this second patient (Index Case Section). Most of them were rigorously normal, including fasting glucose (88 mg/dl, range: 65–110), GH (0.61 ng/ml, normal <0.8), somatomedin-C (225 ng/ml, range: 55–358), IGF-BP3 (4.1 mcg/ml, range: 2.2–7.8), and testosterone (7.18 ng/ml, range: 1.75–7.81 ng/ml). This patient also underwent an oral glucose tolerance test, with normal results. The only tests not within normal range were a low 25-OH-vitamin D (8.01 ng/ml), and a very low leptin (<1 mg/ml).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Aging is a very complex process whose molecular basis remains largely unknown. Progeria syndromes accelerate a subset of the pathological changes that together drive the normal aging process. In these diseases, different tissues show age-related phenotypes. However, they are segmental in nature, as only a subset of tissues seems to age prematurely [Burtner and Kennedy, 2010]. Understanding the differences between progeroid syndromes with different manifestations may help to dissect the normal aging process [Ramirez et al., 2007].

We believe that the two patients reported in this work, who strongly resemble one another, represent a unique chronic disorder distinct from all previously described progeroid syndromes. Severe osteolysis, osteoporosis, generalized lipoatrophy, and a relatively long survival determine the patients´ phenotype. Although certain clinical features of NGPS overlap those of Hutchinson–Gilford progeria syndrome (HGPS) and MAD [Agarwal et al., 2003; Hennekam, 2006; Merideth et al., 2008; Cunningham et al., 2010], NGPS patients lack cardinal features of classical progerias such as atherosclerosis, metabolic complications, and very early death. Therefore, NGPS, a progeria caused by BANF1 deficiency [Puente et al., 2011] and with a relatively long lifespan, can be defined as a novel chronic segmental progeria.

We consider that NGPS can be included in the group of diseases collectively referred as laminopathies. The inner nuclear membrane is in contact with a protein network called the nuclear lamina, composed of type V intermediate filaments termed lamins and several lamina-associated proteins. Phenotypic expression of laminopathies is highly variable. Patients with HGPS (the most common progeria syndrome), usually carry heterozygous mutations in the LMNA gene (90% de novo C-to-T change at codon 608 in exon 11 of LMNA), which encodes two major components of the nuclear envelope: lamins A and C [De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003]. MAD patients carry homozygous LMNA mutations or compound heterozygous LMNA or ZMPSTE24/FACE1 mutations (ZMPSTE24 encodes a metalloprotease involved in prelamin A maturation) [Pendas et al., 2002; Agarwal et al., 2003]. BANF1 gene product (BAF) is implicated in nuclear envelope assembly and interacts with lamin A [Puente et al., 2011]. Restrictive dermopathy, familial partial lipodystropy, atypical Werner syndrome, Emery–Dreifus muscular dystrophy, type 1A dilated cardiomyopathy, Charcot–Marie–Tooth syndrome, or limb–girdle muscular dystrophy are examples of other laminopathies, which in most cases are due to mutations in LMNA or ZMPSTE24.

NGPS clinical findings differ from classical HGPS in several aspects [Hennekam, 2006; Gordon et al., 2007; Merideth et al., 2008]. In NGPS, growth is less retarded than in HGPS, patients are taller and their lifespan is increased. Scalp hair starts to fall out later in NGPS and it does not disappear completely, whereas eyebrows and eyelashes persist. Osteolysis is more severe in NGPS than in HGPS in all affected bones (mandible, clavicles, ribs, distal phalanges, and long bones). Patients with HGPS are affected by accelerated, premature arteriosclerotic disease that leads to fatal heart attacks and strokes at a mean age of 13 years. Additionally, concentric ventricular hypertrophy and systemic arterial hypertension are often present. None of our NGPS patients had signs of atherosclerosis, cardiac isquemia, arterial hypertension, or cerebral vascular disease, at 24 and 32 years of age. Our index case has evidence of severe pulmonary hypertension and biventricular hypertrophy, secondary to his severe scoliosis. As in classical acute progeria, in NGPS the typical appearance of patients develops gradually and diagnosis could not be made before the age of 2 years. Hennekam [2006] coined the term non-classical progeria to define a group of patients whose clinical features involved the same body systems as classical HGPS, but with variations in the course and severity of the symptoms. According to Hennekam´s description, NGPS patients´ cardinal features overlap with the phenotype of non-classical HGPS patients (height, hair growth pattern, generalized lipodystrophy, very severe osteolysis, and relatively long lifespan). The salient features of these conditions are set forth in Table I.

Table I. Comparative Analysis of Molecular and Clinical Findings in Patients 1 and 2 (Néstor–Guillermo Progeria Syndrome Patients), Mandibuloacral Dysplasia (MAD), Non-Classical Hutchinson–Gilford Progeria Syndrome (HGPS), and HGPS
Clinical findingsPatient 1aPatient 2aMADNon-classical HGPSHGPS
  • AD, autosomal dominant; AR, autosomal recessive; NR, not reported.

  • a

    Severe osteolysis, osteoporosis, and generalized lipoatrophy, without atherosclerosis, and metabolic complications determine the NGPS phenotype.

Gene mutationBANF1BANF1LMNA or ZMPSTE24UnknownLMNA
InheritanceARARARAR?AD
Prematurely aged appearance+++++
Growth retardation++++++
Delayed closure of anterior fontanel+++++
Sparse scalp hair+++
Sparse eyebrows/lashes+++
Prominent eyes+++++
Thin nose+++++
Underdeveloped midface++++++
Small chin+++++
Premature loss of teeth+
Decreased subcutaneous fat++++++++++
Patchy hyperpigmentation+++++
Hypoplastic or absent clavicles+++++++++
Thorax deformity+++++++
Thin limbs+++NR+
Stiff joints+++++
Joint contractures++++
Acro-osteolysis+++++++++
Osteoporosis++++NR+
Hypertension+
Premature arteriosclerosisAdulthood+
Metabolic complications++
Hypogonadism+

Mandibuloacral dysplasia is a rare syndrome with variable clinical features including bone alterations and several characteristics of metabolic syndrome [Agarwal et al., 2003; Cunningham et al., 2010]. There are phenotypic similarities and differences between our patients and MAD subjects (Table I). Both types of patients have mandibular and clavicular hypoplasia, acro-osteolysis, joint contractures, or skin atrophy. However, despite their relatively advanced ages, our patients do not have insulin resistance, diabetes mellitus, or hypertriglyceridemia, all of them usual features of MAD. Mild fasting hypoglycemia was observed in one of our patients. More cases are needed to clarify whether hypoglycemia represents a manifestation of the syndrome. The absence of atherosclerosis and metabolic alterations in NGPS could explain their chronic course and therefore, their longer survival. In MAD, lipodystrophy usually is “patched” (MAD type A), although occasionally diffuse lipodystrophy has been also described (MAD type B) [Cunningham et al., 2010]. In NGPS, as in classical HGPS, lipodystropy is clearly not “patched” but rather diffuse.

Our findings suggest that patients with NGPS have a more severe skeletal phenotype than those with LMNA or ZMPSTE24 mutations, although some form of osteolysis is invariably present in any patient with HGPS or MAD. In NGPS patients, unloaded bone seems to suffer more intense resorption phenomena (i.e., jaw without teeth, due to previous extractions to prevent dental crowding, disappeared completely). On the other hand, bone under structural stress seems to react. The exostosis of the proximal humerus and a long and thick styloid process are examples of persistent and well developed bone structures, secondary to recurrent and intense muscle traction (deltoid muscles acting on the humerus compensating for stiff elbows and wrists, and degluttition muscles from the styloid process compensating for oral malformations). Therefore, focused intense physical rehabilitation could paliate the consequences of the disease in this regard. Since symptomatic treatment is the only current approach to treat NGPS patients, bone forming and antiresorptive agents may also be a rational approach in the treatment of musculoskeletal abnormalities in these patients. Therefore, even though there is some overlap of features between NGPS, MAD, and HGPS, the differences are of utmost importance to patients and their families. Acute myocardial infarcts, cerebrovascular accidents, or diabetes mellitus are not a special concern for chronic progeria patients, at least in their first four decades of life. However, skeletal abnormalities affect their quality of life (patients experience pain, dysfunction, and disability), and occasionally may derive in life-threatening complications, such as the pulmonary hypertension described in our index case. Therefore, palliation of osseous manifestations is a priority in chronic progeria patients, given their relatively long lifespan.

Synthetic growth hormone was prescribed to one of our patients by his treating physicians at age 3. Even though key features of NGPS include postnatal growth delay, growth hormone production appears to be adequate, and when compared with the untreated patient, growth hormone treatment did not seem to modify the natural history of the disease. In the same way, there is little convincing evidence that dental extractions and mandibular surgery were effective in limiting mandibular resorption. Moreover, dental extractions may have accelerated the lysis of the uncharged bone. Aminobisphosphonates are being used in combination with statins for the treatment of children with HGPS, based on their preclinical success in extending the lifespan and improving the general condition of a mouse model of progeria (ClinicalTrials.gov, NCT00731016, NCT00425607, NCT00916747) [Varela et al., 2008; Worman et al., 2009]. Their primary pharmacological action involves inhibition of osteoclast-mediated bone resorption, and they are usually used in the treatment of osteoporosis or to reduce the incidence of skeletal-related events in patients with cancer and bone involvement. They have also proven to be beneficial in children with inherited multicentric osteolysis, improving bone mineral density and even retarding the natural history of the disease [Lee et al., 2010]. Nonetheless, to date, their use has been precluded in our patients, because of the concerns about jaw osteonecrosis. This complication is extremely uncommon in patients with osteoporosis. However, its incidence is known to increase with dental surgery, to the extent that in patients with cancer, their use is now strongly discouraged if not accompanied by preventive dental monitoring [Aapro et al., 2008].

In our patients, the only treatment shown to reduce bone loss and increase bone mineral density was teriparatide, a recombinant human parathyroid hormone, commonly used for the treatment of osteoporosis [Neer et al., 2001]. Teriparatide has been successfully used off-label for the treatment of mandibular osteonecrosis [Harper and Fung, 2007; Lau and Adachi, 2009; Cheung and Seeman, 2010]. Unlike bisphosphonates, teriparatide stimulates bone remodeling, whereas bisphosphonates decrease it. Moreover, teriparatide seems to enhance bone remodeling preferentially in areas of high bone turnover, such as fractures or surgical sites [Tsiridis et al., 2007; Aspenberg et al., 2010]. This seems especially important in NGPS patients, since their bones seem particularly sensitive to physical stimulation. However, current treatment with teriparatide is limited to 2 years, because of evidence from a preclinical study showing a potentially increased risk of osteosarcoma during long-term exposure [Vahle et al., 2002]. Further evaluation of safety and efficacy of therapies based on the use of aminobisphosphonates and/or teriparide for conditions such as NGPS are needed to maximize the possibilities of obtaining beneficial effects from them. Also, as proven for HGPS, the development of mouse models of NGPS would provide invaluable tools to test novel therapeutic approaches to tackle this dramatic disease [Osorio et al., 2009].

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Our patients´ genetic and clinical findings, including marked osteolysis, severe osteoporosis, and generalized lipoatrophy, together with the absence of cardiovascular and metabolic features in their early adulthood, and a relatively long lifespan, are strongly suggestive of a new chronic progeroid disorder, secondary to BANF1 homozygous mutations. Heterozygous BANF1 mutation carriers have a normal phenotype, indicating that a single copy of normal BANF1 is sufficient to avoid the development of this syndrome. NGPS constitutes a model for the study of normal aging manifestations such as bone, cutaneous, or mesenchymal alterations. The knowledge gained with these rare diseases might provide pertinent lessons and treatment strategies for common skeletal conditions, as well as for other aspects of aging. Moreover, a comparison with other “progeroid” syndromes without mutations in LMNA or ZMPSTE24 may identify other cases that have been misclassified with important implications for the clinical management of patients and their families.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

We wish to thank the patients and their families for participating in this study, and especially N.M.O. and G.R.P. for their courage and enthusiasm. The authors thank the staff of the Centro Médico de Asturias for their kind assistance and practical help. This work has been supported by grants from Fundación Centro Médico de Asturias and Fundación María Cristina Masaveu Peterson. C.L.-O. is an Investigator of the Botin Foundation. The Instituto Universitario de Oncología and The Instituto de Medicina Oncológica y Molecular de Asturias are supported by Obra Social Cajastur. The authors declare no conflicts of interest.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. CLINICAL REPORTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES
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