8.11 Progeria syndromes

Progeroid syndrome(s), premature aging syndromes, segmental progeroid syndromes, laminopathies (Lamin A gene mutation syndromes).

Laminopathies are extremely rare disorders. Hutchinson–Gilford progeria syndrome only affects one child per 4.000.000 births worldwide.

The prevalence of atypical Werner syndrome is 0.1-0.2 out of 100.000 live births.

Cutis laxa syndromes are a heterogeneous group of rare (incidence < 1:1,000,000) connective tissue disorders.

Wiedemann–Rautenstrauch syndrome is a newly identified progeroid syndrome with approx. 50 patients described to date.

Werner syndrome is estimated to occur in 0.5-1 out of 100.000 live births worldwide. It has a high prevalence in Japan, where the frequency has been reported to be as high as 2,5-5 in 100.000 live births.

Syndromes characterized by premature aging signs, namely hair loss and alopecia, skin atrophy, sclerotic skin changes, teleangiectasias, poikiloderma and increased prevalence of skin tumors may occur.

Premature aging only affects certain types of tissues in each syndrome.

The majority of progeria syndromes are rare autosomal recessive genetic conditions and show gene defects in DNA replication, recombination, repair and transcription as well as mitochondrial function. Several of these syndromes are laminopathies, namely diseases caused by mutations in components of the nuclear lamina due to Lamin A (LMNA) gene mutations.

• Hutchinson-Gilford progeria syndrome: Its main cause is a sporadic autosomal dominant point mutation

• in LMNA gene resulting in differently spliced lamin A protein known as progerin. Accumulation of progerin under nuclear lamina and activation of its downstream effectors cause perturbation in cellular morphology and physiology which leads to a systemic disorder that mainly impairs the cardiovascular system, bones, skin, and overall growth.

• Restrictive dermopathy: Neonatal lethal disease caused by a LMNA or ZMPSTE24 gene mutation.

• Mandibuloacral dysplasia (types A and B) is caused by a LMNA (type A) or ZMPSTE24 (type B) gene mutation.

• LEMD2-associated progeroid syndrome is caused by a de novo mutation in LEMD2 gene, which encodes the nuclear envelope protein LEM domain-containing protein 2.

• Atypical Werner syndrome: Roughly 20% of patients clinically diagnosed with Werner syndrome do not carry WRN mutations, but harbour mutations in the LMNA gene. 24 such LMNA mutations have been identified to date and these patients are classified as atypical Werner syndrome.

• The Wiedemann–Rautenstrauch syndrome is caused by mutations in the RNA polymerase III subunit A (POLR3A) gene.

• CAV1-associated neonatal progeroid syndrome is caused by a de novo, heterozygous, frame-shift mutation in the Caveolin 1 (CAV1) gene.

• PYCR1-related Cutis laxa syndrome is a pyrrolin-5 carboxylate reductase-1 (PYCR1) gene-related disorder. Werner syndrome is caused by a truncating mutation in the WRN gene due to the production of a stop codon from a nonsense or frameshift mutation. The WRN gene encodes a 142 amino acid protein that is part of the Rec Q DNA helicase family. Its function is to unwind the 2 DNA strands and act as an exonuclease. The WRN gene plays a role in maintaining proper DNA replication and repair through base excision repair, non-homologous end-joining, and homologous recombination. It is also involved in maintaining telomere stability, which is pivotal for genomic stability. Gene expression comparisons of patient skin cells vs skin cells of aged and young healthy donors exhibited a 91% homology, indicating that the defect skin cell function in Werner syndrome is similar with the defect cell function in aged skin. In progeria syndromes, a disturbed ribosomal biogenesis is considered as the major reason for the observed accelerated ageing signs. It is postulated that epigenetic changes to histones can contribute to the pathogenesis of Werner syndrome, but there is not enough data to support this theory.

• The Cockayne syndrome is caused by mutations in either the ERCC8 (type A) or ERCC6 (type B) genes. Néstor-Guillermo progeria syndrome is caused by a Barrier to Autointegration Factor 1 (BNF1) gene mutation.

• The Ruijs–Aalfs syndrome has been associated with mutations in the Spartan (SPRTN) gene. SPRTN encodes the DNA dependent metalloprotease Spartan, which is intimately involved in the repair of protein-linked DNA breaks.

• Lessel-Kubisch syndrome is caused by mutations at the MDM2 gene, which encodes the E3 ubiquitin ligase.

Among the typical signs of premature ageing in progeria syndromes the premature onset of the following symptoms or disorders occur:

• Graying/loss of hair

• Hearing loss

• Cataract

• Scleroderma-like skin changes

• Type 2 diabetes mellitus

• Osteoporosis

• Atherosclerosis and coronary heart disease

• Various malignant tumors

Hutchinson–Gilford progeria syndrome is a systemic disorder that affects the majority of the organs of the body including the skin, bone, skeletal muscle, adipose tissues, heart, and large and small arteries. Certain tissues and organs like bones, joints, and the blood vascular system are more prominently affected. The children affected start exhibiting the symptoms of the disease at the age of 1-2. They present growth reduction, alopecia, loss of hairs of eyebrows and eyelashes, prominent scalp veins, sclerodermatous skin, loss of subcutaneous fat, high pitched voice, horseman stance, protruding ears, lacking ear lobes, reduction in hearing capability, sharp nose, cyanotic face, micrognathia, retarded and aberrant dentition, increased platelet number, prolonged prothrombin time, lean body, absence of puberty, alteration in metabolic pathways, extra-skeletal calcification, short dystrophic clavicles, pyriform thorax, thin legs, and stiff joints. In addition, patients experience angina, hypertension, and hip dislocation. Mental and cognitive abilities of the patients remain unaffected.

Restrictive dermopathy is a very severe lethal neonatal disease characterized by tightly adherent and translucent skin, dermal thinning, disorganized collagen fibers and an almost complete loss of elastic fibers in the dermis. The first signs appear during gestation and include severe intrauterine growth defects, reduced fetal movement and pre-term delivery.

Mandibuloacral dysplasia type A: Onset 4-5 years after birth, partial lipodystrophy, thin and rigid skin, aberrant skin pigmentation, bone and growth defects, insulin resistance.

Mandibuloacral dysplasia type B: Onset at 2 years of age, lipodystrophy, altered skin pigmentation, alopecia, severe bone and growth defects, insulin resistance.

Patients with atypical Werner syndrome exhibit a late onset at mid to late 30’s, occurring with sclerotic skin, hair greying and alopecia, loss of subcutaneous fat, altered skin pigmentation, cardiovascular disease.

The Wiedemann–Rautenstrauch syndrome patients show prenatal growth retardation, resulting in reduced weight and length at birth. Typical clinical features include sparse hair, prominent scalp veins, triangular shape of face, sunken eyes, microstomia with maxillary hypoplasia, natal teeth, and a prominent chin. Perinatal respiratory problems are common among these patients.

CAV1-associated neonatal progeroid syndrome patients present lipodystrophy, pulmonary hypertension, cutis marmorata, feeding disorder and failure to thrive.

Clinical signs of PYRC1-related cutis laxa syndrome patients that typically manifest in the first 2 years after birth include osteopenia or osteoporosis, finger contractures, cataract, corneal opacity, and movement disorders. Significant progression of these signs is rare in children older than 2 years of age. Patients typically show prenatal growth retardation. In addition, many patients present with poor sucking ability, sparse hair, thin and transparent skin with prominent veins, mandibular hypoplasia, and lipodystrophy.

Patients with Werner syndrome develop skin ulcers, cataracts, graying or even loss of their hair, and hypogonadism. The loss of subcutaneous fat and dermal atrophy produces a scleroderma- like appearance. They typically have a bird-like face with short stature, high pitched voice, dental abnormalities, decreased body weight, and body mass index (BMI). Patients also experience a rapid loss of muscle mass, most notably in the limbs with sparing of the trunk. They also have a decrease in their grip strength and skeletal muscle index, reaching the level of sarcopenia before the age of 40.

They have impaired mobility and suffer from osteoporosis of the distal limb bones more so than the vertebral column. Soft tissue calcifications can occur, most commonly in the Achilles tendon. Pes planus, hallux valgus, and flexion contractures can occur in the feet with subsequent development of ulceration, osteitis, and osteomyelitis. Metabolic abnormalities also occur, including the development of type 2 diabetes mellitus and an increase in visceral fat accumulation. Cardiovascular abnormalities develop as well, which can include atherosclerosis, mitral regurgitation, and aortic stenosis. Werner syndrome patients are at an increased risk of tumor formation, with up to 10% of patients developing a malignancy. However, the types of tumors that develop are unusual compared to the aging population. Up to 50% of the malignancies reported are soft tissue sarcomas, such as schwannoma, rhabdomyosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and osteosarcoma of the upper extremities. Patients have also been reported to develop meningiomas, malignant melanoma, and thyroid carcinomas.

Myotonic dystrophy type 1 is a progressive multisystem disorder, which typically manifests no earlier than about the age of 20 years and is primarily characterized by muscular dystrophy. Although there is a very rare congenital form—characterized by muscular hypotonia and very poor sucking ability, global developmental delay (frequently associated with respiratory insufficiency) are the first clinical signs. The Cockayne syndrome causes short stature, premature ageing, severe photosensitivity and moderate to severe learning delay. This syndrome also includes failure to thrive in the newborn, microcephaly and impaired nervous system development. Other symptoms may include hearing loss, tooth decay, vision problems, and bone abnormalities. There are three subtypes according to the severity of the disease and the onset of the symptoms: Cockayne syndrome type 1 (type A), sometimes called “classic” or “moderate” Cockayne syndrome, diagnosed during early childhood; Cockayne syndrome type 2 (type B), sometimes referred to as the “severe” or “early-onset” type, presenting with growth and developmental abnormalities at birth; Cockayne syndrome type 3 (type C), a milder form of the disorder.

Néstor-Guillermo progeria syndrome: Onset at 2 years of age, altered skin pigmentation, lipodystrophy, growth and severe bone defects, alopecia. Lack of cardiovascular complications.

The main features of Ruijs–Aalfs syndrome are evident in skeleton and face (triangular face). Patients develop hepatoma in the teens.

Lessel-Kubisch syndrome is characterized by short stature and progeroid features, including prematurely gray hair, pinched facies, and scleroderma-like skin changes. Renal failure-associated hypertension and hypogonadism have also been observed.

More than 100 syndromes with clinical signs of premature aging have so far been described in the scientific literature, but only in recent years the genetic defects causing these syndromes have been identified by analyses performed on very few patients, using high-throughput sequencing (next- generation sequencing). The list of the most prominent progeria syndromes includes:

A. Congenital progeroid syndromes

I. Laminopathies

• Hutchinson-Gilford progeria syndrome (commonly called progeria)

• Restrictive dermopathy

• Mandibuloacral dysplasia

• LEMD2-associated progeroid syndrome

• Atypical Werner syndrome (atypical progeroid syndrome)

II. Other progeroid syndromes

• Wiedemann–Rautenstrauch syndrome (neonatal progeroid syndrome)

• CAV1-associated neonatal progeroid syndrome

• PYCR1-related Cutis laxa syndrome

B. Juvenile/adult progeroid syndromes

• Werner syndrome (adult progeria)

• Myotonic dystrophy type 1

• Cockayne syndrome

• Néstor–Guillermo syndrome

• Ruijs–Aalfs syndrome

• Lessel-Kubisch syndrome (MDM2-associated progeroid syndrome)

Genetic testing: multigene panel that includes LMNA, ZMPSTE24, and other genes of interest. Patients diagnosed with Werner syndrome should undergo regular screening tests for hyperlipidemia, breast and colorectal cancer, diabetes, and thyroid abnormalities. Given the number of musculoskeletal abnormalities and high prevalence of soft tissue sarcomas in Werner syndrome patients, clinicians should perform an X-ray, CT, or MRI studies in the appropriate clinical scenario to evaluate for underlying disorders, infections or tumors thoroughly. DEXA scans should also be performed regularly to evaluate and monitor osteoporosis.

A common characteristic among laminopathies is that many are caused by an accumulation of unprocessed pre-lamin A. Skin biopsies from patients carrying LMNA or ZMPSTE24 mutations reveal increased nuclear size and an atrophic epidermis with focal hyperkeratosis and hypoplastic sebaceous glands. Patient cells exhibit nuclear abnormalities that become worse with extended in vitro culture and a mislocalization of other lamina-associated proteins.

Hutchinson-Gilford progeria syndrome is characterized by accelerated ageing in affected children leading to premature death at an average age of 14.5 years due to cardiovascular complications.

Wiedemann–Rautenstrauch syndrome: The further course of the disease is characterized by growth delays, thin and atrophic skin, generalized lipodystrophy with local fat pads, joint contractures, progressive ataxia and tremor, as well as a global developmental delay. Clinical signs of premature ageing include thin and atrophic skin, progressive ataxia and tremor, as well as lipodystrophy with associated cachectic appearance. The life expectancy in patients with Wiedemann–Rautenstrauch syndrome is not yet known, but it is likely to be strongly associated with the severity of perinatal respiratory problems.

Patients with PYRC1-related cutis laxa syndrome may show with increasing age a global developmental delay (in some cases with cerebral malformations) with mild to moderate intellectual dis ability, microcephaly, and muscular hypotonia. In addition, characteristics of wrinkled, redundant and inelastic skin may become prevalent, resulting in a progeroid appearance. The life expectancy remains unknown to date.

Werner syndrome patients appear unaffected at birth and develop normally until the adolescent period or second decade of life when they start to exhibit signs and symptoms of accelerated aging. Patients develop skin ulcers, cataracts, graying or even loss of their hair, and hypogonadism. The loss of subcutaneous fat and dermal atrophy produces a scleroderma-like appearance. They typically have a bird-like face with short stature, high pitched voice, dental abnormalities, decreased body weight, and body mass index (BMI).

Werner syndrome patients typically live into the fifth decade of life. Patients usually die of malignancy or cardiovascular disease.

Patients with myotonic dystrophy type 1 may additionally develop primarily frontal alopecia, cataract, sensorineural hearing loss, dysarthria and dysphagia, cardiac arrhythmia, hypogonadism, type 2 diabetes, and hypothyroidism. The average life expectation is 48 to 55 years.

Néstor-Guillermo progeria syndrome progresses more slowly, patients do not exhibit cardiovascular complications and have a relatively longer lifespan.

Classic Hutchinson-Gilford progeria syndrome is identified on the basis of clinical symptoms and the medical history of the patient. Also, its presence can be confirmed by genetic testing for the mutation (c.1824C>T) in the Lamin A gene. However, there is no kit available for its early detection. Atypical Hutchinson-Gilford progeria syndrome is diagnosed on the basis of clinical features similar to the classic syndrome, resulting from a mutation in intron 11 (c.1968+1G>A, c.1968+2T>A, c.1968+2T>C, and c.1968+5G>C) of Lamin A gene. It can also be identified on the basis of c.1822G>A (p. Gly608Ser) variation in exon 11 of the Lamin A gene.

Werner syndrome: Genetic testing through nuclear sequencing by reverse transcription-polymerase chain reaction (PCR) with western blot protein analysis can confirm the diagnosis of Werner syndrome. Prenatal testing with amniocentesis and chorionic villus sampling can be performed in patients at high risk for having infants with this disorder

• Hutchinson-Gilford progeria syndrome: No cure has been found for this catastrophic disorder. In several clinical studies, lonafarnib, a farnesyl transferase inhibitor, demonstrated remarkable improvement in weight gain, vascular architecture and bone structure along with a decreased frequency of headaches and strokes; improvement in the life span; improvement in bone mineral density (in combination with pravastatin and zoledronic acid); and reduction of the prevalence of stroke, transitoric ischemic attacks and headache.

• Werner syndrome: Treatment is aimed at symptomatic relief and control of the secondary organ dysfunction. Treatment of atherosclerosis, hypertension, diabetes, and other diseases is achieved through standard conventional monitoring and medical therapy, but the disorder will continue to progress. It has been reported that bosentan, an endothelin receptor antagonist, can be used to treat severe cutaneous ulcers. Sodium etidronate can help improve symptomatic calcifications in the soft tissue. Orthotics can be used to manage complications with feet deformities. Cataracts should be managed surgically. Sarcopenia can be treated with diets rich in branched amino acids, exercise, vitamin D supplementation, and hormone therapy, although this is controversial given the increased risk of malignancy.

• Cockayne syndrome: Treatment is supportive and may include educational programs for developmental delay, physical therapy, gastrostomy tube placement as needed; medications for spasticity and tremor as needed; use of sunscreens and sunglasses; treatment of hearing loss and cataracts; and other forms of treatment, as needed.