2.1.1 Hutchinson-Gilford Progeria Syndrome (MIM #176670)

HGPS is an early-onset premature aging disorder that occurs approximately in 1:4 to 8 million live births and has been reported in more than 140 cases worldwide.⁹ After normal appearance and development at birth, the main clinical features become obvious in the first 1 to 2 years of life and include severe growth retardation, lipodystrophy, scleroderma, prominent eyes and scalp veins, joint contractures and osteolysis. Its typical facial appearance is caused by progressive hair loss, prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears. Cognitive function is reported as normal.^{9, 38} Patients die at a mean age of 12.6 years⁹ mostly due to progressive atherosclerosis and cardiovascular diseases.^{38, 39} HGPS is predominantly caused by a specific de novo heterozygous silent mutation in the LMNA gene c.1824C>T (p.Gly608Gly).^{10, 11}

2.1.2 Mandibuloacral Dysplasia (MIM #248370, #608612)

Mandibuloacral dysplasia is an autosomal recessive progeroid syndrome that has been reported in approximately 50 molecularly confirmed cases worldwide.^{40, 41} Typical clinical signs encompass mandibular hypoplasia and progressive osteolysis of clavicles and distal phalanges, which are recognizable as retrognathia, sloping shoulders, bulbous finger and toe tips. Further clinical manifestations include postnatal growth retardation, dental anomalies, joint contractures, mottled skin pigmentation, insulin resistance, lipodystrophy, and absent or sparse hair.^{31, 33} Mandibuloacral dysplasia can be divided into two subtypes: type A is caused by biallelic missense mutations in LMNA and is associated with an onset in early childhood (mean age 4-5 years), and a partial lipodystrophy at torso and limbs. In contrast, type B is due to biallelic mutations in ZMPSTE24 (encoding the protease that cleaves prelamin A at the C-terminal end) mainly with a null mutation on one allele and a missense mutation on the other allele. Clinically, individuals with type B exhibit an earlier onset (mean age 2 years), a more severe phenotype and a general lipodystrophy.^{31, 33, 35} In addition, an autosomal dominant form of mandibuloacral dysplasia has been described in fewer than 25 patients.⁴² Featuring mandibular hypoplasia, deafness, progeroid appearance, and generalized lipodystrophy, it is termed MDPL syndrome (MIM #615381) and caused by de novo missense mutations or the recurrent in-frame deletion (p.Ser605del) in POLD1.^{43, 44} POLD1 encodes the catalytic subunit of DNA polymerase delta, which is involved in DNA synthesis during replication.³¹

2.1.3 Nestor-Guillermo Progeria Syndrome (MIM #614008)

Nestor-Guillermo progeria syndrome has so far been described only in two unrelated patients. It shares phenotypic features with HGPS including facial progeroid appearance, growth retardation, generalized lipodystrophy, and joint contractures. However, both patients do not suffer from cognitive involvement, atherosclerosis or metabolic complications until their early adulthood and show a slow clinical course and a relatively long lifespan. Characteristically, they exhibit severe osteoporosis and marked osteolysis.^{37, 45} Exome sequencing identified in both patients a homozygous point mutation (c.34G>A; p.Ala12Thr) in BANF1, which encodes the BAF protein.³⁷ The mutation reduces the ability of BAF to bind DNA, leading to the disruption of the nuclear envelope, which contributes to the cellular phenotype of Nestor-Guillermo progeria syndrome.⁴⁶

2.1.4 Restrictive Dermopathy (MIM #275210)

Restrictive dermopathy is a severe congenital genodermatosis with approximately 80 cases reported worldwide, which is lethal mostly within the first weeks of life. Main clinical features are thin, tightly adherent translucent skin with erosions at flexure sites, prominent vessels, characteristic facial dysmorphism, generalized joint contractures, dysplasia of clavicles, and respiratory insufficiency. Prenatally, intrauterine growth retardation, fetal hypokinesia, and polyhydramnios can be observed.^{34, 47, 48} In most cases, compound heterozygous or homozygous null mutations in the ZMPSTE24 gene are causative of restrictive dermopathy. Less frequently, autosomal dominant mutations in the LMNA gene are causative of restrictive dermopathy, leading to a truncated prelamin A protein, which cannot undergo full posttranslational maturation and accumulates inside the nucleus. Mutations in both genes, thereby, induce nuclear structural and functional alterations.³⁴

2.2.1 Ataxia-Telangiectasia (MIM #208900)

Ataxia-telangiectasia is an autosomal recessive neurodegenerative disorder with the mostly early-childhood onset and an estimated prevalence of 1:40 000-1:100 000 live births.⁶⁷ Apart from premature aging signs, characteristic clinical features include progressive cerebellar ataxia, oculomotor apraxia, oculocutaneous telangiectasia, immunodeficiency, recurrent infections, and hypersensitivity to radiation with increased risk for malignancy (especially leukemia and lymphoma).^{67, 68} Patients can also present with endocrine abnormalities such as growth retardation, reproductive dysfunction, and diabetes.⁶⁹ Ataxia-telangiectasia is due to biallelic mutations in ATM (ataxia-telangiectasia mutated), which are mainly truncations.^{70, 71} ATM encodes a serine/threonine kinase that is a member of the phosphatidylinositol 3-kinase family of proteins^{72, 73} and is known to have an essential function in cell cycle progression, DDR, and telomere maintenance.^{74, 75}

2.2.2 Bloom Syndrome (MIM #210900)

Bloom syndrome is a rare “chromosomal breakage syndrome” with approximately 300 affected individuals documented in the Bloom Syndrome Registry.^{76, 77} Patients typically present with an erythematous rash in a butterfly distribution across the nose and cheeks in the first years of life that is exacerbated by sun exposure and spreads on the dorsum of hands and forearms.⁷⁸ Further clinical features comprise pre- and postnatal growth deficiency, microcephaly, facial dysmorphism, high-pitched voice, predisposition to a wide range of malignancies, immunodeficiency, premature menopause in females and azoospermia or oligozoospermia in males, type 2 diabetes mellitus, and gastroesophageal reflux.^79-81 A characteristic diagnostic pattern of Bloom syndrome is an increased number of sister chromatid exchanges and anaphase bridges visible on cytogenetic testing.⁵⁴ Bloom syndrome is caused by biallelic loss-of-function mutations in the BLM (RECQL3) gene, encoding DNA helicase of the RecQ family, which plays a key role in the maintenance of genomic stability and DNA replication.^81-83 About 1% of the Eastern European Jewish population carries the common founder mutation termed blm^Ash, which is associated with a higher prevalence of about 1:48 000 in this population. In addition, further recurrent founder mutations are known from other populations.⁷⁸ Recently, biallelic mutations in TOP3A, RMI1, and RMI2 genes have been identified in a few patients to cause a clinical phenotype that overlaps with Bloom syndrome and is accompanied by an elevated number of sister chromatid exchanges on cytogenetic analysis.^{84, 85} Although multiple café-au-lait patches were observed, the classical erythematous facial rash and malignancies have so far not been reported in patients with TOP3A, RMI1, and RMI2 mutations. Considering that none of these patients reached adulthood, a cancer predisposition remains uncertain.^{84, 85} Together with BLM protein, topoisomerase III alpha (encoded by TOP3A) and RecQ-mediated genome instability proteins 1 and 2 (encoded by RMI1 and RMI2, respectively) form the BTR complex, which contributes to the resolution of double Holliday junctions generated during HR.^85-88

2.2.3 Cockayne Syndrome (MIM #133540, #216400)

Cockayne syndrome is a rare developmental and neurodegenerative disorder with more than 120 genetically confirmed patients worldwide.⁸⁹ The annual incidence is estimated at approximately 1:250 000 and the prevalence at approximately 2.5 per million.⁹⁰ The typical phenotype is characterized by cachectic dwarfism with sunken eyes and progressive microcephaly with structural brain anomalies, severe developmental delay and mental retardation. The clinical spectrum also includes cutaneous photosensitivity, pigmentary retinopathy, cataracts, sensorineural hearing loss, atherosclerosis, feeding difficulties, and dental anomalies. Most patients die from progressive multiorgan degeneration in the first or second decade with a mean age of death of 12 years.^{90, 91} Two genes have been identified to be mainly associated with the disease in an autosomal recessive inheritance pattern: Cockayne syndrome type A is linked to mutations in ERCC8 (one-third of the patients) and Cockayne syndrome type B to mutations in ERCC6 (two-thirds of the patients).⁸⁹ The majority of the mutations are truncating, but missense substitutions are also reported. Both genes encode components involved in the NER of UV-induced and oxidative DNA damage and play a role in mitochondrial DNA metabolism and neuronal differentiation.⁹² Pathogenic mutations in ERCC6 are also known to cause cerebrooculofacioskeletal syndrome (MIM #214150), De Sanctis-Cacchione syndrome (MIM #278800), UV-sensitive syndrome (MIM #600630) and premature ovarian failure (MIM #616946).

2.2.4 Dyskeratosis Congenita and Hoyeraal-Hreidarsson Syndrome (MIM #127550, #224230, #305000, #613987, #613988, #613989, #613990, #615190, #616353, #616553)

Dyskeratosis congenita is a “telomere shortening disorder” with more than 500 cases reported in the literature⁹³ and an estimated prevalence of approximately 1 per million.⁹⁴ The typical mucocutaneous triad comprises reticular skin pigmentation of the upper chest and neck, nail dystrophy and oral leukoplakia. Patients have also an increased risk for bone marrow failure, squamous cell carcinoma, hematolymphoid neoplasms, pulmonary fibrosis, and hepatic complications such as liver fibrosis and cirrhosis.^{95, 96} Mutations in 11 genes encoding telomerase and telomere components have so far been described in patients with dyskeratosis congenita, which can be inherited in an X-linked, autosomal dominant, or autosomal recessive pattern. However, in approximately 30% to 40% of the patients who meet the diagnostic criteria for dyskeratosis congenita, the molecular cause cannot be identified in the known dyskeratosis congenita-associated genes.^{95, 97} Hoyeraal-Hreidarsson syndrome is a clinically severe variant of dyskeratosis congenita with additional clinical features such as cerebellar hypoplasia, prenatal growth retardation, severe immunodeficiency and developmental delay.⁹⁸ Mutations in the RTEL1 gene, encoding an essential helicase for telomere maintenance and DNA repair,⁹⁹ and the ACD gene, encoding the shelterin TPP1 protein,¹⁰⁰ have been identified to cause Hoyeraal-Hreidarsson syndrome. Patients with dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome show premature telomere shortening, which might be associated with premature stem cell exhaustion and cancer predisposition.^{99, 101}

2.2.5 Microcephalic Osteodysplastic Primordial Dwarfism Type II (MIM #210720) and Seckel Syndrome (MIM #210600, #606744, #613676, #613823, #614728, #614851, #615807, #616777, #617253)

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is one of the most common disorders characterized by severe pre- and postnatal growth retardation and microcephaly with large clinical overlap to the heterogeneous group of Seckel syndrome. More than 150 MOPDII cases have been described in the literature worldwide.^{102, 103} Characteristic facial features comprise sloping forehead, prominent nose, downslanting palpebral fissures, mild dysplastic ears and micrognathia.¹⁰³ In addition, MOPDII patients exhibit typical skeletal dysplasia, dental anomalies, insulin resistance, variable mental retardation, and cerebrovascular and neurological manifestations.¹⁰² MOPDII is caused by biallelic truncating mutations in PCNT,¹⁰⁴ whereas biallelic mutations in ATR,¹⁰⁵ ATRIP,¹⁰⁶ CDK5RAP2,¹⁰⁷ CENPJ,¹⁰⁸ CEP63,¹⁰⁹ CEP152,¹¹⁰ DNA2,¹¹¹ NIN,¹¹² NSMCE2,¹¹³ PLK4,^{114, 115} RBBP8,¹¹⁶ and TRAIP¹¹⁷ have been identified in patients reported as Seckel syndrome. All these genes are predominantly involved in maintaining genomic stability and DDR.

2.2.6 Nijmegen Breakage Syndrome (MIM #251260)

Nijmegen breakage syndrome is an autosomal recessive chromosomal instability syndrome with an overall prevalence estimated at 1:100 000, whereas it is more common in Eastern Europe with an estimated carrier frequency of 1:177 in Slav populations.^{118, 119} The phenotype typically encompasses progressive microcephaly, pre- and postnatal growth retardation, immunodeficiency with recurrent infections, and predisposition to cancer, specifically mainly non-Hodgkin lymphoma, but also medulloblastoma, glioma, and rhabdomyosarcoma. A distinct craniofacial dysmorphism includes sloping forehead, upslanted palpebral fissures, prominent midface, large dysplastic ears, and retrognathia. After normal development in the first years of life, most patients exhibit developmental decline and mild to moderate mental retardation. Other clinical features involve skin abnormalities, hip dysplasia, brain malformations, hydronephrosis, anal atresia, and premature ovarian failure.¹²⁰ Cytogenetic analysis of peripheral blood lymphocytes reveals multiple spontaneous rearrangements mainly involving chromosome 7 and 14.^{121, 122} Nijmegen breakage syndrome is caused by biallelic loss-of-function mutations in NBN with the majority of patients carrying the founder mutation c.657_661del5 (p.Lys219Asnfs). NBN is coding for nibrin, which interacts with ATM in DDR and DNA repair.¹¹⁸

2.2.7 Rahman Syndrome (MIM #617537)

Rahman syndrome, also called HIST1H1E syndrome, has been very recently described in about 45 cases with a moderate to severe intellectual disability phenotype and a distinct facial gestalt characterized by a high frontal hair line, frontal bossing, bitemporal narrowing and deep-set eyes. Notably, patients also exhibited a characteristic overgrowth during infancy, which was no longer observable in adulthood. Further clinical manifestations of Rahman syndrome encompass behavioral problems, hypotonia, abnormal dentition, cardiac and skeletal anomalies, hypothyroidism, cryptorchidism, and corpus callosum abnormalities.^123-125 Rahman syndrome is caused by protein-truncating variants in HIST1H1E, encoding the widely expressed human linker histone H1.4. All variants described so far cluster to a 94-bp region in the C-terminal end of HIST1H1E, resulting in a frameshift of translation and a truncated protein.¹²⁵ The aberrant protein binds to chromatin in the nucleus and disrupts the compaction of DNA, which contributes to a reduced proliferation rate and an accelerated senescence of the affected cells and is also associated with a specific hypomethylation signature profile.^{124, 126}

2.2.8 Rothmund-Thomson Syndrome (MIM #268400, #618625)

Rothmund-Thomson syndrome manifests typically by a sun-sensitive erythema of the face at the mean age of 3 to 6 months, which spreads over time and develops into chronic reticulated pigmentation, telangiectases and areas of punctate atrophy known as poikiloderma.¹²⁷ Additional clinical features of Rothmund-Thomson syndrome include short stature, sparse hair, increased risk for malignancies (eg, osteosarcomas and skin cancers), juvenile cataracts, and skeletal, dental, and nail abnormalities.^{128, 129} Rothmund-Thomson syndrome is subdivided into two different types. The majority of more than 300 reported cases belong to Rothmund-Thomson syndrome type 2, which is due to biallelic truncating and missense mutations in RECQL4 gene^130-132 and is associated more often with increased cancer risk and skeletal anomalies.¹³³ RECQL4 is coding for a DNA helicase of the RecQ family and is linked to genomic instability, carcinogenesis and aging processes.¹³⁴ Biallelic mutations in RECQL4 have also been identified in patients with Rapadilino syndrome (MIM #266280) and Baller-Gerold syndrome (MIM #218600),¹³⁵ which share clinical features with Rothmund-Thomson syndrome such as growth retardation, skeletal anomalies and increased cancer risk.¹³³ Recently, biallelic mutations in the ANAPC1 gene were described as cause of Rothmund-Thomson syndrome type 1, which is characterized by the presence of juvenile cataracts. All 10 patients reported so far exhibit a deep intronic splicing mutation in ANAPC1 either in homozygous state or compound heterozygous with another truncating mutation.¹³³ ANAPC1 belongs to an anaphase-promoting complex/cyclosome that is known to be involved in DNA replication and repair, cell differentiation, cell senescence metabolism and neuronal function.¹³⁶

2.2.9 Ruijs-Aalfs Syndrome (MIM #616200)

Until now, only three patients from two unrelated families have been described with Ruijs-Aalfs syndrome, who presented with hepatocellular carcinoma at an early age as well as low body weight, muscular atrophy, lipodystrophy, delayed bone age and mild joint restrictions. One patient also showed short stature, bilateral cataracts and premature hair graying.^{137, 138} By genome-wide linkage analysis and exome sequencing biallelic mutations in the SPRTN gene have been identified. One patient carried a homozygous 1-bp deletion, whereas the two affected brothers were compound heterozygous for a splice site mutation and a missense mutation.¹³⁷ SPRTN encodes the DNA-dependent metalloprotease spartan, which contributes to the repair of DNA-protein crosslinks.^{139, 140}

2.2.10 Werner Syndrome (MIM #277700)

Werner syndrome is the most common premature aging disorder of adult onset. More than 350 confirmed cases are enrolled in the International Registry of Werner Syndrome and the Japanese Werner Consortium.^{141, 142} The overall prevalence is estimated at 1:380 000-1:1 000 000, whereas the prevalence is as high as 1:20 000-1:40 000 in Japan and 1:50 000 in Sardinia due to founder variants.¹⁴³ The clinical phenotype is characterized by normal development until adolescence, followed by growth failure during the early teen years as a first sign, which is often recognized retrospectively as short stature in adulthood. Further cardinal signs beginning in the early third decade of life encompass bilateral cataracts, premature graying and thinning of hair, and characteristic dermatologic changes such as tight and atrophic skin, pigmentary alterations, ulceration, hyperkeratosis, and regional subcutaneous atrophy. Patients also show characteristic pinched facial features, a high-pitched voice, and age-related disorders including type 2 diabetes mellitus, hypogonadism, osteoporosis, atherosclerosis, and malignancies.¹⁴⁴ Life expectancy is reduced to a mean age of 54 years.¹⁴⁵ Werner syndrome is due to homozygous or compound heterozygous loss-of-function mutations in the WRN (RECQL2) gene, which is member of the RecQ helicase family and contributes to DNA repair, replication, transcription as well as maintenance of telomere and genomic stability.^{144, 146}

2.2.11 Wiedemann-Rautenstrauch Syndrome (MIM #264090)

Wiedemann-Rautenstrauch syndrome is a well-known neonatal progeroid disorder. Reviewing literature core features have been defined in a group of 18 reliably diagnosed patients¹⁴⁷: severe pre- and postnatal growth retardation, dental anomalies with neonatal teeth as well as distinctive facial dysmorphism involving sparse scalp hair, prominent scalp veins, triangular face, low-set eyeballs and a small mouth. Specific for the clinical diagnosis is a generalized lipodystrophy with local fatty tissue accumulations. Exome sequencing identified specific combinations of biallelic splicing or truncating mutations in POLR3A as molecular cause of Wiedemann-Rautenstrauch syndrome.^147-150 POLR3A encodes a subunit of the DNA-dependent RNA polymerase III. Autosomal recessive loss-of-function mutations in POLR3A are already known to be associated with 4H leukodystrophy syndrome (MIM #607694)¹⁵¹ and autosomal recessive adolescent-onset progressive spastic ataxia.¹⁵² As the main clinical features of 4H leukodystrophy syndrome are hypomyelination, hypodontia and hypogonadotrophic hypogonadism,¹⁵³ there are major differences to Wiedemann-Rautenstrauch syndrome but also same overlaps as, for example, hypomyelination has been reported in patients with Wiedemann-Rautenstrauch syndrome before.^{147, 154}

Recently, a patient with a neonatal progeroid phenotype characterized by severe pre- and postnatal growth retardation, facial dysmorphism, finger contractures, axial hypotonia, heart anomalies and early eruption of two teeth has been reported. In contrast to almost all patients with Wiedemann-Rautenstrauch syndrome, neither lipodystrophy nor fatty tissue accumulations were observed. Therefore, the phenotype is clinically not regarded as Wiedemann-Rautenstrauch syndrome. Exome sequencing detected a homozygous loss-of-function mutation in POLR3GL, which is also coding for a subunit of DNA-dependent RNA polymerase III.¹⁵⁵ In addition, biallelic POLR3GL mutations leading to aberrant splicing were described in three patients with endosteal hyperostosis, oligodontia, short stature and mild facial dysmorphism.¹⁵⁶

2.2.12 Xeroderma Pigmentosum (MIM #278700, #278720, #278730, #278740, #278750, #278760, #278780, #610651)

Xeroderma pigmentosum is an autosomal recessive disorder associated with impaired NER of ultraviolet-induced DNA lesions. More than 1000 cases have been described worldwide with variable incidences, ranging from 2.3 per million in Western Europe to 1 per million in the United States, and about 45 per million in Japan.^{157, 158} About 60% of the patients present with increased sun sensitivity such as dermatitis solaris in the first weeks of life, whereas early hyperpigmentation in sun-exposed areas is typically observed in nearly all patients. Further phenotypic features include premature aging of the skin, poikiloderma, ocular changes as well as basal cell and squamous epithelial cell carcinoma and cutaneous melanoma within the first decade of life.^{159, 160} Additional neurological symptoms can be observed in about 25% of the patients including diminished or absent tendon reflexes, progressive sensorineural hearing loss, speech and gait disturbances, acquired microcephaly, and cognitive impairment.^{160, 161} Biallelic mutations in DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, and XPC have been identified to be causative of xeroderma pigmentosum, leading to varying severity of tumor development and neurological degeneration.¹⁶⁰

2.3.1 Fontaine Progeroid Syndrome (MIM #612289)

Fontaine syndrome and Gorlin-Chaudhry-Moss syndrome are two overlapping phenotypes that have been recently summarized as Fontaine progeroid syndrome with overall 11 genetically confirmed cases reported in the literature.^{6, 190, 191, 194} The two entities share main clinical features such as pre- and postnatal growth retardation, skin wrinkling, lipodystrophy, and small distal phalanges of the fingers and toes. The typical triangular facial appearance is characterized by microphthalmia, midface hypoplasia, narrow forehead, depressed nasal bridge, and low hairline. Furthermore, Fontaine progeroid syndrome is associated with coronal craniosynostosis, cardiovascular abnormalities, hypertrichosis, hypoplastic external genitalia, and umbilical hernia.¹⁹⁰ Patients with Fontaine syndrome mostly die within the first year of life,⁶ whereas Gorlin-Chaudhry-Moss syndrome is associated with a milder phenotype and slower disease progression.¹⁹¹ Exome sequencing identified specific de novo missense mutations in SLC25A24, a member of the solute carrier 25 family coding for the calcium-binding mitochondrial carrier protein SCaMC-1, as the genetic cause of both entities of Fontaine progeroid syndrome; all variants described so far result in an exchange of arginine at position 217.^{6, 190, 191} SLC25A24-mutant fibroblasts from affected patients show mitochondrial swelling, impaired mitochondrial ATP synthesis and increased mitochondrial membrane potential, suggesting that mitochondrial dysfunction is involved in the pathomechanism of Fontaine progeroid syndrome.^{6, 191}

2.3.2 Progeroid Cutis Laxa Syndromes (MIM #219150, #219200, #231070, #612940, #614438, #617402, #617403, #618000)

Cutis laxa, loose, hypoelastic, and wrinkled skin, is a hallmark of a heterogeneous group of conditions that can be inherited in an autosomal dominant, autosomal recessive or X-linked manner and is usually associated with additional multisystemic manifestations.¹⁹⁵ Progeroid cutis laxa phenotypes have been described in more than hundred cases with autosomal recessive cutis laxa IIB (ARCL2B MIM #612940), De Barsy syndrome (ARCL3A MIM #219150, ARCL3B MIM #614438) and gerodermia osteodysplastica (MIM #231070) being the most common forms. In addition, progeroid cutis laxa features were also reported in patients with autosomal recessive cutis laxa IIA (ARCL2A MIM #219200), autosomal recessive cutis laxa IIC (ARCL2C MIM #617402), autosomal recessive cutis laxa IID (ARCL2D MIM #617403) as well as Ehlers-Danlos syndrome classic-like 2 (MIM #618000).

ARCL2B is characterized by prenatal growth retardation, skin wrinkling limited to the dorsum of hands and feet, visible veins on the chest, and mental retardation. Affected patients additionally present with microcephaly, triangular face, blue sclerae, cataract, hypotonia, brain anomalies, and skeletal anomalies.^{185, 195, 196} ARCL2B is caused by biallelic mutations in PYCR1 which are predominantly missense or splice site mutations clustering in exons 4 to 6.¹⁸⁵ PYCR1 encodes for the mitochondrial protein pyrroline-5-carboxylate reductase 1 which is involved in proline de novo biosynthesis.¹⁹⁷

The De Barsy syndrome is classified as autosomal recessive cutis laxa type III (ARCL3) and shares many clinical features with ARCL2B, albeit in a more severe form, especially growth retardation, hypotonia, mental retardation, and movement disorders.^{186, 196, 198} In addition, corneal dystrophy is a distinguishing hallmark. De Barsy syndrome is divided into two subtypes: ARCL3A is due to biallelic mutations in ALDH18A1,^{186, 199} whereas ARCL3B is caused by biallelic mutations in PYCR1.¹⁸⁵ ALDH18A1 encodes the mitochondrial protein pyrroline-5-carboxylate synthase (P5CS), which catalyzes the synthesis of pyrroline-5-carboxylate, the substrate of pyrroline-5-carboxylate reductase 1.²⁰⁰

Gerodermia osteodysplastica represents a milder progeroid cutis laxa phenotype. Characteristic hallmarks include skin wrinkling at the abdomen, and the dorsum of hands and feet, but neither skin translucency nor mental retardation. Maxillary hypoplasia and sagging cheeks give a typical facial appearance. Clinically most relevant is a congenital or juvenile osteoporosis leading to frequent vertebral and peripheral fractures.^201-203 Gerodermia osteodysplastica is due to biallelic loss-of-function mutations in GORAB coding for SCY1-like 1 binding protein 1 (also called NTKL-binding protein 1), which is localized at the Golgi apparatus and involved in retrograde trafficking and glycosylation processes.^180-183 Biallelic mutations in PYCR1 have also been identified in individuals initially classified as gerodermia osteodysplastica indicating the clinical overlap of progeroid cutis laxa syndromes.^{185, 195}

While over 50 patients with ARCL2A have been documented, ARCL2C and ARCL2D have been described in only 10 patients sharing cutis laxa, lipodystrophy, progeroid facial dysmorphism, hypotonia, joint contractures, congenital hip dysplasia and cardiopulmonary manifestations. All three genes encode subunits of the V-ATPase complex involved in ion and pH homeostasis in different intracellular compartments with large effects on the Golgi apparatus.^{188, 204, 205}

Moreover, four individuals from three unrelated families with Ehlers-Danlos syndrome classic-like 2 phenotype (MIM #618000) were reported in the literature featuring cutis laxa, hyperextensible joints, severe osteopenia, progeroid skin changes, delayed wound healing with atrophic scarring, and characteristic facial dysmorphism including sagged face, bilateral ptosis and large ears. Further clinical signs include gastrointestinal and genitourinary manifestations, vascular abnormalities, and skeletal deformities. Exome sequencing revealed in all affected individuals biallelic truncating mutations in AEBP1.^{204, 206} The encoded aortic carboxypeptidase-like protein (ACLP) is also associated with the extracellular matrix and plays a significant role in tissue repair mechanisms.²⁰⁶

2.4.1 GAPO Syndrome (MIM #230740)

GAPO syndrome was first described in 1947 and later defined by its acronym consisting of growth retardation, alopecia, pseudoanodontia, and optic atrophy.²⁰⁷ Until now, about 60 patients have been reported worldwide.²⁰⁸ The phenotype is highly recognizable due to the typical coarse craniofacial features with alopecia, frontal bossing, mid-facial hypoplasia, hypertelorism, depressed nasal bridge, anteverted nares, micrognathia, and thick eyelids and lips.²⁰⁹ Apart from these main clinical features, patients can also present with a wide spectrum of other manifestations including an involvement of the cardiovascular, the skeletal, the central nervous, the pulmonary and the auditory systems.^209-212 Autosomal recessively inherited mutations in ANTXR1, encoding anthrax toxin receptor 1, have been described as causative of GAPO syndrome with a wide spectrum of mutations.^{208, 209, 213, 214}

2.4.2 Hallermann-Streiff Syndrome (MIM %234100)

Hallermann-Streiff syndrome is a congenital disorder with a highly recognizable phenotype that is reported in fewer than 200 patients worldwide. Its main clinical manifestations were first described by dyscephaly with the typical “bird-like” facies, beaked nose and hypoplastic mandible, congenital cataracts, microphthalmia, abnormal dentation, hypotrichosis, skin atrophy, and proportionate short stature.^{215, 216} Dental anomalies encompass neonatal and supernumerary teeth, but also absence or delayed eruption of teeth, and enamel hypoplasia.²¹⁷ The clinical diagnosis of Hallermann-Streiff syndrome is particularly based on the characteristic craniofacial dysmorphism.²¹⁸ Mental development is not affected in most cases.^{216, 219} However, even in the era of whole-exome and whole-genome sequencing the molecular basis of Hallermann-Streiff syndrome has not yet been uncovered. In view of the mostly sporadic occurrence of Hallermann-Streiff, de novo mutation(s) in (an) autosomal dominantly inherited gene(s) have been assumed as the genetic cause, but a more complex type of inheritance might also be possible.²¹⁸

2.4.3 Lenz-Majewski Hyperostotic Dwarfism (MIM #151050)

Lenz-Majewski hyperostotic dwarfism is an autosomal dominantly inherited disorder reported in about 20 cases worldwide.²²⁰ The phenotype is typically characterized by cutis laxa and distinct limb anomalies such as brachydactyly, symphalangism, progressive hyperostosis and generalized osteosclerosis. Moreover, patients exhibit severe growth retardation, intellectual disability, enamel hypoplasia, and distinct craniofacial dysmorphism with progeroid appearance including large head, sparse hair, and prominent hypertelorism.^221-223 Heterozygous missense mutations in the PTDSS1 gene have been shown to be causative.²²⁴ PTDSS1 is coding for the enzyme phosphatidylserine synthase 1 involved in phosphatidylserine synthesis and gain-of-function mutations in PTDSS1 are known to dysregulate phosphatidylserine metabolism. However, the exact molecular pathogenesis of the phenotype of Lenz-Majewski hyperostotic dwarfism is still not well understood.²²⁴

2.4.4 Marfanoid-Progeroid-Lipodystrophy Syndrome (MIM #616914)

The clinical phenotype of marfanoid-progeroid-lipodystrophy syndrome has been described in only a few patients worldwide. The typical triad is characterized by incomplete signs of Marfan syndrome, neonatal progeroid facial appearance and congenital generalized lipodystrophy, which in most cases does not involve the breast and the iliac region.^{225, 226} Signs of Marfan syndrome mainly include lens dislocation, myopia, aortic root dilatation, mitral valve prolapse, dural ectasia, arachnodactyly, pectus excavatum, hyperextensible joints and scoliosis.²²⁷ A wide range of autosomal dominantly inherited connective tissue disorders such as Marfan syndrome (MIM #154700), familial ectopa lentis (MIM #129600), stiff skin syndrome (MIM #184900), Weill-Marchesani syndrome (MIM #608328), geleophysic dysplasia (MIM #614185), and acromicric dysplasia (MIM #102370) result from mutations in the FBN1 gene. However, only heterozygous truncating mutations in the final exons 64 and 66 are known to cause marfanoid-progeroid-lipodystrophy syndrome.^{225, 226, 228, 229} The C-terminal pro-peptide of FBN1 encoded by these exons is also called asprosin, a hormone regulating energy metabolism.²³⁰

2.4.5 Penttinen Syndrome (MIM #601812)

Penttinen syndrome was first defined in 1997 as a novel progeroid disorder.²³¹ Until now, fewer than 10 patients have been reported, who all share a highly recognizable phenotype characterized by prematurely aged appearance, lipodystrophy, underdeveloped cheekbones, hyperkeratotic skin lesions forming scars as well as marked acro-osteolysis with severe contractures and shortening of the fingers and toes. Further clinical features encompass craniosynostosis, delayed dentition, and progressive scoliosis.^232-235 In five patients with classical Penttinen syndrome the identical de novo mutation c.1994T>C (p.Val665Ala) was identified in PDGFRB,^{233, 234} whereas two patients with a more severe phenotype involving corneal neovascularization carried the de novo mutation c.1997A>G (p.Asn666Ser)²³² and an additional patient with an atypical phenotype the de novo mutation c.1996A>C (p.Asn666His) in PDGFRB.²³⁶ PDGFRB encodes the platelet-derived growth factor receptor β, a homodimeric tyrosine-kinase receptor. Distinct autosomal dominant mutations in PDGFRB can also be causative of infantile myofibromatosis (MIM #228550), idiopathic basal ganglia calcification (MIM #615007), Kosaki overgrowth syndrome (MIM #616592), and a myoproliferative disorder with eosinophilia (MIM #131440).²³³

2.4.6 SHORT Syndrome (MIM #269880)

SHORT syndrome is a rare malformation disorder, which is clinically characterized by its acronym with short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly and teething delay.²³⁷ Main clinical features in more than 30 molecularly confirmed cases also include intrauterine growth retardation, lipodystrophy, and a typical progeroid facial gestalt with triangular appearance of the face, broad forehead, deep-set eyes, hypoplastic or thin alae nasi, low-hanging columella, small chin, and prominent ears.²³⁸ SHORT syndrome is caused by heterozygous, mainly de novo, missense mutations in the PIK3R1 gene. In several affected patients, the recurrent mutation c.1945C>T in PIK3R1 was detected.^239-241 PIK3R1 encodes a regulatory subunit of phosphatidyl inositol-3 kinase of class IA (PI3K), which is involved in the AKT-mTOR pathway and thereby important for cellular proliferation and growth.^{240, 242} Mutations in PIK3R1 seem also to disrupt the insulin signaling pathway, which explains the additional predisposition to insulin resistance and diabetes in patients with SHORT syndrome.²⁴¹ A recent exome sequencing study identified in one PIK3R1-negative patient with typical features of SHORT syndrome a de novo mutation in PRKCE, which also causes impaired AKT activation and therefore suggests PRKCE as a second gene associated with SHORT syndrome.²⁴³