Alternative titles; symbols
SNOMEDCT: 1295485009; ORPHA: 2962, 35664; DO: 0070132;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q24.1 | Cutis laxa, autosomal recessive, type IIIA | 219150 | Autosomal recessive | 3 | ALDH18A1 | 138250 |
A number sign (#) is used with this entry because this form of de Barsy syndrome (ARCL3A) is caused by homozygous or compound heterozygous mutation in the ALDH18A1 gene (138250) on chromosome 10q24.
Heterozygous mutation in ALDH18A1 can cause an autosomal dominant form of cutis laxa (ADCL3; 616603).
De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100.
Genetic Heterogeneity of de Barsy Syndrome
Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25.
De Barsy et al. (1968) described a 22-month-old girl who had cutis laxa with defective development of elastic fibers in the skin. The corneas were cloudy due to degeneration in the Bowman membrane. Psychomotor development was retarded and she was generally hypotonic. There was no known parental consanguinity, the father being Greek and the mother Flemish.
Hoefnagel et al. (1971) reported a male with similar features. The patient had congenital bilateral athetosis. The authors pointed out that the case of de Barsy et al. (1968) also had athetosis. Burck (1974) reported the same condition. All of these were sporadic cases.
Pontz et al. (1986) described a 6-month-old Turkish boy, the son of first-cousin parents, who had typical features of this condition at 7 days of age. He was admitted to hospital for surgical treatment of a large inguinal hernia. Superficial blood vessels were unusually evident because of a translucent quality of the skin. A wizened face was a striking feature. The corneas were cloudy, with arcus senilis bilaterally and a polar cataract on the right. The thumbs and great toes as well as both hips were dislocated. Elastic fibers in the skin were frayed and reduced in number and density. The collagen fibril network was judged to be normal.
Morris and Clark (1990) reported a case and reviewed the findings in 15 reported cases.
Rabier et al. (1992) reported 2 children, born of consanguineous Algerian parents, who presented in early infancy with failure to thrive, vomiting, and progressive neurologic dysfunction. Bilateral subcapsular cataracts were noted by age 2 years. Both had mental retardation (IQ of 50), hypotonia with joint laxity, and hyperelastic skin. Motor handicap resulted in loss of walking ability by age 12 years. Metabolic studies repeatedly showed hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia, and hypoprolinemia. Kamoun et al. (1998) and Baumgartner et al. (2000) reported the same family.
Kivuva et al. (2008) reported a female infant, the second child of first-cousin parents from a multiply consanguineous family of Pakistani origin, who presented at birth with growth retardation, cutis laxa, and a progeria-like appearance. She had thin, overlapping fingers and adducted thumbs, blue sclerae, cloudy corneas, and myopia. She showed failure to thrive and had marked developmental delay and abnormal athetoid movements. During the first year of life, she developed pectus excavatum, and her facial appearance became more aged. The findings were typical of classic de Barsy syndrome. Kivuva et al. (2008) stated that 27 cases had been reported in the literature.
Bicknell et al. (2008) reported a New Zealand Maori family in which 4 sibs had a syndrome characterized by microcephaly, global neurodevelopmental delay with no speech development, and connective tissue abnormalities. The skin over the hands, feet, abdomen, chest, and face was very wrinkled and lax, although not hyperelastic; wounds healed normally without excessive scarring. The wrinkliness of the skin disappeared with age and was no longer clinically evident by adolescence. All had hypermobility of the joints, 3 with hip dislocation, and mild short stature. A progeroid appearance was noted, although no photographs were provided. At ages 22, 12, 11, and 4 years, respectively, affected individuals had difficulty walking associated with increased tone in the lower limbs and distal muscle wasting. One patient had bilateral lamellar nuclear cataracts. Extensive biochemical investigations showed no abnormalities. Bicknell et al. (2008) noted the phenotypic similarities to de Barsy syndrome but suggested that the disorder in the family they described differed by the lack of corneal clouding.
Skidmore et al. (2011) reported a male infant born to consanguineous Pakistani parents. Decreased fetal movements and severe intrauterine growth retardation (IUGR) were noted, and the child was delivered at term by cesarean section with a weight of 1.52 kg. Scalp hair was sparse and dry; skin was thin, wrinkled, and loose, with a parchment paper-like texture and poor elasticity especially over the upper arms and face. Blood vessels were clearly visible through the skin covering the torso. The patient had a high forehead with frontal bossing, depressed nasal bridge, short upturned nose with hypoplastic nasal alae, and thin lips. Eyes were deep-set with cloudy corneas, jowls of the cheek were prominent, palate was high-arched but intact, and micrognathia was present. Overall appearance was progeroid. He had multiple joint contractures with clenched fists. Breathing was irregular. Chest radiographs showed eventration of the medial aspect of the right diaphragm, thin ribs, and normal lung parenchyma. Echocardiography showed ventricular septal defect, persistent foramen ovale, and mild proximal pulmonary artery branch stenosis. Brain MRI showed tortuosity of all blood vessels, including the middle cerebral artery, and bifurcation of the basilar artery. Corneal transplant was undertaken in infancy but no vision developed. Examination of the corneal explant demonstrated absence of the Bowman membrane. The corneal epithelium was thickened and there was increased cellularity in the substantia propia. The infant had poor suck and swallow and developed seizures at 2 weeks of age. Over the next several months, the translucency of the skin decreased but did not normalize and the scalp hair remained sparse. The loose redundant folds of skin with poor elasticity became more marked over time and the appearance became more in keeping with cutis laxa. By age 3 months, bilateral inguinal hernias were present. The child remained in hospital with severe failure to thrive, and was discharged home at age 3 months. He died suddenly at age 6 months. His development was never formally assessed, but little developmental progression was noted.
Fischer et al. (2014) reported 2 patients with classic features of de Barsy syndrome. The female patient was the first child of a consanguineous Tunisian couple. She exhibited intrauterine growth restriction, and at age 18 months had disseminated tremors. She had no structural brain abnormalities. Craniofacial dysmorphic features included a triangular face, malar hypoplasia, prognathism, and prominent ears, leading to a prematurely aged appearance. She had mild cataract as well as thin, lax, and wrinkled skin at the abdomen and the dorsum of hands and feet. Visibility of veins was also observed. She had hand and foot contractures, hypotonia, kyphosis, bilateral hearing loss, and cardiovascular problems, including ventricular septal defect, atrial septal defect (ostium secundum type), patent ductus arteriosus, and persistence of superior left vena cava. The second patient was the male offspring of a consanguineous Turkish couple. He had intrauterine growth restriction and agenesis of the corpus callosum. He presented with seizures and had a typical facial gestalt, prominent ears, and corneal clouding. He had remarkably thin, translucent, lax, and wrinkled skin as well as a narrow aortic arch without a clear stenosis. He died at 3 months of age due to progressive respiratory failure and urosepsis.
Wolthuis et al. (2014) described a 2-year-old boy, born to consanguineous parents, who was noted at birth to have severely wrinkled skin on the thorax and abdomen with visible veins, bilateral hip dislocations, wrist contractures, and adducted thumbs. He also exhibited kyphosis and calcaneovalgus feet. Other features included large anterior fontanel, microcephaly, high-arched palate, dysmorphic ears, right inguinal hernia, undescended testes, and abnormal fat pads on the buttocks and upper thighs. The child had growth delay and failure to thrive, and developed seizures and spasticity. Ophthalmologic examination revealed blue sclerae but no cataract, and there was abnormal pigmentation in the retinal periphery with salt-and-pepper appearance of the fundus. Cerebral MRI showed diffuse thinning of the corpus callosum and mild enlargement of temporal horns.
Lefebvre et al. (2018) reported a fetus who had shortened long bones, agenesis of the corpus callosum, and cerebellar hypoplasia identified on an ultrasound performed at 20 weeks' gestation. Examination of the fetus after pregnancy termination at 27 weeks' gestation showed growth retardation, dysmorphic features (low-set ears, macrostomia, hypertelorism, malar hypoplasia), cutis laxa, short limbs, agenesis of the corpus callosum, colpocephaly, and ureteral dilation. The fetus also had shortened ribs and irregular vertebral bodies.
Colonna et al. (2023) reported 4 patients from 2 families, including 3 sibs, with global developmental delay, hypotonia, and visible subcutaneous veins. All 3 sibs had skin hyperelasticity, joint hypermobility, and short stature. Three patients had microcephaly, 2 patients had hypogenesis of the corpus callosum, and 1 patient had cataracts. One patient had hypertonia and spasticity.
Riebel (1976) described affected sibs; Kunze et al. (1985) followed up on the family with report of 2 more affected sibs and suggested an autosomal recessive inheritance pattern.
Pontz et al. (1986) and Kivuva et al. (2008) reported patients born of consanguineous parents, suggesting autosomal recessive inheritance.
Karnes et al. (1992) performed elastin gene (ELN; 130160) expression studies on fibroblasts cultured from the skin of a patient with this disorder. They found reduced steady-state levels of elastin mRNA, suggesting reduced elastin synthesis.
In the 2 sibs described by Rabier et al. (1992), Baumgartner et al. (2000) identified a homozygous mutation in the ALDH18A1 gene (R84Q; 138250.0001). The mutation resulted in decreased enzymatic activity.
In affected individuals from a New Zealand family with mental retardation, joint hypermobility, and skin laxity without metabolic abnormalities, Bicknell et al. (2008) identified a homozygous mutation in the ALDH18A1 gene (H784Y; 138250.0002). In vitro functional expression studies indicated that the H784Y-mutant protein retained normal P5CS activity and did not impair proline synthesis. The findings indicated that impaired enzymatic activity does not account for the phenotype, as was suggested for the patients reported by Baumgartner et al. (2000).
In a Pakistani infant with features consistent with de Barsy syndrome, Skidmore et al. (2011) identified homozygosity for a 1923G-A+1 mutation in the ALDH18A1 gene (138250.0003), resulting in the production of 2 anomalous transcripts that were predicted to encode proteins lacking the catalytic site for the enzyme. Immunostaining also showed pronounced reduction in expression of P5CS. Electron microscopy of skin fibroblasts showed diminished production of type I collagen (see 120150) and type III collagen (see 120180), altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts.
In 2 patients with classic features of de Barsy syndrome from consanguineous families, Fischer et al. (2014) identified homozygosity for a deletion (138250.0004) and a frameshift mutation (138250.0005), respectively, in the ALDH18A1 gene.
In a 2-year-old boy with cutis laxa, seizures, and spasticity, as well as abnormal fat pad distribution and retinopathy, who was negative for mutation in the ATP6V0A1 (611716), COG7 (606978), GORAB (607983), and PYCR1 genes, Wolthuis et al. (2014) performed whole-exome sequencing and identified homozygosity for a missense mutation in the ALDH18A1 gene (Y780C; 138250.0016). The authors concluded that the clinical features of ALDH18A1-associated cutis laxa are highly variable, but always include neurologic symptoms.
In a fetus with ARCL3A from a pregnancy terminated at 27 weeks' gestation, Lefebvre et al. (2018) identified compound heterozygous mutations in the ALDH18A1 gene (R425C, 138250.0017 and c.177delG, 138250.0018). The mutations were identified by whole-exome sequencing. Functional studies were not performed.
In 4 patients, including 3 sibs, from 2 families with ARCL3A, Colonna et al. (2023) identified a homozygous mutation in the ALDH18A1 gene (T331P; 138250.0019). In an HEK293 cell line expressing ALDH18A1 with the T331P mutation, the mutant ALDH18A1 had comparable expression levels to wildtype and normal mitochondrial localization. However, analysis in fibroblasts from patient 2 demonstrated that the mutant P5CS protein had decreased oligomerization compared to wildtype. Metabolomic analysis in patient fibroblasts demonstrated decreased proline, glutamine, glutathione, and putrescine compared to wildtype. Colonna et al. (2023) hypothesized that the decreased glutathione reflected increased oxidative stress in patient cells and that the decreased putrescine may have reflected increased flux towards synthesis of spermidine and spermine as part of an antioxidant response.
Leao-Teles et al. (2010) stated that 1 of the patients diagnosed with ARCL2A (219200) and found to have a mutation in the ATP6V0A2 gene (611716) (patient 'CoFe') by Kornak et al. (2008) displayed the full clinical picture of de Barsy syndrome, including cutis laxa, facial dysmorphism, dwarfism, psychomotor retardation, dystonia, congenital hip dysplasia, and corneal dystrophy requiring repeated corneal transplantation. Leao-Teles et al. (2010) suggested that a subgroup of patients with de Barsy syndrome belongs to the spectrum of ATP6V0A2-associated congenital disorders of glycosylation (CDG), and recommended that mutations in the ATP6V0A2 gene be sought in patients diagnosed with de Barsy syndrome. Morava et al. (2010) noted that none of their cohort of 6 patients with de Barsy syndrome had N-linked or O-linked glycosylation abnormalities or mutations in ATP6V0A2; they stated that further description and photographs of patient CoFe would be helpful, since corneal abnormalities with a movement disorder would widen the range of symptoms evoking glycosylation studies in patients with cutis laxa.
Baumgartner, M. R., Hu, C. A., Almashanu, S., Steel, G., Obie, C., Aral, B., Rabier, D., Kamoun, P., Saudubray, J.-M., Valle, D. Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta-1-pyrroline-5-carboxylate synthase. Hum. Molec. Genet. 9: 2853-2858, 2000. [PubMed: 11092761] [Full Text: https://doi.org/10.1093/hmg/9.19.2853]
Bicknell, L. S., Pitt, J., Aftimos, S., Ramadas, R., Maw, M. A., Robertson, S. P. A missense mutation in ALDH18A1, encoding delta-1-pyrroline-5 -carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome. Europ. J. Hum. Genet. 16: 1176-1186, 2008. [PubMed: 18478038] [Full Text: https://doi.org/10.1038/ejhg.2008.91]
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Colonna, M. B., Moss, T., Mokashi, S., Srikanth, S., Jones, J. R., Foley, J. R., Skinner, C., Lichty, A., Kocur, A., Wood, T., Stewart, T. M., Casero, R. A., Flanagan-Steet, H., Edison, A. S., Lyons, M. J., Steet, R. Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. Hum. Molec. Genet. 32: 732-744, 2023. [PubMed: 36067040] [Full Text: https://doi.org/10.1093/hmg/ddac226]
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Hoefnagel, D., Pomeroy, J., Wurster, D., Saxon, A. Congenital athetosis, mental deficiency, dwarfism and laxity of skin and ligaments. Helv. Paediat. Acta 26: 397-402, 1971. [PubMed: 5123306]
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Leao-Teles, E., Quelhas, D., Vilarinho, L., Jacken, J. De Barsy syndrome and ATP6V0A2-CDG. (Letter) Europ. J. Hum. Genet. 18: 526 only, 2010. [PubMed: 20010974] [Full Text: https://doi.org/10.1038/ejhg.2009.218]
Lefebvre, M., Beaufrere, A. M., Francannet, C., Laurichesse, H., Poe, C., Jouan, T., Troude, B., Dechelotte, P., Vabres, P., Briard, M., Mosca-Boidron, A. L., Duffourd, Y., Faivre, L., Thevenon, J., Thauvin-Robinet, C. Extending the ALDH18A1 clinical spectrum to severe autosomal recessive fetal cutis laxa with corpus callosum agenesis. Am. J. Med. Genet. 176A: 2509-2512, 2018. [PubMed: 30244529] [Full Text: https://doi.org/10.1002/ajmg.a.40515]
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Pontz, B. F., Zepp, F., Stoss, H. Biochemical, morphological and immunological findings in a patient with a cutis laxa-associated inborn disorder (de Barsy syndrome). Europ. J. Pediat. 145: 428-434, 1986. [PubMed: 3491758] [Full Text: https://doi.org/10.1007/BF00439254]
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Wolthuis, D. F. G. J., van Asbeck, E., Mohamed, M., Gardeitchik, T., Lim-Melia, E. R., Wevers, R. A., Morava, E. Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature. Europ. J. Paediat. Neurol. 18: 511-515, 2014. [PubMed: 24767728] [Full Text: https://doi.org/10.1016/j.ejpn.2014.01.003]