The infant presented in the above clinical case had novel homozygous mutation in PYCR1 gene which is likely pathogenic variant of autosomal recessive cutis laxa type 2B/3B [3]. PYCR1 gene helps in synthesis of proline from glutamate. [link.springer.com]

The index patient presented with seizures and generalized hypotonia. [idoj.in]

ARCL I patients have a striking presentation with systemic involvement and life-threatening organ symptoms. [nature.com]

[…] autosomal recessive type IIA Cutis laxa with bone dystrophy Cutis laxa with congenital disorder of glycosylation Cutis laxa with growth and developmental delay Cutis laxa with joint laxity and retarded development Any medical or genetic information present [uniprot.org]

The specific symptoms present, severity and prognosis can vary greatly depending upon the specific type of cutis laxa and the presence and extent of associated symptoms. [rarediseases.org]

• Developmental Delay

  delay and neurological abnormalities. [uniprot.org]

  Title Other Names: ARCL2A; Cutis laxa with joint laxity and retarded development; Cutis laxa with growth and developmental delay; ARCL2A; Cutis laxa with joint laxity and retarded development; Cutis laxa with growth and developmental delay; Cutis laxa [rarediseases.info.nih.gov]

• Feeding Difficulties

  Symptoms cutis laxa dysmorphism failure to thrive feeding difficulties, poor feeding growth retardation, poor growth hair, abnormal (thin, brittle, fine) hypotonia joint hypermobilty, dislocations, laxity joint laxity lipodystrophia microcephaly (<2 SD [metagene.de]

  difficulties in infancy 0008872 Flat face Flat facial shape 0012368 Frontal bossing 0002007 Generalized hypotonia Decreased muscle tone Low muscle tone [ more ] 0001290 High palate Elevated palate Increased palatal height [ more ] 0000218 Inguinal hernia [rarediseases.info.nih.gov]

• Short Stature

  Other features include puffy eyelids, flat feet, loose joints, and short stature. MACS is an autosomal recessive disorder caused by mutations in the RIN2 gene. Acquired Cutis Laxa Acquired cutis laxa typically occurs in older adults. [cutislaxa.org]

  These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. [mdpi.com]

  Joint laxity, hernias, frequent hip dislocations, and varying degrees of growth deficiency and short stature can also occur. Osteoporosis may also present, resulting in fragile bones that are prone to fracture. [rarediseases.org]

• Failure to Thrive

  Symptoms cutis laxa dysmorphism failure to thrive feeding difficulties, poor feeding growth retardation, poor growth hair, abnormal (thin, brittle, fine) hypotonia joint hypermobilty, dislocations, laxity joint laxity lipodystrophia microcephaly (<2 SD [metagene.de]

  […] to thrive Faltering weight Weight faltering [ more ] 0001508 Feeding difficulties in infancy 0008872 Flat face Flat facial shape 0012368 Frontal bossing 0002007 Generalized hypotonia Decreased muscle tone Low muscle tone [ more ] 0001290 High palate [rarediseases.info.nih.gov]

• Cutis Laxa

  Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica. [pubmed.ncbi.nlm.nih.gov]

  Discriminative features in three autosomal recessive cutis laxa syndromes: cutis laxa IIA, cutis laxa IIB, and geroderma osteoplastica. Int J Mol Sci. 2017;18(3):635. [link.springer.com]

  Title Other Names: ARCL2A; Cutis laxa with joint laxity and retarded development; Cutis laxa with growth and developmental delay; ARCL2A; Cutis laxa with joint laxity and retarded development; Cutis laxa with growth and developmental delay; Cutis laxa [rarediseases.info.nih.gov]

• Skin Lesion

  Keywords: ATP6V0A2-related cutis laxa; Ehlers-Danlos-like skin lesions; autosomal recessive cutis laxa; type 2A (ARCL2A). © 2014 Wiley Periodicals, Inc. [pubmed.ncbi.nlm.nih.gov]

  lesions very similar to those found in classical Ehlers–Danlos syndrome. [scinapse.io]

  Type 2 usually develops following acute inflammatory skin lesions, in which the areas affected by the skin lesions develop cutis laxa skin symptoms. [rarediseases.org]

• Low Set Ears

  ears Low set ears Lowset ears [ more ] 0000369 Malar flattening Zygomatic flattening 0000272 Microcephaly Abnormally small skull Decreased circumference of cranium Decreased size of skull Reduced head circumference Small head circumference [ more ] 0000252 [rarediseases.info.nih.gov]

  Child had dysmorphism in the form of sagging cheeks, maxillary hypoplasia, prognathism, posteriorly placed large and low set ears, hypertelorism, down slanting palpebral fissures, wide open anterior fontanelle, medial epicanthal folds, depressed nose, [idoj.in]

• Hip Dislocation

  Other common manifestations include enlarged anterior fontanelle, congenital hip dislocation, high myopia, strabismus, and seizures caused by malformation of cortical and cerebella tissues. [preventiongenetics.com]

  dislocation Dislocated hip since birth 0001374 Cutis laxa Loose and inelastic skin 0000973 Dandy-Walker malformation 0001305 Downslanted palpebral fissures Downward slanting of the opening between the eyelids 0000494 Failure to thrive Faltering weight [rarediseases.info.nih.gov]

• Small Head

  Wrinkly Skin Syndrome, which causes wrinkled skin, small head size, and mental retardation, as well as muscle and skeletal problems, is caused by mutations in the same ATP6V0A2 gene. [cutislaxa.org]

  head circumference [ more ] 0000252 Midface retrusion Decreased size of midface Midface deficiency Underdevelopment of midface [ more ] 0011800 Motor delay 0001270 Muscular hypotonia Low or weak muscle tone 0001252 Myopia Close sighted Near sighted Near [rarediseases.info.nih.gov]

• Skeletal Dysplasia

  Dysplasia (WES based NGS panel of 531 genes, including CNV analysis, including CNV analysis) Menkes disease | Spinal muscular atrophy, X-linked | Occipital horn syndrome (sequence analysis of ATP7A gene) Autosomal recessive cutis laxa type 2A (sequence [cgcgenetics.com]

  Genital anomalies are also present in combination with skeletal dysplasia in the extremely rare SCARF Syndrome (MIM 312830). [nature.com]

• Muscle Hypotonia

  Developmental delay was observed in the majority of the children, partially due to muscle hypotonia, and in some degree hyperflexible joints. [nature.com]

• Mental Deterioration

  Some affected individuals develop seizures and mental deterioration later in life, whereas the skin phenotype tends to become milder with age. At the molecular level, an abnormal glycosylation of serum proteins is observed in many cases. [uniprot.org]

We suggest a simple and practical diagnostic approach for the workup of patients with a suspected autosomal recessive cutis laxa (Figure 5). [nature.com]

You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments. [rarediseases.info.nih.gov]

Legend How to query Individual ID ID_report Reference Remarks Gender Consanguinity Country Population Age at death VIP Data_av Treatment Disease Phenotype details Genes screened Variants in genes Variants Panel size Owner 00289442 3022 - - F no Italy [databases.lovd.nl]

Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. [rarediseases.org]

The presence of the metabolic alteration has consequences both for organ involvement, prognosis assessment and counselling. [nature.com]

Next generation sequencing was performed in genetically unsolved patients with progeroid features, neurological and eye involvement to assess the underlying etiology. [scinapse.io]

In cutis laxa patients mutations have been demonstrated in elastin or fibulin genes, but in the majority of patients the underlying genetic etiology remains unknown. [nature.com]

Pathophysiological aspects in ARCL type II patients with a ATP6V0A2 defect As described above, a large number of families with ARCL type II or WSS2, 22 with a distinct phenotype showed loss-of-function mutations in the a2-subunit of the V-type H+-ATPase [nature.com]

In ARCL1A, the mutations in both copies of this gene cause an altered structure of the protein product, preventing its transport out of the cells where it is produced and into the extracellular matrix. [cutislaxa.pitt.edu]

Variants in ATP6V0A2 impair Golgi vesicle trafficking and prevent the production of functional glycosylation. This results in reduced or abnormal elastic fiber formation. [preventiongenetics.com]

Management of individuals with cutis laxa includes treatment of symptoms, such as surgical repair of hernias, medications such as beta-blockers may be considered to prevent growth of aortic aneurysms, and pulmonary emphysema is treated symptomatically [cutislaxa.org]

In addition, some subtypes of cutis laxa have only been reported in a handful of individuals, which prevents physicians from developing a complete picture of associated symptoms and prognosis. [rarediseases.org]

In the follow up, one should emphasize the importance of caloric intake, developmental assessment, physiotherapy and evaluation of possible osteoporosis to prevent frequent fractures in some of the ARCL II and GO patients. [nature.com]