Indian Journal of Dermatology
  Publication of IADVL, WB
  Official organ of AADV
Indexed with Science Citation Index (E) , Web of Science and PubMed
 
Users online: 2123  
Home About  Editorial Board  Current Issue Archives Online Early Coming Soon Guidelines Subscriptions  e-Alerts    Login  
    Small font sizeDefault font sizeIncrease font size Print this page Email this page


 
Table of Contents 
E-IJD CASE REPORT
Year : 2015  |  Volume : 60  |  Issue : 5  |  Page : 521
The diagnostic dilemma of cutis laxa: A report of two cases with genotypic dissimilarity


1 Department of Pediatrics, Division of Genetics and Metabolism, Maulana Azad Medical College, New Delhi, India
2 Department of Pediatrics, Lady Harding Medical College and Associated Kalawati Saran Children Hospital, New Delhi, India
3 Institute for Medical Genetics, Charité Universtaetsmedizin, Berlin, Germany

Date of Web Publication4-Sep-2015

Correspondence Address:
Seema Kapoor
Department of Pediatrics, Division of Genetics and Metabolism, Maulana Azad Medical College, New Delhi
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.164434

Rights and Permissions

   Abstract 

Cutis laxa is a heterogeneous group of diseases, with loose, wrinkled skin folds and hyperelasticity of the skin. There are overlapping of clinical features of the group of syndrome associated with cutis laxa, including congenital cutis laxa, wrinkly skin syndrome and gerodermia osteodysplastica. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. We hereby describe two Indian patients with wrinkled skin and mild craniofacial dysmorphic features who had molecular confirmation of autosomal recessive cutis laxa.


Keywords: Autosomal recessive, cutis laxa, wrinkled skin


How to cite this article:
Goyal M, Singh A, Kornak U, Kapoor S. The diagnostic dilemma of cutis laxa: A report of two cases with genotypic dissimilarity. Indian J Dermatol 2015;60:521

How to cite this URL:
Goyal M, Singh A, Kornak U, Kapoor S. The diagnostic dilemma of cutis laxa: A report of two cases with genotypic dissimilarity. Indian J Dermatol [serial online] 2015 [cited 2020 Sep 22];60:521. Available from: http://www.e-ijd.org/text.asp?2015/60/5/521/164434

What was known?
Cutis laxa is a group of disorders that are characterized by loose and/or wrinkled skin that produces prematurely aged appearance. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to presentation and severity.



   Introduction Top


Cutis laxa (CL) is a phenotypic term contributed by heterogeneous group of diseases with loose, wrinkled skin folds presenting as an inherited and acquired form. [1] Clinical features of different CL syndromes including congenital cutis laxa, wrinkly skin syndrome (WSS [OMIM#278250]), and geroderma osteodysplastica (GO [OMIM#231070]) are broadly overlapping. Congenital CL can be autosomal dominant, autosomal recessive or X-linked recessive. Autosomal recessive form (ARCL) is further subdivided into three subtypes. ARCL1 is characterized by severe systemic involvement and is caused by mutations in FBLN5 and EFEMP2 genes. ARCL2 is characterized by variable severity of cutis laxa, cranio-facial dysmorphism, connective tissue weakness, growth and developmental delay and associated skeletal abnormalities [2] and is divided into two subgroups. ARCL2A is due to mutations in the ATP6V0A2 gene. [3] ARCL2B is a segmental progeroid type of CL caused by mutations in the PYCR1 gene encoding the pyrroline-5-carboxylate reductase 1. [4] ARCL3/De Barsy syndrome is the severe form of ARCL spectrum characterized by progeroid appearance with short stature, corneal clouding, hypotonia and intellectual disability. [5] All these conditions present with a nearly similar phenotype. This poses a diagnostic dilemma to the treating clinician. We describe two Indian patients with wrinkled skin and mild craniofacial dysmorphology. Molecular confirmation of ARCL was made. We discuss the salient features in this group and the limitations of a pure phenotypic diagnosis.


   Case Reports Top


Case 1

A 4-year-old girl was referred for evaluation of blue sclera and wrinkled skin. She was the only child of a 3 rd degree consanguineous marriage (age of father - 30 years, mother - 24 years) born by LSCS at term with birth weight of 2.25 kg. Perinatal period was uneventful. She had motor developmental delay with mild learning difficulty. On physical examination her weight, height and head circumference were 12 kg (<3 rd percentile), 97 cm (3 rd -10 th percentile), and 44 cm (<3 rd percentile), respectively. There was palpebral down slant, bilateral epicanthal folds, blue sclera, flat nasal bridge, sagging cheeks and prominent ears. There were generalized loose wrinkled skin folds, particularly on face neck, abdomen and extremities [Figure 1]. Systemic examinations were normal. Skeletal evaluation showed bilateral dislocation of hip [Figure 2]. Ophthalmologic examination demonstrated blue sclera and shallow anterior chambers. Echocardiography and abdominal ultrasonography were normal. Isoelectric focusing for transferrin revealed mildly elevated levels of A-, mono- and di-sialotransferrin, whereas those for tetra-sialotransferrin were slightly reduced. This pattern was suggestive of CDG syndrome type IIx. Since this constellation of symptoms indicates an ATP6V0A2-related form of cutis laxa, this gene was screened for mutations as previously described. [3] Mutation analysis showed mutations c. 826-2A > G in intron 9 and c. 1973_1976del (p.Val660LeufsX682) in exon 16 of the ATP6V0A2 gene in a compound heterozygous state.
Figure 1: Facial features of case 1. (a) Wrinkled skin folds on face and neck and (b) on hands

Click here to view
Figure 2: X-ray showing bilateral dislocation of hip

Click here to view


Case 2

A 19-month-old girl presented with developmental delay, failure to thrive and lower limbs length discrepancy with the right limb being 2 cm more than the left limb. She was first born of consanguineous couple (father - 32 years, mother - 21 years), delivered normally at term. Her birth weight was 1.25 kg (growth retardation). The perinatal history was unremarkable. On physical examination, her weight, height and head circumference were 5.7 kg, 66 cm, and 42.5 cm all less than 3 rd percentile, respectively. She had global developmental delay with a DQ of 52 by DASII (developmental assessment Scale for Indian Infants). Facial examination revealed open anterior fontanel, sparse light colored hair, frontal bossing, deep set eyes, blue sclera, prominent ears, long philtrum, high arched palate thin upper and lower lips and camptodactyly of right little finger. Skin demonstrated an excessive wrinkling of dorsum of hands, feet and abdomen with deep creases [Figure 3]. Systemic examinations were normal. Skeletal examination revealed left-sided dislocation of hip [Figure 4]. Abdominal ultrasonography and chest X-ray were normal. Thyroid profile, ANA and anti-dsDNA were negative. Due to the facial gestalt and the camptodactyly, we suspected a PYCR1-related form of CL ARCL2B. Mutation analysis was performed as described previously [6] and showed the mutation c. 593delC (p. Pro198GlnfsX290) in exon 5 of the PYCR1 gene in a homozygous state. [6]
Figure 3: Facial features of case 2. (a) Open anterior fontanel, frontal bossing, deep set eyes, blue sclera, prominent ears, long philtrum. (b) Wrinkling on abdomen and (c) on dorsum of hands

Click here to view
Figure 4: X-ray showing dislocation of left hip

Click here to view



   Discussion Top


CL is characterized by prematurely wrinkled, pendulous and inelastic skin and is associated with variable involvement of other organs. Both acquired and inherited forms of CL exist and the latter show extensive locus heterogeneity. Acquired form is often associated with some form of preceding or accompanying cutaneous eruption like eczema, urticaria, erythema multiform, sweet's syndrome or multiple myloma. [7] Molecular diagnosis is required as the phenotype does not allow clinical categorization. For the pediatrician and dermatologist, it is a difficult situation to deal with and make a correct diagnosis. In the presence of consanguinity it is important to distinguish between ARCL, WSS and GO.

WSS is caused by the ATP6V0A2 gene mutation. The occurrence of the same gene mutation in WSS and ARCL2A indicates that they represent variable manifestations of the same genetic defect. [2],[8] Growth retardation, developmental, delay, microcephaly, wrinkling of skin on the abdomen, hernia, joint laxity, and dislocation are seen in both the syndromes. Severity of skin changes and facial dysmorphic features such as antimongoloid slant, sagging jowls, hypertelorism, long philtrum, blue sclera and large fontanelles are very prominent in CL type II. The facial dysmorphism in WSS is minimal and limited to mid-face hypoplasia. [2] An association of congenital disorder of glycosylation (CDG type II) with CL phenotype and wrinkly skin has been described. [9] GO is characterized by skin wrinkling limited to the dorsum of the hands, feet, and abdomen, osteoporosis with frequent fractures, maxillary hypoplasia, prognathism, platyspondyly and usually normal intellectual development. The gene responsible is the GORAB gene.

We present the salient features of these in reference to our cases [Table 1]. Our first case had features resembling ARCL2 and WSS [Table 1] and we detected a splice side and a frameshift mutation in ATP6VOA2, both in a heterozygous state. Both mutations are novel, but fit well into the ATP6V0A2 mutation spectrum which contains many frameshift and splice site mutations. [10] Greater severity of skin changes and associated dysmorphology in the first case pointed to ARCL2 rather than WSS. [2] The second case had lax skin which was segmental, IUGR, delay and dysmorphology like a triangular face, blue sclera and microcephaly. She was detected with novel homozygous frameshift mutation of PYCR1 gene pointing towards diagnosis of PYCR1 related form of CL ARCL2B. This is only the second frameshift mutation described in PYCR1. [4] The genotype-phenotype analysis by Dimopoulou et al. revealed that nonsense and frameshift mutations leading to an early abrogation of the protein rather lead to slightly milder manifestation of the disorder. [4]

In summary, in a child with cutis laxa, systemic evaluation including skeletal survey, ophthalmologic and cardiac evaluation, MRI brain, CDG screening and skin biopsy may help in reaching a diagnosis. Molecular diagnosis forms the mainstay of approach. In the absence of definite treatment, emphasis on developmental assessment, physiotherapy and evaluation of osteoporosis to prevent frequent fractures is required. Though molecular diagnosis confirms the condition and as it is not a lethal condition, prenatal diagnosis in not indicated. However, the associated complications which need surveillance, proactive management of a multidisciplinary nature would be an obvious benefit of confirming the diagnosis by molecular means. Also, long-term mutation modulation may help therapeutics for a given disease.

 
   References Top

1.
Mehregan AH, Lee SC, Nabai H. Cutis laxa (generalized elastolysis): A report of four cases with autopsy findings. J Cut Path 1978;5:116-26.  Back to cited text no. 1
    
2.
Gupta N, Phadke SR. CutisLaxa Type II and Wrinkly Skin Syndrome: Distinct Phenotypes. Pediatr Dermatol 2006;23:225-30.  Back to cited text no. 2
[PUBMED]    
3.
Kornak U, Reynders E, Dimopoulou A, Van Reeuwijk J, Fischer B, Mundlos S, et al. Impaired glycosylation and cutis laxa caused bymutations in the vesicular H+- ATPase subunit ATP6V0A2. Nat Genet 2008;40:32-4.  Back to cited text no. 3
    
4.
Dimopoulou A, Fischer B, Gardeitchik T, Schröter P, Kayserili H, Schlack C, et al. Genotype-phenotype spectrum of PYCR1 related autosomal recessive cutis laxa. Mol Genet Metab 2013;110:352-61.  Back to cited text no. 4
    
5.
Kunze J, Majewski F, Montgomery P, Hockey A, Karkut I, Riebel T. De Barsy Syndrome-an autosomal recessive, progeroid syndrome. Eur J Pediatr 1985;144:348-54.  Back to cited text no. 5
[PUBMED]    
6.
Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, et al. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet 2009;41:1016-21.  Back to cited text no. 6
    
7.
Turner RB, Haynes HA, Granter SR, Miller DM. Acquired cutis laxa following urticarial vasculitis associated with IgA myeloma. J Am Acad Dermatol 2009;60:1052-7.  Back to cited text no. 7
    
8.
Gazit E, Goodman RM, Katznelson MB, Rotem Y. The wrinkly skin syndrome: A new heritable disorder of connective tissue. Clin Genet 1973;4:186-92.  Back to cited text no. 8
[PUBMED]    
9.
Morava E, Wopereis S, Coucke P, Gillessen-Kaesbach G, Voit T, Smeitink J, et al. Defective protein glycosylation in patients with cutis laxa syndrome. Europ J Hum Genet 2005;13:414-21.  Back to cited text no. 9
    
10.
Fischer B, Dimopoulou A, Egerer J, Gardeitchik T, Kidd A, Jost D, et al. Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Hum Genet 2012;131:1761-73.  Back to cited text no. 10
    

What is new?
Molecular diagnosis may help in anticipatory active surveillance for co-morbidities like orthopedic and ophthalmic complications.


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

Top
Print this article  Email this article
 
 
  Search
 
  
    Similar in PUBMED
 Related articles
    Article in PDF (626 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Case Reports
   Discussion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed2442    
    Printed25    
    Emailed0    
    PDF Downloaded55    
    Comments [Add]    

Recommend this journal