The Diagnostic Dilemma of Cutis Laxa: A Report of Two Cases with Genotypic Dissimilarity.

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.

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

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

Case 1

A 4-year-old girl was referred for evaluation of blue sclera and wrinkled skin. She was the only child of a 3rd 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 (<3rd percentile), 97 cm (3rd-10th percentile), and 44 cm (<3rd 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

Figure 2

X-ray showing bilateral dislocation of hip

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 3rd 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

Figure 4

X-ray showing dislocation of left hip

Discussion

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.[28] 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]

Table 1

Demonstrating salient features in three cases with respect to variants of wrinkly skin

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.

What is new?

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