Cutis Laxa—Clinically Decoding the Complex Genodermatoses

Dear Editor,

The term cutis laxa (CL) implies a specific skin anomaly with loose, redundant skinfolds and abnormal elasticity of the skin, occurring both as an inherited and acquired condition.[1] The inborn types of cutis laxa have a diverse genetic background including autosomal dominant (ADCL; MIM 123700), autosomal recessive (ARCL; MIM 219100, MIM 219200, MIM 219150, MIM 231070), and X-linked inheritance (XRCL; MIM 304150). The ARCL conditions have been categorized into types I, II, and III, with type II further subdivided into type IIA (ARCL2A, OMIM#219200) and IIB (ARCL2B, OMIM#612940). Geroderma osteodysplastica (GO), previously considered an allelic variant of ARCL type II, is a clinically distinct entity.[2] In this report, we highlight a case of a boy who presented with generalized skin laxity and systemic involvement.

A 5-year-old boy presented with complaints of loose skin and facial dysmorphism since birth. Patient’s father gave a history of inability to gain weight or height in the child despite adequate nutrition. The child was 5^th progeny of third-degree consanguineous marriage with uneventful antenatal history. The pedigree chart is presented in Figure 1. The child was diagnosed with progressive myoclonic seizure after an episode of sudden fall. There was no history of hypermobility of joints, hearing or visual difficulty, easy bruisability, joint dislocation, or fractures.

Figure 1.

Pedigree chart. - Patient is the 5^th child of asymptomatic parents from third-degree consanguineous marriage. 2^nd, 3^rd, 4^th, and 6^th sibling died at the age of day 7, 9 years, day 3, and 1 year of age, respectively. 1^st and 7^th siblings (both girls) are alive and healthy

On developmental examination, he was found to have gross developmental delay with intellectual disability. The child was active and playful with weight, height, and head circumference of 15 kg [-2 SD] [below 25^th centile], 103 cm [-2 SD] [below 10^th centile], and 48.5 cm [-1 SD], respectively. Systemic examination was within normal limits. Musculoskeletal examination showed decreased muscle bulk and power with broad-based gait due to scoliosis and developmental dysplasia of hip (DDH). Knee joint had genu valgum deformity but there was no joint laxity [Beighton score: 1/9].[3] The dysmorphic features typified by dolichocephaly, broad forehead, hypertelorism, slanting palpebral fissures, retrognathia, and sagging cheeks are evident in Figure 2. The skin over the abdomen, hands, and feet was wrinkled with decreased elasticity and recoil. He had a protuberant abdomen with everted umbilicus. Three atrophic scars with paper-thin skin were present over the lower limbs. Dental evaluation revealed caries in multiple teeth. Hair, scalp, nails, and genitalia appeared normal. Based on the history and examination, differentials of autosomal recessive cutis laxa, wrinkly skin syndrome, and syndromic associations of cutis laxa were considered, and further evaluation was done [Table 1].

Figure 2.

Clinical image of the patient showing prominent widow’s peak, broad forehead, broad flat nasal bridge, prominent epicanthal fold, hypertelorism, atrophic scar over forehead, downward slanting palpebral fissure, low set ears, short columella, long philtrum, sagging cheeks, micrognathia, and retrognathia

Table 1.

Differential diagnosis of cutis laxa

Syndrome	Genetic[4]	Epidemiology[4]	Points in favor	Points against
Arterial Tortuosity Syndrome	SLC2A10 Gene	Rare, 100 cases worldwide <1:1,000,000 live births	Facial manifestations, cutis laxa, aneurysm	Absence of arterial tortuosity
MACS	RIN 2 deficiency	Rare, <1:1,000,000 live births	Cutis laxa, scoliosis	Macrocephaly, alopecia
SCARF syndrome	XLR Unknown	<1:1,000,000 live births	Cutis laxa, skeletal abnormalities, facial abnormalities	Craniostenosis, ambiguous genitalia
Costello Syndrome	HRAS mutation	100–1500 people worldwide. 1 in 300,000 to 1 in 1.25 million people.	Coarse facies, short stature, cutis laxa	Feeding difficulty, failure to thrive, cardiac anomalies, facial warts, other ectodermal defects
Wrinkly skin syndrome	ATP6V0A2 gene	Rare, <1:1,000,000 About 30 cases are described in literature.	Facial laxity, post-natal growth delay	Delayed closure of fontanelle, hip dislocation, delayed motor development

MACS=Macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, SCARF=Skeletal abnormalities, cutis laxa, craniostenosis, ambiguous genitalia, psychomotor retardation, and facial abnormalities

Hematological evaluation showed microcytic hypochromic anemia with eosinophilia. Biochemical profile was normal. Hematoxylin and eosin staining for skin biopsy was largely unremarkable [Figure 3]. Staining with Verhoeff–van Gieson stain demonstrated near complete absence of elastic fibers in the dermis [Figure 4]. Electrocardiogram was normal but echocardiogram (ECHO) showed the presence of aortic aneurysm of size 1.1 × 1.4 cm. Skeletal evaluation revealed superior displacement of right femoral head suggesting DDH. DEXA scan was suggestive of osteopenia. Ultrasound of abdomen and pelvis revealed mesenteric lymphadenitis. Electroencephalogram showed abnormal awake pattern. ENT evaluation, ophthalmological evaluation, and pulmonary function (PFT) tests were within normal limits. Magnetic resonance imaging (MRI) revealed pachygyria and abnormally enlarged perivascular spaces in bilateral frontal distribution with tortuous intracranial vessels, prominent cisterns, and ventricular system with few T2/FLAIR hyperintensities with features suggestive of focal cortical dysplasia.

Figure 3.

Largely unremarkable epidermis and dermis. (H&E, 200×)

Figure 4.

Near complete absence of elastic fibers in the dermis (Verhoef–van Gieson stain, 200X)

Based on the above investigations, the patient was diagnosed as ARCL type II. ARCL I has predominant systemic involvement in the form of cardiac anomaly, bladder diverticula, emphysema, etc., while ARCL type III has athetoid movements and corneal clouding, which were absent in our patient. A close differential that was considered was GO. ARCL2A, ARCL2B, and GO manifest with many of the same features, making a definitive clinical diagnosis difficult. A few clinical pointers like post-natal growth delay, intellectual disability, persistent open fontanelle, and intracranial changes, which are more prominent in ARCL, can be used to differentiate between the two conditions [Table 2].[5]

Table 2.

Autosomal recessive cutis laxa type IIB vs geroderma osteodysplastica (GO)

Clinical Features	ARCL TYPE II B	GO
Intrauterine growth retardation	94% +++++	0
Post-natal growth delay	67% ++++	15% +
Aged appearance	98% +++++	92% +++++
Persistent open fontanelle	75% ++++	17% +
Blue sclera	48% +++	5% +
Intellectual disability	93%+++++	6% +
Microcephaly	65% ++++	2% +
Hypotonia	72% ++++	34% ++
Seizures	23% ++	2% +
Athetoid/dystonic movements	20% +	0%
Corpus callosum dysgenesis	49% +++	0%
Strabismus	35% ++	0%
Cataract/corneal clouding	15% +	0%
Osteopenia	73% ++++	96% +++++
Fractures	13% +	74% ++++
Congenital hip dislocation	62% ++++	68% ++++
Wormian bones	63% ++++	42% +++
Hyperextensibility of joints	95% +++++	98% +++++
Wrinkled skin	100% +++++	100% +++++
Visible veins on chest	87% +++++	21% ++
Hernia	39% ++	2% +

Patient’s parents were counseled regarding the genetic nature of disease and screening of family members. Annual PFT and ECHO are advised for early detection of emphysema and monitor the size of aortic aneurysm. Levetiracetam 250 mg twice daily was initiated for myoclonic seizures. Physiotherapy and surgery are planned for the DDH.

The accurate diagnosis of such conditions often requires genetic analysis which may not be possible in resource-poor settings. The lack of mutational diagnosis results in lack of accurate diagnosis and genetic counseling and screening. Therefore, it becomes important to distinguish and diagnose the subtypes based on clinical differentiating features and associated systemic involvement which was done in our case.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.