The Indian Journal of Pediatrics

CUTIS LAXA SYNDROME – IN TWO SIBLINGS A CASE REPORT

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Full Title: CUTIS LAXA SYNDROME – IN TWO SIBLINGS A CASE REPORT

Article Type: Clinical Brief

Keywords: CLS , EDS , MS

Corresponding Author: Sunil Mulgund, MD Paediatrics

VIMS: Vydehi Institute of Medical Sciences and Research Centre
Bangalore, KA INDIA

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Corresponding Author's Institution: VIMS: Vydehi Institute of Medical Sciences and Research Centre

Corresponding Author's Secondary

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First Author: Sunil Mulgund, MD Paediatrics

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Order of Authors: Sunil Mulgund, MD Paediatrics

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Abstract: A 13 year old female child and 7 year old male child who are siblings born to non
consanguineous married couple, presented with wrinkling and hyperextensibility of skin
since early childhood, suspecting collagen deficiency disorders (Ehler Danlos, Cutis
laxa syndrome, etc..) molecular genetic studies were conducted, and the results were
used to counsel the parents about the inheritance pattern of the disease. This case
emphasizes the value of using molecular genetic testing for definitive diagnosis in
patients with suspected inherited diseases.

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CUTIS LAXA SYNDROME – IN TWO SIBLINGS

1
2 A CASE REPORT
3
4
5 AUTHORS- DR. SUNIL MULGUND 1
6
AFFILIATION1 :DEPARTMENT OF PAEDIATRICS , VYDEHI INSTITUTE OF MEDICAL SCIENCES AND
7
RESEARCH CENTRE ,CITY: BANGALORE , STATE: BANGALORE , COUNTRY :INDIA
8
9
10
11 ABSTRACT: CASE DESCRIPTION:
12
13 A 13 year old female child and 7 Two siblings one a 13 year old
14
15 year old male child who are siblings born to female child and other a 7 year old male
16 non consanguineous married couple , child born to non consanguineous married
17 presented with wrinkling and couple , with no significant antenatal and
18
19 hyperextensibility of skin since early natal history ,both of them presented with
20 childhood , suspecting collagen deficiency complaints of wrinkling of skin ,
21 disorders (Ehler Danlos , Cutis laxa hyperextensibilty of skin all over the body,
22
23 syndrome , etc..) molecular genetic studies noticed since early childhood by parents.
24 were conducted, and the results were used There was no similar complaints in the
25 to counsel the parents about the inheritance family and developmentally both siblings
26
27
pattern of the disease. This case emphasizes were normal. There was history of
28 the value of using molecular genetic testing abdominal hernia surgeries in both the
29 for definitive diagnosis in patients with siblings . History of repeated easy
30
31
suspected inherited diseases. bruisibility of skin and scarring of skin was
32 also present. Height and weight was
33 appropriate according to the age for both
34 siblings.
35
BACKGROUND:
36
Cutis laxa syndrome is On examination both siblings had
37
38 distinguished by the presence of loose and elongated ,old man like facies , large ears
39 redundant skin that has a slow rate of with normal size of the head, skin over the
40 face appeared loose , fragile and wrinkled
41
returning to its original position after being
42 stretched. This condition is often and lower limbs had multiple atrophic scars
43 accompanied by heart valve regurgitation, secondary to injuries. Skin over the chest
44 as well as other vascular issues, hernias, and and abdomen too was hyperextensible as
45
46 emphysema. It can be inherited in either an shown in figure 1. Wrist and finger joints
47 autosomal recessive or dominant fashion. were hyperextensible . There was also
48 On the other hand, individuals with Ehlers- abdominal surgical scar seen post hernia
49
50 Danlos syndrome (EDS) may also have repair surgery. Elder sibling had genu
51 skin that is easily stretchable, but in this valgum deformity with Trendelenburg type
52 case, the skin is hyperextensible and has a of gait on examination. Other systemic
53
54 quick rate of returning to its original examination like abdominal , respiratory ,
55 position after being stretched. This is a key cardiovascular and central nervous system
56 difference that sets the skin changes seen in for both siblings were normal.
57
58 EDS apart from those observed in cutis
59 laxa.
60
61
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 VARIANT DESCRIPTION:
1
2 A homozygous mutation in PYCR1
3 gene in chromosome 17q25.3 , in
4
5 locus/gene number 179035 was detected
6 first by Kunze et al. (1985) (3). Reversade
7 et al. (4 )(2009) sequenced the PYCR1 gene
8
9 and identified homozygosity for mutations
10 in the PYCR1 gene.
11
12
13
14 DISCUSSION:
15
16 Cutis laxa type is a genetic disorder
17 that affects multiple body systems and is
18
19 inherited in an autosomal-recessive
20 manner. The hallmark feature of this
21 disorder is prematurely aged-looking skin,
22
23
which appears wrinkled and loose with
24 reduced elasticity. The single nucleotide
25 change leads to a missense mutation
26
adjacent to a splice junction in the gene
27
28 Figure – 1 , Head to toe findings encoding pyrroline-5-carboxylate reductase
29 1 (PYCR1). PYCR1 plays a critical role in
30 Siblings were evaluated further , proline biosynthesis.
31 complete blood count , Liver function test ,
32 Proline is an amino acid that plays a
33 Renal function tests were within normal
34 limits . USG abdomen showed crucial role in the synthesis of collagen,
35 infraumbilical midline defect . 2 D ECHO which is the main structural protein in the
36 extracellular matrix of connective tissues
37 was done which was normal.
38 Ophthalmological evaluation showed such as skin, tendons, and ligaments.
39 normal fundus. Chest X ray and Spinal X Proline deficiency can cause cutis laxa
40 syndrome and various other connective
41 ray was normal.
42 tissue disorders, by impairing the normal
43 Need of genetic evaluation was synthesis and cross-linking of collagen,
44 counselled and whole exome sequencing leading to weak and unstable connective
45 was done in both siblings which showed
46 tissues, resulting in the characteristic loose,
47 homozygous likely pathogenic variant - wrinkled appearance of the skin seen in
48 g.(81936194_81936747)_(81937239_?)del cutis laxa syndrome.
49 , with autosomal recessive inheritance
50 Cutis laxa is a group of connective
51
caused by substitution in exon 1-2 of
52 PYCR1 gene , which confirmed the tissue disorders that can affect multiple
53 diagnosis of Cutis laxa type IIIB organ systems, including the cardiovascular
54 system, respiratory system, and
(OMIM#614438) (1) , Cutis laxa type IIB ,
55
56 (OMIM#612940) (2) musculoskeletal system. One of the
57 common features of cutis laxa is heart valve
58 regurgitation and other vascular
59
60
61
62 2|Page
63
64
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 involvement, along with the presence of easily stretched skin, the skin changes in
1 hernias and emphysema. EDS are characterized by
2
3 hyperextensibility and rapid return from
Cutis laxa can be inherited in both
4 distention, which is different from the loose
5 autosomal recessive and dominant fashion,
and wrinkled skin seen in cutis laxa. Table
6 and there are several different forms of the
7
-1 gives the key differences between Ehler
disorder. While patients with Ehlers-
8 Danlos syndrome (5) , Cutis Laxa
9 Danlos Syndrome (EDS) may also have
syndrome and Marfans syndrome.(6)
10
11 TABLE – 1 , KEY DIFFERENCES BETWEEN EDS, CLS, AND MARFAN SYNDROME
12
13
14
15 CHARACTERISTIC EHLERS-DANLOS CUTIS LAXA SYNDROME MARFAN SYNDROME
16 SYNDROME
17
18
UNDERLYING Genetic mutations Genetic mutations Genetic mutations affecting
19
20 CAUSE affecting collagen affecting elastin fibrillin-1 synthesis/structure
21 synthesis/structure synthesis/structure
22
23
24 INHERITANCE Mostly autosomal Mostly autosomal Autosomal dominant
25 PATTERN dominant, some recessive, some dominant
26 recessive
27
28 CLINICAL Hypermobile joints, Loose, sagging skin that Tall stature, long limbs,
29
PRESENTATION stretchy and easily may be extra wrinkled, scoliosis, and other skeletal
30
31 bruised skin, fragile respiratory issues, and abnormalities, as well as
32 blood vessels, and other other symptoms cardiovascular and eye
33 symptoms depending on depending on subtype problems depending on
34 subtype subtype
35
36 SKIN TEXTURE Stretchy, soft, and Loose, sagging, and extra Normal or slightly stretchy
37 velvety wrinkled
38
39
JOINT MOBILITY Hypermobile joints and Joint mobility may or may Joint hypermobility without
40
41 increased risk of not be affected increased risk of dislocations
42 dislocations
43
44
45 VASCULAR Fragile blood vessels, May or may not have Cardiovascular complications,
46 COMPLICATIONS increased risk of vascular complications such as aortic aneurysms and
47
aneurysms, and other depending on subtype mitral valve prolapse
48
49 vascular complications
50 depending on subtype
51
52
OTHER Gastrointestinal issues, Respiratory issues, Eye problems, such as lens
53
54 COMPLICATIONS scoliosis, and dental hernias, and dislocation and near
55 problems depending on developmental delays sightedness, as well as chest
56 subtype depending on subtype wall abnormalities
57
58
59
60
61
62 3|Page
63
64
65
 The management of cutis laxa 4 Reversade B, Escande-Beillard N,
1 involves regular cardiovascular and . Dimopoulou A, Fischer B, Chng SC, Li
2
3 pulmonary follow-up, treating symptoms Y, et al. Mutations in PYCR1 cause cutis
4 such as hernias and emphysema, and laxa with progeroid features. Nat Genet
5 avoiding environmental triggers. Plastic [Internet]. 2009 [cited 2023 Apr
6
surgery may be an option for some 18];41(9):1016–21. Available from:
7 https://www.nature.com/articles/ng.413
8 individuals,but they may not be permanent,
9 as the loose skin may reoccur.(7)
10 5 Phenotypic series - PS130000 - OMIM
11 . [Internet]. Omim.org. [cited 2023 Apr
12
13
18]. Available from:
CONCLUSION: https://www.omim.org/phenotypicSeries/
14
15 Cutis Laxa is a rare congenital PS130000
16
17 disorder , and currently no effective
18 treatment is available , but with next 6 Entry - #154700 - MARFAN
19 generation sequencing-based testing, the . SYNDROME; MFS - OMIM [Internet].
20
exact mutations could be identified, which Omim.org. [cited 2023 Apr 18]. Available
21 from:
22 helped in confirmation of the diagnosis of
https://www.omim.org/entry/154700
23 the proband, in providing accurate genetic
24
counselling to the family and in offering
25 7 FAQ [Internet]. Pitt.edu. [cited 2023 Apr
26 prenatal diagnosis for their next planned
. 18]. Available from:
27 pregnancy.
28 http://cutislaxa.pitt.edu/faq.php
29
30 REFERENCES:
31
32 1 Entry - #614438 - CUTIS LAXA,
33 . AUTOSOMAL RECESSIVE, TYPE
34 IIIB; ARCL3B - OMIM [Internet].
35
Omim.org. [cited 2023 Apr 18]. Available
36
37 from:
38 https://www.omim.org/entry/614438?sea
39 rch=614438&highlight=614438
40
41
42 2 Entry - #612940 - CUTIS LAXA,
43 . AUTOSOMAL RECESSIVE, TYPE IIB;
44 ARCL2B - OMIM [Internet]. Omim.org.
45
[cited 2023 Apr 18]. Available from:
46
47 https://www.omim.org/entry/612940?sea
48 rch=612940&highlight=612940
49
50
51 3 Kunze J, Majewski F, Montgomery P,
52 . Hockey A, Karkut I, Riebel T. De Barsy
53 syndrome--an autosomal recessive,
54 progeroid syndrome. Eur J Pediatr
55
[Internet]. 1985;144(4):348–54.
56
57 Available from:
58 http://dx.doi.org/10.1007/bf00441776
59
60
61
62 4|Page
63
64
65
Title Page

CUTIS LAXA SYNDROME – IN TWO SIBLINGS

A CASE REPORT
AUTHORS- DR. SUNIL MULGUND 1
AFFILIATION1 :DEPARTMENT OF PAEDIATRICS , VYDEHI INSTITUTE OF MEDICAL SCIENCES AND
RESEARCH CENTRE ,CITY: BANGALORE , STATE: BANGALORE , COUNTRY :INDIA
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Date: 10/4/2023
Figure Click here to access/download;Figure;My project-1.jpg
Table

TABLE – 1 , KEY DIFFERENCES BETWEEN EDS, CLS, AND MARFAN SYNDROME

CHARACTERISTIC EHLERS-DANLOS CUTIS LAXA SYNDROME MARFAN SYNDROME

SYNDROME

UNDERLYING Genetic mutations Genetic mutations Genetic mutations affecting

CAUSE affecting collagen affecting elastin fibrillin-1 synthesis/structure
synthesis/structure synthesis/structure

INHERITANCE Mostly autosomal Mostly autosomal Autosomal dominant

PATTERN dominant, some recessive, some dominant
recessive

CLINICAL Hypermobile joints,
PRESENTATION stretchy and easily
bruised skin, fragile
blood vessels, and other
symptoms depending on
subtype
Loose, sagging skin that Tall stature, long limbs,
may be extra wrinkled, scoliosis, and other skeletal
respiratory issues, and abnormalities, as well as
other symptoms cardiovascular and eye
depending on subtype problems depending on
subtype

SKIN TEXTURE Stretchy, soft, and velvety Loose, sagging, and extra Normal or slightly stretchy
wrinkled

JOINT MOBILITY Hypermobile joints and Joint mobility may or may Joint hypermobility without
increased risk of not be affected increased risk of dislocations
dislocations

VASCULAR Fragile blood vessels,
COMPLICATIONS increased risk of
aneurysms, and other
vascular complications
depending on subtype
May or may not have Cardiovascular complications,
vascular complications such as aortic aneurysms and
depending on subtype mitral valve prolapse

OTHER Gastrointestinal issues, Respiratory issues, Eye problems, such as lens

COMPLICATIONS scoliosis, and dental hernias, and dislocation and near
problems depending on developmental delays sightedness, as well as chest
subtype depending on subtype wall abnormalities