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Disease Profile

Tight skin contracture syndrome, lethal

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Antenatal

ICD-10

Q82.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hyperkeratosis-contracture syndrome; Restrictive dermopathy, lethal; Fetal hypokinesia sequence due to restrictive dermopathy

Categories

Congenital and Genetic Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 1662

Definition
A congenital genodermatosis with skin/mucosae involvement, characterized by very tight and thin skin with erosions and scaling, associated to a typical facial dysmorphism, arthrogryposis multiplex, fetal akinesia or hypokinesia deformation sequence (FADS) and pulmonary hypoplasia without neurological abnormalities.

Epidemiology
To date, approximately 80 children with restrictive dermopathy (RD) have been described in the world literature.

Clinical description
RD is a congenital disorder and newborns are usually born prematurely (due to premature rupture of membranes with delivery at about 30-32 weeks of gestation). They present at birth with a very typical and recognizable clinical phenotype including tight, thin, rigid and translucent skin with epidermal hyperkeratosis and shedding, erosions and scaling at flexure sites, protruding nipples. Skeletal defects include: bone mineralization defects, large fontanelles, thin dysplastic clavicles, narrow chest, overtubulated long bones, generalized arthrogryposis with rocker-bottom feet. Facial dysmorphism is also characteristic and includes telecanthus, short, down-slanting palpebral fissures, sparse/absent eyelashes and eyebrows, a small and pinched nose, posteriorly rotated low-set ears, retromicrognathism and a small mouth fixed in the ''O'' position with expressionless facies. Additional features may include congenital anonychia, neonatal teeth, ectropion, choanal atresia, patent ductus arteriosus, interatrial septal defects, kyphoscoliosis, camptodactyly, hypospadias (males), ureteral duplication, adrenal hypoplasia. Intrauterine growth retardation (IUGR) with polyhydramnios, and decreased fetal movements are almost always reported. Pulmonary hypoplasia most often leads to respiratory insufficiency and death. Neither structural central nervous system nor visceral defects occur in RD.

Etiology
RD can be caused by heterozygous, de novo mutations of the LMNA gene (primary Laminopathy) or, much more frequently, by homozygous or compound heterozygous null mutations of the ZMPSTE24 gene (secondary Laminopathy). Defects in ZMPSTE24 impair the processing of Prelamin A into mature Lamin A, causing the massive intranuclear accumulation of wild type Prelamin A which exerts sytemic toxic effects and leads to the development of RD.

Diagnostic methods
The diagnosis is based upon physical examination at birth and skin histology (flat dermis with paucity/hypoplasia of appendages, abnormally dense collagen bundles parallel to the dermo-epidermic basal lamina and almost total depletion of elastic fibers), cerebral imagery, blood analysis. Molecular genetic testing for mutations confirms the diagnosis and allows genetic counselling.

Differential diagnosis
Yunis-varon syndrome, Neu-laxova syndrome, Pena-Shokeir syndrome, cerebrooculofacioskeletal syndrome, Paraná hard-skin syndrome, aplasia cutis congenita, lethal multiple pterygium syndrome.

Antenatal diagnosis
Earliest manifestations are only apparent in the late second trimester/early third trimester and include intrauterine growth retardation, decreased fetal movements, eventual joint contractures, and mouth fixed in an 'O' position. However, these signs are too nonspecific to suggest the diagnosis prenatally in cases with no family history.

Genetic counseling
The ZMPSTE24 mutations are inherited recessively, leading to the possibility of genetic counseling and prenatal diagnosis for further pregnancies if the molecular bases of the disease are identified (25% risk of having an affected child for two mutation carriers). The rare dominant mutations in the LMNA gene are de novo and the risk of recurrence of the disorder is very low (eventual germinal mosaicism).

Management and treatment
Corticosteroids are administered for fetal lung maturation. Gavage feeding may be necessary. Supportive treatment consists of mechanical ventilation, broad-spectrum antibiotics, parenteral nutrition, and intravenous analgesia.

Prognosis
The affected babies who are liveborn often die within the first week of life.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
100% of people have these symptoms
Stiff skin
0030053
80%-99% of people have these symptoms
Abnormal cellular phenotype
0025354
Aplasia/Hypoplasia involving the nose
Decreased nasal size
Decreased size of nose

[ more ]

0009924
Aplasia/Hypoplasia of the clavicles
Absent/small collarbone
Absent/underdeveloped collarbone

[ more ]

0006710
Aplasia/Hypoplastia of the eccrine sweat glands
0007592
Arthrogryposis multiplex congenita
0002804
Decreased fetal movement
Less than 10 fetal movements in 12 hours
0001558
Decreased skull ossification
Decreased bone formation of skull
0004331
Dermal atrophy
Skin degeneration
0004334
Dermal translucency
0010648
Downslanted palpebral fissures
Downward slanting of the opening between the eyelids
0000494
Entropion
Eyelid turned in
0000621
Epidermal hyperkeratosis
Increased thickness of skin epidermis
0007543
Generalized hyperkeratosis
0005595
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Increased anterioposterior diameter of thorax
0005253
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation

[ more ]

0001511
Low-set ears
Low set ears
Lowset ears

[ more ]

0000369
Micrognathia
Little lower jaw
Small jaw
Small lower jaw

[ more ]

0000347
Multiple joint contractures
0002828
Narrow mouth
Small mouth
0000160
Osteopenia
0000938
Patent ductus arteriosus
0001643
Premature delivery because of cervical insufficiency or membrane fragility
0005267
Pulmonary hypoplasia
Small lung
Underdeveloped lung

[ more ]

0002089
Scaling skin
flaking skin
peeling skin
scaly skin

[ more ]

0040189
Short palpebral fissure
Short opening between the eyelids
0012745
Short umbilical cord
0001196
Skin erosion
0200041
Small placenta
0006266
Sparse eyebrow
Sparse eyebrows
0045075
Sparse hair
0008070
Sparse or absent eyelashes
0200102
Structural foot deformity
0010219
Submucous cleft hard palate
0000176
Telecanthus
Corners of eye widely separated
0000506
Temporomandibular joint ankylosis
Freezing of jaw joint
0012478
Thin clavicles
Thin collarbone
0006645
Thin ribs
Slender ribs
0000883
Widely patent fontanelles and sutures
0004492
5%-29% of people have these symptoms
Ascending tubular aorta aneurysm
Bulging of wall of large artery located above heart
0004970
Atrial septal defect
An opening in the wall separating the top two chambers of the heart
Hole in heart wall separating two upper heart chambers

[ more ]

0001631
Camptodactyly of finger
Permanent flexion of the finger
0100490
Choanal atresia
Blockage of the rear opening of the nasal cavity
Obstruction of the rear opening of the nasal cavity

[ more ]

0000453
Congenital adrenal hypoplasia
0008244
Dextrocardia
Heart tip and four chambers point towards right side of body
0001651
Hypospadias
0000047
Large placenta
0006267
Microcolon
0004388
Natal tooth
Born with teeth
Teeth present at birth

[ more ]

0000695
Polyhydramnios
High levels of amniotic fluid
0001561
Short nail
Short nails
0001799
Thoracic kyphoscoliosis
0005659
Transposition of the great arteries
0001669
Ureteral duplication
Double ureter
0000073
Webbed neck
Neck webbing
0000465
Percent of people who have these symptoms is not available through HPO
Abnormality of the pinna
Abnormally shaped ears
Auricular malformation
Deformed ears
Malformed ears

[ more ]

0000377
Absent eyelashes
Failure of development of eyelashes
0000561
Adrenal hypoplasia
Small adrenal glands
0000835
Ankylosis
0031013
Aplasia/Hypoplasia of the eyebrow
Absence of eyebrow
Lack of eyebrow
Missing eyebrow

[ more ]

0100840
Autosomal recessive inheritance
0000007
Blepharophimosis
Narrow opening between the eyelids
0000581
Congenital pseudoarthrosis of the clavicle
0006585

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Tight skin contracture syndrome, lethal. Click on the link to view a sample search on this topic.

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