What are the other Names for this Condition? (Also known as/Synonyms)

• Fetal Hypokinesia Sequence due to Restrictive Dermopathy
• Hyperkeratosis-Contracture Syndrome
• Lethal Restrictive Dermopathy

What is Lethal Tight Skin Contracture Syndrome? (Definition/Background Information)

• Lethal Tight Skin Contracture Syndrome, or Restrictive dermopathy (RD), is a neonatal lethal genetic disease 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
• Lethal Tight Skin Contracture Syndrome is a congenital disorder and newborns are usually born prematurely (due to premature rupture of the membranes with subsequent delivery at about 30-32 weeks of gestation) with a very tight, thin, rigid and shiny skin with erosions and scaling, epidermal hyperkeratosis, prominent skin vessels, that results in limited joint movement and restricted growth of the underlying tissues, often rupturing and lacerating at flexure sites during delivery
• Facial dysmorphism is also a characteristic feature of RD and includes telecanthus, short, down-slanting palpebral fissures, sparse/absent eyelashes and eyebrows, a small and pinched nose, posteriorly rotated low-set ears, micrognathia, and mouth fixed in the ''O'' position
• Additional features include congenital anonychia, narrow chest, dysplastic clavicles, rocker-bottom feet and arthrogryposis multiplex. Intrauterine growth retardation (IUGR), polyhydramnios, decreased fetal movements, FADS, large placenta, neonatal teeth, choanal atresia, pterygium colli, patent arterial duct, interauricular communication, dorsal kyphoscoliosis, camptodactyly, hypospadias, ureteral duplication, adrenal hypoplasia, have been occasionally reported
• Pulmonary hypoplasia most often leads to respiratory insufficiency and death. Neither structural central nervous system nor visceral defects occur in RD
• The rare mutations in the LMNA gene have a dominant effect (de novo, heterozygous mutations with putative, low risk of germinal mosaic in the parents) while the frequently observed ZMPSTE24 mutations are inherited recessively, leading to the possibility of prenatal diagnosis for further pregnancies (25% risk of having another affected child for two mutation carriers), if the molecular bases of the disease are identified
• To date, approximately 80 children with RD have been described in the world literature

(Source: Restrictive Dermopathy; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Lethal Tight Skin Contracture Syndrome? (Age and Sex Distribution)

• Lethal Tight Skin Contracture Syndrome is an extremely rare congenital disorder. The presentation of symptoms is known to occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Lethal Tight Skin Contracture Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Lethal Tight Skin Contracture Syndrome can be inherited
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Lethal Tight Skin Contracture Syndrome? (Etiology)

• Lethal Tight Skin Contracture Syndrome can be caused by heterozygous, de novo mutations of the LMNA (1q22) gene (primary laminopathy) or, much more frequently, by homozygous null mutations of the ZMPSTE24(1p34) gene (secondary laminopathy)
• Defects in ZMPSTE24 impair the processing of prelamin A into mature lamin A, leading to the massive intranuclear accumulation of prelamin A isoforms which exert toxic effects and lead to the development of RD
• The rare mutations in the LMNA gene have a dominant effect (de novo, heterozygous mutations with putative, low risk of germinal mosaic in the parents) while the frequently observed ZMPSTE24 mutations are inherited recessively, leading to the possibility of prenatal diagnosis for further pregnancies (25% risk of having another affected child for two mutation carriers), if the molecular bases of the disease are identified

(Source: Restrictive Dermopathy; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Lethal Tight Skin Contracture Syndrome?

The signs and symptoms of Lethal Tight Skin Contracture Syndrome may include:

• Abnormality of the pinna
• Adrenal hypoplasia
• Blepharophimosis
• Congenital pseudoarthrosis of the clavicle
• Decreased calvarial ossification
• Flexion contracture
• Hydropic placenta
• Kyphoscoliosis
• Large fontanelles
• Narrow nasal ridge
• Overtubulated long bones
• Premature birth
• Premature rupture of membranes
• Prominent superficial blood vessels
• Rocker bottom foot
• Sparse eyelashes

Obligate present symptoms in 100% of the cases: Stiff skin

Very frequently present symptoms in 80-99% of the cases:

• Abnormal cellular phenotype
• Aplasia/hypoplasia involving the nose
• Aplasia/hypoplasia of the clavicles
• Aplasia/hypoplasia of the eccrine sweat glands
• Decreased fetal movement
• Decreased skull ossification
• Dermal atrophy
• Dermal translucency
• Downslanted palpebral fissures
• Entropion
• Epidermal hyperkeratosis
• Generalized hyperkeratosis
• Hypertelorism
• Increased anterioposterior diameter of thorax
• Intrauterine growth retardation
• Low-set ears
• Narrow mouth
• Osteopenia
• Patent ductus arteriosus
• Premature delivery because of cervical insufficiency or membrane fragility
• Pulmonary hypoplasia
• Scaling skin
• Short palpebral fissure
• Short umbilical cord
• Skin erosion
• Small placenta
• Sparse eyebrow
• Sparse hair
• Sparse or absent eyelashes
• Structural foot deformity
• Submucous cleft hard palate
• Telecanthus
• Temporomandibular joint ankylosis
• Thin clavicles
• Thin ribs
• Widely patent fontanelles and sutures

Frequently present symptoms in 30-79% of the cases:

• Atrial septal defect
• Camptodactyly of finger

Occasionally present symptoms in 5-29% of the cases:

• Choanal atresia
• Congenital adrenal hypoplasia
• Dextrocardia
• Dilatation of the ascending aorta
• Hypospadias
• Large placenta
• Microcolon
• Natal tooth
• Polyhydramnios
• Short nail
• Thoracic kyphoscoliosis
• Transposition of the great arteries
• Ureteral duplication
• Webbed neck

(Source: Lethal Tight Skin Contracture Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Lethal Tight Skin Contracture Syndrome Diagnosed?

Lethal Tight Skin Contracture Syndrome is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Lethal Tight Skin Contracture Syndrome?

The complications of Lethal Tight Skin Contracture Syndrome may include:

• Severe abnormalities involving several organs
• Preterm birth
• Stillbirth (in many cases)

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Lethal Tight Skin Contracture Syndrome Treated?

There is no cure for Lethal Tight Skin Contracture Syndrome, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complications that develops.

How can Lethal Tight Skin Contracture Syndrome be Prevented?

Currently, Lethal Tight Skin Contracture Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Lethal Tight Skin Contracture Syndrome? (Outcomes/Resolutions)

• The prognosis of Lethal Tight Skin Contracture Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications. However, typically, the prognosis is poor

Additional and Relevant Useful Information for Lethal Tight Skin Contracture Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/