HUT (Hutterite)

DGM (Dutch-German Mennonite)

Inheritance: autosomal recessive
Genes: LMNA
ZMPSTE24

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

Intrauterine growth retardation
Contractures
Ectropion
Hyperkeratosis
“Pinched facies"
Skin atrophy
Respiratory distress
Low-set ears
Hypokinesia

Tight Skin Contracture Syndrome

Clinical Characteristics

General description (for patients):  

This is a congenital disorder of tight, thin skin causing contractures and a ‘pinched’ looking face. The head is somewhat enlarged, the ears are low-set, and the nose is small.  The skin breaks and erodes easily. Respiratory distress is a common symptom and death usually occurs days after birth.  The jaw is small and infants may not be able to open their mouths.

Medical description:  

Restrictive dermopathy is a lethal, congenital disorder with skin hyperkeratosis, contractures, and camptodactyly.  Severe contractures are present.  The skin is thin and erodes easily.  The head appears enlarged with wide sutures but the nose and mouth are small with micrognathia and the ears are set low.  Lashes and eyebrows may be missing.  Severe respiratory distress is a common but intubation is difficult due to the small mouth and taut facial skin. No internal malformations have been found.  Most live a few hours to a few days, and death is associated with respiratory distress.

Genetics:

Two possible mutation sites have been identified for this presumed autosomal recessive disorder: one in the LMNA gene (1q21.2) and another in the ZMPSTE24 (1p34) gene.  It seems that heterozygous splicing mutations in LMNA can be causative (autosomal dominant?), while heterozygous, homozygous and compound heterozygous mutations in the ZMPSTE24 gene likewise can lead to restrictive dermopathy (autosomal recessive?).  The presence of consanguinity among some parents of multiple affected children also suggests autosomal recessive inheritance.  Three documented children of two consanguineous Hutterite couples, and one from unrelated Mennonite parents have been reported.  Recently, homozygosity of a c.1085dupT mutation in the ZMPSTE24 gene was found in a newborn Mennonite infant.  The four Hutterite parents could be traced to a single ancestral couple but no relationship with the Mennonite parents was found.  No information is available on the genotypes of these cases.

Treatment:

No treatment is available.

Prognosis:

This is a lethal disorder.

Ancillary treatments and support:

Comfort care.

Specialists and specialty centers:

Dermatologist, Anesthesiologist.

References:

Lowry, R.B., Machin, G.A., Morgan, K., Mayock, D., and Marx, L.:  Congenital contractures, edema, hyperkeratosis, and intrauterine growth retardation: a fatal syndrome in Hutterite and Mennonite kindreds.  Am. J. Med. Genet. 22: 531-543, 1985.  PubMed ID: 3840649

Mau, U., Kendziorra, H., Kaiser, P., and Enders, H.:  Restrictive dermopathy: report and review.  Am. J. Med. Genet. 71: 179-185, 1997.  PubMed ID: 9217218

Navarro, C.L., Cadinanos, J., De Sandre-Giovannoli, A., Bernard, R., Courrier, S., Boccaccio, I., Boyer, A., Kleijer, W.J., Wagner, A., Giuliano, F., Beemer, F.A., Freije, J.M., Cau, P., Hennekam, R.C., Lopez-Otin, C., Badens, C., and Levy, N.: Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. Hum. Mol. Genet. 14: 1503-1513, 2005.  PubMed ID: 15843403

Chumel, L.: Homozygosity for the common mutation c.1085dupT gene in a Mennonite baby with restrictive dermopathy and placenta abruption.  Am. J. Med. Genet. (Letter) 152A: 262-263, 2009.  PubMed ID: 20034068