Unrestricted fascination with restrictive dermopathy
By Warren R. Heymann, MD, FAAD
Nov. 16, 2022
Vol. 4, No. 46
Barely a week into our fellowships at the University of Pennsylvania in 1984, my wife (a geneticist) asked her favorite dermatologist (me) if I had any thoughts about a neonate with skin that was thin, taut, and translucent. Nearly four decades later I can still visualize the apparent vasculature on the trunk and the “O” shaped mouth of this neonate who expired within weeks of birth. There were other features such as scaling skin and joint contractures. Other than being astounded by the presentation, I had nothing to offer. My wife presented this case as an abstract entitled “A lethal ichthyosis variant with arthrogryposis” at the American Society of Human Genetics in 1985. (1)
In the early 1980s, scattered similar reports were under the umbrella of aplasia cutis. In 1986, Witt et al introduced the term restrictive dermopathy (RD); the following is an excerpt from their abstract: “A brother and sister from consecutive pregnancies had rigid and tightly adherent skin in association with generalized contractures, unusual facies, pulmonary hypoplasia, an abnormal placenta, and a short umbilical cord. Both died shortly after birth…It is postulated that the defective skin severely restricted movement and secondarily led to the other abnormalities. Familial occurrence is most consistent with autosomal recessive transmission. These patients and the primary skin defect are discussed within the framework of the Fetal Akinesia or Hypokinesia Deformation Sequence.” (2)
A seminal breakthrough in understanding the pathogenesis of RD occurred in 2004, when Navarro et al studied 9 fetuses/newborn children with RD, observing that defects of the nuclear lamina and matrix are involved in all RD cases. (3) RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations. (3)
The nuclear lamina (NL) is present in all animals and is composed of type V intermediate filaments called lamins plus lamin-associated proteins. Mammalian genomes contain 3 lamin genes: LMNA, which encodes lamin A and lamin C (A-type lamins), as well as LMNB1 and LMNB2 that encode lamin B1 and B2 (B-type lamins), respectively. The lamin A precursor also contains a CaaX motif and is initially farnesylated. Proteolytic cleavage by the ZMPSTE24 protease removes the last 15 amino acid residues and the hydrophobic farnesyl group to produce mature lamin A, which is found both at the NL and in the nuclear interior. (4) The laminopathy most familiar to dermatologists is the Hutchinson-Gilford progeria syndrome (HGPS), previously discussed in DWI&I. (5)
Navarro et al determined that 2 patients had a heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Seven patients displayed a unique heterozygous insertion leading to the creation of a premature termination codon in the gene ZMPSTE24. As previously stated, this gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. (3) Multiple studies have confirmed that most cases of RD are due to mutations in ZMPSTE24.
Scott et al reported 3 new patients with RD with ZMPSTE24 mutations and reviewed the literature on 113 patients, 93 of whom had clinical features detailed. RD may be considered prenatally, based on ultrasound findings such as polyhydramnios and decreased fetal movement. Premature birth and small size are characteristic. The authors state: “Key physical findings which raise suspicion for RD include tight, fragile skin, superficial erosions or ulcerations, and prominent superficial vasculature. Typical facial findings included a small “pinched” nose, low-set ears, and micrognathia or a small “O”-shaped mouth. Joint contractures, reported in our 3 patients, were described in over 90% of the patients in the literature. Ancillary testing can corroborate clinical suspicion of RD. Hypoplastic clavicles, seen in our 3 patients, were the most frequently reported radiographic abnormality and provides an important clue to making the diagnosis.” (6) The clinical features of RD are so characteristic; the diagnosis may be made by teledermatology. (7)
Histological features of RD include hyperkeratosis, effacement of rete pegs, absent skin appendages, abnormally aligned collagen bundles arranged parallel to the epidermis, and a paucity of dermal elastic bundles. Ultrastructural evaluation of skin by electron microscopy demonstrates dense collagen bundles with reduced or absent elastic fibers. (8)
As this disorder is lethal within weeks of presentation, genetic confirmation of either the LMNA or ZMPSTE24 mutations is essential to help guide families for potential future pregnancies. Paraphrasing myself from my commentary on HGPS (5), understanding orphan diseases such as RD provides unique insights into aging mechanisms that may be applied to the general population. Perhaps the use approaches being studied for HGPS, such as farnesyl transferase inhibitors (lonafarnib is approved for HGPS), gene therapy (using CRISPR/Cas9-based genome editing), antisense oligonucleotides targeting RNA, and other inhibitors (of prenylation, methylation, or Progerin-Lamin A interaction) (9) could be attempted in RD. Last week I watched the first installment of the PBS presentation of Jules Verne’s Around the World in Eighty Days. In 1872, the concept of circumnavigating the globe in that timeframe was preposterous, while we now have ordinary citizens (wealth aside) approaching the exosphere. Although much remains to be discovered about RD, I anticipate that advances in understanding and potential therapy will no longer be in the realm of science fiction.
Point to Remember: Restrictive dermopathy is a lethal laminopathy. Despite its rarity, it is essential to recognize the disorder, confirm the diagnosis by genetic testing, and help guide family planning. Advances in understanding the pathogenesis of RD may translate into novel anti-aging therapies.
Our experts’ viewpoint
Karina L. Vivar, MD, FAAD
Health System Clinician of Pediatrics (Dermatology)
Ann & Robert H. Lurie Children’s Hospital of Chicago
Northwestern University Feinberg School of Medicine
Anthony J. Mancini, MD, FAAD
Professor of Pediatrics & Dermatology
Ann & Robert H. Lurie Children’s Hospital of Chicago
Northwestern University Feinberg School of Medicine
As detailed by Dr. Heymann, our understanding of restrictive dermopathy (RD) dramatically advanced from descriptive reports in the 1980s and the pivotal discovery of the pathogenesis and genetic basis of this lethal laminopathy in the early 2000s. In the last five years, our institution has cared for three patients with RD. Despite being a tertiary children’s hospital, this incidence of RD is remarkably unusual given the rarity of this condition, with only 113 unique patients previously described. This series of patients and review of the literature reinforce essential clinical features which, if promptly recognized, allow for early diagnosis. Additionally, the increasing availability of expedited genetic testing can culminate in enhanced compassionate care and well-informed clinical decision making for patients and families as they face a uniformly-fatal diagnosis. Families should also be offered appropriate genetic counseling for parents and unaffected siblings to assist in future family planning. Research into potential therapies may benefit RD patients in the future, providing hope in the face of a devastating diagnosis, and may perhaps be applicable more broadly to aging and other conditions affecting the nuclear lamina.
Schnur R.E., Ashmead J., Kelley R.I. A lethal ichthyosis variant with arthrogryposis. Platform presentation: American Society of Human Genetics, Salt Lake City. Am J Hum Genet 1985; 37: A7.
Witt DR, Hayden MR, Holbrook KA, Dale BA, Baldwin VJ, Taylor GP. Restrictive dermopathy: a newly recognized autosomal recessive skin dysplasia. Am J Med Genet. 1986 Aug;24(4):631-48. doi: 10.1002/ajmg.1320240408. PMID: 2426945.
Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, Geneviève D, Hadj-Rabia S, Gaudy-Marqueste C, Smitt HS, Vabres P, Faivre L, Verloes A, Van Essen T, Flori E, Hennekam R, Beemer FA, Laurent N, Le Merrer M, Cau P, Lévy N. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet. 2004 Oct 15;13(20):2493-503. doi: 10.1093/hmg/ddh265. Epub 2004 Aug 18. PMID: 15317753.
Dobrzynska A, Gonzalo S, Shanahan C, Askjaer P. The nuclear lamina in health and disease. Nucleus. 2016 May 3;7(3):233-48. doi: 10.1080/19491034.2016.1183848. Epub 2016 May 9. PMID: 27158763; PMCID: PMC4991244.
Heymann WR. Becoming pro-geriatric by understanding progeria. https://www.aad.org/dw/dw-insights-and-inquiries/dermatopathology/becoming-pro-geriatric-by-understanding-progeria
Scott JB, Yanes AF, Vivar KL, Yun D, Wagner A, Kruse L, Mancini AJ. Restrictive dermopathy: Three new patients with ZMPSTE24 mutations and a review of the literature. Pediatr Dermatol. 2021 Nov;38(6):1535-1540. doi: 10.1111/pde.14822. Epub 2021 Oct 14. PMID: 34647350.
Diociaiuti A, D'Amico P, Pisaneschi E, Giancristoforo S, Pappalardo MG, Di Guardo V, Zambruno G, El Hachem M. Teledermatology diagnosis of the first Italian patient affected with restrictive dermopathy due to ZMPSTE24 homozygous mutation. J Eur Acad Dermatol Venereol. 2019 Mar;33(3):e139-e140. doi: 10.1111/jdv.15351. Epub 2018 Dec 7. PMID: 30461078.
Pradeep I, Gowrishankar K, Shanmugasundaram L. Lethal Restrictive Dermopathy with ZMPSTE24 Mutation. Pediatr Dev Pathol. 2021 Dec 27:10935266211065316. doi: 10.1177/10935266211065316. Epub ahead of print. PMID: 34961372.
Macicior J, Marcos-Ramiro B, Ortega-Gutiérrez S. Small-Molecule Therapeutic Perspectives for the Treatment of Progeria. Int J Mol Sci. 2021 Jul 3;22(13):7190. doi: 10.3390/ijms22137190. PMID: 34281245; PMCID: PMC8267806.
Zhang H, Chen X, Guo Y, Liang J, Tang L, Yu H, Yao Z. Hutchinson-Gilford progeria syndrome: report of 2 cases and a novel LMNA mutation of HGPS in China. J Am Acad Dermatol. 2013 Oct;69(4):e175-6. doi: 10.1016/j.jaad.2011.07.002. PMID: 24034385.
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