The journey of focal dermal hypoplasia: From description to inspired therapy

By Warren R. Heymann, MD
Oct. 9, 2017

The dermatologic community lost a giant in 2014 with the passing of Robert W. Goltz, MD at the age of 90. Dr. Goltz was not only responsible for describing focal dermal hypoplasia (FDH), but also multicentric reticulohistiocytosis, generalized elastolysis, and the nevoid basal cell carcinoma syndrome (with his good friend Robert Gorlin). (1)

In the initial paragraph of his classical paper on FDH, Goltz et reported: “Three patients [all female] having a remarkable congenital decrease in the connective tissue of the skin have been reported under the title of focal dermal hypoplasia. This defect appears as linear areas of thinning of the skin and herniations of adipose tissue in the form of yellowish papules. This anomaly seems always to be accompanied by a number of other defects of ectodermal and mesodermal tissues and may represent only one part of a syndrome.” Although FDH is now known as FDH of Goltz, the authors acknowledged that there had been 2 other distinct examples of the syndrome reported in 1934 by Liebermann under the title “atrophoderma linearis maculosa et papillomatosis congenitalis”. (2) [As an aside, it was fascinating to look at the all-star cast of authors in the referenced papers in the manuscript — Rook, Whimster, the brothers Hailey, Lynch, Worringer, and Laugier — whew!]
 
In his last published manuscript (two years after his death), in which Dr. Goltz was the senior author, Bree et al reviewed the clinical data derived from participants who convened for the International Research Symposium for Goltz Syndrome held in Houston, Texas in 2013. The following is the abstract from the article that detailed the symposium (3):

Goltz syndrome, caused by mutations in PORCN, is an X-linked dominant ectodermal dysplasia which is also known as focal dermal hypoplasia. This name is derived from the predominant pathologic skin findings of the syndrome. Nineteen Goltz-affected participants attended a multidisciplinary scientific and clinical conference convened by the National Foundation for Ectodermal Dysplasia which allowed further characterization of the features of this very rare condition. At birth, the affected areas of skin are typically erythematous and fragile. The hallmark cutaneous features, which vary widely due to mosaicism and X-inactivation, include the previously described skin changes of asymmetric Blaschko-linear and reticulated atrophy, pigmentary changes, and telangectasias. Lipomatous changes and papillomas as characteristically defined were reported in the majority of patients. A newly recognized skin finding was progressive hyperpigmented freckling that occurred within the hypopigmented areas which were noted to be photosensitive. Many patients also had a pebbly texture to the central face, dorsal hands and feet. Punctate erosions within the atrophic areas and hypohidrosis were also common. Most had patchy alopecia and many had diffusely thin hair. Scanning electron microscopy of the hair shafts revealed abnormalities in the majority of participants with several different features identified, including atrophic hairs with reduced diameters, markedly flattened hairs as noted in cross-sectional views, trichorrhexis nodosa, pili torti, and pili trianguli et canaliculi. Nail changes included V-nicking and longitudinal ridging of the nail plate, in addition to micronychia. Early recognition of the dermatologic features, in addition to the variable but universal limb anomalies, of Goltz syndrome will allow early and accurate diagnosis without the need for extensive diagnostic studies, while also allowing for accurate prognosis and appropriate genetic counseling.

FDH is a rare disorder with approximately 250 patients described in the literature. To date, 165 variants representing 119 different mutations have been logged in the Leiden open (source) variation database. Phenotypic variants are due to mutations scattered throughout the entire coding sequence of the PORCN gene. Large deletions and splice site mutations have also been reported. The PORCN gene encodes a 461 amino acid 52-kDa protein involved in the secretion and signaling of WNT proteins, which plays a role in embryonic tissue development. Conditional inactivation of PORCN in mice reproduces alopecia and limb defects seen in patients with FDH. In humans, approximately 90% of individuals with FDH are female and 95% of all cases are de novo. Only mosaic males are thought to survive as non-mosaic male PORCN pathogenic variants are presumed lethal. (4)
 
The goals of acquiring molecular understanding of a genodermatosis are to identify those at risk for disease prevention, or to develop gene therapy for the afflicted. WNT signaling molecules are dysregulated in bone disorders, cancer, cardiovascular disease and neuropsychiatric illness. Current research for WNT targeted therapeutics is underway. (5)

For FDH specifically, it may not be necessary to wait for gene therapy to improve the lives of these patients. Krakowski et al treated skin lesions of a girl with FDH by utilizing an ablative microfractionated carbon dioxide laser. Histologic study of mosaically affected areas of FDH treated with the laser thickened the atrophic dermis, compared with internal controls of uninvolved skin. A marked shift in collagen predominance from type III (fetal/early wound) to type I (adult/mature) was observed. The authors concluded that thermal microtrauma caused by ablative fractional laser resurfacing may create a unique environment to activate latent genes, inducing neocollagenesis and allowing patients with FDH to adaptively produce the collagen subtype that was specifically deficient at baseline. (6)

I never had the privilege of meeting Dr. Goltz. I suspect that he would be ecstatic seeing these molecular and therapeutic advances offering hope to those patients afflicted with the disease he described more than half a century ago.

1. Burgdorf WH, et al. In memoriam: Robert W. Goltz (1923-2014). J Am Acad Dermatol 2014; 71: e163-5.
2. Goltz RW, et al. Focal Dermal Hypoplasia. Arch Dermatol 1962; 86; 708-17.
3. Bree AF, et al. Dermatologic findings of focal dermal hypoplasia (Goltz syndrome). Am J Med Genet C Semin Med Genet 2016; 172C: 44-51.
4. Bostwick B, et al. Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals. Am J Med Genet C Semin Med Genet 2016; 172C; 9-20.
5. Katoh M, Katoh M. Molecular genetic and targeted therapy of WNT-related human diseases. Int J Mol Med 2017; 40: 587-606.
6. Krakowski AC, et al. Laser-induced neocollagenesis in focal dermal hypoplasia associated with Goltz syndrome in a girl. JAMA Dermatol 2017; Sept 20 [Epub ahead of print].

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