Focal Dermal Hypoplasia Syndrome

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Background

Focal dermal hypoplasia (FDH) is an uncommon genetic disorder affecting tissues of ectodermal and mesodermal origin. It is also known as Goltz syndrome or Goltz-Gorlin syndrome and was first described in 1962. Focal dermal hypoplasia is a multisystem disorder characterized by dermatologic, skeletal, ocular, urinary, gastrointestinal, cardiovascular, neurologic, and oral abnormalities.[1] It is usually, but not always, X-linked dominant (lethal in males except if male is mosaic). About 90% of affected individuals are female. Ninety-five percent are new mutations. Affected individuals often are recognized at birth or occasionally prenatally, but cases involving a minor expression of the syndrome may be diagnosed later in life. The mnemonic FOCAL can be used to remember some of the key features of this syndrome: female sex; osteopathia striata; coloboma; absent ectoderm-, mesoderm-, and neuroderm-derived elements; and lobster claw deformity.[2, 3, 4, 5, 6]

The eponyms of focal dermal hypoplasia should not to be confused with Gorlin syndrome or Gorlin-Goltz syndrome, which is the nevoid basal cell carcinoma syndrome.[7] Focal dermal hypoplasia is identified as entry #305600 in the Online Mendelian Inheritance of Man database.

Pathophysiology

The focal dermal hypoplasia (FDH) genetic defect has been associated with at least 80 different mutations in the PORCN gene of the X chromosome (Xp11.23).[8] Nonsense, frameshift, aberrant splicing, and missense mutations have all been identified in patients with focal dermal hypoplasia.[9] No genotype-phenotype correlation has been found thus far.

The biochemical functions of the human PORCN gene still are not completely characterized. However, much is known about PORCN signaling in the mouse and in humans. This gene provides instructions for making a protein that is responsible for modifying other proteins, including Wnt proteins. Wnt signaling is critical for normal embryonic development of the skin, bones, and other structures. Since Wnt signaling proteins cannot be released without the PORCN protein, and Wnt signaling is important for normal embryonic development, the defects found in this disorder are related to lack of Wnt signaling.[10, 11, 12, 13]

The severity of defects in focal dermal hypoplasia is variable, and this variability is due to random X-chromosome inactivation (lyonization) within cells. In females, one of the two X chromosomes is randomly inactivated in every cell. The result is functional mosaicism of cells. Tissues in which cells select for the defective PORCN gene show anomalies. In the skin, these abnormalities follow the embryonic lines of Blaschko.

Approximately 10% cases occur in males; postzygotic somatic mosaicism accounts for the findings in these affected males. Postzygotic somatic mosaicism is also postulated for the sporadic female cases with negative family pedigree analysis.

Etiology

Studies indicate that focal dermal hypoplasia (FDH) is usually caused by mutations of the PORCN gene, mapped to locus Xp11.23. At least 80 different mutations have been identified. These include nonsense, missense, and frameshift mutations, as well as abnormal splicing.[9, 14, 15, 16, 17, 18] No genotype-phenotype correlation has been found. Somatic and germline mutations may occur.

PORCN, a member of the porcupine (PORC) gene family, encodes transmembrane endoplasmic reticulum proteins that target Wnt signaling proteins. Wnt proteins are key regulators of embryonic development.

Although biochemical functions of the human PORCN gene are not well characterized, Wnt signaling may be involved in the phenotypic expression of focal dermal hypoplasia where defective/deficient Wnt signaling could affect cell fate or result in failure of a progenitor cell line to expand.

Drosophila melanogaster porcupine and its mouse homologue PORCN gene encode transmembrane bound endoplasmic reticulum proteins needed for the secretion of Wnt (Wingless and INT-1) proteins. (In Drosophila melanogaster, the PORCN gene is involved in the processing of the wingless protein.)

Investigators have detected embryonic mouse expression of PORCN in cartilage, primordia of long bones and digits, calvaria, the facial skeleton, molar tooth buds, the petrous part of the temporal bone, as well as affecting developing skin of the anterior body wall and limbs; and in the developing cerebral cortex and retina. These findings correlate with the developmental defects seen in persons with focal dermal hypoplasia.

Deletion of the PORCN gene has been achieved in mice. Conditional inactivation of mouse PORCN early in development leads to increased embryonic lethality. Mesenchyme-specific inactivation leads to limb defects, while ectoderm-specific inactivation leads to thin skin, alopecia, and abnormal dentition.[8]

Cell culture assays show that knock down of expression of PORCN by siRNA causes retention of Wnt3a in cells.[8]

Disorders that may be subsets of focal dermal hypoplasia

Angioma serpiginosum (OMIM #300652)

This is an X-linked skin disorder characterized by nonpurpuric red punctate lesions seen histologically as capillary ectasias in the superficial papillary dermis. The lesions often follow Blaschko lines. In 2007, Blinkenberg et al suggested that the disorder may be a mild variant of focal dermal hypoplasia.[19] Blinkenberg et al (2007) and Houge et al (2008) identified a 112-kb deletion on Xp that removed the PORCN gene and four other genes.[19, 20]

Pentalogy of Cantrell (OMIM #313850)

This is an X-linked disorder characterized by the combination of midline supraumbilical abdominal wall defects and absent or cleft lip. Overlap cases have been described with patients displaying these typical features in association with more typical focal dermal hypoplasia features and mutation in PORCN.[21]

Van-Allen Myhre syndrome (Listed in OMIM under focal dermal hypoplasia)

These children described first in 1997 by Van-Allen and Myhre and then by Hancock in 2002 showed intrauterine growth restriction; bilateral split foot–split hand malformations; a broad-based, skin-covered periumbilical abdominal wall herniation; areas of cutis aplasia congenita and bullous vesicles; microphthalmia, and colobomata of the iris, retina, and optic nerve bilaterally. This is likely a severe phenotype of focal dermal hypoplasia.[22, 23]

Epidemiology

Focal dermal hypoplasia (FDH) is an uncommon disorder. The exact prevalence is unknown. Only 200-300 cases have been reported in the literature. All races have been affected. The syndrome occurs predominantly in females. In males, it is usually X-linked and lethal in utero. A small number of male patients have been reported, mostly with postzygotic somatic mutations. Focal dermal hypoplasia is present at birth but may evolve thereafter and, in mildly affected individuals, may be recognized only later in life.

Prognosis

The prognosis is good; most individuals live to adulthood. However, many severely affected individuals die in infancy; family pedigree analysis shows a high incidence of miscarriages and stillbirths.

Most of the numerous organ abnormalities in the syndrome are present at birth and remain essentially unchanged thereafter. The morbidity and mortality depend on what organ systems are affected.

In the skin, an initial inflammatory stage may occur, but this usually subsides in the first few months after birth. Older patients report that the atrophic skin lesions are tender and sore. Periorificial fibrovascular papillomas may continue to appear during adulthood; these papillomas require repeated surgical intervention.

Patient Education

Information for patients and families with focal dermal hypoplasia (FDH) can be found through the National Institutes of Health Genetics Home Reference: Focal dermal hypoplasia. The first international research symposium was held July 22-23, 2013.[24] Other organizations are as follows:

History

In 1962, Goltz reported three female children with linear areas of thinning of the skin and herniations of adipose tissue. All cases were accompanied by a number of defects of ectodermal and mesodermal tissues.[5] The name focal dermal hypoplasia (FDH) derives from the characteristic skin changes. Lesions are present at birth, but they may progress and evolve over time. Since then, more than 300 cases have been reported from around the world. In 2013, the first International Research Symposium on Goltz Syndrome was held in Houston, Texas.

Physical Examination

Aspects of the physical examination in focal dermal hypoplasia (FDH) are as follows:

Cutaneous features

Symmetric, linear, reticulated, frequently tender, pink or red, thin skin is characteristic. Involved areas may be angular, atrophic, slightly raised, or depressed. The lesions generally follow the lines of Blaschko and can be a few millimeters to several centimeters in width. See the images below.



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Photograph shows characteristic linear, erythematous, raised and depressed macules that follow the lines of Blaschko. Also note oligodactyly of the ha....



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Characteristic lesions that follow the lines of Blaschko.



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Close-up view of reticulate, mildly atrophic, erythematous macules and soft, rounded nodules.

In pigmented skin, the lesions may be hypopigmented or hyperpigmented rather than erythematous. See the images below.



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Hyperpigmentation that follows the lines of Blaschko on the upper extremity.



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Slightly raised and pigmented macules and soft tumors are noted on this extremity.

Ulcerations may occur, presumably due to complete absence of dermis at these sites. This is one of several causes of aplasia cutis congenita and cutis verticis gyrata. Telangiectasias are reported. Rarely, inflammation is reported, with vesicular lesions in early postnatal months.

Skin lesions may occur anywhere on the body; they are prominent on the legs (especially the thighs), the forearms, and the cheeks (where lines radiate from the angles of the mouth). In mild cases, focal dermal hypoplasia involves only limited, sometimes unilateral, areas of skin. In severe cases, all areas of the body are involved.

The dermis may be totally or partially replaced by accumulations of adipose cells, which appear as striking hernialike outpouchings of fatty tissue; this feature is unique to focal dermal hypoplasia.

A striking abnormality is the appearance of raspberrylike papillomas. These papillomas are multiple, often arising at junctions between the mucosa and the skin (ie, perioral, perivulvar, perianal, periocular junctions). Less commonly, the ears (pinnae and external auditory canal), fingers and toes, groin, umbilicus, gums, and base of the tongue are involved. Such papillomas may cause obstruction in the larynx, esophagus, and stomach. New papillomas may continue to appear throughout childhood and into adulthood and can be mistaken for warts. One case report described lentigolike pigmented macules occurring at the periphery of atrophic skin lesions and periorificial papillomas.[25] These lesions have been described to develop progressively during adolescence and do not follow the lines of Blaschko.

Cutaneous adnexal abnormalities

Apocrine nevi, multiple hydrocystomas, hypohidrosis, and anhidrosis are occasional features. Scalp and body hair are usually sparse, and the hair may be brittle. Complete absence of hair on the scalp or pubic area is reported. Sparse eyebrows and eyelashes have also been observed. A variety of nail abnormalities occur, such as atrophy, dystropy, spooning, and grooving; they often accompany skeletal abnormalities.

Facial abnormalities

Asymmetry of the face with hemiatrophy is a feature. Eyebrows and eyelashes are sparse. Ears are low set, protruding, and sometimes asymmetric. Narrow nasal bridge and a broad nasal tip with a unilateral notching of the nasal alae are noted. The chin is commonly pointed. See the image below.



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Typical facial features are asymmetry of the face with mild hemiatrophy, low-set protruding ears, a narrow nasal bridge, a broad nasal tip with unilat....

Stature

Patients are usually of short stature, with sloping shoulders and truncal and limb asymmetry. Patients are noted to be below mean weight at birth. Mean weight for age, height for age, head circumference for age, and body mass index for age also are lower than reference populations.[24]

Skeletal features

Abnormalities are numerous and often severe. The spectrum is variable, ranging from short stature to aplasia of the bones with complete or partial absence of an extremity. Syndactyly is reported in 60% of the cases. Split hands and feet, claw hands, clinodactyly, adactyly, polydactyly, oligodactyly, and syndactyly are noted. See the images below.



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Characteristic lobster claw deformity.



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Syndactyly.



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Image shows oligodactyly of the feet. Also note the reticular erythematous hyperpigmentation on the limbs.

Abnormal vertebrae with kyphoscoliosis, sloped shoulders, abnormal clavicles and ribs, spina bifida occulta, hypoplasia of the pelvic bones, and generalized osteopenia may be present.

Multiple bone lesions that resemble giant cell tumors, osteochondromas, and vertebral bone cysts are reported. Giant cell tumors of the bone are osteoclastomas, which express increased levels of the nuclear factor kappaB ligand RANKL, which is regulated by Wnt signaling and essential for osteoclast formation. The aberrant Wnt signaling in focal dermal hypoplasia may disrupt RANKL expression, leading to increased osteoclast activity.[10, 11]

Osteopathia striata is a radiographic finding seen in approximately 20% cases, but it is not diagnostic of focal dermal hypoplasia (see Imaging Studies). When it occurs as an isolated finding, with no associations, it is known as Voorhoeve disease, an asymptomatic condition. Osteopathia striata may also be associated with other skeletal disorders, such as the autosomal dominant genodermatosis Buschke-Ollendorf syndrome, in which the striations are accompanied by mottling of bones (ie, osteopoikilosis). It can also be associated with bone condensation and osteopetrosis.

Central nervous system features

Cognitive impairment is not uncommon, although normal cognition is noted in many otherwise severely affected individuals. The extent of the cutaneous lesions is not correlated with central nervous system involvement. Diffuse cortical cerebellar atrophy can occur with microcephaly, postencephalitic cysts, and meningomyelocele with congenital hydrocephalus.[26] Seizures are rare. Withdrawn behavior and other difficulty with behavior has been reported.[24]

Ear abnormalities

Malformation, protrusion, and asymmetry of the ears is reported, as are auricular appendages, hypoplasia of the helix, and cholesteatoma. Patients have neurosensory and conductive hearing loss. Cochlear dysplasia and papillomas in or near the ear canal are features. The auditory nerve may be affected.

Ocular features

Ocular abnormalities are present in at least 40% of cases, and this rate may be higher. Colobomata of the iris, retina, and choroid have been reported in one third of cases, and, less frequently, anophthalmia, microphthalmia, strabismus, nystagmus, and ectopia lentis have also been reported. Other findings include the following:

Oral and dental defects [27]

A variety of oral and dental defects include prognathism, overbite, agenesis or dysplasia of the teeth, delayed tooth formation/eruption, microdontia, irregular spacing and malocclusion, enamel defects, and notching of the incisors or extra incisors.

Other reported oral findings include high-arched palate; double lingual frenulum; cleft lip; cleft palate; absence of a labial sulcus; hypertrophy of the gums; taurodontism; and papillomas of the gums, tongue, palate, and buccal mucosa.

Cardiopulmonary features

These can include anomalous pulmonary venous drainage and mediastinal dextroposition.

Gastrointestinal features

These can include the following:

Genitourinary findings

Abnormalities of the kidneys or ureters (eg, bifid ureter, renal pelvis) are reported. Features can include horseshoe kidney, hypoplastic or absent kidney, short perineum body, labia minora hypoplasia, and vulvar papillomas.

Infection-related features

Patients can be affected by recurrent respiratory infections, cellulitis, conjunctivitis, otitis media, and urinary tract infections. These have been secondary consequences of the organ systems affected; no primary regulatory dysfunction has been identified.

Complications

The presence of fibrovascular papillomas around, near, or within body orifices may result in functional or aesthetic problems. Large perianal papillomas may cause difficulties in defecation and hygiene. Rarely, papillomas in the esophagus or stomach wall cause obstruction. Perioral and genital papillomas can be mistaken for viral warts and inappropriately managed.

Other complications are as follows:

Imaging Studies

Radiography in focal dermal hypoplasia (FDH) may reveal osteopathia striata. Osteopathia striata consists of longitudinal striations in the metaphyses of the bones. The lesions are usually bilateral and symmetric, mainly involving the long bones and the sacral bone. In contrast, the vertebrae and iliac bones are typically spared.

Osteopathia striata is an idiopathic finding, which radiographically is manifested by linear vertical opacities that originate at an articular surface and extend into the diaphysis, where they gradually narrow and disappear. The thickened striations of lamellar bone are parallel to the axis of the long bones. The shape, density, and cortex of the affected bones are normal.

Osteopathia striata is commonly present in focal dermal hypoplasia patients; however is not a specific diagnostic feature. When osteopathia striata occurs as an isolated finding, with no associations, it is known as Voorhoeve disease. This is an asymptomatic finding that is often an incidental radiologic finding.

The radiographic diagnosis of osteopathia striata is a useful clue in individuals who have minimal phenotypic disease. A careful clinical history taking and dermatologic examination may lead to the diagnosis of focal dermal hypoplasia.

Prenatal ultrasonographic findings are variable. Imaging studies may reveal findings that range from nonspecific fetal growth delay to specific organ and/or developmental anomalies; all findings are contingent on the degree to which an individual is affected.

Consideration should be given to imaging of the reproductive tract in affected individuals.

Other Tests

Parents and siblings of patients with new, apparently sporadic cases of focal dermal hypoplasia (FDH) should be closely examined for subtle skin findings or other abnormalities. Prenatal testing/karyotype analysis, sequence analysis, and deletion analysis are available. Deletion analysis can be completed using fluorescence in situ hybridization (FISH) or array-based genomic hybridization.

Bidirectional sequence analysis of all coding exons and their intron-exon boundaries of the PORCN gene is now commercially available. In addition, targeted array comparative genomic hybridization (CGH) analysis with exon-level resolution (ExonArrayDx) is performed concurrently to evaluate for a deletion or duplication of one or more exons of this gene. The Genetic Testing Registry is a resource through the National Institutes of Health that provides information on laboratories offering genetic testing.

Clinicians should routinely screen persons with focal dermal hypoplasia to rule out cognitive and emotional/behavioral difficulties and offer timely treatment. Future research should focus on identifying risk factors for psychoeducational problems in this population. According to a 2016 study examining emotional, behavioral, adaptive, and intellectual ability in 17 subjects aged 3-55 years with focal dermal hypoplasia attending the 2013 Annual Family Conference of the National Foundation for Ectodermal Dysplasias, there was wide variability, with three participants (18%) exhibiting overall cognitive ability in the borderline-to-impaired range.[28] These findings are consistent with previous reports suggesting intellectual impairment in 15% of persons with focal dermal hypoplasia.

Procedures

Biopsy of the skin may be performed.

Histologic Findings

Early lesions demonstrate small perivascular lipocytes. Lipocytes may sometimes be noted in the papillary dermis. The atrophic reticulated patches of skin reveal attenuation of dermal collagen fibers with partial-to-complete loss of dermal collagen. Note the image below.



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Photomicrograph shows the histopathologic findings in a skin biopsy sample. The image depicts the characteristic absence of dermal collagen and the ac....

In mild cases, adipocytes may be noted only around dermal blood vessels; in severe cases, they may replace all or part of the dermal connective tissue. A layered effect sometimes occurs, with attenuated collagenous connective tissue lying both above and beneath an adipose layer. If the accumulation of adipose tissue is pronounced, it may cause the apparent herniation of subcutaneous tissue through the thinned skin.

The papillomatous lesions typically consist of a fibrovascular stalk composed of loose connective tissue with dilated vessels and a variable perivascular admixture of inflammatory cells.

The lentigolike, pigmented-macule lesions indicate increased amounts of melanin deposition in the basal epidermal keratinocytes, with an underlying mild dermal infiltrate of lymphocytes with numerous dermal melanophages.

In ultrastructural studies of affected skin, fibroblasts are diminished in number, small, and ovoid, with poorly developed cytoplasm and dilated, rough endoplasmic reticulum. A conspicuous feature is a marked and irregular thickening of the nuclear fibrous lamina.

Medical Care

Regular surveillance, with frequency increased as needed during and after adolescence, facilitates early detection of anomalies and timely preventative and/or corrective treatment planning in focal dermal hypoplasia (FDH) patients.

Medical management is targeted toward the various soft-tissue, dental, and skeletal anomalies, with the goal of achieving optimal functional and aesthetic results. Treatment with a flashlamp-pumped pulse dye laser may ameliorate the pruritic symptoms that sometimes are noted in affected skin, and it may improve the clinical appearance of the telangiectatic and erythematous skin lesions.[29]

Surgical Care

Surgical management of focal dermal hypoplasia (FDH) is targeted toward the various soft-tissue, dental, and skeletal anomalies, with the goal of achieving optimal functional and aesthetic results. Periorificial fibrovascular papillomas may continue to appear during adulthood; these papillomas require repeated surgical intervention.

Consultations

Consultations may include the following:

Long-Term Monitoring

Variable disease expression of focal dermal hypoplasia (FDH) may delay the initial diagnosis. Clinical follow-up with evidence of phenotypic evolution can assist in making a definitive diagnosis.

Surveillance may include the following:

Author

Wasim Haidari, Clinical Research Fellow, Center for Dermatology Research, Wake Forest University School of Medicine; MD Candidate, Georgetown University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

William W Huang, MD, MPH, FAAD, Associate Professor and Residency Program Director, Department of Dermatology, Wake Forest Baptist Health, Wake Forest University School of Medicine

Disclosure: Research PI for Sponsored Trial for: Gilead; Genentech;.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Leslie Castelo-Soccio, MD, PhD, Assistant Professor of Pediatrics and Dermatology, The Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.

Acknowledgements

Robert W Goltz, MD Professor Emeritus, University of Minnesota Medical School, University of California, San Diego, School of Medicine

Robert W Goltz, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society of Dermatopathology, California Medical Association, and Pacific Dermatologic Association

Disclosure: Nothing to disclose.

Wendy Lee, MD Assistant Professor of Dermatology, Department of Dermatology, Uniformed Services University of Health Sciences

Wendy Lee is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology

Disclosure: Nothing to disclose.

References

  1. Bree AF, Grange DK, Hicks MJ, Goltz RW. Dermatologic findings of focal dermal hypoplasia (Goltz syndrome). Am J Med Genet C Semin Med Genet. 2016 Mar. 172C (1):44-51. [View Abstract]
  2. Goltz RW. Focal dermal hypoplasia syndrome. An update. Arch Dermatol. 1992 Aug. 128(8):1108-11. [View Abstract]
  3. Goltz RW. Focal dermal hypoplasia. Pediatr Dermatol. 1990 Dec. 7(4):313-4. [View Abstract]
  4. Goltz RW, Henderson RR, Hitch JM, Ott JE. Focal dermal hypoplasia syndrome. A review of the literature and report of two cases. Arch Dermatol. 1970 Jan. 101(1):1-11. [View Abstract]
  5. Goltz RW, Peterson WC, Gorlin RJ, Ravits HG. Focal dermal hypoplasia. Arch Dermatol. 1962 Dec. 86:708-17. [View Abstract]
  6. Gorlin RJ, Meskin LH, Peterson WC Jr, Goltz RW. Focal dermal hypoplasia syndrome. Acta Derm Venereol. 1963. 43:421-40. [View Abstract]
  7. Nathwani S, Martin K, Bunyan R. Focal dermal hypoplasia: A novel finding in disguise. J Oral Biol Craniofac Res. 2018 May-Aug. 8 (2):143-146. [View Abstract]
  8. Wang X, Reid Sutton V, Omar Peraza-Llanes J, et al. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet. 2007 Jul. 39(7):836-8. [View Abstract]
  9. Lombardi MP, Bulk S, Celli J, et al. Mutation update for the PORCN gene. Hum Mutat. 2011 Jul. 32(7):723-8. [View Abstract]
  10. Grzeschik KH, Bornholdt D, Oeffner F, et al. Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet. 2007 Jul. 39(7):833-5. [View Abstract]
  11. Wang X, Reid Sutton V, Omar Peraza-Llanes J, et al. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet. 2007 Jul. 39(7):836-8. [View Abstract]
  12. Bornholdt D, Oeffner F, Konig A, Happle R. PORCN mutations in focal dermal hypoplasia: coping with lethality. Human Mutation. Oct 2009. 30(10):1472-3.
  13. Garavelli L, Simonte G, Rosato S, Wischmeijer A, Albertini E, Guareschi E, et al. Focal dermal hypoplasia (Goltz-Gorlin syndrome): a new case with a novel variant in the PORCN gene (c.1250T>C:p.F417S) and unusual spinal anomaly. Am J Med Genet A. 2013 Jul. 161A(7):1750-4. [View Abstract]
  14. Froyen G, Govaerts K, Van Esch H, et al. Novel PORCN mutations in focal dermal hypoplasia. Clin Genet. 2009 Dec. 76(6):535-43. [View Abstract]
  15. Clements SE, Wessagowit V, Lai-Cheong JE, Arita K, McGrath JA. Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene. J Dermatol Sci. 2008 Jan. 49(1):39-42. [View Abstract]
  16. Clements SE, Mellerio JE, Holden ST, McCauley J, McGrath JA. PORCN gene mutations and the protean nature of focal dermal hypoplasia. Br J Dermatol. 2009 May. 160(5):1103-9. [View Abstract]
  17. Maas SM, Lombardi MP, van Essen AJ, et al. Phenotype and genotype in 17 patients with Goltz-Gorlin syndrome. J Med Genet. 2009 Oct. 46(10):716-20. [View Abstract]
  18. Maas SM, Lombardi MP, van Essen AJ, et al. Phenotype and genotype in 17 patients with Goltz-Gorlin syndrome. J Med Genet. 2009 Oct. 46(10):716-20. [View Abstract]
  19. Blinkenberg EO, Brendehaug A, Sandvik AK, Vatne O, Hennekam RC, Houge G. Angioma serpiginosum with oesophageal papillomatosis is an X-linked dominant condition that maps to Xp11.3-Xq12. Eur J Hum Genet. 2007 May. 15(5):543-7. [View Abstract]
  20. Houge G, Oeffner F, Grzeschik KH. An Xp11.23 deletion containing PORCN may also cause angioma serpiginosum, a cosmetic skin disease associated with extreme skewing of X-inactivation. Eur J Hum Genet. 2008 Sep. 16(9):1027-8. [View Abstract]
  21. Smigiel R, Jakubiak A, Lombardi MP, et al. Co-occurrence of severe Goltz-Gorlin syndrome and pentalogy of Cantrell - Case report and review of the literature. Am J Med Genet A. 2011 May. 155A(5):1102-5. [View Abstract]
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  23. Hancock S, Pryde P, Fong C, Brazy JE, Stewart K, Favour A, et al. Probable identity of Goltz syndrome and Van Allen-Myhre syndrome: evidence from phenotypic evolution. Am J Med Genet. 2002 Jul 15. 110(4):370-9. [View Abstract]
  24. Fete TJ, Fete M. International research symposium on Goltz syndrome. Am J Med Genet C Semin Med Genet. 2016 Feb 1. 9999:1-4. [View Abstract]
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  26. Peters T, Perrier R, Haber RM. Focal dermal hypoplasia: report of a case with myelomeningocele, Arnold-Chiari malformation and hydrocephalus with a review of neurologic manifestations of goltz syndrome. Pediatr Dermatol. 2014 Mar. 31(2):220-4. [View Abstract]
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Photograph shows characteristic linear, erythematous, raised and depressed macules that follow the lines of Blaschko. Also note oligodactyly of the hand (entire rays are absent).

Characteristic lesions that follow the lines of Blaschko.

Close-up view of reticulate, mildly atrophic, erythematous macules and soft, rounded nodules.

Hyperpigmentation that follows the lines of Blaschko on the upper extremity.

Slightly raised and pigmented macules and soft tumors are noted on this extremity.

Typical facial features are asymmetry of the face with mild hemiatrophy, low-set protruding ears, a narrow nasal bridge, a broad nasal tip with unilateral notch of the nasal alae, and a pointed chin. Also note the reticular hyperpigmentation of the skin, sparse hair, and raspberrylike papillomas on the lips.

Characteristic lobster claw deformity.

Syndactyly.

Image shows oligodactyly of the feet. Also note the reticular erythematous hyperpigmentation on the limbs.

Photomicrograph shows the histopathologic findings in a skin biopsy sample. The image depicts the characteristic absence of dermal collagen and the accompanying appearance of adipose tissue in the dermis.

Typical facial features are asymmetry of the face with mild hemiatrophy, low-set protruding ears, a narrow nasal bridge, a broad nasal tip with unilateral notch of the nasal alae, and a pointed chin. Also note the reticular hyperpigmentation of the skin, sparse hair, and raspberrylike papillomas on the lips.

Photograph shows characteristic linear, erythematous, raised and depressed macules that follow the lines of Blaschko. Also note oligodactyly of the hand (entire rays are absent).

Photomicrograph shows the histopathologic findings in a skin biopsy sample. The image depicts the characteristic absence of dermal collagen and the accompanying appearance of adipose tissue in the dermis.

Characteristic lobster claw deformity.

Syndactyly.

Image shows oligodactyly of the feet. Also note the reticular erythematous hyperpigmentation on the limbs.

Characteristic lesions that follow the lines of Blaschko.

Hyperpigmentation that follows the lines of Blaschko on the upper extremity.

Slightly raised and pigmented macules and soft tumors are noted on this extremity.

Close-up view of reticulate, mildly atrophic, erythematous macules and soft, rounded nodules.