Version May 2024
INTRODUCTION — Focal dermal hypoplasia (FDH; MIM #305600), also known as Goltz syndrome or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder that is lethal in utero in males [1]. The primary feature of FDH is patchy dermal hypoplasia, with herniation of fat through defects in the dermis. There are a number of associated anomalies, including dental, hair, nails, extremities, central nervous system (CNS), and facial clefting.
This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of FDH. Other ectodermal dysplasias are discussed separately. (See "Ectodermal dysplasias" and "Tumor protein p63 (TP63)-related ectodermal dysplasias".)
EPIDEMIOLOGY — Focal dermal hypoplasia (FDH) is a very rare disorder. Its incidence and prevalence are not known. Approximately 300 cases have been reported in the literature since the first description in 1962 [2]. Approximately 90 percent of affected individuals are females.
PATHOGENESIS — Focal dermal hypoplasia (FDH) is an X-linked dominant disorder caused by mutations or deletions in the porcupine O-acyltransferase gene (PORCN), located at Xp11.23. Over 200 variants of PORCN have been identified [3]. In mice and Drosophila, the protein product of PORCN has been shown to be required for the secretion of Wnt proteins, which are needed for the activation of target genes in many developmental pathways [4-6].
Approximately 90 percent of individuals with FDH are females. They are heterozygous or mosaic for a pathogenic variant in PORCN. Of the affected females, 95 percent have a de novo mutation, and 5 percent inherit the gene defect from a parent. The mosaic distribution of skin lesions in females reflects lyonization.
Males with FDH are mosaic for a de novo PORCN pathogenic mutation or may have Klinefelter syndrome with a 47,XXY karyotype. Hemizygosity for a pathogenic variant in PORCN is believed to be lethal in male fetuses [1].
CLINICAL MANIFESTATIONS
Cutaneous — Patchy skin atrophy with fat herniation, typically following the lines of Blaschko, is a constant finding and is reported at birth in nearly 75 percent of affected individuals (picture 1A-B) [7]. Atrophic areas are susceptible to recurrent or persistent, punctate, crusted erosions. The hypoplastic lesions typically become hypopigmented, often with hyperpigmented freckling and/or telangiectasias within the hypoplastic lesions.
Hyperpigmentation or hypopigmentation follow the lines of Blaschko (picture 2). Papillomas are reported in nearly two-thirds of individuals, occurring primarily in the perioral area, groin, and distal extremities. Patchy alopecia and/or diffusely, sparse scalp hair is common. One cross-sectional survey noted that the majority of subjects reported skin or scalp symptoms of pruritus, stinging, and tenderness [8]. Nail changes are common, including longitudinal ridging, micronychia, and anonychia.
Extracutaneous — There are a variety of craniofacial manifestations associated with focal dermal hypoplasia (FDH), including microcephaly, facial asymmetry, notched nasal alae, cleft lip/palate, ocular abnormalities, dental anomalies, and dental malocclusions [9].
Oral soft tissue defects occur in approximately 70 percent of subjects and hard oral tissue defects in over 90 percent. More than one-half of patients have vertical dental enamel grooving, peg-shaped teeth, and/or enamel hypoplasia. Some patients are reported to have cleft lip/palate.
Intraoral lipomas or papillomas are common. Papillomas can also develop in the nose, pharynx, larynx, trachea, and esophagus [10]. There is one case report of squamous cell carcinoma of the esophagus [11]. Speech problems or difficulty chewing have been reported in up to three-fourths of individuals.
Limb abnormalities occur in over one-half of individuals with FDH [12]. Syndactyly and ectrodactyly are each reported in roughly two-thirds of affected individuals. Leg length discrepancy and reduction defects of long bones each occur in over one-half of affected individuals. Other reported orthopedic anomalies include congenital absence of foot and ankle, giant cell tumor of the bone, and osteopathia striata (striated appearance of bones on radiographs).
Short stature and low body weight are reported in up to three-fourths of affected individuals [13]. One study suggests growth hormone deficiency in a minority of patients [14]. Difficulty with feedings, chewing problems, and difficulty with swallowing are commonly reported, as are gastroesophageal reflux, gastroparesis, and constipation. Diaphragmatic hernia, hiatal hernia, umbilical hernia, and omphalocele have been reported.
Three-fourths of patients report ophthalmologic problems, including coloboma of the iris, retina, or choroid in over one-half of patients [15]. Nearly one-half have microphthalmia and 10 percent have anophthalmia. Additional ocular findings include coloboma, cataracts, nystagmus, and strabismus, as well as papillomas of the eyelid and conjunctiva. Vision ranges from 20/20 to only light perception.
Central nervous system manifestations can include sensorineural hearing loss, hydrocephalus, agenesis of the corpus callosum, and Arnold-Chiari malformation (see "Hydrocephalus in children: Physiology, pathogenesis, and etiology", section on 'Congenital' and "Chiari malformations"). Overall, adaptive and intellectual function is reported as average, with significant variability [16]. Approximately 15 percent of individuals are reported to have cognitive ability in the borderline to impaired range and 50 percent need educational support at school. Behavioral and emotional problems, usually withdrawn, shy behavior, are common.
Urogenital anomalies most commonly observed in affected girls are labia minora hypoplasia and short perineum body [17]. Asymmetry of the breast/nipples occur in one-third of individuals. There are case reports of bicornuate uterus, unilateral absent kidney, hypoplastic kidney, fused/horseshoe kidney, or cystic renal dysplasia. (See "Congenital uterine anomalies: Clinical manifestations and diagnosis" and "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)
PATHOLOGY — Histopathologic findings in areas of dermal hypoplasia include increased capillaries in the papillary dermis, attenuated dermis, and adipocytes within/below the attenuated dermis [18]. A decrease and fragmentation of elastic fibers may represent histopathologic clues to the diagnosis of focal dermal hypoplasia (FDH), and FDH should be included in the differential diagnoses of elastolytic disorders. The absence of dermal hypoplasia does not exclude the diagnosis of FDH [19].
DIAGNOSIS — Proposed clinical diagnostic criteria for focal dermal hypoplasia (FDH) include at least three of the major characteristic skin findings and one major limb malformation [20].
Major skin findings:
●Congenital patchy skin aplasia
●Congenital nodular fat herniation
●Congenital hyper- or hypopigmentation in Blaschko-linear distribution
●Telangiectasia
●Congenital ridged dysplastic nails
Major limb malformations:
●Split hand/foot (ectrodactyly)
●Transverse limb defects
●Syndactyly
●Oligodactyly
●Marked long bone reduction
Prenatal clinical findings suggesting possibility of FDH are the association of intrauterine growth retardation or low average weight, limb malformations, and thoracoabdominal wall defect or diaphragmatic hernia [21].
The diagnosis is confirmed by the identification of a germline heterozygous PORCN pathogenic variant or deletion in a female or a somatic mosaic hemizygous PORCN pathogenic variant in a male [1]. Genetics experts recommend sequence analysis of PORCN on a blood sample as first-tier testing. If no pathogenic variant is identified, intragenic deletion/duplication analysis of PORCN should be performed as well as chromosome microarray analysis to detect larger deletions/duplications that include PORCN [1].
If the suspicion for FDH is high, additional testing should include PORCN sequencing and deletion/duplication analysis on deoxyribonucleic acid (DNA) from saliva, a buccal swab, or an affected tissue (eg, skin, papillomas, surgical specimens), which increases the sensitivity for detecting somatic mosaicism [22]. Sanger sequencing alone may miss mosaic variants. Next-generation sequencing is more likely to allow for the detection of low-level mosaicism, especially in females with minimal clinical manifestations [22]. If this testing does not reveal a PORCN variant or deletion, a multigene panel that includes PORCN and other genes of interest may be considered. (See 'Differential diagnosis' below.)
Affected individuals with somatic mosaicism may also have germline mosaicism and are at risk of having affected offspring. Genetic counseling should be offered regarding recurrence risk and prenatal testing. Preimplantation genetic testing is also an option.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of focal dermal hypoplasia (FDH) includes [1]:
●Linear skin defects with multiple congenital anomalies 1 – Linear skin defects with multiple congenital anomalies 1, also called microphthalmia with linear skin defects (MLS; MIM #309801) syndrome, can present with skin and eye findings similar to FDH, but limb and skeletal deformities are uncommon. It is caused by deletions and variants in the mitochondrial holocytochrome c-type synthase gene HCCS on Xp22.2.
●Incontinentia pigmenti – Incontinentia pigmenti (IP; MIM #308300) affects skin, hair, teeth, nails, eyes, and the central nervous system but rarely has skeletal findings. IP is due to mutation in IKBKG (NEMO) on Xq28. (See "Incontinentia pigmenti".)
●Tumor protein p63-associated disorders – Tumor protein p63 (TP63)-associated disorders may have limb malformations and skin findings, but the skin findings are not typically along Blaschko distribution; ocular colobomas and microphthalmia are rare. TP63 maps to 3q28. (See "Tumor protein p63 (TP63)-related ectodermal dysplasias".)
●Oculocerebrocutaneous syndrome – The primary features of oculocerebrocutaneous syndrome (Delleman syndrome; MIM #164180) are microphthalmia/anophthalmia, orbital cysts, and linear skin and dermal hypoplasia [23,24]. In contrast with FDH, this entity occurs primarily in males. Brain malformations (frontal microgyria, periventricular nodular heterotopia, agenesis of the corpus callosum) distinguish this condition from FDH.
●Rothmund-Thompson syndrome – Rothmund-Thompson syndrome (RTS; MIM #268400) is an autosomal recessive disorder due to pathogenic variants in RECQL4 at 8q24.3 and characterized by poikiloderma, sparse hair, short stature, skeletal and dental anomalies, cataracts, and increased risk for cancer [25]. In contrast with FDH, in RTS, the skin lesions are typically not present at birth but develop over time. (See "Kindler epidermolysis bullosa", section on 'Differential diagnosis'.)
MANAGEMENT — The management of focal dermal hypoplasia (FDH) involves a multidisciplinary approach based upon the clinical findings in the individual patient [1]:
●Cutaneous manifestations – Close follow-up by a dermatologist to manage erosive lesions and cutaneous papillomas is crucial.
●Airway papillomas – Regular follow-up by a pediatric otolaryngologist to assess for airway papillomas, treatable with surgery or laser surgery, is indicated. Airway evaluation for papillomas is recommended prior to planned surgical procedures [26,27].
●Dental and oral manifestations – Assessment by a pediatric dentist by one year of age and potential management with orthodontic and prosthodontic specialists, as indicated. Cleft lip and/or palate management by plastic surgery and cleft team.
●Growth and nutrition – Close follow-up by pediatrician, nutritionist, and possibly gastroenterology for feeding and growth problems. Endocrinology assessment for short stature, including consideration for testing for growth hormone deficiency.
●Ocular manifestations – Early eye examination for assessment and management of ocular abnormalities is indicated.
●Limb and skeletal manifestations – Radiographic evaluation and consultation by orthopedic surgeon and/or plastic surgeon is appropriate.
●Renal and urogenital anomalies – Renal ultrasound to assess for structural anomalies of the kidneys and collecting system. Evaluation by a pediatric gynecologist prior to puberty is recommended.
●Neurologic manifestations – Hearing evaluation to rule out sensorineural or conductive hearing loss should be performed.
●Cognitive development – Close monitoring for evidence of developmental delay and behavior issues, with management by developmental pediatrician; psychologist; and occupational, physical, or speech therapists, as indicated.
Information on FDH for patients and families/caregivers can be found online at the National Center for Advancing Translational Sciences website.
PROGNOSIS — The prognosis for patients with focal dermal hypoplasia (FDH) is dependent upon the degree of involvement of cognitive function and neurosensory systems. Close monitoring of growth and development and multidisciplinary team management will improve outcomes.
SUMMARY AND RECOMMENDATIONS
●Definition – Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare X-linked dominant multisystem disorder characterized by patchy dermal hypoplasia and multiple cutaneous and extracutaneous abnormalities. (See 'Introduction' above.)
●Clinical features – The mucocutaneous manifestations of FDH include patchy skin atrophy, often with crusted erosions, hypo- or hyperpigmented lesions that follow the lines of Blaschko, oral soft tissue defects, and papillomatosis of oropharyngeal and respiratory mucosa (picture 1A-B and picture 2). Extracutaneous manifestations include microcephaly, facial asymmetry, dental anomalies, cleft lip/palate, limb defects, ocular abnormalities, central nervous system abnormalities, and urogenital anomalies. (See 'Clinical manifestations' above.)
●Diagnosis – The clinical diagnosis of FDH in a neonate is based upon the finding of congenital major skin manifestations (eg, patchy skin aplasia, nodular fat herniation, dysplastic nails) and major limb malformations (eg, split hand/foot, syndactyly, oligodactyly). The diagnosis is confirmed by the identification of a germline heterozygous PORCN pathogenic variant or deletion in a female or somatic mosaic hemizygous PORCN pathogenic variant in a male. (See 'Diagnosis' above.)
●Management – The management of FDH involves a multidisciplinary approach involving a pediatrician and pediatric dermatologist, otolaryngologist, dentist, plastic surgeon, ophthalmologist, neurologist, and geneticist, as indicated. (See 'Management' above.)
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