PORCN-Related Developmental Disorders

Clinical characteristics: PORCN-related developmental disorders include a spectrum of highly variable multisystem disorders caused by developmental abnormalities in mesodermal and ectodermal structures primarily involving the skin, limbs, eyes, and face. The manifestations vary among affected individuals, and many have only a subset of the characteristic features. Skin manifestations present at birth include atrophic and hypoplastic areas of skin; cutis aplasia; fat nodules in the dermis manifesting as soft, yellow-pink cutaneous nodules; and pigmentary changes. Verrucous papillomas of the skin and mucous membranes may appear later. The nails can be ridged, dysplastic, or hypoplastic; hair can be sparse or absent. Limb malformations include oligo- and syndactyly and split hand/foot. Developmental abnormalities of the eye can include anophthalmia/microphthalmia, iris and chorioretinal coloboma, and lacrimal duct abnormalities. Craniofacial findings can include facial asymmetry, notched alae nasi, cleft lip and palate, pointed chin, and small, underfolded pinnae. Dental anomalies can include hypodontia, enamel defects, and/or abnormally shaped teeth. Occasional findings include abdominal wall defects, diaphragmatic hernia, and renal anomalies. Psychomotor development is usually normal; some individuals have cognitive impairment and/or behavioral issues.

Diagnosis/testing: A PORCN-related developmental disorder can be diagnosed in a proband with characteristic clinical features and a heterozygous pathogenic variant in PORCN identified by molecular genetic testing.

Management: Treatment of manifestations: Care by a dermatologist for painful and pruritic erosive lesions that are prone to infection; laser therapy for atrophic areas and granulation tissue may be helpful; lotion for pruritic lesions; preoperative evaluation by an otolaryngologist for hypopharyngeal and/or tonsillar papillomas; management of large papillomas of the larynx, trachea, and/or esophagus per otolaryngologist or gastroenterologist; referral to a physical/occupational therapist and hand surgeon for management of hand and foot malformations; standard management of structural abnormalities of the eyes, kidneys, diaphragmatic hernia, and abdominal wall defects; visual aids or other resources for reduced vision; dental care, good oral hygiene, dietary counseling; consider fissure sealants to reduce dental caries; orthodontic care as needed for malocclusion, veneers as needed; hearing aids and community hearing services as needed; developmental services and educational support; standard management for behavioral issues.

Surveillance: Annual evaluation with a dermatologist; monitor for gastroesophageal reflux disease, swallowing difficulties, and symptoms of obstructive sleep apnea at each visit; annual physical examination for scoliosis, particularly in individuals with costovertebral segmentation abnormalities; annual eye examinations; dental examination every six months; annual hearing evaluation or as needed; assess growth and body composition to determine need for nutritional intervention at each visit; annual screening for cognitive, emotional, behavioral, and adaptive issues.

Agents/circumstances to avoid: Prevent exposure to extreme heat in those with hypohidrosis.

Genetic counseling: PORCN-related developmental disorders are inherited in an X-linked manner. Females (90% of affected individuals) are heterozygous or mosaic for a PORCN pathogenic variant; most live-born affected males (10% of affected individuals) are mosaic for a de novo PORCN pathogenic variant. It is presumed that most non-mosaic hemizygous males are not viable. Approximately 95% of females with PORCN-related developmental disorders have a de novo pathogenic variant; ~5% inherited the pathogenic variant from a parent. The risk that the PORCN pathogenic variant will be transmitted by an affected heterozygous female is 50%; however, because most male conceptuses with a PORCN pathogenic variant are presumed to be spontaneously aborted, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. If the affected female is mosaic for a PORCN pathogenic variant, the risk to her female offspring of inheriting the pathogenic variant depends on the level of mosaicism in her germline and can be as high as 50%. Once the PORCN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.