Focal Dermal Hypoplasia Syndrome Clinical Presentation

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.

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

• Complete total body skin examination to note features and contribute to early diagnosis and genetic testing
• Careful clinical assessment and intervention to optimize nutrition and growth (weight, height, head circumference, and body mass index)
• Careful examination of limbs to look for limb-length discrepancy and early consultation with orthopedic and plastic surgeons
• Ophthalmologic examination
• Screening for developmental delay, cognitive ability, and behavioral difficulties
• Oral examination, including evaluation for cleft palate and lip and dental anomalies
• Thorough examination of external genitalia and consideration of imaging studies of reproductive tract

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.

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

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.

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.

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:

• Heterochromia

• Irregularity of the pupils

• Aniridia

• Colobomas of the iris, choroid, retina, or optic disc

• Corneal defects

• Cloudiness of the vitreous

• Blue sclerae

• Blockage of the tear ducts with tearing

• Widely spaced eyes

• Anophthalmia

• Optic nerve hypoplasia

• Ectropion

• Ptosis

• Photophobia

• Papillomas at the lid margin or conjunctiva

• Retinal neovascularization

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:

• Malrotation of the intestine

• Papillomatous lesions of the esophagus leading to obstruction

• Gastric polyps

• Gastric reflux with laxity of the hiatus

• Diaphragmatic hernia

• Omphalocele

• Hernias, rectal prolapse, and perianal papillomas

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.

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:

• Speech and chewing problems from dental and oral changes
• Changes in visual acuity
• Gastroparesis, constipation, and gastroesophageal reflux
• Limitations in movement due to bony changes and limb changes