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What is This Syndrome?

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Author: 
Katherine Szyfelbein Masterpol, MD, and Daniel S. Loo, MD

Patient Presentation

Derm DXDerm DXA full-term African-American female was born with an ichthyosiform dermatitis following Blaschko’s lines that spared only her face (Figure 1). An ultrasound of the fetus at 29 weeks’ gestation revealed shortened long bones (arms and legs). Chromosome analysis was normal. X-rays performed on day 3 of life confirmed the ultrasound findings and also revealed stippled epiphyses at numerous sites (Figure 2). On physical examination, the right lower extremity was longer than the left.

WHAT IS YOUR DIAGNOSIS?

DIAGNOSIS: Conradi-Hünermann Syndrome

Conradi-Hünermann syndrome, also known as Conradi-Hünermann-Happle syndrome or X-linked dominant chondrodysplasia punctata, is linked to mutations in the emopamil binding protein gene, which encodes 3β-hydroxysteroid-Δ8-Δ7-isomerase. This enzyme catalyzes an intermediate step in the conversion of lanosterol to cholesterol.1 As a result, affected patients have elevated tissue and blood levels of cholesterol intermediates 8(9)-cholesterol and 8-dehydrocholesterol. These sterol precursors accumulate in the epidermis and cannot substitute for cholesterol to form competent lamellar membrane. This disturbance in the stratum corneum lipid composition results in the scaling phenotype.2 Significant variation in severity exists and is thought to be a result of X-chromosomal inactivation causing genetic mosaicism.3

Clinical Presentation

Conradi-Hünermann syndrome typically presents in neonates as hyperkeratotic plaques in a Blaschkoid distribution, often accompanied by erythroderma. Frequently, there is resolution of the erythroderma and scale after 3 to 6 months of age. Residual follicular atrophoderma and hypo- or hyperpigmented streaks are often observed. Persistent psoriasiform lesions may remain in intertriginous sites. Cicatricial alopecia of the scalp and eyebrows is not uncommon. Nails may appear flattened and exhibit onychoschizia.4,5,6 Frontal bossing, a flat nasal root and macrocephaly can be additional features.4,5,6 Skeletal involvement typically manifests as asymmetric shortening of the long bones, particularly the humerus and femur, although rare symmetric shortening has been reported.7 Punctate calcification or stippling of the epiphyses can be seen on radiologic imaging of various bones during infancy and usually disappears within the first few years of life.8 Kyphoscoliosis and hip dislocation may develop. Cataracts, unilateral or bilateral, are common. Rarely, mental retardation may accompany the syndrome.5,6

Differential Diagnosis

The clinical differential diagnosis includes Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome, autosomal recessive rhizomelic chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata with steroid sulfatase deficiency and incontinential pigmenti.

Pathology

Histopathology is not pathognomonic, but distinctive. Neonatal skin biopsy demonstrates thick laminated orthokeratosis and dilated ostia of pilosebaceous units.7,9 Histology can also show calcium salts in the stratum corneum. Prominent follicular plugs containing dystrophic calcification seen by von Kossa stain.7,9

Management

Ichthyosiform dermatitis in a Blaschkoid distribution is an early clue to the diagnosis of Conradi-Hünermann syndrome. Confirmatory genetic testing for mutations in the emopamil-binding protein gene will enable prompt referrals to orthopedics, ophthalmology and genetic counseling. Generally, these children experience a normal lifespan; morbidity depends largely on neurologic, orthopedic and ophthalmologic involvement.

Based on clinical suspicion of Conradi-Hünermann syndrome, the patient was referred for an eye examination, which revealed a dense left-side cataract. Genetic testing for the emopamil-binding protein gene found a mutation consistent with the diagnosis of Conradi-Hünermann syndrome. Over a period of one month, the infant’s ichthyosiform dermatitis improved significantly without treatment, leaving a residual whorled hyperpigmentation with nearly resolved scale. Her cataract was extracted. She is currently followed by orthopedics for monitoring of potential bone complications.

Dr. Szyfelbein Masterpol is with Boston University School of Medicine and Boston Medical Center in Boston, MA.

Dr. Loo is with Tufts University School of Medical and Tufts Medical Center in Boston, MA.

Disclosure: The authors have no conflicts of interest to disclose.