Novel NSDHL gene variant for congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome

Background

Congenital hemidysplasia with ichthyosis and limb defects (CHILD) syndrome is a rare X-linked dominant disorder of postsqualene cholesterol metabolism characterised clinically by unilateral limb reduction defects and ipsilateral ichthyosiform skin lesions; chondrodysplasia punctata and visceral anomalies.1 This disorder primarily affects women with prenatal lethality in men. It is caused by a defect in NSDHL, a gene that encodes 3β-hydroxysteroid dehydrogenase (3β-HSD), an enzyme involved in cholesterol biosynthesis.

Cholesterol is a key component of cell membranes and is important in many biosynthetic pathways. A number of disorders of cholesterol biosynthesis, like CHILD syndrome, are known to cause congenital malformation syndromes.

Cholesterol is synthesised from acetate in a series of enzymatic reactions divided into presqualene and postsqualene cholesterol metabolism.2 Postsqualene cholesterol synthesis begins with the conversion of squalene to lanosterol, followed by a series of 19 additional reactions converting lanosterol to cholesterol. 3β-HSD, the enzyme deficient in CHILD syndrome, is one component of the C4 demethylase complex.1 3 A deficiency of this enzyme leads to increased levels of 4α-methylsterols that can be detected in affected skin and cultured cells; however, plasma sterol levels are often normal.

In this report, we present a case of CHILD syndrome with a novel variant in NSDHL. We describe the clinical, radiologic, biochemical and molecular features of this case and discuss clinical management.

Case presentation

We are presented with a 1-year and 2-month-old girl referred for dysmorphologic evaluation. She was born full-term 37 weeks age of gestation via spontaneous vaginal delivery. At birth, the patient was noted to have sharply demarcated erythematous to hyperpigmented patches on the right side of the body, not crossing the midline (right upper extremity, right side of the trunk and abdomen and right lower extremity) and syndactyly.

At 1 week of age, the lesions were noted to increase in thickness, now being erythematous, verrucous plaques with prominent yellow crusting. Areas of weeping were also noted, most extensively on the hands and feet. The patient was subsequently referred to our institution and evaluated by paediatrics, orthopaedics, dermatology and genetics services. She is the youngest of a sibship of four born to a healthy non-consanguineous couple of Filipino descent.

On physical examination, the patient is proportionately small for age with a weight of 5 kg (Z score −3), length of 59 cm (Z score −3) and head circumference of 39 cm (Z score <−2). Anterior fontanel is soft and flat. She has a flat nasal bridge and multiple verrucous plaques with crusting on an erythematous base over the nape. Examination of the chest/cardiac, lungs and abdomen was unremarkable. The right side of the labia majora was erythematous. She has a single transverse palmar crease on the right hand, syndactyly of the second,third, fourth and fifth digits on the right hand, multiple verrucous plaques on the right upper extremity following the lines of Blaschko, hypoplastic nails on the right upper extremity and right lower extremity; syndactyly of the fourth and fifth digits right lower extremity (figure 1). The left side of the body is unremarkable.

Investigations

With note of increase in thickness of the lesions, a 3 mm punch biopsy was obtained from a chest plaque. Histopathologic findings revealed psoriasiform epidermal hyperplasia, spongiosis, papillomatosis, alternating parakeratosis and orthokeratosis with hypergranulosis.

Skeletal survey (figure 2) showed the absence of the middle and distal phalanges of the second and third digits of the hand. There is fusion of the soft tissues of the fourth and fifth phalanges and third metacarpal of the right hand. There is also absence of the metatarsal and phalanges of the third digit of the right foot, and distal phalanx of the second digit of the right foot. Fusion of the soft tissues in the fourth and fifth digits of the right foot was also seen.

Ophthalmologic evaluation was unremarkable. Sterol analysis of plasma showed a mildly increased level 4-alpha methyl 5-alpha cholest-8(9)-en-3ß-ol suggesting an abnormality of cholesterol metabolism involving the 4-alpha-methylsterol-4-demethylase complex. Sterol analysis from skin flakes revealed an increased level of this mono 4-alpha methyl sterol, as well as a significant amount of 4-alpha-carboxy-4-methyl-cholest-8(9)-en-3beta-ol, the presence of which is pathognomonic for a defect in the NSDHL component of the 4-alpha-methylsterol-4-demethylase complex.

In addition, two ketosterols normally below the limit of detection by our analysis were detected. Because the clinical phenotype of our patient was consistent with an NSDHL defect, sequencing of NSDHL was performed (via Invitae), which revealed the presence of a variant of uncertain significance, c.130G>A (p.Gly44Ser). This missense mutation currently is not included in population databases (ExAC no frequency). It has not yet been reported literature in any individual with an NSDHL-related condition. Parental studies showed that neither parent carries this NSDHL variant. Based on the clinical presentation, the functional deficient of the NSDHL demonstrated by abnormal sterol metabolites and the exclusion of parental transmission, this variant has been reclassified as likely pathogenic.

Treatment

Bland emollients, such as white petrolatum, were applied with an addition of a keratolytic lotion (urea 10%) to decrease plaque thickness. Plain sodium soaks were also applied to the weeping areas. Intermittent application of ketoconazole cream once per day provided decrease in waxy scaling, however, crusting and scaling would recur after around 5 days. The patient was maintained on bland emollients and mild cleansers.

Outcome and follow-up

The application of emollients, mild cleansers and ketoconazole provided improvement of the skin lesions. The family underwent pre-test and post-test genetic counselling. They were also introduced to a rare disease patient support group in the Philippines (Philippine Society for Orphan Disorders). The patient is being followed with multidisciplinary services that include General Paediatrics, Dermatology, Developmental Paediatrics, Rehabilitation Medicine, Genetics and Orthopaedics.