This case report describes a girl aged 19 months old, whom we diagnosed with Conradi-Hünermann-Happle (CHH; OMIM#302960) syndrome or X-linked dominant chondrodysplasia punctata type 2 (CDPX2). This is a congenital combined skeletal and ectodermal dysplasia with an estimated incidence of less than 1:400,000.
The patient is the first child of Dutch parents. At 24 weeks of gestation, skeletal dysplasia with rhizomelia (bilateral shortening of the humeral and femoral bones) was diagnosed on ultrasound examination. The patient was born at 38+3 weeks of pregnancy (Apgar scores 9-9-10 respectively 1, 5 and 10 minutes post partum) with a birth weight of 2570 grams (P10). Immediately after birth the patient was erythrodermic for 24 hours followed by linear hyperkeratotic plaques. The dermatologist and clinical geneticist were consulted. They made a diagnosis of CHH. When examined, the mother had linear alopecia, said to have been present from birth. She also had ichthyosis during childhood and a difference in leg length for which she had undergone several orthopaedic corrections. The mother was therefore also diagnosed with CHH syndrome. This was confirmed by DNA analysis - both mother and child have a pathogenic mutation in the EBP gene (c.329G>A, p. Arg110Gln). Typical stippling of epiphyses of femoral and tarsal bones was observed.
CHH syndrome is a congenital disorder of cholesterol biosynthesis, caused by a mutation in the EBP gene on the X-chromosome (Xp11.23-p11.22), coding for 3-ß-hydroxysteroid-δ(8),δ(7)-isomerase. This is a central component of cholesterol biosynthesis that catalyses the conversion of 8(9)-cholestenol in lathosterol. Dysfunction of this enzyme leads to increased levels of 8-dehydrocholesterol and, typically, to the presence of 8(9)-cholestenol in serum. As expected, CHH syndrome shares characteristics with other disorders associated with defects in the cholesterol synthesis pathways, notably CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects; OMIM #308050) and SLO syndrome (Smith-Lemli-Opitz syndrome; OMIM #270400). The variation in phenotypes seen in CHH syndrome and other X-linked dominant disorders results from X-inactivation. The absence of sufficient cholesterol results in aberrant Hedgehog signalling during embryologic development, which can explain several of the symptoms listed above.
CHH syndrome has an X-linked dominant inheritance pattern and is usually lethal for boys. The risk of recurrence for a daughter with CHH is 25%; for a healthy son or daughter without CHH it is 50% and for a son with CHH it is 25%. However, most affected boys will die during pregnancy.
CHH syndrome can cause rhizomelia. Furthermore, scoliosis can develop due to congenital vertebral anomalies. Congenital (sectoral) cataract, midface hypoplasia, wide/flat nose, hypothelorism and structural brain anomalies with mental retardation can be present. Sometimes there is a linear alopecia. Most girls born with CHH syndrome are born with erythrodermia that usually disappears within 24 hours. They can also present as collodion babies. Later on, ichthyosis in Blaschko lines will develop. The ichthyosis disappears during childhood and mild atrophic, hypopigmented skin lesions persist. Cutaneous adnexa such as hairs and sweat glands in the affected areas can be absent.
The patient presented has rhizomelia, progressive scoliosis because of vertebral anomalies, bilateral peripheral cataract and ichthyosis. The children’s physiatrist had prescribed semi-orthopedic anti-varus shoes with correction for her difference in leg length to stimulate her walking independently and prevent further feet deformities. The patient will be monitored by the children’s physiatrist, paediatrician, orthopaedic surgeon, ophthalmologist, and dermatologist, forming a multidisciplinary team.
This case shows that rare complex disorders such as CHH syndrome need a multidisciplinary approach for adequate diagnostic decision making as well as follow-up and treatment. A multidisciplinary team approach is essential to provide a tailor-made follow-up program for patient and family.
This supplementary information is presented as submitted by the corresponding author. It has not been copy-edited by NTvG.